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. 
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).
- Most common cause in the US (∼ 80–90% of all cases of primary adrenal insufficiency)
- Associated with other autoimmune endocrinopathies (see “) ”
- Infectious adrenalitis
Adrenal hemorrhage 
- Sepsis: especially meningococcal sepsis (endotoxic shock) → hemorrhagic necrosis (Waterhouse-Friderichsen syndrome)
- Disseminated intravascular coagulation (DIC)
- Anticoagulation: especially heparin (heparin-induced thrombocytopenia) 
- Venous thromboembolism, especially in antiphospholipid syndrome (APS) Recurrent thromboses are a typical manifestation of APS. 
- Adrenal tumor (most commonly pheochromocytoma) → intratumoral bleeding 
- (Short-term) steroid usage 
- Trauma (mostly blunt trauma, can also occur postoperatively) 
- In neonates: birth trauma, difficult labor (e.g., breech delivery, forceps/vacuum delivery, prolonged labor), maternal diabetes 
- Infiltration of the adrenal glands
- Impaired activity of enzymes that are responsible for cortisol synthesis
- Vitamin B5 deficiency 
Secondary adrenal insufficiency
- Sudden discontinuation of chronic glucocorticoid therapy or stress (e.g., infection, trauma, surgery) during prolonged glucocorticoid therapy
- Hypopituitarism: ↓ ACTH → ↓ endogenous cortisol
Tertiary adrenal insufficiency
- 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): ↓ CRH → ↓ ACTH → ↓ cortisol release
- Loss of libido
- Impaired spermatogenesis (in men)
Hypocortisolism leads to:
- ↑ ACTH → ↑ production of POMC (in order to increase ACTH production) → ↑ melanocyte-stimulating hormone (MSH) → hyperpigmentation of the skin (bronze skin) 
- ↑ ADH level → retention of free water → dilutional hyponatremia
- ↓ Expression of enzymes involved in gluconeogenesis → ↓ rate of gluconeogenesis → hypoglycemia
- Lack of potentiation of catecholamines action → hypotension
- Hypoaldosteronism → hypotension (hypotonic hyponatremia and volume contraction), hyperkalemia, metabolic acidosis
- ↓ ACTH → hypoandrogenism and hypocortisolism
- Aldosterone synthesis is not affected (mineralocorticoid production is controlled by RAAS and angiotensin II, not by ACTH).
|Clinical features||Laboratory findings||Primary adrenal insufficiency||Secondary adrenal insufficiency||Tertiary adrenal insufficiency|
| ||✓|| || |
|Hypoandrogenism|| || ||✓||✓||✓|
|Elevated ACTH|| ||✓|| || |
- Acute adrenal insufficiency: Make a clinical diagnosis and defer detailed testing until after empiric glucocorticoids are given (see “Adrenal crisis”).
- Chronic adrenal insufficiency: Use stepwise endocrine testing in all patients.
- Primary adrenal insufficiency: Screen for hypoaldosteronism and hypoandrogenism.
- Secondary and tertiary adrenal insufficiency: Differentiating between the two is often not required, as it does not influence management. 
- All patients: Investigate for an underlying cause.
|Endocrine testing for adrenal insufficiency |
|↓||↑||No increase in serum cortisol after stimulation|
Secondary/tertiary adrenal insufficiency
|↓||Increase in serum cortisol after stimulation|
Longstanding secondary/tertiary adrenal insufficiency 
|↓||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. 
Routine laboratory studies
- Primary adrenal insufficiency 
- Secondary adrenal insufficiency: potentially only ↓ Na or hypoglycemia 
Endocrine testing is typically performed sequentially (see “Approach”).
Morning cortisol level: initial test 
- Levels ≥ 18 mcg/dL have a high negative predictive value for ruling out adrenal insufficiency. 
- Levels < 3 mcg/dL strongly suggest hypocortisolism. 
- Random cortisol levels are of limited value, as cortisol secretion varies diurnally and with physiological stress. 
- Cortisol levels are influenced by cortisol-binding globulin (CBG) and albumin levels. 
Morning ACTH level: obtain if morning cortisol is low 
- Primary adrenal insufficiency: elevated ACTH levels > 100 pg/mL
- Secondary/tertiary adrenal insufficiency: ACTH levels low to normal
- ACTH secretion is subject to diurnal variation, which is why a morning sample is desirable. 
- Exogenous glucocorticoids (via any route) can suppress ACTH secretion through negative feedback.
Standard-dose ACTH stimulation test (cosyntropin test): gold standard to confirm the diagnosis of primary adrenal insufficiency 
- Administration of 250 mcg exogenous ACTH to stimulate cortisol secretion
- Measurement of cortisol levels before and 30 and/or 60 minutes after injection
- Physiological response: exogenous ACTH → ↑ cortisol
- If a patient is on prednisone, prednisolone, or dexamethasone, temporarily switch them to hydrocortisone and hold hydrocortisone 24 hours prior to testing.
- Variant: low-dose (1 mcg) ACTH stimulation test 
Screening for hypoaldosteronism and hypoandrogenism 
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.
