Context: The diagnosis of Cushing's syndrome (CS) requires the use of tests of unregulated hypercortisolism that have unclear accuracy.

Objective: To summarize evidence on the accuracy of common tests for diagnosing CS.

Data Sources: We searched electronic databases (MEDLINE, EMBASE, Web of Science, Scopus, citation search for key articles) from 1975 through September 2007 and sought additional references from experts.

Study Selection: Eligible studies reported on the accuracy of urinary free cortisol (UFC), dexamethasone suppression (DST), and midnight cortisol (MC) assays vs. reference standard in patients suspected of CS.

Data Extraction: Reviewers working in duplicate and independently extracted study characteristics and quality, and data to estimate the likelihood ratio (LR) and the 95% confidence interval (CI) for each result.

Data synthesis: We found 27 eligible studies, with a high prevalence (794 (9.2%) of 8631 patients had CS) and severity of CS. The tests had similar accuracy: UFC (n=14 studies, LR+ 10.6, CI 5.5, 20.5; LR- 0.16, CI 0.08, 0.33), salivary MC (n=4, LR+ 8.8, CI 3.5, 21.8; LR- 0.07, CI 0, 1.2), and the 1-mg overnight DST (n=14, LR+ 16.4, CI 9.3, 28.8; LR- 0.06, CI 0.03, 0.14). Combined testing strategies (e.g., a positive result in both UFC and 1-mg overnight DST) had similar diagnostic accuracy (n=3, LR+ 15.4, CI 0.7, 358; LR- 0.11, CI 0.007, 1.57).

Conclusions: Commonly used tests to diagnose CS appear highly accurate in referral practices with samples enriched with patients with CS. Their performance in usual clinical practice remains unclear.