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Human chorionic gonadotropin: Testing in pregnancy and gestational trophoblastic disease and causes of low persistent levels

Barbara Goff, MD
Section Editor
Barbara Goff, MD
Deputy Editor
Sandy J Falk, MD, FACOG


Human chorionic gonadotropin (hCG) is produced by trophoblast, a layer of tissue on the outside of the blastocyst that provides the embryo with nutrients and later forms part of the placenta and the fetal membranes. Laboratory tests for hCG are almost 100 percent sensitive and specific for diagnosis of the trophoblast-related conditions, ie, pregnancy and the gestational trophoblastic diseases. Rarely, very low levels of hCG are detected in the absence of one of these conditions. Understanding the complexity of hCG molecules and the nuances of hCG testing is critical to managing these patients. (See "Placental development and physiology", section on 'Implantation and invasion'.)

Basic issues related to hCG testing will be reviewed in this topic. The clinical use of this test in the follow-up of women with gestational trophoblastic disease is discussed separately:

(See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)

(See "Initial management of low-risk gestational trophoblastic neoplasia".)

(See "Hydatidiform mole: Management".)


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Literature review current through: Sep 2016. | This topic last updated: Apr 27, 2016.
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  1. Elliott MM, Kardana A, Lustbader JW, Cole LA. Carbohydrate and peptide structure of the alpha- and beta-subunits of human chorionic gonadotropin from normal and aberrant pregnancy and choriocarcinoma. Endocrine 1997; 7:15.
  2. Kobata A, Takeuchi M. Structure, pathology and function of the N-linked sugar chains of human chorionic gonadotropin. Biochim Biophys Acta 1999; 1455:315.
  3. Cole LA. The O-linked oligosaccharide structures are striking different on pregnancy and choriocarcinoma HCG. J Clin Endocrinol Metab 1987; 65:811.
  4. Cole LA, Kardana A, Andrade-Gordon P, et al. The heterogeneity of human chorionic gonadotropin (hCG). III. The occurrence and biological and immunological activities of nicked hCG. Endocrinology 1991; 129:1559.
  5. Valmu L, Alfthan H, Hotakainen K, et al. Site-specific glycan analysis of human chorionic gonadotropin beta-subunit from malignancies and pregnancy by liquid chromatography--electrospray mass spectrometry. Glycobiology 2006; 16:1207.
  6. Narayan P, Gray J, Puett D. Yoked complexes of human choriogonadotropin and the lutropin receptor: evidence that monomeric individual subunits are inactive. Mol Endocrinol 2002; 16:2733.
  7. Birken S, Kovalevskaya G, O'Connor J. Immunochemical measurement of early pregnancy isoforms of HCG: potential applications to fertility research, prenatal diagnosis, and cancer. Arch Med Res 2001; 32:635.
  8. Muller CY, Cole LA. The quagmire of hCG and hCG testing in gynecologic oncology. Gynecol Oncol 2009; 112:663.
  9. Cole LA. Immunoassay of human chorionic gonadotropin, its free subunits, and metabolites. Clin Chem 1997; 43:2233.
  10. Flam F, Hambraeus-Jonzon K, Hansson LO, Kjaeldgaard A. Hydatidiform mole with non-metastatic pulmonary complications and a false low level of hCG. Eur J Obstet Gynecol Reprod Biol 1998; 77:235.
  11. Lei ZM, Reshef E, Rao V. The expression of human chorionic gonadotropin/luteinizing hormone receptors in human endometrial and myometrial blood vessels. J Clin Endocrinol Metab 1992; 75:651.
  12. Herr F, Baal N, Reisinger K, et al. HCG in the regulation of placental angiogenesis. Results of an in vitro study. Placenta 2007; 28 Suppl A:S85.
  13. Zygmunt M, Herr F, Münstedt K, et al. Angiogenesis and vasculogenesis in pregnancy. Eur J Obstet Gynecol Reprod Biol 2003; 1:S10.
