Bilateral inferior petrosal sinus sampling with human CRH stimulation in ACTH-dependent Cushing's syndrome: results from a retrospective multicenter study

Objective: Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as the gold standard to differentiate between Cushing´s disease (CD) and ectopic Cushing’s syndrome (ECS). However, published data on the diagnostic value of additional prolactin analysis are controversial. Thus, we evaluated the diagnostic performance of BIPSS with and without prolactin in a multicenter study. Design and methods: Retrospective study in five European reference centers. Patients with overt adrenocorticotropin (ACTH)-dependent Cushing’s syndrome at the time of BIPSS with human corticotropin–releasing hormone stimulation were eligible. Cut-offs for the inferior petrosal sinus (IPS) to peripheral (P) ACTH ratio and the normalized ACTH:prolactin IPS:P ratio were calculated via receiver operator characteristic analyses (reference: CD). Results: 156 patients with BIPSS were identified. Of these, 120 patients (92 [77%] females; 106 [88%] CD, 14 [12%] ECS) had either histopathologically confirmed tumors or biochemical remission and/or adrenal insufficiency after surgery; only this subgroup was analyzed by ROC analysis. The optimal cut-offs for the ACTH IPS:P ratio were ≥1.9 at baseline (sensitivity 82.1% [95% CI, 73.2-88.6], specificity 85.7% [95% CI, 56.2-97.5], AUC 0.86) and ≥2.1 at 5 minutes post-CRH (sensitivity 91.3% [95% CI, 83.6-95.7], specificity 92.9% [95% CI, 64.1-99.6], AUC 0.96). A subgroup underwent additional prolactin analysis. An optimal cut-off of ≥1.4 was calculated for the normalized ACTH:prolactin IPS:P ratio (sensitivity 96.0% [95% CI, 77.7-99.9], specificity 100% [95% CI, 56.1-100], AUC 0.99). Conclusion: Our study confirms the high accuracy of BIPSS in the differential diagnosis of ACTH-dependent Cushing’s syndrome and suggests that the simultaneous measurement of prolactin might further improve the diagnostic performance of this test.