Adrenal insufficiency

Jump to navigation Jump to search

Adrenal insufficiency Microchapters


Patient Information


Historical Perspective




Differentiating Xyz from other Diseases

Epidemiology and Demographics

Risk Factors


Natural History, Complications and Prognosis


Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings



Echocardiography and Ultrasound

CT scan


Other Imaging Findings

Other Diagnostic Studies


Medical Therapy



Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Adrenal insufficiency On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides


American Roentgen Ray Society Images of Adrenal insufficiency

All Images
Echo & Ultrasound
CT Images

Ongoing Trials at Clinical

US National Guidelines Clearinghouse

NICE Guidance

FDA on Adrenal insufficiency

CDC on Adrenal insufficiency

Adrenal insufficiency in the news

Blogs on Adrenal insufficiency

Directions to Hospitals Treating Psoriasis

Risk calculators and risk factors for Adrenal insufficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayeesha Kattubadi, M.B.B.S[2]


Adrenal Insufficiency is a clinical state where there is reduced production of adrenocortical hormones. The adrenal cortex is divided into three zones- zona glomerulosa, zona fasciculata, and zona reticularis producing mineralocorticoids, glucocorticoids, and androgens respectively. Adrenal Insufficiency causes glucocorticoid and mineralocorticoid deficiency. It is classified as primary, secondary, and tertiary. Its presentation depends on the rapidity and degree of hormone depletion. It can present acutely as adrenal crisis, especially when the body is under stress due to infections, trauma, etc. If it presents chronically it is called Addison disease. The mainstay of treatment includes replacement therapy with glucocorticoids i.e hydrocortisone. Whereas, primary adrenal insufficiency requires additional mineralocorticoid replacement as well. [1]

Historical Perspective

In 1885, Thomas Addison first defined Adrenal Insufficiency as a disorder of impaired adrenocortical function leading to deficiency in glucocorticoids, mineralocorticoids, and adrenal androgens. Earlier, salt supplementation was used in the treatment of Adrenal Insufficiency. Hench, Kendall, and Reichstein were awarded the Nobel Prize in Physiology or Medicine in 1950 "for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects" which broadened the treatment options for Adrenal Insufficiency. The most common cause of primary adrenal insufficiency has been changing. In the 1920s, the most common cause of Adrenal Insufficiency was Tuberculosis, since the 1950s it has been autoimmune polyglandular syndrome.


Adrenal insufficiency is classified based on the location of the pathology into [2] [3] :

In Primary adrenal insufficiency, the pathology lies in the adrenal glands leading to decreased production of cortisol and aldosterone.The most common cause of primary adrenal insufficiency is autoimmune adrenalitis. In secondary adrenal insufficiency, the pathology lies in the pituitary gland leading to reduced ACTH production, whereas in tertiary adrenal insufficiency the pathology lies in the hypothalamus leading to reduced CRH production. The most common cause of tertiary adrenal insufficiency is chronic glucocorticoid therapy. Secondary and tertiary adrenal insufficiency together are categorised into central adrenal insufficiency. The following table summaries the causes of adrenal insufficiency.

Causes of adrenal insufficiency
Primary adrenal insufficiency
(Addison's disease)
Secondary adrenal insufficiency Tertiary adrenal insufficiency


The pathogenesis of adrenal insufficiency varies based on the etiology as follows:

Autoimmune adrenalitis [4] [5]: Humoral as well as cell mediated immune mechanisms attack various enzymes involved in the synthesis of adrenal cortical enzymes. Strong genetic association has bene seen with HLA DR3/DQ2 and DR4/DQ8. On gross anatomy the adrenal gland is atrophied with preservation of adrenal medulla. Histopathology shows lymphocytic infiltration with fibrosis of the parenchyma. The patients are asymptomatic until up to 90% of the cortex is destroyed. Autoantibodies against 21-hydroxylase, an essential enzyme required in the biosynthesis of steroid hormones of the adrenal cortex are seen.

