Secondary and Tertiary Adrenal Insufficiency Key Points

• Secondary adrenal insufficiency results from ACTH deficiency and is often seen in panhypopituitarism or after chronic glucocorticoid excess.

• Lack of production of CRH from the hypothalamus results in tertiary adrenal insufficiency.

• In secondary adrenal insufficiency, mineralocorticoid production is maintained by the renin-angiotensin system. Thus, hyperkalemia is absent while hyponatremia may result from loss of glucocorticoid effect on free-water clearance.

• Low ACTH and cortisol levels suggest secondary or tertiary adrenal insufficiency.

Secondary adrenal insufficiency is defined as a deficiency of ACTH. Isolated ACTH deficiency is rare and may be congenital or caused by lymphocytic hypophysitis. Secondary AI more often occurs in the setting of panhypopituitarism from underlying causes such as pituitary or metastatic tumors, craniopharyngioma, infections (TB, histoplasmosis), infiltrative disease (sarcoidosis), head trauma, or postpartum pituitary necrosis (Sheehan's syndrome). Chronic glucocorticoid excess, either exogenous (glucocorticoid treatment for more than 4 weeks) or endogenous (Cushing's syndrome), causes secondary AI by prolonged suppression of CRH production. Tertiary adrenal insufficiency results from the lack of CRH production from the hypothalamus.

Clinical Presentation

Signs and symptoms are similar to those of primary AI, but electrolyte and fluid abnormalities and hypotensive symptoms are absent because the mineralocorticoid production is still maintained by the renin-angiotensin system. Hyper-pigmentation is not seen. Menstrual dysfunction, headache and visual symptoms, hypothyroidism, and diabetes insipidus may be present as a result of panhypopituitarism (see Pituitary Disorders).

Laboratory Evaluation

Plasma cortisol and ACTH levels should be checked initially. Low ACTH (<5 pg/mL) and cortisol levels suggest secondary or tertiary adrenal insufficiency, and pituitary CT or MRI is indicated. The cosyntropin stimulation test may be helpful in identifying adrenal insufficiency. With an abnormal result, ACTH level may determine primary (high ACTH) versus secondary (normal or low ACTH) disease. However, in secondary AI the ACTH-stimulation test might not be abnormal because sufficient ACTH might be present to prevent adrenal gland atrophy. In these patients, CRH stimulation test can assess ACTH response. Secondary AI shows little or no increase in the ACTH or cortisol level throughout the test, but in tertiary AI the ACTH increases in an exaggerated fashion and remains elevated longer. The insulin tolerance test and the metyrapone test are also available (but less often used) to assess the integrity of the hypothalamic-pituitary-adrenal (HPA) axis by its response to hypoglycemia or the inhibited cortisol synthesis, respectively.


As described in primary AI, treatment of underlying disorders and glucocorticoid replacement are necessary in secondary and tertiary AI, but not mineralocorticoid replacement.

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