Insulin tolerance test (also insulin hypoglycemia test) 
- Physiological response: administration of insulin → hypoglycemia (strong stimulator for ACTH and cortisol secretion) → stress-induced ↑ in plasma ACTH → ↑ in cortisol levels 
- Secondary adrenal insufficiency: no incremental rise in ACTH and cortisol levels
- Unsafe in the elderly and in patients with known seizures and cardiac disease
Overnight metyrapone stimulation test 
- Physiological response: metyrapone inhibits 11β hydroxylase → impaired conversion of 11-deoxycortisol to cortisol (last step of cortisol synthesis) → ↓ serum cortisol → ↑ in CRH and plasma ACTH (negative feedback) → ↑ in adrenal steroidogenesis → ↑ in 11-deoxycortisol level
- In primary adrenal insufficiency: metyrapone → ↓ cortisol synthesis → ↑ in CRH/ACTH → no increase in adrenal steroid production → no increase in 11-deoxycortisol or cortisol levels
- In secondary/tertiary adrenal insufficiency: metyrapone → ↓ cortisol → no increase in CRH/ACTH → no increase in adrenal steroid production → no increase in 11-deoxycortisol or cortisol levels
- CRH stimulation test: used to distinguish between secondary and tertiary adrenal insufficiency 
The following tests are used to investigate underlying causes.
- Antibodies against 21-hydroxylase
- Consider further screening for autoimmune polyendocrine syndromes if antibodies against 21-hydroxylase are present:
Secondary/tertiary adrenal insufficiency 
- Primary adrenal insufficiency: replacement for hypocortisolism, hypoaldosteronism, and hypoandrogenism
- Secondary/tertiary adrenal insufficiency: replacement for hypocortisolism and hypoandrogenism
- Underlying causes: Identify and treat reversible conditions in all patients.
- Prevention of adrenal crisis: See “ .”
- The total daily replacement dose should be given in divided doses, with the highest dose given in the morning to mimic diurnal fluctuations.
- Educate patients about increasing their glucocorticoid dose according to outpatient sick day rules.
- Side effects may arise due to overtreatment (see “Cushing syndrome”).
- Agent: fludrocortisone; (a synthetic mineralocorticoid with mostly mineralocorticoid and limited glucocorticoid effects) 
- Advise patients not to restrict their salt intake.
- A temporary increase may be advised if increased sweating is anticipated (e.g., in the summer)
- Monitor for adequate replacement and consider a dose reduction if hypertension develops. 
- Side effects are analogous to glucocorticoids (e.g., hyperpigmentation).
- Additional side effects include:
Consider treatment in anatomically female patients with low libido, depressive symptoms, and low energy levels.
- Agent: DHEA 
Treatment of the underlying cause and associated conditions
- Drug-induced adrenal insufficiency : Consider medication adjustment. 
- Hypopituitarism: Substitute other pituitary hormones; see “Hypopituitarism.”
- Infectious adrenalitis: See “Tuberculosis,” “HIV,” and “Cytomegalovirus infection.”
- Adrenal hemorrhage: e.g., .
- Infiltration of the adrenal glands: Treat malignancy, e.g., via tumor resection.
- Autoimmune adrenalitis: Treat other associated autoimmune endocrinopathies.
Stress-dose steroids 
- 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.
Inpatient stress-dose steroids 
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 
- Perioperative patients
Outpatient sick day rules  
- Sick day rule one: circumstances requiring double the routine oral glucocorticoid dose
- Sick day rule two: circumstances requiring IM/IV glucocorticoids or suppositories
Precipitating factors for adrenal crisis
Stress in patients with underlying adrenal insufficiency e.g.: 
- Gastrointestinal illness (most common)
- Other infections
- Perioperative period
- Physical stress or pain
- Psychological stress
- Sudden discontinuation of glucocorticoids after prolonged glucocorticoid therapy
- Bilateral adrenal hemorrhage or infarction (e.g., Waterhouse-Friderichsen syndrome)
- Pituitary apoplexy 
Signs and symptoms 
- Hypotension, shock
- Impaired consciousness, coma
- Vomiting, diarrhea
- Severe abdominal pain (which can resemble peritonitis)
- Based on clinical suspicion: Maintain a low threshold for diagnosis in at-risk patients , especially those with shock refractory to fluids and/or vasopressors. 
- Point-of-care testing and routine laboratory studies
- Endocrine testing: Consider if the diagnosis is uncertain (e.g., first presentation).
- Empiric glucocorticoid replacement
- Consider adding mineralocorticoid replacement, e.g., fludrocortisone (off-label) for the following: 
- Fluid resuscitation
- Hypoglycemia: IV dextrose, e.g., 50% dextrose
- Identify and treat underlying causes (e.g., sepsis).
- Consider higher-level monitoring, e.g., intensive care
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).
Acute management checklist for adrenal crisis
- 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.
- Definition: a set of conditions characterized by autoimmune disease that causes multiple endocrine deficiencies, which affect the hormone-producing (endocrine) glands
Type 1: (APS-1, Whitaker syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, or APECED)
- Less common than APS-2 (1:100,000)
- Autosomal recessive inheritance; no HLA association
- Caused by a mutation in the autoimmune regulator gene (AIRE)
- Age of onset: usually in childhood
- Associated endocrine deficiencies (two or more of the following should be present)
Type 2 (APS-2, Schmidt syndrome): defined by the occurrence of primary adrenal insufficiency with thyroid autoimmune disease and/or type 1 diabetes mellitus 
- More common than APS-1 (1.4 - 2:100,000)
- Associated with HLA‑DR3 and/or HLA‑DR4 haplotypes
- Age of onset: usually in adulthood
- Main manifestation: primary adrenal insufficiency
- Type 1: (APS-1, Whitaker syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, or APECED)
- Diagnostics: condition‑specific antibody tests (e.g., TPO antibodies in Hashimoto thyroiditis, antiparietal cell antibodies in pernicious anemia)
- Therapy: depends on the endocrine deficiency