Adrenal insufficiency

Last updated: September 7, 2023

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]

Etiologytoggle arrow icon

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!

Pathophysiologytoggle arrow icon

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

Signs of aldosterone deficiency can help differentiate primary adrenal insufficiency from secondary and tertiary adrenal insufficiency.

Tertiary adrenal insufficiency


Clinical featurestoggle arrow icon

Hormonal changes

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


  • Absent
  • Absent


  • 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).


Diagnosticstoggle arrow icon


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

Endocrine testing is typically performed sequentially (see “Approach”).

  1. Morning cortisol level: initial test [17]
  2. Morning ACTH level: obtain if morning cortisol is low [17]
  3. Standard-dose ACTH stimulation test (cosyntropin test): gold standard to confirm the diagnosis of primary adrenal insufficiency [17]

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]

Treatmenttoggle arrow icon


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 (Addisonian crisis)toggle arrow icon

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

Precipitating factors for adrenal crisis

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).

Acute management checklist for adrenal crisistoggle arrow icon

Autoimmune polyglandular syndromestoggle arrow icon


Referencestoggle arrow icon

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