Identification of Patients with Cushing’s Disease with Negative Pituitary Adrenocorticotropin Gradients during Inferior Petrosal Sinus Sampling: Prolactin as an Index of Pituitary Venous Effluent

Inferior petrosal sinus sampling for ACTH differentiates pituitary ACTH-dependent Cushing’s (CD) from the ectopic ACTH syndrome (EAS). Petrosal sinus to peripheral (IPS:P) ACTH ratios greater than 2.0 in the basal state or a peak greater than 3.0 after CRH are diagnostic of CD. However, false-negative rates of 1–10% have been reported. We report three patients with features of CD with peak IPS:P ACTH ratios less than 3.0 after CRH suggesting EAS. We compared IPS:P prolactin (PRL) as an index of pituitary venous effluent in these three index cases with 44 patients with CD and five with EAS. The dominant basal IPS:P PRL ratio was greater than 1.8 in all 49 patients but was less than 1.2 in the three index cases. The IPS:P ACTH ratio normalized to IPS:P PRL was greater than 0.8 in all CD patients but was less than 0.6 in EAS patients. The IPS:P ACTH ratios normalized to IPS:P PRL were greater than 1.2 in the index cases, which was similar to those with CD. The three index cases had clinical and biochemical remissions after pituitary surgery. PRL is an index of pituitary venous effluent during inferior petrosal sinus sampling in patients with CD who fail to have a peak IPS:P ACTH ratio greater than 3.0 after CRH. IPS:P PRL should be measured when results indicate EAS.