CoChat
Sign Up
Cited by 68Pituitary Gland Disorders and TreatmentsAdrenal Hormones and DisordersAdrenal and Paraganglionic Tumors

Urine Free cortisol in the diagnosis of cushing’s syndrome: Is It worth doing and, If so, how?

Open access
Raff, Hershel, Auchus, Richard J., Findling, James W., Nieman, Lynnette K.·2015·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2014-3766PMC PMC4318888
Open this paper in CoChat — free accountOpen PDF

Abstract

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. The recognition of unsuspected endogenous hypercortisolism in patients with adrenal nodules, diabetes mellitus, hypertension, and osteoporosis has increased our awareness of this enigmatic disorder and mandates better diagnostic tools (4, 5). The three first-line screening tests recommended for the diagnosis of Cushing's syndrome interrogate different aspects of the pathophysiology of this challenging disease (1, 5). These are: 1) failure to achieve the nadir of the cortisol circadian rhythm—evaluated using the measurement of late-night salivary cortisol (LNSC); 2) attenuated sensitivity to glucocorticoid negative feedback—tested using low-dose dexamethasone suppression testing; and 3) increased production of cortisol—assessed by 24-hour UFC measurement. Although all of these tests have strengths and weaknesses. LNSC has the best diagnostic performance as an initial screening test for patients with suspected hypercortisolism, with the exception of mild ACTH-independent hypercortisolism, for which a low-dose dexamethasone suppression test is most sensitive (6). Although most direct immunoassays for salivary cortisol show cross-reactivity with similar steroids (in particular, cortisone), there is evidence that immunoassays paradoxically might perform better diagnostically than the more analytically specific LC-MS/MS method (reviewed in Ref. 6). Longitudinal studies in patients after pituitary surgery for Cushing's disease have shown that increases in late-night cortisol secretion are the earliest biochemically detectable abnormality during recurrence and that increased UFC is a later event (6). Some patients with endogenous mild hypercortisolism do not have Cushing's syndrome, leading to concerns about false-positive results. Newer assays with lower, narrower reference ranges appear to have reduced the infamous false-positive problem. However, many patients with mild Cushing's syndrome have normal UFC with these assays (7). This problem is only partially explained by within-subject variability, which is as high as 50% in patients with proven Cushing's syndrome (8). Part of the reason for this modern dilemma is that free cortisol only appears in the urine when its concentration exceeds the binding capacity of plasma. A patient with a serum cortisol of 12 μg/dL all day long is likely to have Cushing's syndrome but might have a normal 24-hour UFC measurement. Another important factor is cortisol metabolism. Although the daily cortisol production rate is 6–8 mg/m2/d (∼10 mg/d) (9), the reference range for UFC measured by LC-MS/MS is only < 40 μg/d—so where does the other 9960 μg go? Over 99% of cortisol is metabolized and glucuronidated in the liver, and then it is further metabolized and excreted by the kidney (10). The tetrahydrocortisols and cortisones, cortols, and other metabolites, which are excreted in milligrams per day quantities, have been measured in research laboratories for decades using gas chromatography with mass spectrometry (GC/MS), but these assays are too cumbersome and difficult for routine use in clinical laboratories (10). These metabolites, however, are not heavily protein-bound like cortisol, and many cross-react slightly with cortisol immunoassays. Consequently, as hypercortisolism develops, these integrated cortisol metabolites—if measured—increase before the UFC is convincingly abnormal (11). This situation begs the

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1210/jc.2014-3766

Cites

15 of 15 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Raff, H., Auchus, R. J., Findling, J. W., & Nieman, L. K.
Affiliations
  • Medical College of Wisconsin (US)
  • University of Michigan (US)
  • National Institutes of Health (US)
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2015-02-01
Volume
100
Issue
2
Pages
395-397
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2014-3766
PMC
PMC4318888
OpenAlex
W2080169901
Cited by
68
References
15
Citations by year
2026: 3 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 2 · 2017: 7 · 2016: 12 · 2015: 8
FWCI
7.24
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020572)
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
Keywords
urinary free cortisol, Cushing's syndrome, hypercortisolism, sensitivity and specificity, tandem mass spectrometry, immunoassay, late-night salivary cortisol, dexamethasone suppression test, adrenal incidentaloma, screening test, reference values, Cushing's disease
MeSH terms
Humans, Gonadal Steroid Hormones, Mass Spectrometry

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review