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Adrenal Crisis

Editor: Jordan M. Jeong Updated: 9/13/2023 3:41:49 PM


Adrenal crisis, or Addisonian crisis, is a severe, life-threatening condition characterized by acute adrenal insufficiency. This condition has a substantial mortality rate of 0.5 per 100 patient-years and remains a significant cause of death in individuals with adrenal insufficiency.[1] Patients can experience rapid deterioration without timely intervention, potentially resulting in fatal outcomes either at home or shortly after hospital admission.

This endocrine emergency arises when the production of cortisol, the primary glucocorticoid (GC) adrenal hormone, is inadequate either due to internal or external factors. Early recognition and immediate intervention are crucial for saving a patient's life and improving survival rates.[2] 

Clinicians must distinguish between adrenal insufficiency and adrenal crisis, as the latter can be fatal if not treated promptly. Despite the well-described characteristics of this condition, its recognition can be challenging, resulting in delayed treatment initiation and increased morbidity and mortality rates.[3] 

Essential measures in preventing adrenal crises include educating patients and their families about sick day rules and ensuring the availability of intramuscular hydrocortisone at home.[4]

The ongoing debate among experts in the field has led to a lack of consensus on the definition of adrenal crisis. Several expert reviews have tried to establish their definitions of adrenal crisis. Among the numerous descriptions available for this condition, we will adhere to the one put forth by Rushworth et al in 2019 for this activity, as mentioned below.[5]

Adrenal crisis is defined by an acute deterioration in health status that is associated with the following conditions:

  • Absolute hypotension with a systolic blood pressure <100 mm Hg.
  • Relative hypotension with a systolic blood pressure ≥20 mm Hg lower than the patient's usual baseline.

Typically, these features should improve and resolve within 1 to 2 hours after administering parenteral GCs, marked by a significant reduction in hypotension within the first hour. Furthermore, there should be a gradual improvement in patients' clinical symptoms over the subsequent 2 hours.[5]


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History of Adrenal Crisis

In 1855, Thomas Addison's pioneering work provided the earliest description of adrenal insufficiency, marking a significant milestone in comprehending this condition.[6] The discovery of cortisone by Hench, Kendall, and Reichstein in the late 1940s revolutionized the treatment of adrenal insufficiency, leading to a remarkable enhancement in the life expectancy of individuals affected by this condition.[7][8] 

In the 1930s, tuberculosis was the most prevalent cause of this condition, accounting for approximately 70% of cases. In recent times, autoimmune adrenalitis, or Addison's disease, has emerged as the leading cause of primary adrenal insufficiency in developed countries. In contrast, tuberculosis remains the leading cause of adrenal insufficiency in developing countries.[9]

Precipitating Factors for Adrenal Crisis

Acute adrenal crisis can be the initial presentation of undiagnosed adrenal insufficiency, potentially occurring in up to 50% of patients who have already been diagnosed with this condition.[10][11][12] In a previous study, approximately 10% of patients exhibited no identifiable cause for their adrenal crisis.[13] The primary causes of adrenal crises are as follows:

  • Bacterial, mycobacterial, fungal, parasitic, or viral, such as COVID-19, infections [13][14]
  • Gastrointestinal and flu-like illnesses [5][15]
  • Trauma, pregnancy, childbirth, surgery, exposure to extreme hot or cold weather, or other stressful situations
  • Significant emotional distress [13]
  • Strenuous physical activity [16]
  • Nonadherence to GC replacement therapy [17]
  • Abrupt cessation of chronic GC therapy [17]
  • Thyrotoxicosis, as it accelerates cortisol metabolism.
  • Levothyroxine therapy initiation in a previously untreated case of adrenal insufficiency
  • Antiadrenal medications, including mitotane, metyrapone, ketoconazole
  • Anticancer medications, including immunotherapy with checkpoint inhibitors and tyrosine kinase inhibitors [18][19][20][21] 


Determining the exact frequency of adrenal crises in the general population poses a significant challenge. Patients with adrenal insufficiency have been estimated to experience an adrenal crisis in 6% to 8% of cases annually.[15][22] The incidence of adrenal crises remains high even among patients who have received extensive education on managing and preventing adrenal insufficiency.[13] A study revealed a 6% mortality rate associated with adrenal crises among this well-informed group of patients.[13] The annual frequency of adrenal crisis in patients with Addison's disease remains at 8%.[23]

Risk Factors for Adrenal Crisis

The risk factors associated with adrenal crisis are as follows:

  • A known history of adrenal insufficiency or previous adrenal crisis
  • Primary adrenal insufficiency diagnosis, which carries a higher risk than secondary adrenal insufficiency [10][24]
  • Ongoing GC therapy, including topical and inhalation forms, which poses a risk for an adrenal crisis due to the potential suppression of the hypothalamic-pituitary-adrenal (HPA) axis, if abruptly discontinued
  • Medications, including levothyroxine, phenytoin, phenobarbital, rifampin, carbamazepine, St John's wort, ketoconazole, etomidate, and fluconazole, which affect cortisol metabolism or reduce its production [25][26][27][28]
  • Anticoagulation agents, which increase the risk of adrenal hemorrhage
  • Additional medications, including megestrol acetate and medroxyprogesterone [29][30][31]
  • Pregnancy, particularly during the third trimester [32]
  • Advanced age [5]
  • The presence of comorbidities [10][24]
  • Patients with type 1 diabetes[5] 
  • Adrenal metastasis or adrenal hemorrhage [33][34]
  • Polyglandular autoimmune syndromes 1 and 2 [35][36]


The pathophysiology of adrenal crisis is not fully understood; however, examining the functions of GCs can provide insight into clinical manifestations. GCs exhibit various roles in stress responses by demonstrating permissive, suppressive, stimulatory, and preparative effects. Although these functions have been described in greater detail in a different activity, a concise overview is provided below.[37]

Cardiovascular System

GCs have a permissive effect on the functioning of adrenergic receptors in the heart and vasculature. Without GCs, catecholamines cannot exert their full impact on these receptors.[38] Consequently, during an adrenal crisis, patients often experience hypotension, and in severe cases, they may develop profound shock that remains unresponsive to fluid resuscitation and vasopressor therapy.

