Biochemical diagnosis of hypercortisolism: When and how?

Hypercortisolism constitutes several symptoms and signs due to inappropriately high and prolonged exposure to excess glucocorticoids (GCs), known as Cushing's syndrome (CS). While iatrogenic corticosteroid administration is the most frequent cause of CS, pituitary corticotroph adenoma, is the most common cause of endogenous excessive GC secretion. Since chronic exposure to high GC levels has been associated with an increased multisystemic morbidity and mortality, prompt identification and treatment are mandatory to minimize long-term complications. The main abnormalities and diagnostic biochemical tests to evaluate cortisol secretion include loss of the normal circadian rhythm assessed by late night salivary cortisol, reduced GC feedback assessed by overnight 1mg dexamethasone suppression test and elevated levels of biologically active cortisol measured by 24-h urinary free cortisol. This chapter addresses the biochemical diagnosis of hypercortisolism. It outlines when to suspect the condition, which biochemical tests are recommended and how they should be performed, providing tools and recommendations for the initial biochemical evaluation. It also discusses challenges, potential pitfalls, and accuracy of each test to aid interpretation and optimize their clinical use.