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. 1985 Jul;76(1):350–356. doi: 10.1172/JCI111968

Carboxyterminal peptide fragments of the beta subunit are urinary products of the metabolism of desialylated human choriogonadotropin.

S Amr, C Rosa, S Birken, R Canfield, B Nisula
PMCID: PMC423782  PMID: 4019785

Abstract

Previous investigations of patients with gestational trophoblastic neoplasia have shown that their urines often contain carboxyterminal peptide (CTP) fragments of the choriogonadotropin (hCG) beta-subunit as well as forms of hCG deficient in sialic acid. In order to determine whether beta-CTP fragments are among the urinary products of the peripheral degradation of desialylated hCG (as-hCG), using a continuous infusion technique, we gave highly purified as-hCG to humans. Six healthy subjects were given a loading dose of 0.8 mg of as-hCG followed by an infusion of the same preparation. An overall mean infusion rate of 62.9 micrograms/min was maintained for 6 h, and the mean serum concentration of as-hCG achieved during the infusion was 72.1 ng/ml. In all six subjects, beta-CTP fragments were the predominant immunoreactive forms of as-hCG in urine obtained during the infusion. In contrast, the urine of subjects infused with hCG has been shown to contain hCG itself, but nil beta-CTP fragments or as-hCG. After the as-hCG infusion was stopped, the excretion of the beta-CTP fragments in urine declined rapidly. There were no beta-CTP fragments detectable in sera obtained during the infusion or in sera incubated with as-hCG at 37 degrees C. After incubation with as-hCG for 4 h, the urine of normal subjects contained small amounts of beta-CTP fragments; however, the apparent proteolytic activity was too low to account for either the quantity of beta-CTP fragments produced during the infusion or the extremely low levels of as-hCG in the urine. These data demonstrate the existence in humans of a peripheral metabolic pathway that cleaves beta-CTP fragments from as-hCG and allows their excretion in urine. Thus, the frequent presence of beta-CTP fragments in the urines of patients with gestational trophoblastic neoplasia can be accounted for in part by the metabolism of the forms of hCG that bear an altered carbohydrate structure, which are prevalent in this disease.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amir S. M., Sullivan R., Ingbar S. H. The effect of desialylation on the in vitro interaction of human chorionic gonadotropin with human thyroid plasma membranes. Endocrinology. 1981 Oct;109(4):1203–1211. doi: 10.1210/endo-109-4-1203. [DOI] [PubMed] [Google Scholar]
  2. Amr S., Rosa C., Wehmann R., Birken S., Nisula B. Unusual molecular forms of hCG in gestational trophoblastic neoplasia. Ann Endocrinol (Paris) 1984;45(4-5):321–326. [PubMed] [Google Scholar]
  3. Amr S., Wehmann R. E., Birken S., Canfield R. E., Nisula B. C. Characterization of a carboxyterminal peptide fragment of the human choriogonadotropin beta-subunit excreted in the urine of a woman with choriocarcinoma. J Clin Invest. 1983 Feb;71(2):329–339. doi: 10.1172/JCI110773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aquino D., Wong R., Margolis R. U., Margolis R. K. Sialic acid residues inhibit proteolytic degradation of dopamine beta-hydroxylase. FEBS Lett. 1980 Apr 7;112(2):195–198. doi: 10.1016/0014-5793(80)80178-5. [DOI] [PubMed] [Google Scholar]
