Dexamethasone (Dex) suppression tests (DSTs) were devised by Grant Liddle1 60 years ago for the purpose of ascertaining cortisol autonomy and determining whether Cushing syndrome (CS) is of adrenal origin or secondary to adrenocorticotrophic hormone. The advocated doses (2 mg/d and 8 mg/d for 2 days) were later replaced by a single overnight 1-mg dose, as it is currently prescribed.2,3

DST is based on the ability of Dex to suppress cortisol secretion by inhibiting the hypothalamic-pituitary-adrenal (HPA) axis, which does not occur in patients with autonomous secretion (CS or mild autonomous cortisol secretion [MACS]).1,4 A post-TSD serum cortisol (Fs) value greater than 1.8 μg/dL is generally indicative of MACS or CS, when evaluating individuals suspected of hypercotisolism and adrenal incidentalomas; in fact, Fs post-TSD can be considered a marker of cardiovascular risk, especially in women up to 65 years of age, in which values between 1.8 and 5.0 μg/dL can increase the cardiovascular risk by 13% , despite its moderate specificity (80%).4, 5, 6

Interpretation of the DST to screen CS/MACS depends on serum Dex levels and total Fs concentration, which can be impaired by changes in drug absorption and metabolism, HPA sensitivity, and clinical situations that may increase or decrease cortisol-binding proteins (cortisol-binding globulin [CBG] and albumin), resulting in false-positive or false-negative results, respectively.7,8

Several drugs can interfere with the enzyme activity of the hepatic and intestinal CYP3A4 complex, which is involved in the metabolism of Dex and other medications and may impair or enhance Dex activity, subsequently altering test results.

Since the 1-mg overnight DST (1-mg DST) is an unassisted, unsupervised outpatient test, concomitant measurement of Fs and Dex can be used to help validate the test.8,9 In most studies, post-DST serum Dex levels between 120 and 180 ng/dL are considered adequate for test interpretation; despite improving test accuracy, simultaneous Fs and Dex determination during DST is not widely used.6,9, 10, 11, 12, 13 Because the frequency and performance of the DST in the lowest range of serum Dex values (so-called “invalid” tests) are largely unknown, in the present study, we examined the results of the Dex-controlled 1-mg DST below our previously established cutoff to validate the test.12 We also evaluated the possible interferents responsible for low serum Dex levels to predict which groups are more likely to be affected by a false-positive result during screening for CS or MACS.