  • Isolated autoimmune adrenalitis accounts for 30-40% cases.
  • Autoimmune Polyglandular Syndrome (APS) account for 60-70%. Which is further subclassified as follows:

Autoimmune Polyglandular Syndrome Type 1 (APS type 1): Exhibits autosomal recessive mode of inheritance. It is also known as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED). Caused due to mutations in the autoimmune regulator gene (AIRE). Apart from Adrenal Insufficiency it presents with chronic mucocutaneous candidiasis, hypoparathyroidism, total alopecia.

Autoimmune Polyglandular Syndrome Type 2 (APS type 2): It is more common than APS type 1 and has polygenic inheritance. Strong association has been shown with HLA DR3 of MHC. Apart from Adrenal Insufficiency it presents with autoimmune thyroiditis, vitiligo, premature ovarian failure, type 1 diabetes mellitus, pernicious anemia.

X linked Adrenoleukodystrophy(X-ALD) [6] [7] : X-ALD occurs due to mutations in the peroxisomal ATP-binding cassette (ABC) transporter encoded by the ABCD1 gene. Disruption of this transport protein leads to the accumulation of Very Long Chain Fatty Acids (VLCFA). Male patients usually present in childhood or adolescence, whereas heterozygous females present between 40-50 years. The phenotypic expression is variable and can present as pre-symptomatic, cerebral inflammatory demyelination, myelopathy, Adrenal Insufficiency. The lifetime prevalence of adrenal insufficiency is 80% in males, with the highest risk being in the first decade. Adrenal Insufficiency is extremely rare in females.

Chronic glucocorticoid use [8] [9]: Secondary or Tertiary adrenal insufficiency induced by chronic use of glucocorticoids is the most common cause of Adrenal Insufficiency. HPA axis suppression has been reported with oral, inhaled, topical, injectable, intraarticular, intradermal, paraspinal, or rectal glucocorticoid preparations. Exogenous glucocorticoid use causes feedback inhibition of the HPA axis leading to reduced synthesis of CRH and ACTH by hypothalamus and pituitary. As a consequence of reduced ACTH, the adrenal cortex slowly loses the ability to synthesise cortisol. The mineralocorticoid synthetic function of the adrenal cortex is retained as it depends on RAAS. HPA axis function recovers quickly if glucocorticoids were used for less than 10-14 days. If glucocorticoids were used for >2weeks, weaning and assessment of HPA integrity are recommended. In some cases the HPA axis may remain suppressed for as long as 6-12 months after glucocorticoid withdrawal.

The other causes of adrenal insufficiency are due to the destruction of the adrenal, pituitary or hypothalamus due to various causes as mentioned in the table above.

Differential diagnosis

Addison's disease differential diagnosis


The most common cause of adrenal insufficiency is glucocorticoid-induced adrenal insufficiency. The most common cause of primary adrenal insufficiency varies based on geography. In the developed world, Tuberculosis was the most common cause, whereas, since the 1950s, the incidence of autoimmune adrenalitis is rising. The autoimmune polyglandular syndrome shows a female: male preponderance of 2:1, usually presenting in the age group of 30-50 years. In developing countries, Tuberculosis remains the most common cause. [10] [11] [12] [13]

Clinical Presentation

The presentation of adrenal insufficiency is non-specific and depends on the extent of loss of adrenal hormones. Common symptoms that are seen in Adrenal insufficiency [14] [15] [16]:

  • Fatigue and anorexia are the most common, seen in almost all cases. The fatigue worsens at night and with disease progression.
  • Gastrointestinal symptoms include abdominal pain, nausea, vomiting, constipation, and diarrhea.
  • Musculoskeletal symptoms include arthralgia, myalgia.

