Evaluation of the pathogenic mechanisms underlying Cushing disease (CD) is limited partly by the inaccessibility of the pituitary gland for biopsy. We used bilateral inferior petrosal sinus sampling (BIPSS), the gold standard in diagnosing pituitary sources of CD, to obtain central blood samples for in vivo metabolomic analysis of pathways involved in pituitary adenomas. We evaluated 16 samples from eight patients who underwent BIPSS to measure adrenocorticotropic hormone (ACTH) levels in the inferior petrosal sinus (IPS) bilaterally. Seven patients had CD with concordant BIPSS, surgical, and pathologic findings. Samples from the IPS contralateral to histologically proven lesions were used as controls. BIPSS of the eighth patient revealed no central pituitary ACTH source, and these samples were also included as controls. Plasma samples were profiled using a combination of three liquid chromatography tandem mass spectrometry methods, which assessed 259 metabolites. Following Bonferroni correction for multiple comparisons, three small compound biomarkers of CD (pyridoxate, deoxycholic acid, and 3-methyladipate) were identified to be significantly altered in pituitary adenomas. The pathway most significantly impacted in CD samples is one previously shown to be upregulated in other cancers. Exploiting the BIPSS technique, we showed a complete metabolite and lipid profile of pituitary adenomas in CD. These potential biomarkers of CD may elucidate tumor biology and suggest possible diagnostic molecular imaging probes as well as therapeutic targets in patients with recurrent disease after surgery.
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