Immune System

Infectious or noninfectious stressors can trigger the activation of the immune system, leading to an elevated release of cytokines. Interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor (TNF)-α, and TNF-γ have pivotal roles in this immune response. This immune activation subsequently leads to the activation of the HPA axis, resulting in elevated GC levels.[39][40] 

GCs mitigate immune response by inhibiting cytokine production, release, and effects, thereby playing a crucial role in immune regulation.[41][42] During an adrenal crisis, any significant stressor can trigger an uncontrolled cytokine response, such as inflammation, resulting in fever, widespread vasodilation, and heightened capillary permeability. This can result in hypovolemia and shock as a consequence of fluid shifting from capillaries into tissues, thereby contributing to the development of hypovolemic shock.

To sum up, during an adrenal crisis, the dysregulation of the immune response, marked by an excessive cytokine release, can result in systemic inflammation, fever, vasodilation, capillary leakage, hypovolemia, and shock.

Intravascular Volume

GCs can potentially suppress the expression and secretion of antidiuretic hormone (ADH) in the hypothalamic neurons.[43][44] During an adrenal crisis, there is an upsurge in the activity of ADH, leading to increased diuresis and volume depletion.

Glucose Homeostasis

GCs increase glucose levels in response to stress through various mechanisms, including promoting glycogenolysis and stimulating gluconeogenesis.[45] In addition, GCs also induce insulin resistance, which reduces glucose uptake by the peripheral cells.[45] During an adrenal crisis, the deficiency of GCs hinders these normal stress responses. As a result of the GC-deficient state, hypoglycemia can occur due to insufficient glucose production and improved peripheral utilization.

Appetite Regulation

Corticotropin-releasing hormone (CRH) is a potent appetite suppressant in response to stress.[46] GCs are potent inhibitors of CRH release that can lead to increased appetite.[43] During an adrenal crisis, the release of CRH remains uninhibited in the GC-deficient state and leads to anorexia.

Electrolyte Disturbances

Primary adrenal insufficiency causes mineralocorticoid deficiency due to direct destruction of the adrenal cortex. However, the cortex remains intact in secondary and tertiary adrenal insufficiency. The renin-angiotensin-aldosterone system regulates aldosterone production and secretion.[47] An isolated deficiency of adrenocorticotropic hormone (ACTH) secretion observed in secondary or tertiary adrenal insufficiency does not significantly affect aldosterone levels.[48][47] In primary adrenal insufficiency, aldosterone deficiency leads to volume loss, hyponatremia, and hyperkalemia.[12] 

History and Physical

The most prevalent clinical manifestations of adrenal crises include weakness, severe fatigue, unintentional weight loss, nausea, vomiting, abdominal pain, reduced appetite, back or limb pain, dizziness, somnolence, confusion, and loss of consciousness.[5][49] 

In children, adrenal crises can manifest as weight loss with failure to thrive and are accompanied by other features, such as hypoglycemic crises, which may result in seizures. Less frequently observed presentations in individuals of all age groups include clinical scenarios resembling surgical emergencies, such as an acute abdomen, and symptoms, such as salt cravings, amenorrhea, loss of libido, and depression. 

Assessing a patient's vital signs when evaluating for an adrenal crisis is essential. Patients experiencing an adrenal crisis may exhibit several symptoms, including fever, tachycardia, and orthostatic hypotension.[49] During physical examination, patients may appear visibly unwell. Individuals with primary adrenal insufficiency might display signs such as skin and buccal mucosa hyperpigmentation and scarring.[50]

When evaluating a patient suspected of adrenal crisis, it is crucial to conduct a comprehensive review of the patient's medical history and past surgical history. In addition, the healthcare practitioner should perform a comprehensive review of the patient's list of home medications and supplements.[51]

Identifying any precipitating factors that may trigger an adrenal crisis in individuals is essential. Inquiring about a history of long-term GC use is necessary because abrupt cessation or acute illness in these patients can precipitate adrenal crises.[52]. Evaluating other autoimmune diseases in patients while obtaining their history is crucial, as individuals with autoimmune polyglandular endocrinopathy can manifest multiple autoimmune disorders. Furthermore, recurrent hypoglycemia in patients with type 1 diabetes on insulin can indicate adrenal insufficiency. Patients with adrenal crisis usually present with an unexplained shock resistant to standard fluid resuscitation and vasopressor therapy.[53] 


In the context of an adrenal crisis, there may be several laboratory abnormalities. However, the classic laboratory features that may be revealed include:

  • Hyponatremia, resulting from mineralocorticoid deficiency
  • Hyperkalemia, resulting from mineralocorticoid deficiency
  • Hypoglycemia, stemming from decreased gluconeogenesis and glycogenolysis
  • Low or low normal ACTH levels, as observed in secondary adrenal insufficiency
  • High or high normal ACTH levels, as observed in primary adrenal insufficiency
  • Hypercalcemia, resulting from hypovolemia
  • Elevated creatinine levels, attributed to prerenal failure
  • Low aldosterone levels, due to mineralocorticoid deficiency in primary adrenal insufficiency
  • High renin levels, as typically seen in primary adrenal insufficiency due to increased urinary sodium loss and reduced blood volume
  • Normocytic normochromic anemia, lymphocytosis, and eosinophilia, resulting from GC deficiency
  • Increased thyroid-stimulating hormone (TSH) levels, owing to coexisting hypothyroidism in autoimmune polyglandular endocrinopathy or the absence of cortisol's inhibitory effect on TSH production

Evaluation of Cortisol Levels

Treatment of adrenal crises should never be delayed to obtain blood work for etiological assessment. Prompt administration of hydrocortisone is of utmost importance in managing adrenal crises. However, if there is no anticipated delay in treatment, blood work can be done quickly before initiating hydrocortisone administration.