Signs and symptoms that are specific to primary adrenal insufficiency: Salt craving, postural dizziness, Hypotension, weight loss, vitiligo, auricular calcification, postural hypotension. Lab findings:

  • Electrolytes: hyponatremia, hyperkalemia, hypercalcemia
  • Hypoglycemia
  • Azotemia
  • Eosinophilia
  • Anemia

Adrenal Crisis [17] [18]: About 50% of people with undiagnosed adrenal insufficiency present with adrenal crisis. It is also known as the Addisonian crisis. A life-threatening emergency arising due to an acute deficiency of adrenal cortisol. The mortality rate is 0.5/100 patients/year. It is often triggered by an acutely stressful event like infection, surgery, dehydration, etc. Presentation: Acute onset of Abdominal pain, nausea, vomiting, diarrhea, severe dehydration, dizziness, hypotension, shock, fever. Labs: Hyponatremia, hyperkalemia, hypercalcemia, eosinophilia, hypoglycemia.


The diagnosis of adrenal insufficiency is a three-step process that can be performed simultaneously or in sequential order. [3] [19]

  1. Prove the existence of adrenal insufficiency i.e. Syndromic Diagnosis.
  2. Determine the nature of adrenal insufficiency i.e. Primary, Secondary, Tertiary Adrenal insufficiency by identifying the location of the defect in the HPA axis.
  3. Determine the cause i.e. etiological diagnosis.

Tests used in syndromic diagnosis:

Serum basal cortisol: As cortisol secretion follows a circadian rhythm with a nadir around midnight and peak between 6-8 AM, serum basal cortisol measurement should be taken between 8 AM-9 AM. Serum cortisol level <5µg/dL confirms the presence of adrenal insufficiency. Total serum cortisol is composed of the protein-bound fraction (90%) and free cortisol (10%) which is the biologically active form. Corticosteroid-binding globulin (CBG) is the major transporter for cortisol. Conditions that alter CBG also alter the total serum cortisol, with no effect on free cortisol. Therefore caution has to be exercised while interpreting the levels of serum cortisol in conditions where CBG levels are altered.

Salivary cortisol levels: Salivary cortisol levels are measured at 8 am. Levels <0.18 µg/dL strongly predict adrenal insufficiency, whereas levels >0.58µg/L rule out adrenal insufficiency. The advantage of this test is that it is noninvasive so can be done by the patient at home and it only measures the free cortisol levels, so it’s not affected by changes in plasma proteins. The disadvantage is that it’s not a universally standardized test.

Urine free cortisol measurement: Low sensitivity and therefore not useful in diagnostic confirmation.

Dynamic tests: They are used in patients with indeterminate levels of basal plasma cortisol i.e. in between 5 µg/dL to 18 µg/dL. The different typed of dynamic tests are as follows –

Name of the test Insulin Hypoglycemia test ACTH stimulation test Low dose ACTH stimukation test Metyrapone stimulation Glucagon stimulation
Agent to be administered Regular insulin 0.1-1.15U/kg I.V Cosyntropin 250mcg I.V Consyntropin 1mcg I.V Metyrapone 30mg/kg P.O Glucagon 1mg I.M
Timing of sample collection 0-30-45-60-90 min 0-30-60 min 0-30-60 min 8 hours post metyrapone 90-120-150-180-210-240min
Parameter Tested Plasma cortisol Plasma cortisol Plasma cortisol 11 deoxycortisol Plasma cortisol
Comments Gold standard Safe Manual preparation Assesses whole HPA Less accurate

Diagnostic algorithm:

Adrenal Insufficiency suspected
Serum basal cortisol
<5 µg/dL
5-18 µg/dL
>18 µg/dL
Confirms Adrenal Insufficiency
Dynamic tests
Rules out Adrenal Insufficiency
Primary Adrenal Insufficiency suspected
Secondary Adrenal Insufficiency suspected
ACTH stimulation test
ACTH stimulation test
Serum cortisol <18 µg/dL
Serum cortisol >18µg/dL
Serum cortisol <18 µg/dL
Serum cortisol 18-23µg/dL
Serum cortisol >23 µg/dL
Confirms Adrenal Insufficiency
Rules out Adrenal Insufficiency
Confirms Adrenal Insufficiency
Rules out Adrenal Insufficiency
Insulin hypoglycemic test
Serum cortisol <18µg/dL
Serum cortisol >18µg/dL
Confirms Adrenal Insufficiency
Rules out Adrenal Insufficiency

Diagnosing the location of defect:

Primary Adrenal Insufficiency Secondary Adrenal Insufficiency
Clinical Hyperpigmentation of skin and mucous membranes No hyperpigmentation
Labs Hyperkalemia, Hyponatremia Hyponatremia
ACTH Increased to two times upper limit of normal Normal or decreased


Treatment of adrenal insufficiency: [3] [20]

Management of adrenal insufficiency consists of glucocorticoid and mineralocorticoid replacement.