  5. Ascoli M., Liddle R. A., Puett D. Renal and hepatic lysosomal catabolism of luteinizing hormone. Mol Cell Endocrinol. 1976 May;4(5):297–310. doi: 10.1016/0303-7207(76)90047-2. [DOI] [PubMed] [Google Scholar]
  6. Baenziger J. U., Maynard Y. Human hepatic lectin. Physiochemical properties and specificity. J Biol Chem. 1980 May 25;255(10):4607–4613. [PubMed] [Google Scholar]
  7. Birken S., Canfield R. E. Labeled asialo-human chorionic gonadotropin as a liver-scanning agent. J Nucl Med. 1974 Dec;15(12):1176–1178. [PubMed] [Google Scholar]
  8. Birken S., Canfield R., Agosto G., Lewis J. Preparation and characterization of an improved beta-COOH-terminal immunogen for generation of specific and sensitive antisera to human chorionic gonadotropin. Endocrinology. 1982 May;110(5):1555–1563. doi: 10.1210/endo-110-5-1555. [DOI] [PubMed] [Google Scholar]
  9. Birken S., Canfield R., Lauer R., Agosto G., Gabel M. Immunochemical determinants unique to human chorionic gonadotropin: importance of sialic acid for antisera generated to the human chorionic gonadotropin beta-subunit COOH-terminal peptide. Endocrinology. 1980 Jun;106(6):1659–1664. doi: 10.1210/endo-106-6-1659. [DOI] [PubMed] [Google Scholar]
  10. Carayon P., Amr S., Nisula B. A competitive antagonist of thyrotropin: asialo-choriogonadotropin. Biochem Biophys Res Commun. 1980 Nov 17;97(1):69–74. doi: 10.1016/s0006-291x(80)80135-5. [DOI] [PubMed] [Google Scholar]
  11. Gaspard U. J., Reuter A. M., Devìlle J. L., Vrindts-Gevaert Y., Bagshawe K. D., Franchimont P. Serum concentration of human chorionic gonadotropin and its alpha and beta subunits. 2. Trophoblastic tumours. Clin Endocrinol (Oxf) 1980 Oct;13(4):319–329. doi: 10.1111/j.1365-2265.1980.tb03391.x. [DOI] [PubMed] [Google Scholar]
  12. Hammond J. M., Bridson W. E., Kohler P. O., Chrambach A. Physical characteristics of immunoreactive chorionic gonadotropin produced in culture. Endocrinology. 1971 Sep;89(3):801–806. doi: 10.1210/endo-89-3-801. [DOI] [PubMed] [Google Scholar]
  13. Hattori M., Yoshimoto Y., Matsukura S., Fujita T. Qualitative and quantitative analyses of human chorionic gonadotropin and its subunits produced by malignant tumors. Cancer. 1980 Jul 15;46(2):355–361. doi: 10.1002/1097-0142(19800715)46:2<355::aid-cncr2820460224>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  14. Hobson B., Wide L. Human chorionic gonadotrophin excretion in men and women with invasive trophoblast assayed by an immunological and a biological method. Acta Endocrinol (Copenh) 1968 Jul;58(3):473–480. doi: 10.1530/acta.0.0580473. [DOI] [PubMed] [Google Scholar]
  15. Lefort G. P., Stolk J. M., Nisula B. C. Evidence that desialylation and uptake by hepatic receptors for galactose-terminated glycoproteins are immaterial to the metabolism of human choriogonadotropin in the rat. Endocrinology. 1984 Oct;115(4):1551–1557. doi: 10.1210/endo-115-4-1551. [DOI] [PubMed] [Google Scholar]
  16. Loh Y. P., Gainer H. Evidence that glycosylation of pro-opiocortin and ACTH influences their proteolysis by trypsin and blood proteases. Mol Cell Endocrinol. 1980 Oct;20(1):35–44. doi: 10.1016/0303-7207(80)90092-1. [DOI] [PubMed] [Google Scholar]
  17. Markkanen S. O., Rajaniemi H. J. Uptake and subcellular catabolism of human choriogonadotropin in the proximal tubule cells of rat kidney. Mol Cell Endocrinol. 1979 Feb;13(2):181–190. doi: 10.1016/0303-7207(79)90018-2. [DOI] [PubMed] [Google Scholar]
