Current Obstetrics and Gynecology Reports

, Volume 3, Issue 1, pp 91–101 | Cite as

The hCG Group: the Key Molecules in Human Evolution, Human Life, and Human Death

  • Laurence A. Cole
Management of Gestational Trophoblastic Diseases (A Cheung, Section Editor)


The term hCG refers to a group of molecules with common amino acid sequence, different glycosylation, and multimeric structure. These molecules include the pregnancy hormone hCG, made by placental syncytiotrophoblast cells, and the pregnancy autocrine hyperglycosylated hCG, made by placental cytotrophoblast cells, which drives placental growth during pregnancy and implantation of the placenta. Most human cancers make hyperglycosylated hCG free β-subunit. This drives cancer malignancy by following the invasive implantation pathway. Whereas hCG functions by acting on an hCG/LH joint receptor, hyperglycosylated hCG and hyperglycosylated hCG free β-subunit function by antagonizing a TGFβ receptor. CG and hyperglycosylated hCG first evolved with early simian primates. The early simian CG and hyperglycosylated CG were nonacidic rapidly clearing molecules. With their evolution evolved a primitive form of hemochorial placentation, primitive in that it was only minimally promoted by CG and hyperglycosylated CG. With the evolution of advanced simian primates came acidic variant of hCG and hyperglycosylated CG. The more acidic CG was longer circulating and more effectively promoted the establishment and growth of hemochorial placentation. With the evolution of humans came a very acidic variant of CG and hyperglycosylated CG. This was very much longer circulating and was an effective stimulant of hemochorial placentation. Early prosimian primates had a brain of 0.07 % of body mass, early simian primates had a brain mass of 0.17 %, advanced simian primates of 0.74 %, and humans of 2.4 %. Research indicates that brain mass grew with improving CG and hyperglycosylated CG activity and improving hemochorial placentation activity. The super CG variant produced by humans plays a key role in human pregnancy implantation and in failures of pregnancy, hypertense pregnancy, and invasion by gestational trophoblastic diseases. Research today shows that hyperglycosylated CG and hyperglycosylated CG free β-subunit drive most human trophoblastic and nontrophoblastic malignancies.


Human chorionic gonadotropin Hyperglycosylated hCG Early simian primate Luteinizing hormone Cancer Choriocarcinoma Failing pregnancy transforming growth factor β Metalloproteinase SMAD Pregnancy Hypertense pregnancy Invasive gestational trophoblastic diseases 


