The limited value of the desmopressin test in the diagnostic approach to Cushing's syndrome

OBJECTIVE: The desmopressin test is generally regarded as an alternative to the CRH test but it is unclear whether desmopressin is as effective as CRH in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, a precise assessment of the operating characteristics of the desmopressin test in comparison with the CRH test has not been reported. The aim of the present study was to make a comparative evaluation of desmopressin and CRH tests in a consecutive cohort of patients with ACTH-dependent Cushing's syndrome and in a group of healthy subjects. DESIGN AND SUBJECTS: We studied 34 patients with Cushing's disease (CD) and nine patients with ectopic ACTH syndrome (EAS). The control group included 30 healthy subjects. Estimates of sensitivity and specificity were determined for a value of ACTH percent increment (Delta%) > 35% and for a Delta % > 50%, following either desmopressin or CRH, to differentiate CD from EAS. The sensitivity and specificity of a composite rule requiring an ACTH net increment (Delta) > 4.5 pmol/l at both values of Delta % was also calculated. When evaluating cortisol responses, the criteria were Delta % > 20% and Delta > 193 nmol/l. Moreover, to allow comparison of individual end points of the desmopressin and CRH tests at multiple levels of Delta % or Delta either for ACTH or cortisol without the bias of predetermined criteria, univariate curves of the receiver operating characteristics (ROC) were constructed by plotting the sensitivity against 1 - specificity at each level. RESULTS: In the patients with CD, the frequency of ACTH response was of 90% after both tests while the figures for cortisol were 73% after CRH and 77% after desmopressin, respectively. In the 15 patients who underwent both tests the magnitude of ACTH and cortisol responses induced by the 2 stimuli were fully comparable. In the patients with EAS a (false) positive ACTH response was found in 2/9 cases (22%) after the CRH test and in 2/5 patients (40%) after the desmopressin test. In the healthy subjects the CRH test was performed in 25 cases and the desmopressin test in 15 cases. The frequency of ACTH response was 52% following CRH and 13% following desmopressin. In the 10 healthy subjects who underwent both tests the ACTH response was significantly greater after CRH than desmopressin. The area under the ROC curve for the ACTH Delta % was significantly different than that occurring by chance following CRH but not desmopressin. The point on the ROC curve closest to 1 corresponded to an ACTH Delta % of 47% (sensitivity 87% and specificity 89%). However, a criterion of 100 % specificity would require an increase in the threshold for the ACTH Delta % to 259%. ROC analysis validated also the use of the ACTH Delta as a method to assess the response to CRH, but not after desmopressin. However, the diagnostic performance of this parameter was reduced in comparison to that of the ACTH Delta %, since the best cut-off for the Delta (6.2 pmol/l) had inferior specificity (79%). The operating characteristics of CRH and desmopressin were worse when considering cortisol responses. CONCLUSIONS: The present data suggest that the CRH test is more reliable than the desmopressin test in determining the aetiology of Cushing's syndrome. The desmopressin test resulted in a high frequency of false positive results in patients with ectopic ACTH secondary to carcinoid tumours. This finding may be due to the capability of these tumours to express the V3 vasopressin receptor through which desmopressin acts. However, the clinical endocrinologist may be confronted with some disturbing cases which are misdiagnosed because it is almost impossible to set a diagnostic criterion providing complete specificity in the differentiation of (occult) ectopic Cushing's syndrome using either CRH or desmopressin tests.