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Secondary Adrenal Insufficiency

by Ashley B. Grossman, MD, FRCP, FMedSci

Secondary adrenal insufficiency is adrenal hypofunction due to a lack of ACTH. Symptoms are the same as for Addison disease, but there is usually less hypovolemia (see Addison Disease : Symptoms and Signs). Diagnosis is clinical and by laboratory findings, including low plasma ACTH with low plasma cortisol. Treatment depends on the cause but generally includes hydrocortisone.

Secondary adrenal insufficiency may occur in panhypopituitarism, in isolated failure of ACTH production, in patients receiving corticosteroids (by any route, including high doses of inhaled, intra-articular, or topical corticosteroids), or after corticosteroids are stopped. Inadequate ACTH can also result from failure of the hypothalamus to stimulate pituitary ACTH production, which is sometimes called tertiary adrenal insufficiency.

Panhypopituitarism (see Symptoms and Signs) may occur secondary to pituitary tumors, various tumors, granulomas, and, rarely, infection or trauma that destroys pituitary tissue. In younger people, panhypopituitarism may occur secondary to a craniopharyngioma. Patients receiving corticosteroids for > 4 wk may have insufficient ACTH secretion during metabolic stress to stimulate the adrenals to produce adequate quantities of corticosteroids, or they may have atrophic adrenals that are unresponsive to ACTH. These problems may persist for up to 1 yr after corticosteroid treatment is stopped.

Symptoms and Signs

Symptoms and signs are similar to those of Addison disease (see Addison Disease : Symptoms and Signs). Differentiating clinical or general laboratory features include the absence of hyperpigmentation and relatively normal electrolyte and BUN levels; hyponatremia, if it occurs, is usually dilutional.

Patients with panhypopituitarism have depressed thyroid and gonadal function and hypoglycemia. Coma may supervene when symptomatic secondary adrenal insufficiency occurs. Adrenal crisis is especially likely if a patient is treated for a single endocrine gland problem, particularly with thyroxine, without hydrocortisone replacement.


  • Serum cortisol

  • Serum ACTH

  • ACTH stimulation testing

  • CNS imaging

Tests to differentiate primary and secondary adrenal insufficiency are discussed under Addison disease (see Addison Disease : Diagnosis). Patients with confirmed secondary adrenal insufficiency should have CT or MRI of the brain to rule out a pituitary tumor or atrophy. Adequacy of the hypothalamic-pituitary-adrenal axis during tapering or after stopping long-term corticosteroid treatment can be determined by injecting cosyntropin 250 mcg IV or IM. After 30 min, serum cortisol should be > 20 μg/dL (> 552 nmol/L); specific levels vary somewhat depending on the laboratory assay in use. An insulin stress test to induce hypoglycemia and a rise in cortisol is the standard for testing integrity of the hypothalamic-pituitary-adrenal axis.

The corticotropin-releasing hormone (CRH) test can be used to distinguish between hypothalamic and pituitary causes but is rarely used in clinical practice. After administration of CRH 100 mcg (or 1 mcg/kg) IV, the normal response is a rise of serum ACTH of 30 to 40 pg/mL; patients with pituitary failure do not respond, whereas those with hypothalamic disease usually do.


  • Hydrocortisone or prednisone

  • Fludrocortisone not indicated

  • Dose increase during intercurrent illness

Glucocorticoid replacement is similar to that described for Addison disease. Each case varies regarding the type and degree of specific hormone deficiencies. Fludrocortisone is not required because the intact adrenals produce aldosterone. During acute febrile illness or after trauma, patients receiving corticosteroids for nonendocrine disorders may require supplemental doses to augment their endogenous hydrocortisone production. In panhypopituitarism, other pituitary deficiencies should be treated appropriately (see Selective Pituitary Hormone Deficiencies).

Key Points

  • Secondary adrenal insufficiency involves ACTH deficiency due to pituitary or, less often, hypothalamic causes (including suppression by long-term corticosteroid use).

  • Other endocrine deficiencies (eg, hypothyroidism, growth hormone deficiency) may coexist.

  • Unlike in Addison disease, hyperpigmentation does not occur and serum Na and K levels are relatively normal.

  • ACTH and cortisol levels both are low.

  • Glucocorticoid replacement is required but mineralocorticoids (eg, fludrocortisone) are not necessary.

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