Adrenal insufficiency can be caused by diseases of the adrenal gland (primary), interference with corticotropin (ACTH) secretion by the pituitary gland (secondary), or interference with corticotropin-releasing hormone (CRH) secretion by the hypothalamus (tertiary). This topic will review the major causes of the latter two disorders; the causes of primary adrenal insufficiency, and the clinical manifestations and approach to diagnosis are discussed separately. (See "Causes of primary adrenal insufficiency (Addison's disease)" and "Clinical manifestations of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults".)
Any process that involves the pituitary and interferes with ACTH secretion can cause secondary adrenal insufficiency. The ACTH deficiency may be isolated, or occur in conjunction with other pituitary hormone deficiencies (panhypopituitarism).
Panhypopituitarism — Pituitary tissue can be destroyed and hormone secretion reduced by large pituitary tumors or craniopharyngiomas, infectious diseases such as tuberculosis or histoplasmosis, infiltrative diseases, lymphocytic hypophysitis, head trauma, and large intracranial artery aneurysms. Pituitary infarction can occur at the time of delivery if excessive blood is lost and hypotension occurs (Sheehan's syndrome), and hemorrhage may occur into a pituitary tumor (pituitary apoplexy). Pituitary metastases are frequently (about 5 percent) found in patients with disseminated cancer at autopsy; however, these metastases rarely reduce hormone secretion . (See "Causes of hypopituitarism".)
ACTH deficiency due to genetic pituitary abnormalities is rare. ACTH and cortisol deficiency have been described in patients with multiple pituitary hormone deficiencies due to mutations in the PROP-1 (Prophet of Pit-1) gene, even though PROP-1 is not expressed in corticotropes. The onset of cortisol deficiency, which may be severe, ranges from childhood to late adulthood [2-5]. Mutations in other transcription factors involved in early pituitary development (HESX1, LHX4) also can result in variable degrees of hypopituitarism that include ACTH deficiency [6,7]. (See "Causes of hypopituitarism".)
Isolated ACTH deficiency — Isolated ACTH deficiency is a rare disorder . The defect is probably at the pituitary level because there is no ACTH secretory response to CRH or vasopressin, as there usually is in hypothalamic disorders [9-11]. Occasional patients may have hypothyroxinemia and hyperprolactinemia that are corrected with glucocorticoid replacement [12,13].