Glucocorticoid replacement therapy: Given in patients with a confirmed diagnosis of adrenal insufficiency.

Drug of choice Hydrocortisone.
Dosage 15-25 mg is given in two or three divided doses.
Dosing frequency Two divided doses – 2/3 of the total dose in the morning on awakening; 1/3 of the total dose in mid-afternoon

Three divided doses (10mg at 7 AM, 5mg at 12 PM, and 2.5-5mg at 4:30 PM. Avoid dosing after 6 PM

Alternate drugs Cortisone acetate 20-25mg, Prednisone (3-5mg/day); Use of dexamethasone is not recommended
Drug interactions Drugs increasing glucocorticoid dose requirement: Anticonvulsants like Barbiturates, Topiramate, Anti-tubercular drugs, Estrogens, Tamoxifen

Drugs decreasing glucocorticoid dose requirement: Licorice, Grapefruit juice, Colestipol

Monitoring Monitoring is done based on clinical improvement.

Symptoms that are suggestive of underdosing- Persistence or the incomplete resolution of fatigue, nausea, postural hypotension, myalgia.

Symptoms that are suggestive of overdosing - weight gain, edema, abdominal striae.

There is no role of measuring ACTH and serum cortisol levels.

Side effects Weight gain, edema, increased appetite, weight gain, osteoporosis, dyslipidemia, increased cardiovascular risk.

Mineralocorticoid replacement therapy: Mineralocorticoids are given only in patients with primary adrenal insufficiency. A synthetic mineralocorticoid, 9 α-fludrocortisone is used in a dose of 0.05-0.2 mg/day in the morning. Dosage adjustments have to be made based on the clinical picture. Symptoms and signs of underdosing include hypovolemia, orthostatic hypotension, hyperkalemia, hyperuricemia, increased plasma renin activity. Symptoms and signs of overdosing include hypertension, hypokalemia, edema. If a patient on fludrocortisone develops hypertension, reduce the dose. If the blood pressure remains elevated, start an antihypertensive medication, and continue fludrocortisone.

The use of dehydroepiandrosterone (DHEA) is not routinely recommended. A six-month trial of DHEA can be considered in patients with significant impairment in quality of life, decreased libido, women, depressed mood despite glucocorticoid and mineralocorticoid therapy. If there is no improvement at the end of six months, its use has to be discontinued. DHEA is contraindicated in people with breast and prostate cancer.

Treatment of acute adrenal crisis: In patients suspected of having adrenal insufficiency, hydrocortisone 100mg IV/IM given immediately followed by a continuous infusion of 200mg in the next 24 hours. Alternately prednisolone can be used. Intravenous fluid replacement with 0.9% NS is also recommended to maintain blood pressure.


