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Renal Clearance of the Thyrotropin-Releasing Hormone-Like Peptide Pyroglutamyl-Glutamyl-Prolineamide in Humans

Department of Internal Medicine and Clinical Endocrinology (W.K., R.D.H.d.B, W.W.d.H, T.J.V.) Department of Endocrinology and Reproduction (E.S.-L., C.A.J., R.A., W.J.d.G.), and Department of Urology (E.R.B.), Erasmus University, 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. W. J. de Greef, Department of Endocrinology and Reproduction, Faculty of Medicine and Health Sciences, Erasmus University, 3000 DR Rotterdam, The Netherlands.

TRH-like peptides have been identified that differ from TRH (pGlu-His-ProNH₂) in the middle aminoacid. We have estimated TRH-like immunoreactivity (TRH-LI) in human serum and urine by RIA with TRH-specific antiserum 8880 or with antiserum 4319, which binds most peptides with the structure pGlu-X-ProNH₂. TRH was undetectable in serum (<25 pg/mL), but TRH-LI was detected with antiserum 4319 in serum of 27 normal subjects, 21 control patients, and 12 patients with carcinoid tumors (range 17–45, 5–79, and 18–16,600 pg/mL, respectively). Because serum was kept for at least 2 h at room temperature, which causes degradation of TRH, pGlu-Phe-ProNH₂, and pGlu-Tyr-ProNH₂, serum TRH-LI is not caused by these peptides. On high-performance liquid chromatography, serum TRH-LI coeluted with pGlu-Glu-ProNH₂ (<EEP-NH₂), a peptide produced in, among others, the prostate. Urine of normals and control patients also contained TRH-LI (range 1.14–4.97 and 0.24–5.51 ng/mL, respectively), with similar levels in males and females. TRH represented only 2% of urinary TRH-LI, and anion-exchange chromatography and high-performance liquid chromatography revealed that most TRH-LI in urine was <EEP-NH₂. In patients with carcinoid tumors, increased urinary TRH-LI levels were noted (range 1.35–962.4 ng/mL). Urinary TRH-LI correlated positively with urinary creatinine, and the urinary clearance rate of TRH-LI was similar to the glomerular filtration rate. In addition, serum TRH-LI was increased in 17 hemodialysis patients (43–373 pg/mL). This suggests that serum <EEP-NH₂ is cleared by glomerular filtration with little tubular resorption. The possible role of the prostate as a source of urinary TRH-LI was evaluated in 11 men with prostate cancer, showing a 25% decrease in urinary TRH-LI excretion after prostatectomy (0.19 ± 0.02 vs. 0.15 ± 0.01 ng/µmol creatinine, mean ± SEM). However, TRH-LI was similar in spontaneously voided urine and in urine obtained through a nephrostomy cannula from 16 patients with unilateral urinary tract obstruction (0.15 ± 0.01 vs. 0.14 ± 0.01 ng/µmol creatinine). These data indicate that: 1) TRH-LI in human serum represents largely <EEP-NH₂, which is cleared by renal excretion; 2) part of urinary <EEP-NH₂ is derived from prostatic secretion into the blood and not directly into urine; and 3) urinary <EEP-NH₂ can be used as marker for carcinoid tumors.

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