• Clinical science

Adrenal insufficiency


Adrenal insufficiency is the decreased production of adrenocortical hormones (glucocorticoids, mineralocorticoids, and adrenal androgens) and can be 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 may 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 a prolonged glucocorticoid therapy or 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. Patients can also present with loss of libido as a result of hypoandrogenism. Patients with primary adrenal insufficiency also tend to 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 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.


Primary adrenal insufficiency (Addison disease)

Primary adrenal insufficiency is caused by conditions that directly impair adrenal function.

Secondary adrenal insufficiency

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

  • Sudden discontinuation of chronic glucocorticoid therapy or stress (e.g., infection, trauma, surgery) during prolonged glucocorticoid therapy
    • Prolonged iatrogenic suppression of the hypothalamic-pituitary-adrenal axis
    • Impaired endogenous cortisol production in addition to discontinuation of steroid treatment, decrease in dosage, or increase in requirement (e.g., stress) → acute glucocorticoid deficiency
  • Hypopituitarism: ACTHendogenous cortisol

Tertiary adrenal insufficiency

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

  • The most common cause is sudden discontinuation of chronic glucocorticoid therapy: prolonged iatrogenic suppression of hypothalamic-pituitary-adrenal axis (endogenous cortisol) and sudden discontinuation of exogenous steroid treatment → acute glucocorticoid deficiency
  • 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.


Clinical features

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


  • Hypotension
  • Absent
  • Absent


  • Weight loss, anorexia
  • Fatigue, lethargy, depression
  • Muscle aches
  • Gastrointestinal complaints (e.g., nausea, vomiting, diarrhea)
  • Sugar/salt cravings
  • (Orthostatic) hypotension
  • Loss of libido
  • Loss of axillary and pubic hair
  • DHEA-S
Elevated ACTH
  • Hyperpigmentation of areas that are not normally exposed to sunlight (e.g., palmar creases, mucous membrane of the oral cavity)
  • 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).



Diagnosis is based on clinical presentation and confirmed via endocrine evaluation.

Diagnosis of adrenal insufficiency

General laboratory findings

Diagnosis of hypocortisolism

Diagnosis of hypoaldosteronism

Diagnosis of adrenal hypoandrogenism

  • DHEA-S

Identifying the underlying cause of adrenal insufficiency



Primary adrenal insufficiency

Secondary and tertiary adrenal insufficiency

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

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

Adrenal crisis (Addisonian crisis)

In order to avoid the development of secondary and tertiary adrenal insufficiency, prolonged steroid therapy must be tapered slowly and should never be stopped abruptly.

The 5 S’s of adrenal crisis treatment are: Salt: 0.9% saline, Sugar: 50% dextrose, Steroids: 100 mg hydrocortisone IV every 8 hours, Support: normal saline to correct hypotension and electrolyte abnormalities, Search for underlying disorder

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


Autoimmune polyglandular syndromes