Healthcare providers suggest the below-mentioned blood tests for the treatment of adrenal crises.

  • ACTH: High ACTH levels with low cortisol and aldosterone indicate primary adrenal insufficiency, whereas low ACTH levels with low cortisol suggest secondary or tertiary adrenal insufficiency.
  • Basic metabolic panel: A basic metabolic profile blood test, including glucose, should also be included in the recommended blood work.
  • Other blood tests: Additional blood work includes determining cortisol, aldosterone, and renin levels.

In situations with uncertainty regarding the diagnosis of adrenal crisis and borderline cortisol levels, performing an ACTH stimulation test in the acute setting is not recommended until the patient's condition has stabilized.[54]

Treatment / Management

The administration of GCs, specifically hydrocortisone, constitutes the definitive treatment for adrenal crisis. In patients with known adrenal insufficiency, symptoms consistent with an adrenal crisis should be sufficient to initiate treatment. If a patient is medically unstable and is strongly suspected of adrenal insufficiency or crisis, stress dose steroids should be administered promptly.[55] The administrative dosing of stress dose steroids and fluid resuscitation differs in children from adults (see Table 1). 

Table 1. Guidelines for Managing Adrenal Crisis During Emergency

 Age Groups Stress Dosing Fluid Resuscitation

The recommended treatment regimen includes administering an initial dose of 100 mg of hydrocortisone through intravenous or intramuscular (IV/IM) bolus injection. This is followed by administering an additional 200 mg of hydrocortisone as IM or IV over the next 24 hours, with a dosage of 50 mg every 6 hours or as a continuous infusion.[5]

The suggested treatment approach for hypoglycemia is administering either 1 L of normal saline or 5% dextrose in 1 L of normal saline, followed by maintenance fluids.[5]


Hydrocortisone dosage is initially calculated as 50 to 100 mg/m² of body surface area. This is followed by an additional 50 to 100 mg/m² over the next 24 hours, administered as IM/IV, divided into equal doses every 6 hours, or as a continuous infusion.[27][56]

The suggested treatment regimen is administering a normal saline bolus at 20 mL/kg of body weight, with repeated doses up to 60 mL/kg within the first hour. If hypoglycemia is present, additional dextrose should be considered at a dose of 0.5 to 1 g/kg.[27]

Recent evidence indicates that continuous infusion is a superior delivery method for hydrocortisone in the management of adrenal crises when compared to intermittent boluses.[57] Continuous hydrocortisone infusion has shown better maintenance of cortisol levels within the therapeutic range.

In cases of adrenal crisis, involving an endocrinologist as soon as possible is crucial to ensure appropriate management of the condition and guidance in patient care.

Once there is clinical improvement, initiating a gradual tapering of steroids is advisable.[58] This approach helps prevent abrupt discontinuation and enables a smoother transition to lower doses. 

The necessity for mineralocorticoid replacement should be assessed individually and in consultation with an endocrinologist. If the GC doses administered to patients exceed 50 mg, mineralocorticoid replacement is unnecessary.[59]

In situations where hydrocortisone is unavailable, alternative parenteral GCs can be considered, as mentioned below.[5][27](A1)

  • Prednisolone: This can be a preferred alternative treatment, administered as an initial bolus of 25 mg and followed by 2 additional 25 mg doses within the first 24 hours. Subsequently, this regimen should be continued with a daily dose of 50 mg of prednisone.
  • Methylprednisolone: This can be administered at a dosage of 40 mg every 24 hours.
  • Dexamethasone: This is the least preferred alternative treatment, with a recommended dosage of 4 mg every 24 hours.

In patients with an infectious process as the precipitating event for adrenal crisis, prompt administration of appropriate antibiotics is necessary to address the underlying infection. 

Differential Diagnosis

An adrenal crisis is rarely an isolated event, and the differential diagnosis may be comprehensive, depending on the presentation and underlying etiology. Although symptoms such as altered mental status, abdominal pain, nausea, vomiting, and fever are frequently encountered during presentations, hypotension typically remains the most significant feature. An adrenal crisis should be considered the primary differential diagnosis for patients with a known history of adrenal insufficiency and experiencing related symptoms.[60] 

Further investigation is necessary to determine the underlying cause of the adrenal crisis. This assessment may encompass the evaluation for conditions such as sepsis, septic shock, circulatory shock, myxedema coma, infection, trauma, physical or emotional stress, myocardial infarction, and other potential triggers. In patients without a known adrenal pathology and exhibiting hypotension resistant to fluid administration and vasopressor support, the diagnosis of adrenal crisis should be strongly considered.[4]


Despite the potential for successful treatment with prompt administration of GCs, the associated mortality rate remains unacceptably high for adrenal crisis, which is a rare diagnosis. Therefore, due to its rarity, many healthcare professionals may have limited familiarity with the presentation and management of adrenal crises. A retrospective study in the United Kingdom revealed that adrenal crisis contributed to 10% of the deaths in patients with primary and secondary adrenal insufficiency.[61] 


An adrenal crisis can result in fatal outcomes, even with timely recognition and appropriate treatment.[2] Besides the risk of death, adrenal crisis is associated with other potential complications. Electrolyte abnormalities, such as hyponatremia, hyperkalemia, and hypoglycemia, can lead to various complications, including seizures, arrhythmias, and coma.[60] If left untreated, hypotension can lead to hypoperfusion, potentially resulting in multiple organ failure. Furthermore, the precipitating disease or event that triggered the adrenal crisis can introduce additional complications.[50]


Patients presenting with an adrenal crisis often require a critical care evaluation and consultation due to the severity of their condition. Common manifestations such as hypotension, altered mental status, and cardiovascular collapse necessitate additional care and monitoring. Treatment in the acute care setting may involve using vasopressors, fluid resuscitation, antibiotics administration, and targeted management, depending on the precipitating etiology of the adrenal crisis.