Compliance with Ethics Guidelines

Conflict of Interest

Laurence A. Cole declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Aschner B. Ueber die function der hypophyse. Pflug Arch Gestational trophoblastic disease. Physiol. 1912;146:1–147.Google Scholar
  2. 2.
    Hirose T. Experimentalle histologische studie zur genese corpus luteum. Mitt Med Fakultd Univ ZU. 1919;23:63–70.Google Scholar
  3. 3.
    Kovalevskaya G, Genbacev O, Fisher SJ, Cacere E, O'Connor JF. Trophoblast origin of hCG isoforms: cytotrophoblasts are the primary source of choriocarcinoma-like hCG. Mol Cell Endocrinol. 2002;194:147–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Strott CA, Yoshimi T, Ross GT, Lipsett MB. Ovarian physiology: relationship between plasma LH and steroidogenesis by the follicle and corpus luteum; effect of HCG. J Clin Endocrinol Metab. 1969;29:1157–67.PubMedCrossRefGoogle Scholar
  5. 5.
    Shi QJ, Lei ZM, Rao CV, Lin J. Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts. Endocrinol. 1993;132:387–95.Google Scholar
  6. 6.
    Zygmunt M, Herr F, Keller-Schoenwetter S, Kunzi-Rapp K, Munstedt K, Rao CV, et al. Characterization of human chorionic gonadotropin as a novel angiogenic factor. J Clin Endocrinol Metab. 2002;87:290–5296.Google Scholar
  7. 7.
    Rao CV, Li X, Toth P, Lei ZM, Cok VD. Novel expression of functional human chorionic gonadotropin/luteinizing hormone receptor in human umbilical cords. J Clin Endocrinol Metab. 1993;77:1706–14.PubMedGoogle Scholar
  8. 8.
    Akoum A, Metz CN, Morin M. Marked increase in macrophage migration inhibitory factor synthesis and secretion in human endometrial cells in response to human chorionic gonadotropin hormone. J Clin Endocrinol Metab. 2005;90:2904–10.PubMedCrossRefGoogle Scholar
  9. 9.
    Reshef E, Lei ZM, Rao CV, Pridham DD, Chegini N, Luborsky JL. The presence of gonadotropin receptors in nonpregnant human uterus human placenta fetal membranes and decidua. J Clin Endocrinol Metab. 1990;70:421–30.PubMedCrossRefGoogle Scholar
  10. 10.
    Eta E, Ambrus G, Rao V. Direct regulation of human myometrial contractions by human chorionic gonadotropin. J Clin Endocrinol Metab. 1994;79:1582–6.PubMedGoogle Scholar
  11. 11.
    Goldsmith PC, McGregor WG, Raymoure WJ, Kuhn RW, Jaffe RB. Cellular localization of chorionic gonadotropin in human fetal kidney and liver. J Clin Endocrinol Metab. 1983;57:54–61.Google Scholar
  12. 12.
    Elliott MM, Kardana A, Lustbader JW, Cole LA. Carbohydrate and peptide structure of the α- and β-subunits of human chorionic gonadotropin from normal and aberrant pregnancy and choriocarcinoma. Endocrine. 1997;7:15–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Valmu L, Alfthan H, Hotakainen K, Birken S, Stenman UH. Site-specific glycan analysis of human chorionic gonadotropin beta-subunit from malignancies and pregnancy by liquid chromatography - electrospray mass spectrometry. Glycobiol. 2006;16:1207–18.CrossRefGoogle Scholar
  14. 14.
    Cole LA, Dai D, Leslie KK, Butler SA, Kohorn EI. Gestational trophoblastic diseases: 1. Pathophysiology of hyperglycosylated hCG-regulated neoplasia. Gynecol Oncol. 2006;102:144–9.Google Scholar
  15. 15.
    Guibourdenche J, Handschuh K, Tsatsaris V, Gerbaud MC, Legul F, Muller D, et al. Hyperglycosylated hCG is a marker of early human trophoblast invasion. J Clin Endocrinol Metab. 2010;95:E240–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Cole LA. Hyperglycosylated hCG and pregnancy failures. J Reprod Immunol. 2012;93:119–22.PubMedCrossRefGoogle Scholar
  17. 17.
    Sasaki Y, Ladner DG, Cole LA. Hyperglycosylated hCG the source of pregnancy failures. Fertil Steril. 2008;89:1871–786.Google Scholar
  18. 18.
    Lapthorn AJ, Harris DC, Littlejohn A, Lustbader JW, Canfield RE, Machin KJ. Crystal structure of hCG. Nature. 1994;369:455–61.PubMedCrossRefGoogle Scholar
  19. 19.
    Sun PD, Davies DR. The cystine-knot growth-factor superfamily. Ann Rev Biophys Biomol Struct. 1995;24:269–91.CrossRefGoogle Scholar
  20. 20.
    • Berndt S, Blacher S, Munuat C, Detilleux J, Evain-Brion D, Noel A, et al. Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-ß receptor activation. J FASEB. 2013;27:1309–21.CrossRefGoogle Scholar
  21. 21.
    Butler SA, Ikram MS, Mathieu S, Iles RK. The increase in bladder carcinoma cell population induced by the free beta subunit of hCG is a result of an anti-apoptosis effect and not cell proliferation. Br J Cancer. 2000;82:1553–6.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Murphy G, Reynolds JJ, Whitham SE, Docherty AJ, Angel P, Heath JK. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. Euro Molec Biol Org J. 1987;6:1899–904.Google Scholar
