Urinary adrenal steroidome modifications by Ketoconazole and Metyrapone alter the urinary free cortisol immunoassay reliability in Cushing Syndrome

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Key messages

• This is the first study showing the effects that ketoconazole and metyrapone have on the urinary adrenal steroidome, altering the reliability of immunoassay (IA) to assess 24h-urinary free cortisol (UFC) in patients with Cushing Syndrome (CS) compared to gold standard gas chromatography-mass spectrometry (GC-MS).
• There is a well-known overestimation bias of IA in the 24h-UFC determinations because of cross-reactive interference with cortisol metabolites, which is sharply reduced in patients taking ketoconazole and metyrapone due to urinary excretion reduction of several cross-reactive adrenal metabolites.
• As IA reference ranges are based on the concept of the known bias, the bias decrement results in critical clinical implications; falsely higher reductions of 24h-UFC and its upper limit normal (ULN) index were found when assessed by IA.
• Accordingly, several patients were classified as biochemically controlled when they remained with high 24h-UFC*ULN using the GC-MS results.
• These variations in IA bias were explained by the extent of urinary abundance of 22 adrenal metabolites; moreover, different changes in the urinary excretion of metabolites explained why larger reductions of the IA overestimation bias were found in patients taking ketoconazole vs those on metyrapone.