On suspecting an adrenal crisis in a patient, seeking an emergent endocrinology consultation is imperative. This consultation can aid in confirming the diagnosis, tailoring the appropriate administration of corticosteroids, and managing any underlying endocrine disorders in long-term treatment during the inpatient and outpatient phases of care.

Deterrence and Patient Education

More than 50% of patients with adrenal crisis do not have a prior diagnosis of adrenal insufficiency. Therefore, it is crucial to enhance the competence of healthcare professionals through education regarding the diagnosis and use of stress dose steroids to manage adrenal crises effectively.[60]

Patients should be educated by their healthcare providers based on the guidelines mentioned below.

  • Patients should be aware of the sick day rules, which involve doubling or tripling their daily oral dose of GCs during an acute illness. This helps mimic the physiological response of increased cortisol levels under stressful situations.[17]
    • For a fever exceeding 38 °C, doubling the oral corticosteroid dose is recommended.
    • For a fever exceeding 39 °C, tripling the oral corticosteroid dose is recommended.
  • Patients should know how to administer stress doses during stressful situations, including trauma, surgery, major procedures, and severe illness (see Table 2). In cases of significant emotional stress, such as the death of a loved one or the anticipation of a significant upcoming examination, patients are recommended to take an additional dose of 10 mg of hydrocortisone to help manage the situation.[17]
  • Patients should be educated about the signs and symptoms of adrenal insufficiency to facilitate early recognition and management. Some common signs and symptoms include nausea, vomiting, abdominal pain, unintentional weight loss, dizziness, confusion, low blood glucose, fever, and a diminished sense of well-being.
  • Patients with adrenal insufficiency should be informed that wearing a medical alert bracelet or necklace is paramount for managing this condition. This simple yet crucial accessory can provide essential information to healthcare providers during emergencies, ensuring the prompt delivery of utmost and appropriate care.[27][58]
  • Patients should also ensure they have additional emergency supplies at home, which should be readily available and can be utilized as and when required.[62] An emergency kit should include injectable vials of 100 mg hydrocortisone sodium succinate or 4 mg dexamethasone, 0.9% sterile normal saline vials, and syringes.
  • Patients should have a steroid card that provides information and instructions for managing an adrenal crisis. This card should be easily accessible and readily available, especially in emergencies or when seeking medical care at a hospital or healthcare facility. Maintaining this card is crucial for patients as healthcare professionals at these facilities may not be familiar with managing adrenal crises. The steroid card should clearly outline the recommended dosing information for GC administration during an adrenal crisis. The recommended dosage is 100 mg of hydrocortisone administered IV/IM, followed by an additional 200 mg of hydrocortisone over the next 24 hours. This should also be administered IM/IV in equally divided doses of 50 mg every 6 hours.
  • Patients should regularly schedule follow-up appointments with an endocrinologist, which is essential for monitoring their condition, optimizing treatment, and discussing stress dosing as needed. The recommended frequency of follow-up is annually for adults and every 3 to 6 months for children.

Table 2. Strategies for Adrenal Crisis Prevention

Stressors  Dosage Adjustments
Infection with fever >38 °C [5][17] Patients should double their dose of oral corticosteroids until recovery and then gradually decrease it to the baseline dose in 2 days.
Infection with fever >39 °C [5][17] Patients should triple the dose of oral corticosteroids until recovery and then gradually decrease it to the baseline dose in 2 days.
Severe infections requiring admission to the intensive care unit (ICU) [5] Patients should receive parenteral IV/IM or subcutaneous (SQ) hydrocortisone administered at 50 to 100 mg every 6 to 12 hours until recovery.
Major surgery [63] Patients should receive parental (IV/IM/SQ) hydrocortisone administered at a dose of 100 mg during the induction of anesthesia, followed by 50 to 100 mg every 6 to 12 hours until recovery.
Minor surgery or major dental surgery [63]

Patients should administer 100 mg of hydrocortisone during the induction of anesthesia, followed by a double oral dose for 24 hours, and then gradually return to the baseline dose.


During labor [63]

Patients should administer 100 mg of hydrocortisone at the onset of labor, followed by an additional 25 to 50 mg every 6 hours, and then gradually reduce the dose over the next 3 days.

Significant emotional stress, such as the death of a loved one or the anticipation of a significant upcoming examination [17]

Patients should administer an additional 10 to 20 mg of hydrocortisone to their baseline dose.


Prolonged intensive strenuous exercise [17]

Patients should administer an additional 10 mg of hydrocortisone 30 to 60 minutes before exercise.

Dental procedure Patients should take an additional dose of hydrocortisone 1 hour before the procedure, followed by a double dose for the next 24 hours. Subsequently, they can return to their regular dosage.
Minor procedure No dosage adjustment is needed.

Pearls and Other Issues

An adrenal crisis should be suspected in patients who exhibit acute refractory shock despite receiving adequate fluid resuscitation and vasopressor support. Adrenal crises may be more frequently observed in older patients and individuals with comorbidities and concurrent endocrine disorders. Patients experiencing altered mental status in conjunction with endocrine disorders may face an increased mortality risk.

Hyponatremia, hyperkalemia, or hypoglycemia, especially with hypotension, may indicate an adrenal crisis. Immediate administration of 100 mg hydrocortisone via IV/IM is crucial in suspected adrenal crisis treatment. Prompt initiation of GC therapy is essential for managing adrenal crises and preventing further deterioration.

