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For more than four decades, the measurement of free cortisol excretion in the urine (UFC) has been considered a reliable test for the diagnosis of Cushing's syndrome (1). Over time, assay methodologies have evolved from competitive binding to immunoassay to liquid chromatography (LC) methods, now coupled to tandem mass spectrometry (MS/MS) in many reference laboratories. With the increasing use of more analytically specific assays, the upper limit of the reference range has decreased, but it is not clear that diagnostic utility has improved. The literature regarding test performance is largely based on immunoassays without direct comparison to newer analytic approaches. Others have questioned the diagnostic utility of UFC measurement in the diagnosis of Cushing's syndrome and have suggested the use of different tests as a first step to screen for hypercortisolism (2).

After almost half a century of use and change, we pause to ask: 1) does the measurement of UFC have adequate diagnostic sensitivity and specificity to be a useful test; and, if so, 2) which analytic methodology has the best diagnostic performance? In a recent editorial about the measurement of androgens and estrogens in submissions to the JCEM, Handelsman and Wartofsky (3) remarked: “It is anticipated that this requirement for MS-based assays [in publications in the JCEM] will extend to adrenal steroids… in the near future.” In light of this statement, we will discuss the current status of UFC measurements and hopefully encourage the endocrine community to evaluate this issue comprehensively.

Issue Section:
Commentary > Special features
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