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The dexamethasone suppression test is used to diagnose endogenous Cushing syndrome by assessing the lack of suppression of the hypothalamic-pituitary-adrenal axis in response to exogenous corticosteroids.[1] The first use of dexamethasone for diagnosing Cushing syndrome was in 1960 by Liddle; he developed a test based on the non-suppressibility of endogenous cortisol production in Cushing syndrome versus the physiological suppression in nonaffected individuals achieved by dexamethasone.[2] Dexamethasone is a potent synthetic corticosteroid (dexamethasone 0.75 mg= prednisone; 5 mg= methylprednisolone; 4 mg= hydrocortisone 20 mg) with high affinity for glucocorticoid receptors and a long duration of action (biological half-life 36-54 hours; plasma half-life 4-5 hours).[3] Furthermore, dexamethasone possesses minimal mineralocorticoid activity, and unlike other glucocorticoids, this corticosteroid does not interfere with cortisol measurement in the plasma, urine, or saliva. These qualities make dexamethasone the preferred steroid for assessing the hypothalamic-pituitary-adrenal axis.[4] The dexamethasone suppression test is also used to investigate mild autonomous cortisol excess in patients with incidentalomas. (See Image. Dexamethasone Suppression Test.) For diagnosing Cushing syndrome and mild autonomous cortisol excess, a serum cortisol concentration of 1.8 µg/dL (50 nmol/L) is the widely recommended cut-off point that increases the diagnostic sensitivity of the test to approximately 95%.[5] Serum cortisol concentrations less than 1.8 µg/dL suggest adequate hypothalamic-pituitary-adrenal axis suppression after dexamethasone administration, effectively excluding Cushing syndrome.[6]

The dexamethasone suppression test is also used to investigate mild autonomous cortisol excess in patients with incidentalomas. (See Image. Dexamethasone Suppression Test.) For diagnosing Cushing syndrome and mild autonomous cortisol excess, a serum cortisol concentration of 1.8 µg/dL (50 nmol/L) is the widely recommended cut-off point that increases the diagnostic sensitivity of the test to approximately 95%.[5] Serum cortisol concentrations less than 1.8 µg/dL suggest adequate hypothalamic-pituitary-adrenal axis suppression after dexamethasone administration, effectively excluding Cushing syndrome.[6] Inappropriately low serum dexamethasone levels during the 1-mg dexamethasone suppression test may result in false-positive results. This phenomenon is associated with recurrent use of cytochrome P450 3A4 (CYP3A4)-inducing drugs or gastrointestinal abnormalities. When serum dexamethasone is undetectable, the primary reason is failure to take the medication appropriately. Chronic use of glucocorticoids can also lead to low dexamethasone levels because exogenous glucocorticoids suppress cortisol and the cortisol receptors, which also bind dexamethasone; this lack of available receptors can cause dexamethasone to be excreted without physiological action.[7] Simultaneous measurement of serum cortisol and dexamethasone allows for dexamethasone suppression test validation, improving accuracy and avoiding unnecessary repetitions. Adherence to verbal or written recommendations is critical for interpreting the test. The measured dexamethasone level should be higher than 200 ng/dL (4.5 nmol/L) for an accurate result.

The hypothalamic-pituitary-adrenal axis, a primary neuroendocrine system, helps maintain homeostatic function and the stress response.[8] Neurons in the paraventricular nucleus of the hypothalamus synthesize corticotropin-releasing hormone, which is transported through the hypophyseal portal blood to the anterior pituitary, which stimulates adrenocorticotropic hormone production.[9] Adrenocorticotropic hormone is transported through the systemic vasculature to the adrenal glands and stimulates the synthesis and secretion of cortisol by zona fasciculata of the adrenal cortex.[10] Under basal conditions, only about 5% to 10% of circulating cortisol is free.[11] The rest is bound to proteins, with approximately 85% binding to transcortin (cortisol-binding globulin) and 5% to 10% binding to albumin. Although the free fraction is physiologically active, the albumin-bound fraction is also available due to the low binding affinity of albumin for cortisol.[12] Unbound cortisol is filtered at the glomerulus and is subsequently excreted. This fraction constitutes less than 1% of the total cortisol synthesized daily; the rest is excreted as soluble metabolites and glucuronide conjugates.[13] The excretory products of cortisol that contain the dihydroxyacetone group are known as 17-hydroxycorticosteroids.[14] Urinary 17-hydroxycorticosteroid was previously used as an indirect measure of cortisol secretion rate. Urinary cortisol reflects free, circulating cortisol levels in the blood.[15] Serum cortisol, also called the stress hormone, exerts negative feedback on both the hypothalamus and the anterior pituitary, inhibiting the secretion of corticotropin-releasing hormone and adrenocorticotropic hormone, respectively. This positive or negative feedback mechanism helps regulate serum cortisol levels and the stress response.[16] When the hypothalamic-pituitary-adrenal axis is intact, exogenously administered corticosteroids exert feedback inhibition on serum corticotropin-releasing hormone and adrenocorticotropic hormone production by binding to the hypothalamic and pituitary glucocorticoid receptors, respectively, which subsequently leads to the suppression of serum cortisol synthesis and secretion.[8] However, in pathological hypercortisolism, the hypothalamic-pituitary-adrenal axis becomes partially or entirely resistant to feedback inhibition by exogenous steroids.[17]

Primary care providers may initially evaluate patients with suspected Cushing syndrome before referring them to an endocrinologist for a more comprehensive evaluation. This collaborative approach requires clear communication and careful coordination between the clinician and patient. The accurate implementation of the dexamethasone suppression test and proper sample collection are critical aspects of this process, as they can significantly influence subsequent diagnostic results. Effective communication ensures that all stakeholders understand the importance of adhering to the testing protocol and the implications of accurate test performance. Coordination among the team members ensures that the dexamethasone suppression test is conducted correctly and that samples are collected and handled appropriately to minimize the risk of errors and ensure reliable results. This collaborative effort maximizes the diagnostic accuracy of the dexamethasone suppression test and facilitates the timely and appropriate management of patients with suspected Cushing syndrome.