Enhancing Healthcare Team Outcomes

Effective management of adrenal crises, particularly in the ICU, requires an interprofessional team approach due to the involvement of multiple organs and a high mortality rate. The interprofessional healthcare team responsible for caring for patients and managing adrenal crises should include an intensivist, endocrinologist, ICU nurse, and pharmacist.

ICU nurses are critical in monitoring vital signs, urine output, and hemodynamics of patients experiencing adrenal crises. Close observation and prompt recognition of changes or deterioration in a patient's condition are essential for early intervention and appropriate management. Patient education is a critical aspect of preventing adrenal crisis episodes. In collaboration with the multidisciplinary healthcare team, nurses should educate patients and their families about this condition and its potential complications and the importance of adhering to sick day rules.[58]

Emphasis should be placed on avoiding the abrupt cessation of exogenous corticosteroids, as this is a common trigger for adrenal crisis. Patients should receive education about the importance of regular monitoring, recognizing signs of adrenal insufficiency, and making appropriate adjustments to their medication doses. The clinician and the pharmacist should educate patients about the adverse effects of corticosteroids. Furthermore, all patients with adrenal insufficiency should be encouraged to wear a medical alert bracelet or necklace that indicates their condition during emergencies.[64]

Patient Outcomes

Despite receiving steroid replacement therapy, individuals who have experienced adrenal crises often face significant challenges in their quality of life. Studies have indicated that many individuals suffer from disabilities and are unable to work due to conditions such as depression and chronic fatigue, thereby leading to a poor quality of life.[65] 

Adrenal crises continue to maintain an unacceptably high mortality rate. Although the exact cause of mortality may not be apparent in all cases, it is believed to be attributed to respiratory infections, adverse cardiovascular events, and stroke.[1]

Despite extensive efforts in patient education, the incidence of adrenal crisis–related mortality remains significant. A study involving 423 participants reported an adrenal crisis–related mortality rate as high as 6%.[13] In a previous study, patient satisfaction with managing adrenal crises in the emergency setting was as low as 66%.[66]



Rushworth RL, Torpy DJ, Stratakis CA, Falhammar H. Adrenal Crises in Children: Perspectives and Research Directions. Hormone research in paediatrics. 2018:89(5):341-351. doi: 10.1159/000481660. Epub 2018 Jun 6     [PubMed PMID: 29874655]

Level 3 (low-level) evidence


Hahner S. Acute adrenal crisis and mortality in adrenal insufficiency: Still a concern in 2018! Annales d'endocrinologie. 2018 Jun:79(3):164-166. doi: 10.1016/j.ando.2018.04.015. Epub 2018 Apr 30     [PubMed PMID: 29716733]


Higham CE, Olsson-Brown A, Carroll P, Cooksley T, Larkin J, Lorigan P, Morganstein D, Trainer PJ, Society for Endocrinology Clinical Committee. SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Acute management of the endocrine complications of checkpoint inhibitor therapy. Endocrine connections. 2018 Jul:7(7):G1-G7. doi: 10.1530/EC-18-0068. Epub     [PubMed PMID: 29930025]


Puar TH, Stikkelbroeck NM, Smans LC, Zelissen PM, Hermus AR. Adrenal Crisis: Still a Deadly Event in the 21st Century. The American journal of medicine. 2016 Mar:129(3):339.e1-9. doi: 10.1016/j.amjmed.2015.08.021. Epub 2015 Sep 9     [PubMed PMID: 26363354]


Rushworth RL, Torpy DJ, Falhammar H. Adrenal Crisis. The New England journal of medicine. 2019 Aug 29:381(9):852-861. doi: 10.1056/NEJMra1807486. Epub     [PubMed PMID: 31461595]


Upadhyay J, Sudhindra P, Abraham G, Trivedi N. Tuberculosis of the adrenal gland: a case report and review of the literature of infections of the adrenal gland. International journal of endocrinology. 2014:2014():876037. doi: 10.1155/2014/876037. Epub 2014 Aug 6     [PubMed PMID: 25165474]

Level 3 (low-level) evidence


Burns CM. The History of Cortisone Discovery and Development. Rheumatic diseases clinics of North America. 2016 Feb:42(1):1-14, vii. doi: 10.1016/j.rdc.2015.08.001. Epub     [PubMed PMID: 26611547]


Gidlöf S, Falhammar H, Thilén A, von Döbeln U, Ritzén M, Wedell A, Nordenström A. One hundred years of congenital adrenal hyperplasia in Sweden: a retrospective, population-based cohort study. The lancet. Diabetes & endocrinology. 2013 Sep:1(1):35-42. doi: 10.1016/S2213-8587(13)70007-X. Epub 2013 Feb 26     [PubMed PMID: 24622265]

Level 2 (mid-level) evidence


Omori K, Nomura K, Shimizu S, Omori N, Takano K. Risk factors for adrenal crisis in patients with adrenal insufficiency. Endocrine journal. 2003 Dec:50(6):745-52     [PubMed PMID: 14709847]

Level 2 (mid-level) evidence


Smans LC, Van der Valk ES, Hermus AR, Zelissen PM. Incidence of adrenal crisis in patients with adrenal insufficiency. Clinical endocrinology. 2016 Jan:84(1):17-22. doi: 10.1111/cen.12865. Epub 2015 Aug 27     [PubMed PMID: 26208266]


Bleicken B, Hahner S, Ventz M, Quinkler M. Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients. The American journal of the medical sciences. 2010 Jun:339(6):525-31. doi: 10.1097/MAJ.0b013e3181db6b7a. Epub     [PubMed PMID: 20400889]

Level 2 (mid-level) evidence


Erichsen MM, Løvås K, Skinningsrud B, Wolff AB, Undlien DE, Svartberg J, Fougner KJ, Berg TJ, Bollerslev J, Mella B, Carlson JA, Erlich H, Husebye ES. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. The Journal of clinical endocrinology and metabolism. 2009 Dec:94(12):4882-90. doi: 10.1210/jc.2009-1368. Epub 2009 Oct 26     [PubMed PMID: 19858318]


