Context: Although bilateral inferior petrosal sinus sampling (BIPSS) with CRH stimulation is the most accurate procedure for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS), 4-15% of patients with Cushing's disease (CD) fail to demonstrate diagnostic gradients. Preliminary data, suggest that a more potent stimulation by the combined administration of CRH plus desmopressin during BIPSS may provide some diagnostic advantage. A crucial issue, however, is whether such an amplified stimulation may affect the specificity of the procedure, and this was the main aim of the present study.

Objective: We investigated the diagnostic accuracy of BIPSS performed by CRH plus desmopressin stimulation.

Design: Retrospective analysis.

Setting: The study was conducted at a single tertiary care centre.

Participants: Fifty-four patients admitted for the investigation of ACTH-dependent CS. CD was diagnosed in 47 patients; occult ectopic ACTH syndrome (oEAS) was histologically confirmed in 7 patients.

Intervention(s): all patients underwent BIPSS with CRH plus desmopressin administration.

Additional non-invasive tests included: CRH test, HDST, desmopressin test and pituitary MRI.

Main Outcome Measures: Gradients of inferior petrosal sinus to peripheral (IPS/P) ACTH were calculated before and after stimulation with CRH plus desmopressin.

Results: The sensitivity for a basal IPS/P gradient > 2 was 61.7%, with 100% specificity and a diagnostic accuracy of 66.7%. After stimulation with CRH plus desmopressin, ROC curve analysis showed that a cut-off gradient of > 2 offers the best test performance. In total, 46/47 patients with CD had an IPS/P gradient> 2 but none of the patients with oEAS, resulting in a sensitivity of 97.9%. The specificity was 100%, diagnostic accuracy 98.2% and the positive and the negative predictive values were 100% and 87.5%, respectively. A subgroup of 18 patients (16 with CD and 2 with oEAS) had contradictory responses to routine tests with CRH and/or HDST; sensitivity, specificity and accuracy of BIPSS in this subgroup were 100%.

Conclusions: The application of a combined stimulation with CRH plus desmopressin during BIPSS is associated with a high sensitivity but no loss of specificity.