Optimizing inferior petrosal sinus sampling: results of a multicenter study

Inferior petrosal sinus sampling (IPSS) confirms a central source of adrenocorticotropic hormone (ACTH) secretion in Cushing's disease (CD). We explored IPSS protocols to optimize diagnostic sensitivity and reduce laboratory testing burden. Patients from the multicenter Registry of Adenomas of the Pituitary and Related Disorders (RAPID) who underwent IPSS for management of CD, and in whom central:peripheral (C:P) ACTH levels were evaluated, were included. A total of 93 patients (mean age 44 ± 13 years, 17% male; 78% MRI-negative, 84% long-term remission) were analyzed. At baseline, 77% of patients showed a C:P ACTH ratio ≥2X, and all of these patients reached ≥3X C:P ACTH after stimulation. Among patients with a baseline ratio <2X, 57% (n = 12/21) crossed the ≥3X threshold after stimulation, prolactin normalization confirmed one additional patient, with two further patients remaining indeterminate. Stimulation produced 3.1-, 2.8-, and 1.9-fold increases in C:P ACTH at 2, 5, and 10 min post-stimulation, respectively, with the best response at 2-5 min. Cumulatively, 77%, 79%, 88%, 90%, and 91% of patients met criteria for CD by 0, 2, 5, 10, and 15 min, respectively. In this confirmed-CD cohort these proportions represent test sensitivity, rising from 77.4% (95% CI 67.6-85.4%) at baseline to 91.4% (95% CI 83.8-96.2%) by 15 min. Because all patients had surgically confirmed CD, these values reflect test sensitivity rather than overall diagnostic accuracy. Diagnostic yield plateaued by 15 min with negligible gain thereafter, and baseline together with a limited number of early post-stimulation samples captured most cases. These retrospective, hypothesis-generating findings suggest that a streamlined protocol may reduce laboratory and interpretive burden while preserving sensitivity, pending prospective validation.