Hahner S, Spinnler C, Fassnacht M, Burger-Stritt S, Lang K, Milovanovic D, Beuschlein F, Willenberg HS, Quinkler M, Allolio B. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. The Journal of clinical endocrinology and metabolism. 2015 Feb:100(2):407-16. doi: 10.1210/jc.2014-3191. Epub 2014 Nov 24     [PubMed PMID: 25419882]


Heidarpour M, Vakhshoori M, Abbasi S, Shafie D, Rezaei N. Adrenal insufficiency in coronavirus disease 2019: a case report. Journal of medical case reports. 2020 Aug 24:14(1):134. doi: 10.1186/s13256-020-02461-2. Epub 2020 Aug 24     [PubMed PMID: 32838801]

Level 3 (low-level) evidence


Hahner S, Loeffler M, Bleicken B, Drechsler C, Milovanovic D, Fassnacht M, Ventz M, Quinkler M, Allolio B. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. European journal of endocrinology. 2010 Mar:162(3):597-602. doi: 10.1530/EJE-09-0884. Epub 2009 Dec 2     [PubMed PMID: 19955259]

Level 2 (mid-level) evidence


Lousada LM, Mendonca BB, Bachega TASS. Adrenal crisis and mortality rate in adrenal insufficiency and congenital adrenal hyperplasia. Archives of endocrinology and metabolism. 2021 Nov 3:65(4):488-494. doi: 10.20945/2359-3997000000392. Epub 2021 Jul 16     [PubMed PMID: 34283908]


Allolio B. Extensive expertise in endocrinology. Adrenal crisis. European journal of endocrinology. 2015 Mar:172(3):R115-24. doi: 10.1530/EJE-14-0824. Epub 2014 Oct 6     [PubMed PMID: 25288693]


Manaka K, Sato J, Takeuchi M, Watanabe K, Kage H, Kawai T, Sato Y, Miyagawa T, Yamada D, Kume H, Sato S, Nagase T, Iiri T, Nangaku M, Makita N. Immune checkpoint inhibitor combination therapies very frequently induce secondary adrenal insufficiency. Scientific reports. 2021 Jun 2:11(1):11617. doi: 10.1038/s41598-021-91032-6. Epub 2021 Jun 2     [PubMed PMID: 34078988]


Joshi MN, Whitelaw BC, Palomar MT, Wu Y, Carroll PV. Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review. Clinical endocrinology. 2016 Sep:85(3):331-9. doi: 10.1111/cen.13063. Epub 2016 Apr 13     [PubMed PMID: 26998595]


Elshimy G, Gandhi A, Guo R, Correa R. Tyrosine Kinase Inhibitors' Newly Reported Endocrine Side Effect: Pazopanib-Induced Primary Adrenal Insufficiency in a Patient With Metastatic Renal Cell Cancer. Journal of investigative medicine high impact case reports. 2020 Jan-Dec:8():2324709620936808. doi: 10.1177/2324709620936808. Epub     [PubMed PMID: 32583692]

Level 3 (low-level) evidence


Lodish MB. Clinical review: kinase inhibitors: adverse effects related to the endocrine system. The Journal of clinical endocrinology and metabolism. 2013 Apr:98(4):1333-42. doi: 10.1210/jc.2012-4085. Epub 2013 Feb 28     [PubMed PMID: 23450053]


Rushworth RL, Torpy DJ, Falhammar H. Adrenal crises: perspectives and research directions. Endocrine. 2017 Feb:55(2):336-345. doi: 10.1007/s12020-016-1204-2. Epub 2016 Dec 19     [PubMed PMID: 27995500]

Level 3 (low-level) evidence


White K, Arlt W. Adrenal crisis in treated Addison's disease: a predictable but under-managed event. European journal of endocrinology. 2010 Jan:162(1):115-20. doi: 10.1530/EJE-09-0559. Epub 2009 Sep 23     [PubMed PMID: 19776201]


Iwasaku M, Shinzawa M, Tanaka S, Kimachi K, Kawakami K. Clinical characteristics of adrenal crisis in adult population with and without predisposing chronic adrenal insufficiency: a retrospective cohort study. BMC endocrine disorders. 2017 Sep 11:17(1):58. doi: 10.1186/s12902-017-0208-0. Epub 2017 Sep 11     [PubMed PMID: 28893233]

Level 2 (mid-level) evidence


Arlt W, Allolio B. Adrenal insufficiency. Lancet (London, England). 2003 May 31:361(9372):1881-93     [PubMed PMID: 12788587]


Bornstein SR. Predisposing factors for adrenal insufficiency. The New England journal of medicine. 2009 May 28:360(22):2328-39. doi: 10.1056/NEJMra0804635. Epub     [PubMed PMID: 19474430]


Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, Torpy DJ. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2016 Feb:101(2):364-89. doi: 10.1210/jc.2015-1710. Epub 2016 Jan 13     [PubMed PMID: 26760044]

Level 1 (high-level) evidence


Shibata S, Kami M, Kanda Y, Machida U, Iwata H, Kishi Y, Takeshita A, Miyakoshi S, Ueyama J, Morinaga S, Mutou Y. Acute adrenal failure associated with fluconazole after administration of high-dose cyclophosphamide. American journal of hematology. 2001 Apr:66(4):303-5     [PubMed PMID: 11279645]

Level 3 (low-level) evidence


Orme LM, Bond JD, Humphrey MS, Zacharin MR, Downie PA, Jamsen KM, Mitchell SL, Robinson JM, Grapsas NA, Ashley DM. Megestrol acetate in pediatric oncology patients may lead to severe, symptomatic adrenal suppression. Cancer. 2003 Jul 15:98(2):397-405     [PubMed PMID: 12872362]

