- Clinical science
Adrenal insufficiency refers to the decreased production of adrenocortical hormones (glucocorticoids, mineralocorticoids, and adrenal androgens). Primary adrenal insufficiency (Addison disease) is caused by a disorder of the adrenal glands. The most frequent cause of primary adrenal insufficiency 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). Decreased levels of ACTH are seen following prolonged glucocorticoid therapy or in pituitary/hypothalamic diseases. Patients with long-standing adrenal insufficiency may present with postural hypotension, nausea, vomiting, weight loss, anorexia, lethargy, depression, and/or chronic hyponatremia. Female patients 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 an adrenal crisis, a severe, acute type of adrenal insufficiency that presents with fever, impaired consciousness, severe abdominal pain, and hypovolemic shock. Adrenal crisis is life-threatening and should be treated immediately with high doses of hydrocortisone and intravenous fluids.
Autoimmune adrenalitis (most common cause; ∼ 80–90% of all cases of primary adrenal insufficiency)
- Autoimmune adrenalitis; is usually associated with other autoimmune endocrinopathies (see )
- Adrenal hemorrhage
- Infiltration of the adrenal glands
- Impaired activity of enzymes that are responsible for cortisol synthesis
Sudden discontinuation of glucocorticoids or stress (e.g., infection, trauma, surgery) after prolonged glucocorticoid therapy
- Prolonged iatrogenic suppression of the hypothalamic-pituitary-adrenal axis eventually shuts down the production and release of CRH, ACTH and, in turn, of cortisol.
- With endogenous production impaired, a sudden discontinuation of steroid treatment, decrease in dosage, or increase in requirement (e.g., stress) will cause a glucocorticoid deficiency.
|Hormone insufficiency||Clinical and/or biochemical features||Primary adrenal insufficiency||Secondary adrenal insufficiency|
|Hypoandrogenism (among female patients only)|| ||✓||✓|
|Elevated ACTH|| ||✓||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!
Diagnosis of adrenal insufficiency
- Diagnosis of hypocortisolism
- Diagnosis of hypoaldosteronism
Diagnosis of adrenal hypoandrogenism
- ↓ DHEA-S
- Additional laboratory findings
Metyrapone stimulation test
Metyrapone inhibits 11-ß hydroxylase → impaired conversion of 11-deoxycortisol to cortisol (last step of cortisol synthesis)
- Normal response: ↓ cortisol → ↑ in CRH and ACTH → ↑ adrenal steroidogenesis
- In primary adrenal insufficiency: ↓ cortisol → ↑ in CRH and ↑ ACTH → no increase in adrenal steroid production
- In secondary or tertiary adrenal insufficiency: ↓ cortisol → no increase in CRH/ACTH → no increase in adrenal steroidogenesis
- Rarely performed in the US in favor of serum ACTH assays
- Metyrapone inhibits 11-ß hydroxylase → impaired conversion of 11-deoxycortisol to cortisol (last step of cortisol synthesis)
Identifying the underlying cause of adrenal insufficiency
- Serum ACTH levels: used to distinguish primary from secondary adrenal insufficiency
- If primary adrenal insufficiency
- If secondary adrenal insufficiency
- Glucocorticoid replacement therapy with hydrocortisone is required in all forms of adrenal insufficiency.
- Patients with primary adrenal insufficiency (Addison disease) may require fludrocortisone; in addition to glucocorticoid replacement therapy.
- Loss of libido in female patients can be treated with dehydroepiandrosterone (DHEA).
- Description: Acute, severe glucocorticoid deficiency that is usually precipitated by one of the following triggers:
- Clinical features
Adrenal crisis can be life-threatening. Therefore, treatment with high doses of hydrocortisone should be started immediately without waiting for diagnostic confirmation of hypocortisolism!
- Definition: Autoimmune polyendocrine syndromes are conditions characterized by multiple endocrine deficiencies as a result of autoimmune disease.
- Type 1 (Whitaker syndrome; juvenile form)
- Type 2 (Schmidt syndrome; adult form)
- Diagnostics: condition‑specific antibody tests (e.g., thyroid peroxidase antibodies, parietal cell antibodies)
- Therapy: hormone replacement therapy
Adrenal insufficiency is the most common endocrinopathy in patients with polyglandular autoimmune syndrome (present in over 50% of cases)!