  23. 23.
    Cole LA. hCG structure: a logical perspective. Asian Pacific J Reprod. 2012;1:287–92.CrossRefGoogle Scholar
  24. 24.
    Carter WB, Sekharem M, Coppola D. Purified hCG induces apoptosis in breast cancer. Breast Cancer Res Treat. 2006;100:S243–4.Google Scholar
  25. 25.
    Iles RK. Ectopic hCGß expression by epithelial cancer: Malignant behavior metastasis and inhibition of tumor cell apoptosis. Molec. Cellul. Endocrinol. 2007;264–270Google Scholar
  26. 26.
    Jankowska A, Andrusiewicz M, Grabowski J, Nowak-Markwitz E, Warchol JB. Coexpression of human chorionic gonadotropin beta subunit and its receptor in nontrophoblastic gynecological cancer. Intl J Gynecol Cancer. 2008;18:1102–7.CrossRefGoogle Scholar
  27. 27.
    Li D, Wen X, Ghali L, Al-Shalabi FM, Docherty SM, Purkis P, et al. hCG beta expression by cervical squamous carcinoma-in vivo histological association with tumour invasion and apoptosis. Histopathol. 2008;53:147–55.CrossRefGoogle Scholar
  28. 28.
    Morgan FJ, Birken S, Canfield RE. The amino acid sequence of human chorionic gonadotropin. J Biol Chem. 1975;250:5247–58.PubMedGoogle Scholar
  29. 29.
    • Cole LA, Butler SA. Hyperglycosylated hCG, hCGß and hyperglycosylated hCGß: interchangeable cancer promotors. Molec Cell Endocrinol. 2012;349:232–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signaling. Nature. 2003;425:577–84.PubMedCrossRefGoogle Scholar
  31. 31.
    Herpin A, Lelong C, Favrel P. Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans. Dev Comp Immunol. 2004;28:461–85.PubMedCrossRefGoogle Scholar
  32. 32.
    Kohll G, Hu S, Clelland E, Di Mucclu T, Rothenstein J, Peng C. Cloning of transforming growth factor-β1 (T and its type II receptor from zebrafish ovary and role of TGFβ1 in oocyte maturation. Endocrinol. 2003;144:1931–41.CrossRefGoogle Scholar
  33. 33.
    Lyons SM, Prasad A. Cross-Talk and Information Transfer in Mammalian and Bacterial Signaling. Plos One. 2012;7:e34488.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Massangue J, Chen YG. Controlling TGF-beta signaling. Genes Dev. 2000;14:627–44.Google Scholar
  35. 35.
    Newfeld S, Wisotzkey RG, Kumar S. Molecular evolution of a developmental pathway: Phlogenetic analyses of transforming growth factor-β family ligands, receptors and Smad signal trasducers. Genetics. 1999;152:783–95.PubMedGoogle Scholar
  36. 36.
    Pang K, Ryan JF, Baxevanis D, Martindale MQ. Evolution of the TGF-β signaling pathway and its potential role in the Ctenophore, Mnemiopsis leidyi. Plos One. 2011;6:1–15.Google Scholar
  37. 37.
    Runyan CE, Schnaper HW, Pocelet AC. The role of internalization in transforming growth factor beta1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells. J Biol Chem. 2005;280:8300–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Farid NR, Szudlinski MW. Minireview: structural and functional evolution of the thyrotropin receptor. Endocrinol. 2004;145:4048–4057.Google Scholar
  39. 39.
    Hsu SY, Nakabayashi K, Bhalla A. Evolution of glycoprotein hormone subunit genes in bilateral metazoa: identification of two novel human glycoprotein hormone subunit family genes, GPA2 and GPB5. Mol Endocrinol. 2002;16:1538–1551.Google Scholar
  40. 40.
    Fiddes JC, Goodman HM. The cDNA for the ß-subunit of human chorionic gonadotropin suggests evolution of a gene by readthrough into the 3’-untranslated region. Nature. 1980;286:684–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Maston GA, Ruvolo M. Chorionic gonadotropin has a recent origin within primates in an evolutionary history of selection. Mol Bio Evol. 2002;19:320–35.CrossRefGoogle Scholar
  42. 42.
    Crawford RJ, Tegear GW, Niall HD. The nucleotide sequence of baboon chorionic gonadotropin ß-subunit genes have diverged from the human. Gene. 1986;46:161–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Cunnane SC, Herbige LS, Crawford MA. The importance of energy and nutrient supply in human brain evolution. Nutr Health. 1993;9:19–35.Google Scholar
  44. 44.
    Lockett WP. Comparative development and evolution of the placenta in primates. Contrib Primatol. 1974;3:42–234.Google Scholar
  45. 45.
    Martin RD. Relative brain size and basal metabolic rate in terrestrial vertebrates. Nature. 1981;293:57–60.PubMedCrossRefGoogle Scholar
  46. 46.