Level 2 (mid-level) evidence


Naing KK, Dewar JA, Leese GP. Megestrol acetate therapy and secondary adrenal suppression. Cancer. 1999 Sep 15:86(6):1044-9     [PubMed PMID: 10491532]


Hellman L, Yoshida K, Zumoff B, Levin J, Kream J, Fukushima DK. The effect of medroxyprogesterone acetate on the pituitary-adrenal axis. The Journal of clinical endocrinology and metabolism. 1976 May:42(5):912-7     [PubMed PMID: 178684]


Yuen KC, Chong LE, Koch CA. Adrenal insufficiency in pregnancy: challenging issues in diagnosis and management. Endocrine. 2013 Oct:44(2):283-92. doi: 10.1007/s12020-013-9893-2. Epub 2013 Feb 2     [PubMed PMID: 23377701]


Tallis PH, Rushworth RL, Torpy DJ, Falhammar H. Adrenal insufficiency due to bilateral adrenal metastases - A systematic review and meta-analysis. Heliyon. 2019 May:5(5):e01783. doi: 10.1016/j.heliyon.2019.e01783. Epub 2019 May 29     [PubMed PMID: 31193734]

Level 1 (high-level) evidence


Ramon I, Mathian A, Bachelot A, Hervier B, Haroche J, Boutin-Le Thi Huong D, Costedoat-Chalumeau N, Wechsler B, Karmali R, Velkeniers B, Touraine P, Coussieu C, Bennani A, Renard-Penna R, Grenier PA, Wahl D, Piette JC, Amoura Z. Primary adrenal insufficiency due to bilateral adrenal hemorrhage-adrenal infarction in the antiphospholipid syndrome: long-term outcome of 16 patients. The Journal of clinical endocrinology and metabolism. 2013 Aug:98(8):3179-89. doi: 10.1210/jc.2012-4300. Epub 2013 Jun 19     [PubMed PMID: 23783099]

Level 2 (mid-level) evidence


Bain A, Stewart M, Mwamure P, Nirmalaraj K. Addison's disease in a patient with hypothyroidism: autoimmune polyglandular syndrome type 2. BMJ case reports. 2015 Aug 3:2015():. doi: 10.1136/bcr-2015-210506. Epub 2015 Aug 3     [PubMed PMID: 26240101]

Level 3 (low-level) evidence


Puttanna A, Cunningham AR, Dainty P. Addison's disease and its associations. BMJ case reports. 2013 Jul 26:2013():. doi: 10.1136/bcr-2013-010473. Epub 2013 Jul 26     [PubMed PMID: 23893277]

Level 3 (low-level) evidence


Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocrine reviews. 2000 Feb:21(1):55-89     [PubMed PMID: 10696570]

Level 3 (low-level) evidence


Malbon CC, Rapiejko PJ, Watkins DC. Permissive hormone regulation of hormone-sensitive effector systems. Trends in pharmacological sciences. 1988 Jan:9(1):33-6     [PubMed PMID: 3072728]


Turnbull AV, Rivier C. Regulation of the HPA axis by cytokines. Brain, behavior, and immunity. 1995 Dec:9(4):253-75     [PubMed PMID: 8903845]

Level 3 (low-level) evidence


Bellavance MA, Rivest S. The HPA - Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain. Frontiers in immunology. 2014:5():136. doi: 10.3389/fimmu.2014.00136. Epub 2014 Mar 31     [PubMed PMID: 24744759]


Pariante CM, Pearce BD, Pisell TL, Sanchez CI, Po C, Su C, Miller AH. The proinflammatory cytokine, interleukin-1alpha, reduces glucocorticoid receptor translocation and function. Endocrinology. 1999 Sep:140(9):4359-66     [PubMed PMID: 10465310]

Level 3 (low-level) evidence


Quatrini L, Ugolini S. New insights into the cell- and tissue-specificity of glucocorticoid actions. Cellular & molecular immunology. 2021 Feb:18(2):269-278. doi: 10.1038/s41423-020-00526-2. Epub 2020 Aug 31     [PubMed PMID: 32868909]


Erkut ZA, Pool C, Swaab DF. Glucocorticoids suppress corticotropin-releasing hormone and vasopressin expression in human hypothalamic neurons. The Journal of clinical endocrinology and metabolism. 1998 Jun:83(6):2066-73     [PubMed PMID: 9626140]


Kim JK, Summer SN, Wood WM, Schrier RW. Role of glucocorticoid hormones in arginine vasopressin gene regulation. Biochemical and biophysical research communications. 2001 Dec 21:289(5):1252-6     [PubMed PMID: 11741329]

Level 3 (low-level) evidence


Kuo T, McQueen A, Chen TC, Wang JC. Regulation of Glucose Homeostasis by Glucocorticoids. Advances in experimental medicine and biology. 2015:872():99-126. doi: 10.1007/978-1-4939-2895-8_5. Epub     [PubMed PMID: 26215992]

Level 3 (low-level) evidence


Sominsky L, Spencer SJ. Eating behavior and stress: a pathway to obesity. Frontiers in psychology. 2014:5():434. doi: 10.3389/fpsyg.2014.00434. Epub 2014 May 13     [PubMed PMID: 24860541]


Bollag WB. Regulation of aldosterone synthesis and secretion. Comprehensive Physiology. 2014 Jul:4(3):1017-55. doi: 10.1002/cphy.c130037. Epub     [PubMed PMID: 24944029]

Level 3 (low-level) evidence


Esposito D, Pasquali D, Johannsson G. Primary Adrenal Insufficiency: Managing Mineralocorticoid Replacement Therapy. The Journal of clinical endocrinology and metabolism. 2018 Feb 1:103(2):376-387. doi: 10.1210/jc.2017-01928. Epub     [PubMed PMID: 29156052]


