Central adrenal insufficiency: open issues regarding diagnosis and glucocorticoid treatment

Background: Central adrenal insufficiency (CAI) is characterized by impaired adrenocorticotropin (ACTH) secretion because of a disease or injury to the hypothalamus or the pituitary, leading to a reduced cortisol production. CAI suspicion arises more frequently in patients with pituitary tumors, cranial irradiation/surgery/injury/infections, as well as after exogenous glucocorticoid withdrawal. Nevertheless, a late diagnosis is not uncommon because CAI may present with nonspecific signs or symptoms, as fatigue or hyponatremia. Content: The PubMed database was searched (years 1980-2018), using "central adrenal insufficiency" and "ACTH deficiency" as keywords. Subsequently, reference sections of the retrieved articles were searched. Summary: Dynamic tests are needed when morning basal cortisol levels are not sufficient to exclude or to confirm CAI. Short Synacthen Test (SST) is the most used, and Endocrine Society's guidelines recommend a cortisol peak >500 nmol/L to exclude CAI. Despite thresholds, understanding the pretest probability of ACTH deficiency (the clinical background of the patient) is essential because the diagnostic accuracy of SST in case of a negative result is suboptimal. Glucocorticoid replacement therapy, able to replicate cortisol circadian rhythm, is required in patients with CAI; fludrocortisone treatment is not necessary. Short-acting glucocorticoid drugs (hydrocortisone or cortisone acetate) are the most used; lower doses than previously used are nowadays recommended to reduce cortisol-related comorbidities. Promising results have been obtained with modified-release hydrocortisone, especially regarding glucose metabolism in patients with primary adrenal insufficiency. Outlook: An accurate clinical diagnosis and a careful individualized therapy are mandatory in patients with CAI.