  18. Mizuochi T., Nishimura R., Derappe C., Taniguchi T., Hamamoto T., Mochizuki M., Kobata A. Structures of the asparagine-linked sugar chains of human chorionic gonadotropin produced in choriocarcinoma. Appearance of triantennary sugar chains and unique biantennary sugar chains. J Biol Chem. 1983 Dec 10;258(23):14126–14129. [PubMed] [Google Scholar]
  19. Morell A. G., Gregoriadis G., Scheinberg I. H., Hickman J., Ashwell G. The role of sialic acid in determining the survival of glycoproteins in the circulation. J Biol Chem. 1971 Mar 10;246(5):1461–1467. [PubMed] [Google Scholar]
  20. Nishimura R., Endo Y., Tanabe K., Ashitaka Y., Tojo S. The biochemical properties of urinary human chorionic gonadotropin from the patients with trophoblastic disease. J Endocrinol Invest. 1981 Jul-Sep;4(3):349–358. doi: 10.1007/BF03349456. [DOI] [PubMed] [Google Scholar]
  21. Odink J., Brand E. C., Van Hall E. V. Ovarian binding and intrinsic biological activity of desialylated human chorionic gonadothrophin (ASIALO-hCG). Acta Endocrinol (Copenh) 1979 Feb;90(2):349–360. [PubMed] [Google Scholar]
  22. Rosa C., Amr S., Birken S., Wehmann R., Nisula B. Effect of desialylation of human chorionic gonadotropin on its metabolic clearance rate in humans. J Clin Endocrinol Metab. 1984 Dec;59(6):1215–1219. doi: 10.1210/jcem-59-6-1215. [DOI] [PubMed] [Google Scholar]
  23. Sarkar M., Liao J., Kabat E. A., Tanabe T., Ashwell G. The binding site of rabbit hepatic lectin. J Biol Chem. 1979 May 10;254(9):3170–3174. [PubMed] [Google Scholar]
  24. Vaitukaitis J. L., Braunstein G. D., Ross G. T. A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obstet Gynecol. 1972 Jul 15;113(6):751–758. doi: 10.1016/0002-9378(72)90553-4. [DOI] [PubMed] [Google Scholar]
  25. Vaitukaitis J. L., Ebersole E. R. Evidence for altered synthesis of human chorionic gonadotropin in gestational trophoblastic tumors. J Clin Endocrinol Metab. 1976 Jun;42(6):1048–1055. doi: 10.1210/jcem-42-6-1048. [DOI] [PubMed] [Google Scholar]
  26. Vaitukaitis J. L. Immunologic and physical characterization of human chorionic gonadotropin (hCG) secreted by tumors. J Clin Endocrinol Metab. 1973 Oct;37(4):505–514. doi: 10.1210/jcem-37-4-505. [DOI] [PubMed] [Google Scholar]
  27. Van Hall E. V., Vaitukaitis J. L., Ross G. T., Hickman J. W., Ashwell G. Effects of progressive desialylation on the rate of disappearance of immunoreactive HCG from plasma in rats. Endocrinology. 1971 Jul;89(1):11–15. doi: 10.1210/endo-89-1-11. [DOI] [PubMed] [Google Scholar]
  28. Wehmann R. E., Nisula B. C. Characterization of a discrete degradation product of the human chorionic gonadotropin beta-subunit in humans. J Clin Endocrinol Metab. 1980 Jul;51(1):101–105. doi: 10.1210/jcem-51-1-101. [DOI] [PubMed] [Google Scholar]
  29. Wehmann R. E., Nisula B. C. Metabolic and renal clearance rates of purified human chorionic gonadotropin. J Clin Invest. 1981 Jul;68(1):184–194. doi: 10.1172/JCI110234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Yazaki K., Yazaki C., Wakabayashi K., Igarashi M. Isoelectric heterogenity of human chorionic gonadotropin: Presence of choriocarcinoma specific components. Am J Obstet Gynecol. 1980 Sep 15;138(2):189–194. doi: 10.1016/0002-9378(80)90034-4. [DOI] [PubMed] [Google Scholar]

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