    Cole LA, Khanlian SA, Kohorn EI. Evolution of the human brain, chorionic gonadotropin and hemochorial implantation of the placenta: insights into origins of pregnancy failures, preeclampsia and choriocarcinoma. J Reprod Med. 2008;53:449–557.Google Scholar
  47. 47.
    Cole LA. hCG and hyperglycosylated hCG in the establishment and evolution of hemochorial placentation. J Reprod Immunol. 2009;82:111–7.CrossRefGoogle Scholar
  48. 48.
    Bahado-Singh RO, Oz AU, Kingston JM, Shahabi S, Hsu CD, Cole LA. The role of hyperglycosylated hCG in trophoblast invasion and the prediction of subsequent pre-eclampsia. Prenat Diagn. 2002;22:478–81.PubMedCrossRefGoogle Scholar
  49. 49.
    Brennan MC, Wolfe MD, Murray-Krezan CM, Cole LA, Rayburn WF. First trimester hyperglycosylated human chorionic gonadotropin and development of hypertension. Prenat Diagn. 2013;33:1075–1079.Google Scholar
  50. 50.
    Wilcox AJ, Weinberg CR, O’Connor JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med. 1988;319:189–94.PubMedCrossRefGoogle Scholar
  51. 51.
    Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345:1400–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Semprini AE, Simon G. Not so efficient reproduction. Lancet. 2000;356:257–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Cole LA, Laidler L, Muller C. USA hCG Reference Service, 10-year report. Clin Biochem. 2010;43:1013–22.PubMedCrossRefGoogle Scholar
  54. 54.
    Pattillo RA, Sasaki S, Katayama KP, Roesler M, Mattingly RF. Genesis of 46, XY hydatidiform mole. Am J Obstet Gynecol. 1981;141:104–5.PubMedGoogle Scholar
  55. 55.
    Seckl MJ, Fisher RA, Salerno G, Rees H, Paradinas FJ, Foskett M, et al. Choriocarcinoma and partial hydatidiform moles. Lancet. 2000;356:36–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Jurka P, Sacharczuk M, Sobczak-Filipiak M. Partial hydatidiform mole diagnosis in a cat: a case report. 2012. 7th Intl Symp Canine and Feline Reproduction, Abstract.Google Scholar
  57. 57.
    Morris FJ, Kerr SM, Laven RA, Collett MG. Large hydatidiform mole: an unusual finding in a calving cow. N Z Vet J. 2008;56:243–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Hancock BW, Seckl MJ, Berkowitz RS, Cole LA. Gestational trophoblastic disease. 2003
  59. 59.
    Chiari H. Uber drei Falle von primarem kacino in findus und corpus des uterus. Med Jahrb. 1877;7:364–7.Google Scholar
  60. 60.
    Saenger M. Deciduoma malignum. Zbl Gyak. 1889;167:537.Google Scholar
  61. 61.
    Butler SA, Iles RK. Ectopic human chorionic gonadotropin beta secretion by epithelial tumors and human chorionic gonadotropin beta-induced apoptosis in Kaposi’s sarcoma: is there a connection? Clin Cancer Res. 2003;9:4666–4673.Google Scholar
  62. 62.
    Hamade AL, Nakabayashi K, Sato A, Kiyoshi K, Takamatsu Y, Laoag-Fernandez JB, Ohara N, Maruo T. Transfection of antisense chorionic gonadotropin ß gene into choriocarcinoma cells suppresses the cell proliferation and induces apoptosis. J Clin Endocrinol Metab 2005;90:4873–4879.Google Scholar
  63. 63.
    Marchand FJ. Uber die sogenannten “decidualen” geshwulskeim im anshluss an normale geburt, abort, blasenmole und extrauterineschwanggerahaft. Monatsschr Geburtshilfe Gynakol. 1895;1:419–38.Google Scholar
  64. 64.
    Ober WB, Fass RO. The early history of choriocarcinoma. J Hist Med Allied Sci. 1861;16:49–73.Google Scholar
  65. 65.
    Beebe JS, Huth JR, Ruddon RW. Combination of the chorionic gonadotropin free beta-subunit with alpha. Endocrinol. 1990;126:384–91.CrossRefGoogle Scholar
  66. 66.
    Ruddon RW, Hanson CA, Bryan AH, Putterman GJ, White EL. Synthesis and secretion of human chorionic gonadotropin subunits by cultured human malignant cells. J Biol Chem. 1980;255:1000–7.PubMedGoogle Scholar
  67. 67.
    Cole LA, Nam J-H, Park S-Y, Koh MW, Tanaka A. Urinary beta core fragment: 7 years later. J Tumor Marker Oncol. 1994;9:53.Google Scholar
  68. 68.
    Acevedo HF, Krichevsky A, Campbell-Acevedo EA, Galyon JC, Buffo MJ, Hartsock RJ. Flow cytometry method for the analysis of membrane-associated human chorionic gonadotropin, its subunits, and fragments on human cancer cells. Cancer. 1992;69:1818–28.PubMedCrossRefGoogle Scholar
  69. 69.
    Regelson W. Have we found the “definitive cancer biomarker”? The diagnostic and therapeutic implications of human chorionic gonadotropin-beta statement as a key to malignancy. Cancer. 1995;76:1299–301.PubMedCrossRefGoogle Scholar
  70. 70.
    Sutton JM. Charge variants in serum and urine hCG. Clin Chem Acta. 2004;341:199–203.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.USA hCG Reference ServiceAngel FireUSA

Personalised recommendations