High serum levels of the thyrotropin-releasing hormone-like peptide pyroglutamyl-glutamyl-prolineamide in patients with carcinoid tumors.

The TRH-like peptide pGlu-Glu-Pro-NH2 ( < EEP-NH2) has been identified in the prostate, the anterior pituitary, and a human neuroblastoma cell line. We here report the determination of TRH-like immunoreactivity (TRH-LI) in serum of control subjects and patients with carcinoid tumors. TRH-LI was distinguished from authentic TRH (pGlu-His-Pro-NH2) in RIAs using the nonspecific antiserum 4319, which recognizes most peptides with the structure pGlu-X-Pro-NH2, or the TRH-specific antiserum 8880. TRH levels were undetectable ( < 25 pg/mL) in unextracted serum from healthy subjects, whereas the TRH-LI level was 42 +/- 22 pg/mL (mean +/- SD; n = 175). TRH levels were also undetectable in unextracted serum from 60 patients with carcinoid tumors, whereas TRH-LI levels ranged from less than 10 to 2540 pg/mL, being elevated in 27 of 60 (45%) patients. Serum TRH-LI was significantly correlated with 1) the number of tumor localizations (tumor load), 2) the presence of liver metastases, and 3) urinary 5-hydroxyindoleacetic acid excretion. Serum TRH-LI was completely extracted with methanol, and its identity was analyzed in serum extracts from 3 patients with carcinoid tumors by QAE-Sephadex A-25 anion exchange chromatography and reverse phase high performance liquid chromatography. With both techniques, TRH-LI predominantly coeluted with synthetic < EEP-NH2, suggesting secretion of this peptide by carcinoid tumors. The mechanism of < EEP-NH2 production by these tumors and its possible biological function remain to be determined.