  14. Zygmunt M, Herr F, Keller-Schoenwetter S, et al. Characterization of human chorionic gonadotropin as a novel angiogenic factor. J Clin Endocrinol Metab 2002; 87:5290.
  15. Cole LA, Khanlian SA, Riley JM, Butler SA. Hyperglycosylated hCG in gestational implantation and in choriocarcinoma and testicular germ cell malignancy tumorigenesis. J Reprod Med 2006; 51:919.
  16. Kovalevskaya G, Genbacev O, Fisher SJ, et al. Trophoblast origin of hCG isoforms: cytotrophoblasts are the primary source of choriocarcinoma-like hCG. Mol Cell Endocrinol 2002; 194:147.
  17. Cole LA, Dai D, Butler SA, et al. Gestational trophoblastic diseases: 1. Pathophysiology of hyperglycosylated hCG. Gynecol Oncol 2006; 102:145.
  18. Handschuh K, Guibourdenche J, Tsatsaris V, et al. Human chorionic gonadotropin produced by the invasive trophoblast but not the villous trophoblast promotes cell invasion and is down-regulated by peroxisome proliferator-activated receptor-gamma. Endocrinology 2007; 148:5011.
  19. Sasaki Y, Ladner DG, Cole LA. Hyperglycosylated human chorionic gonadotropin and the source of pregnancy failures. Fertil Steril 2008; 89:1781.
  20. Cole LA, Khanlian SA, Sutton JM, et al. Hyperglycosylated hCG (invasive trophoblast antigen, ITA) a key antigen for early pregnancy detection. Clin Biochem 2003; 36:647.
  21. O'Connor JF, Ellish N, Kakuma T, et al. Differential urinary gonadotrophin profiles in early pregnancy and early pregnancy loss. Prenat Diagn 1998; 18:1232.
  22. Sutton-Riley JM, Khanlian SA, Byrn FW, Cole LA. A single serum test for measuring early pregnancy outcome with high predictive value. Clin Biochem 2006; 39:682.
  23. Kovalevskaya G, Birken S, Kakuma T, et al. Differential expression of human chorionic gonadotropin (hCG) glycosylation isoforms in failing and continuing pregnancies: preliminary characterization of the hyperglycosylated hCG epitope. J Endocrinol 2002; 172:497.
  24. Chakraborty C, Gleeson LM, McKinnon T, Lala PK. Regulation of human trophoblast migration and invasiveness. Can J Physiol Pharmacol 2002; 80:116.
  25. Cole LA, Butler SA. Hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin free beta-subunit: tumor markers and tumor promoters. J Reprod Med 2008; 53:499.
  26. Khanlian SA, Smith HO, Cole LA. Persistent low levels of human chorionic gonadotropin: A premalignant gestational trophoblastic disease. Am J Obstet Gynecol 2003; 188:1254.
  27. Kelly LS, Birken S, Puett D. Determination of hyperglycosylated human chorionic gonadotropin produced by malignant gestational trophoblastic neoplasias and male germ cell tumors using a lectin-based immunoassay and surface plasmon resonance. Mol Cell Endocrinol 2007; 260-262:33.
  28. Birken S, Maydelman Y, Gawinowicz MA, et al. Isolation and characterization of human pituitary chorionic gonadotropin. Endocrinology 1996; 137:1402.
  29. Cole LA, Gutierrez JM. Production of human chorionic gonadotropin during the normal menstrual cycle. J Reprod Med 2009; 54:245.
  30. Naylor SL, Chin WW, Goodman HM, et al. Chromosome assignment of genes encoding the alpha and beta subunits of glycoprotein hormones in man and mouse. Somatic Cell Genet 1983; 9:757.
  31. Policastro PF, Daniels-McQueen S, Carle G, Boime I. A map of the hCG beta-LH beta gene cluster. J Biol Chem 1986; 261:5907.
  32. Krichevsky A, Campbell-Acevedo EA, Tong JY, Acevedo HF. Immunological detection of membrane-associated human luteinizing hormone correlates with gene expression in cultured human cancer and fetal cells. Endocrinology 1995; 136:1034.