Claessen KMJA, Andela CD, Biermasz NR, Pereira AM. Clinical Unmet Needs in the Treatment of Adrenal Crisis: Importance of the Patient's Perspective. Frontiers in endocrinology. 2021:12():701365. doi: 10.3389/fendo.2021.701365. Epub 2021 Jul 20     [PubMed PMID: 34354671]

Level 3 (low-level) evidence


Dineen R, Thompson CJ, Sherlock M. Adrenal crisis: prevention and management in adult patients. Therapeutic advances in endocrinology and metabolism. 2019:10():2042018819848218. doi: 10.1177/2042018819848218. Epub 2019 Jun 13     [PubMed PMID: 31223468]

Level 3 (low-level) evidence


Robati S, Shahid MK, Vella A, Rang S. Importance of a thorough drug history in presurgical patients. BMJ case reports. 2014 Mar 14:2014():. doi: 10.1136/bcr-2013-202667. Epub 2014 Mar 14     [PubMed PMID: 24632903]

Level 3 (low-level) evidence


Dinsen S, Baslund B, Klose M, Rasmussen AK, Friis-Hansen L, Hilsted L, Feldt-Rasmussen U. Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself. European journal of internal medicine. 2013 Dec:24(8):714-20. doi: 10.1016/j.ejim.2013.05.014. Epub 2013 Jun 25     [PubMed PMID: 23806261]


Hopkins RL, Leinung MC. Exogenous Cushing's syndrome and glucocorticoid withdrawal. Endocrinology and metabolism clinics of North America. 2005 Jun:34(2):371-84, ix     [PubMed PMID: 15850848]


Kazlauskaite R, Evans AT, Villabona CV, Abdu TA, Ambrosi B, Atkinson AB, Choi CH, Clayton RN, Courtney CH, Gonc EN, Maghnie M, Rose SR, Soule SG, Tordjman K, Consortium for Evaluation of Corticotropin Test in Hypothalamic-Pituitary Adrenal Insufficiency. Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis. The Journal of clinical endocrinology and metabolism. 2008 Nov:93(11):4245-53. doi: 10.1210/jc.2008-0710. Epub 2008 Aug 12     [PubMed PMID: 18697868]

Level 1 (high-level) evidence


Oelkers W. Adrenal insufficiency. The New England journal of medicine. 1996 Oct 17:335(16):1206-12     [PubMed PMID: 8815944]


Malikova J, Flück CE. Novel insight into etiology, diagnosis and management of primary adrenal insufficiency. Hormone research in paediatrics. 2014:82(3):145-57. doi: 10.1159/000363107. Epub 2014 Aug 1     [PubMed PMID: 25096886]


Prete A, Taylor AE, Bancos I, Smith DJ, Foster MA, Kohler S, Fazal-Sanderson V, Komninos J, O'Neil DM, Vassiliadi DA, Mowatt CJ, Mihai R, Fallowfield JL, Annane D, Lord JM, Keevil BG, Wass JAH, Karavitaki N, Arlt W. Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery. The Journal of clinical endocrinology and metabolism. 2020 Jul 1:105(7):2262-74. doi: 10.1210/clinem/dgaa133. Epub     [PubMed PMID: 32170323]


Guignat L. Therapeutic patient education in adrenal insufficiency. Annales d'endocrinologie. 2018 Jun:79(3):167-173. doi: 10.1016/j.ando.2018.03.002. Epub 2018 Mar 29     [PubMed PMID: 29606279]


Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. American journal of respiratory and critical care medicine. 2001 Jun:163(7):1520-3     [PubMed PMID: 11401866]


Betterle C, Presotto F, Furmaniak J. Epidemiology, pathogenesis, and diagnosis of Addison's disease in adults. Journal of endocrinological investigation. 2019 Dec:42(12):1407-1433. doi: 10.1007/s40618-019-01079-6. Epub 2019 Jul 18     [PubMed PMID: 31321757]


Ngaosuwan K, Johnston DG, Godsland IF, Cox J, Majeed A, Quint JK, Oliver N, Robinson S. Increased Mortality Risk in Patients With Primary and Secondary Adrenal Insufficiency. The Journal of clinical endocrinology and metabolism. 2021 Jun 16:106(7):e2759-e2768. doi: 10.1210/clinem/dgab096. Epub     [PubMed PMID: 33596308]


Arlt W, Society for Endocrinology Clinical Committee. SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. Endocrine connections. 2016 Sep:5(5):G1-G3     [PubMed PMID: 27935813]


Woodcock T, Barker P, Daniel S, Fletcher S, Wass JAH, Tomlinson JW, Misra U, Dattani M, Arlt W, Vercueil A. Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insufficiency: Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK. Anaesthesia. 2020 May:75(5):654-663. doi: 10.1111/anae.14963. Epub 2020 Feb 3     [PubMed PMID: 32017012]


Burger-Stritt S, Kardonski P, Pulzer A, Meyer G, Quinkler M, Hahner S. Management of adrenal emergencies in educated patients with adrenal insufficiency-A prospective study. Clinical endocrinology. 2018 Jul:89(1):22-29. doi: 10.1111/cen.13608. Epub 2018 Apr 24     [PubMed PMID: 29617051]


Matsubayashi S, Nakatake N, Hara T. Possible adrenal insufficiency among fatigue patients in a psychosomatic medical clinic. Endocrine journal. 2020 Jan 28:67(1):53-57. doi: 10.1507/endocrj.EJ19-0096. Epub 2019 Oct 8     [PubMed PMID: 31597820]


White KG. A retrospective analysis of adrenal crisis in steroid-dependent patients: causes, frequency and outcomes. BMC endocrine disorders. 2019 Dec 2:19(1):129. doi: 10.1186/s12902-019-0459-z. Epub 2019 Dec 2     [PubMed PMID: 31791297]

Level 2 (mid-level) evidence