  1. "Adrenal Insufficiency - StatPearls - NCBI Bookshelf".
  2. Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K; et al. (2000). "Endotext". PMID 25905309.
  3. 3.0 3.1 3.2 Bornstein, Stefan R.; Allolio, Bruno; Arlt, Wiebke; Barthel, Andreas; Don-Wauchope, Andrew; Hammer, Gary D.; Husebye, Eystein S.; Merke, Deborah P.; Murad, M. Hassan; Stratakis, Constantine A.; Torpy, David J. (2016). "Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology & Metabolism. 101 (2): 364–389. doi:10.1210/jc.2015-1710. ISSN 0021-972X.
  4. "Adrenal Insufficiency - StatPearls - NCBI Bookshelf".
  5. Erichsen, Martina M.; Løvås, Kristian; Skinningsrud, Beate; Wolff, Anette B.; Undlien, Dag E.; Svartberg, Johan; Fougner, Kristian J.; Berg, Tore J.; Bollerslev, Jens; Mella, Bjarne; Carlson, Joyce A.; Erlich, Henry; Husebye, Eystein S. (2009). "Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry". The Journal of Clinical Endocrinology & Metabolism. 94 (12): 4882–4890. doi:10.1210/jc.2009-1368. ISSN 0021-972X.
  6. Berger J, Forss-Petter S, Eichler FS (March 2014). "Pathophysiology of X-linked adrenoleukodystrophy". Biochimie. 98: 135–42. doi:10.1016/j.biochi.2013.11.023. PMC 3988840. PMID 24316281.
  7. Huffnagel, Irene C; Laheji, Fiza K; Aziz-Bose, Razina; Tritos, Nicholas A; Marino, Rose; Linthorst, Gabor E; Kemp, Stephan; Engelen, Marc; Eichler, Florian (2019). "The Natural History of Adrenal Insufficiency in X-Linked Adrenoleukodystrophy: An International Collaboration". The Journal of Clinical Endocrinology & Metabolism. 104 (1): 118–126. doi:10.1210/jc.2018-01307. ISSN 0021-972X.
  8. Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland HJ, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP, Nicolaides NC, Pavlaki AN, Maria Alexandra MA, Chrousos GP. PMID 25905379. Missing or empty |title= (help)
  9. {cite journal |vauthors=Younes AK, Younes NK |title=Recovery of steroid induced adrenal insufficiency |journal=Transl Pediatr |volume=6 |issue=4 |pages=269–273 |date=October 2017 |pmid=29184808 |pmc=5682381 |doi=10.21037/tp.2017.10.01 |url=}}
  10. Bensing, Sophie; Hulting, Anna-Lena; Husebye, Eystein S; Kämpe, Olle; Løvås, Kristian (2016). "MANAGEMENT OF ENDOCRINE DISEASE: Epidemiology, quality of life and complications of primary adrenal insufficiency: a review". European Journal of Endocrinology. 175 (3): R107–R116. doi:10.1530/EJE-15-1242. ISSN 0804-4643.
  11. Chabre, Olivier; Goichot, Bernard; Zenaty, Delphine; Bertherat, Jérôme (2017). "Group 1. Epidemiology of primary and secondary adrenal insufficiency: Prevalence and incidence, acute adrenal insufficiency, long-term morbidity and mortality". Annales d'Endocrinologie. 78 (6): 490–494. doi:10.1016/j.ando.2017.10.010. ISSN 0003-4266.
  12. Melmed, Shlomo (2020). Williams textbook of endocrinology. Philadelphia, PA: Elsevier. ISBN 9780323555968.
  13. Gardner, David (2011). Greenspan's basic & clinical endocrinology. New York: McGraw-Hill Medical. ISBN 9780071622431.
  14. Chanson, Philippe; Guignat, Laurence; Goichot, Bernard; Chabre, Olivier; Boustani, Dinane Samara; Reynaud, Rachel; Simon, Dominique; Tabarin, Antoine; Gruson, Damien; Reznik, Yves; Raffin Sanson, Marie-Laure (2017). "Group 2: Adrenal insufficiency: screening methods and confirmation of diagnosis". Annales d'Endocrinologie. 78 (6): 495–511. doi:10.1016/j.ando.2017.10.005. ISSN 0003-4266.
  15. Pazderska A, Pearce SH (June 2017). "Adrenal insufficiency - recognition and management". Clin Med (Lond). 17 (3): 258–262. doi:10.7861/clinmedicine.17-3-258. PMC 6297573. PMID 28572228.
  16. Melmed, Shlomo (2020). Williams textbook of endocrinology. Philadelphia, PA: Elsevier. ISBN 9780323555968.
  17. Elshimy G, Alghoula F, Jeong JM. PMID 29763143. Missing or empty |title= (help)
  18. "StatPearls". 2020. PMID 28722962.