  33. Acevedo HF, Tong JY, Hartsock RJ. Human chorionic gonadotropin-beta subunit gene expression in cultured human fetal and cancer cells of different types and origins. Cancer 1995; 76:1467.
  34. Butler SA, Iles RK. The free monomeric beta subunit of human chorionic gonadotrophin (hCG beta) and the recently identified homodimeric beta-beta subunit (hCG beta beta) both have autocrine growth effects. Tumour Biol 2004; 25:18.
  35. Gillott DJ, Iles RK, Chard T. The effects of beta-human chorionic gonadotrophin on the in vitro growth of bladder cancer cell lines. Br J Cancer 1996; 73:323.
  36. Srivastava P, Russo J, Russo IH. Chorionic gonadotropin inhibits rat mammary carcinogenesis through activation of programmed cell death. Carcinogenesis 1997; 18:1799.
  37. Batzer FR. Hormonal evaluation of early pregnancy. Fertil Steril 1980; 34:1.
  38. Butts SF, Guo W, Cary MS, et al. Predicting the decline in human chorionic gonadotropin in a resolving pregnancy of unknown location. Obstet Gynecol 2013; 122:337.
  39. Steier JA, Bergsjø P, Myking OL. Human chorionic gonadotropin in maternal plasma after induced abortion, spontaneous abortion, and removed ectopic pregnancy. Obstet Gynecol 1984; 64:391.
  40. Billieux MH, Petignat P, Anguenot JL, et al. Early and late half-life of human chorionic gonadotropin as a predictor of persistent trophoblast after laparoscopic conservative surgery for tubal pregnancy. Acta Obstet Gynecol Scand 2003; 82:550.
  41. Mock P, Chardonnens D, Stamm P, et al. The apparent late half-life of human chorionic gonadotropin (hCG) after surgical treatment for ectopic pregnancy. A new approach to diagnose persistent trophoblastic activity. Eur J Obstet Gynecol Reprod Biol 1998; 78:99.
  42. Midgley AR Jr, Jaffe RB. Regulation of human gonadotropins. II. Disappearance of human chorionic gonadotropin following delivery. J Clin Endocrinol Metab 1968; 28:1712.
  43. Genest DR, Laborde O, Berkowitz RS, et al. A clinicopathologic study of 153 cases of complete hydatidiform mole (1980-1990): histologic grade lacks prognostic significance. Obstet Gynecol 1991; 78:402.
  44. Menczer J, Modan M, Serr DM. Prospective follow-up of patients with hydatidiform mole. Obstet Gynecol 1980; 55:346.
  45. Khanlian SA, Cole LA. Management of gestational trophoblastic disease and other cases with low serum levels of human chorionic gonadotropin. J Reprod Med 2006; 51:812.
  46. Cole LA, Khanlian SA. Inappropriate management of women with persistent low hCG results. J Reprod Med 2004; 49:423.
  47. Cole LA, Sutton JM. HCG tests in the management of gestational trophoblastic diseases. Clin Obstet Gynecol 2003; 46:523.
  48. Hancock BW. hCG measurement in gestational trophoblastic neoplasia: a critical appraisal. J Reprod Med 2006; 51:859.
  49. Use of hCG tests for evaluating trophoblastic diseases: Choosing an appropriate hCG assay, false detection of hCG, unexplained elevated hCG, and quiescent trophoblastic disease. In: Gestational Trophoblastic Disease, 2nd, London 2002. p.130.
  50. Hancock BW, Tidy JA. Clinical management of persistent low-level hCG elevation. Tophobl Dis Upd 4.
  51. Kohorn EI. Persistent low-level "real" human chorionic gonadotropin: a clinical challenge and a therapeutic dilemma. Gynecol Oncol 2002; 85:315.
  52. Cole LA, Butler SA, Khanlian SA, et al. Gestational trophoblastic diseases: 2. Hyperglycosylated hCG as a reliable marker of active neoplasia. Gynecol Oncol 2006; 102:151.
  53. Snyder JA, Haymond S, Parvin CA, et al. Diagnostic considerations in the measurement of human chorionic gonadotropin in aging women. Clin Chem 2005; 51:1830.
  54. Braunstein GD, Kamdar V, Rasor J, et al. Widespread distribution of a chorionic gonadotropin-like substance in normal human tissues. J Clin Endocrinol Metab 1979; 49:917.
  55. Odell WD, Griffin J. Pulsatile secretion of chorionic gonadotropin during the normal menstrual cycle. J Clin Endocrinol Metab 1989; 69:528.
  56. Odell WD, Griffin J. Pulsatile secretion of human chorionic gonadotropin in normal adults. N Engl J Med 1987; 317:1688.
  57. Hammond E, Griffin J, Odell WD. A chorionic gonadotropin-secreting human pituitary cell. J Clin Endocrinol Metab 1991; 72:747.
  58. Stenman UH, Alfthan H, Ranta T, et al. Serum levels of human chorionic gonadotropin in nonpregnant women and men are modulated by gonadotropin-releasing hormone and sex steroids. J Clin Endocrinol Metab 1987; 64:730.
  59. Daiter E, Braunstein GD, Snyder PJ, et al. Gonadotropin-releasing hormone-dependent chorionic gonadotropin secretion in a menopausal woman. J Clin Endocrinol Metab 1994; 78:1293.
  60. Patton PE, Hess DL, Cook DM, et al. Human chorionic gonadotropin production by the pituitary gland in a premenopausal woman. Am J Obstet Gynecol 1998; 178:1138.
  61. Cole LA, Khanlian SA, Muller CY. Detection of perimenopause or postmenopause human chorionic gonadotropin: an unnecessary source of alarm. Am J Obstet Gynecol 2008; 198:275.e1.
  62. Placental proteins as tumor markers, Marcel Dekker, New York 1991. p.673.
  63. Marcillac I, Troalen F, Bidart JM, et al. Free human chorionic gonadotropin beta subunit in gonadal and nongonadal neoplasms. Cancer Res 1992; 52:3901.
  64. National Committee for Clinical Laboratory Standards. Choriogonadotropin testing: nomenclature, reference preparations, assay performance, and clinical application; approved guideline. I/LA 10-A (ISBN 1-56238-314-z, NCCLS; PA 1996.
  65. Bidart JM, Bellet D. Human chorionic gonadotropin Molecular forms, detection, and clinical implications. Trends Endocrinol Metab 1993; 4:285.
  66. Boscato LM, Stuart MC. Incidence and specificity of interference in two-site immunoassays. Clin Chem 1986; 32:1491.
  67. Kricka LJ. Human anti-animal antibody interferences in immunological assays. Clin Chem 1999; 45:942.
  68. Selby C. Interference in immunoassay. Ann Clin Biochem 1999; 36 ( Pt 6):704.
  69. Vladutiu AO, Sulewski JM, Pudlak KA, Stull CG. Heterophilic antibodies interfering with radioimmunoassay. A false-positive pregnancy test. JAMA 1982; 248:2489.
  70. Knight AK, Bingemann T, Cole L, Cunningham-Rundles C. Frequent false positive beta human chorionic gonadotropin tests in immunoglobulin A deficiency. Clin Exp Immunol 2005; 141:333.
  71. Covinsky M, Laterza O, Pfeifer JD, et al. An IgM lambda antibody to Escherichia coli produces false-positive results in multiple immunometric assays. Clin Chem 2000; 46:1157.
  72. Cole LA. Phantom hCG and phantom choriocarcinoma. Gynecol Oncol 1998; 71:325.
  73. Cole LA, Rinne KM, Shahabi S, Omrani A. False-positive hCG assay results leading to unnecessary surgery and chemotherapy and needless occurrences of diabetes and coma. Clin Chem 1999; 45:313.
  74. Rotmensch S, Cole LA. False diagnosis and needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropin concentrations. Lancet 2000; 355:712.
  75. Cole, LA, Butler, SA. False positive or phantom hCG result: a serious problem. Clin Lab Intl 2001; 25:9.
  76. Baulieu JL, Lepape J, Baulieu F, Besnard JC. Falsely elevated results of radioimmunoassays using double antibody method: arguments for a third anti-rabbit IgG antibody present in certain human sera. Eur J Nucl Med 1982; 7:121.
  77. Hussa RO, Rinke ML, Schweitzer PG. Discordant human chorionic gonadotropin results: causes and solutions. Obstet Gynecol 1985; 65:211.
  78. Garrett PE, Kurtz SR, Hurd JK Jr. False-positive results for choriogonadotropin in serum. Clin Chem 1983; 29:1871.
  79. Olsen TG, Hubert PR, Nycum LR. Falsely elevated human chorionic gonadotropin leading to unnecessary therapy. Obstet Gynecol 2001; 98:843.
  80. Cole LA, Khanlian SA. Easy fix for clinical laboratories for the false-positive defect with the Abbott AxSym total beta-hCG test. Clin Biochem 2004; 37:344.
  81. Palmieri C, Dhillon T, Fisher RA, et al. Management and outcome of healthy women with a persistently elevated beta-hCG. Gynecol Oncol 2007; 106:35.
  82. Catalona WJ, Vaitukaitis JL, Fair WR. Falsely positive specific human chorionic gonadotropin assays in patients with testicular tumors: conversion to negative with testosterone administration. J Urol 1979; 122:126.
  83. Javadpour N, Soares T. False-positive and false-negative alpha-feto protein and human chorionic gonadotropin assays in testicular cancer: a double blind study. Cancer 1981; 48:2279.
  84. Fowler JE Jr, Platoff GE, Kubrock CA, Stutzman RE. Commercial radioimmunoassay for beta subunit of human chorionic gonadotropin: falsely positive determinations due to elevated serum luteinizing hormone. Cancer 1982; 49:136.
  85. Light PA, Felton T, Eckert H. False-positive markers in testicular tumours. Lancet 1982; 2:1214.
  86. Filstein MR, Cullinan JA, Strauss JF 3rd. Aberrant results of serum beta-human chorionic gonadotropin assays: an infrequent but vexing problem. Fertil Steril 1983; 39:714.
  87. Kurosky A, Markel DE, Peterson JW, Fitch WM. Primary structure of cholera toxin beta-chain: a glycoprotein hormone analog? Science 1977; 195:299.
  88. O'Connor JF, Birken S, Lustbader JW, et al. Recent advances in the chemistry and immunochemistry of human chorionic gonadotropin: impact on clinical measurements. Endocr Rev 1994; 15:650.
  89. Braunstein GD, Bloch SK, Rasor JL, Winikoff J. Characterization of antihuman chorionic gonadotropin serum antibody appearing after ovulation induction. J Clin Endocrinol Metab 1983; 57:1164.
  90. Gleicher N, Dudkiewicz A, Pratt D. Biochemical pregnancies or heterophil antibodies? Fertil Steril 1992; 57:1363.
  91. Johnson GF, Feld RD, Beranek JM, Roberts PL. Two cases of immunoassay interference with clinical consequences. Clin Chem 2000; 46:A37.
  92. Committee on Gynecologic Practice, The American College of Obstetricians and Gynecologists. ACOG. Committee opinion: number 278, November 2002. Avoiding inappropriate clinical decisions based on false-positive human chorionic gonadotropin test results. Obstet Gynecol 2002; 100:1057.
  93. Delbeke FT, Van Eenoo P, De Backer P. Detection of human chorionic gonadotrophin misuse in sports. Int J Sports Med 1998; 19:287.
  94. Simeons AT. The action of chorionic gonadotropin in the obese. Lancet 1954; 2:946.
  95. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility, Lippincott AND Williams (Ed), Philadelphia, PA 2005.