Elsevier

Placenta

Volume 31, Issue 8, August 2010, Pages 653-664
Placenta

Current Topic
Hyperglycosylated hCG, a review

https://doi.org/10.1016/j.placenta.2010.06.005Get rights and content

Abstract

Hyperglycosylated hCG (hCG-H) is a glycoprotein with the same polypeptide structure as hCG, and much larger N- and O-linked oligosaccharides. The oligosaccharides increase the molecular weight of hCG from 36,000 – 37,000 u to 40,000 – 41,000 u, depending on the extent of hyperglycosylation. hCG-H has triantennary N-linked oligosaccharides and double molecular size O-linked oligosaccharides (hexasaccharide compared with predominantly trisaccharide structures). hCG is produced by syncytiotrophoblast cells while hCG-H is made by extravillous cytotrophoblast cells. hCG-H promotes trophoblast invasion during choriocarcinoma, growth of cytotrophoblast cells and placental implantation in pregnancy. hCG-H is an independent molecule to hCG with totally separate biological functions. hCG has numerous functions during pregnancy, it promotes progesterone production, promotes angiogenesis in uterine vasculature, immuno-suppresses the invading placental tissue, promotes the growth of the uterus in line with the growth of the fetus during pregnancy, promotes the differentiation of growing cytotrophoblast cells, promotes the quiescence of contractions in the uterine myometrium during the course of pregnancy, and also has function in growth and development of fetal organs.

Monoclonal antibody B152 uniquely binds hCG-H. Using this monoclonal antibody in immunometric assays permits detection of pregnancy. It also permits management of gestational trophoblastic diseases and detection of quiescent gestational trophoblastic disease. This same test can be used to differentiate of aggressive and minimally-aggressive gestational trophoblastic disease, and discrimination of patients that respond to chemotherapy and who are chemorefractory. The hCG-H test can be used to screen for Down syndrome pregnancies and predict patients likely to generate hypertensive disorder in pregnancy. It also can be used to differentiate pregnancies that will miscarry and pregnancies that will go to term.

Introduction

Human chorionic gonadotropin (hCG) has always been thought of as one molecule, a hormone which promotes progesterone production by corpus luteal cell. The last 20 years has seen big changes in this concept. Firstly, hCG has been shown to comprise 3 independent molecules and not one, all have a common β-subunit peptide structure so that the name hCG stays attached to all three molecules. These are hCG, which has been shown to have multiple functions extending way beyond promoting progesterone production by corpus luteal cells [1], [2], [3]; hyperglycosylated hCG (hCG-H), a major glycosylation variant of hCG which has a different 3 dimensional structure, is also produced by placenta. hCG-H has critical functions in invasion and growth of choriocarcinoma cells and implantation of pregnancy [4], [5]. hCG free β-subunit is produced by most human cancers. It promotes cancer cell growth and malignancy [6], [7], [8]. Here we review over 100 published articles regarding hCG-H, its structure, its biological function, its evolution, hCG-H assays and clinical uses of hCG-H measurements.

Section snippets

hCG-H structure

hCG-H shares a common amino acid sequence with hCG. The structural difference between hCG and hCG-H strictly lies in the carbohydrate structure. Here we focus on the carbohydrate structure of hCG-H. The structure story begins in 1983 when Mizouchi et al. used basic biochemical methods to show a difference between the N-linked oligosaccharides on hCG in urine from pregnancies and urine from choriocarcinoma cases [9]. We now know that the molecule produced by choriocarcinoma cases hCG-H. In 1985,

Site of hCG-H synthesis

It is only in recent years that the site of hCG-H production has been firmly established. As shown by Kovolevskaya et al. [21], cytotrophoblast cells produce hCG-H and syncytiotrophoblast cells make hCG. This was confirmed by Cole et al. [4]. More recently it has been shown that specifically extravillous cytotrophoblast cells make hCG-H [22].

As shown in Table 1, hCG-H accounts for 90% of total hCG during the 3rd week of gestation (since last menstrual period), or the week following implantation

Biological functions of hCG-H

The biological functions of hCG-H appear to be independent of the numerous biological function of hCG [1], [2], [3]. hCG promotes progesterone production be corpus luteal cells, hCG promotes angiogenesis in uterine vasculature so that it can optimally supply blood to the invading placenta, hCG immuno-blands the invading placental tissue to prevent rejection from the mother, hCG promotes the growth of the uterus in line with growth of the fetus [1], [2], [3], hCG promotes the differentiation of

hCG-H in pregnancy implantation

Is hCG-H the signal that drives implantation of pregnancy? One might predict this when one considers that hCG-H is most prominent at 3 weeks of gestation, the time of implantation of pregnancy. One also might predict this when considering that hCG-H appears to be the invasion and malignancy signal when one examine choriocarcinoma. hCG0H also promotes invasion by first trimester cytotrophoblast cells through Matrigel membranes (Table 2). A study by Sasaki et al. [18] appears to confirm the

hCG-H assay

In 1999 Birken at al. developed a monoclonal antibody to choriocarcinoma hCG preparation C5 [13]. This antibody was called B152 [13]. This antibody specifically bound hCG-H with 25% crossreactivity with hCG-H free β-subunit. It had 0.0% crossreactivity with hCG and its free β-subunit. Despite multiple attempts by several investigators using intact hCG-H, hCG-H β-subunit, and hCG β-subunit C-terminal peptide as epitopes, no other hCG-H-specific monoclonal antibody has ever been successfully

hCG-H ultimate pregnancy test

As illustrated in Table 1, hCG-H is the principal form of total hCG made in early pregnancy. In serum it accounts for 90 ± 11% of total hCG in the 3rd complete week of gestation and 54 ± 27% of total hCG during the 4th complete week of gestation. As such it is the principal hCG element during the 2 weeks in which most women are pregnancy tested. Interestingly, some serum hCG, point-of-care and home pregnancy tests poorly detect hCG-H, very much limiting their use in early pregnancy testing [38]

hCG-H in the management of gestational trophoblastic diseases

Gestational trophoblastic diseases are governed and regulated by the presence of hCG-H. As published in an article on evolution [23], it is the presence of hCG-H in humans only that drives gestational trophoblastic neoplasms and choriocarcinoma and causes people to get these humans-only diseases. As discussed above, hCG-H drives pregnancy implantation through regulatory mechanisms involving blockage of apoptosis and metalloproteinases. It is these same processes that drive cancer invasion when

hCG-H in the management of quiescent gestational trophoblastic diseases

The USA hCG Reference Service has consulted 134 cases of quiescent gestational trophoblastic disease, or inactive gestational trophoblastic disease or disease which has halted producing hCG-H, stopping all growth [42], [43], [44]. In the Reference Service’s experience, it is probably the most common cause for persistent low hCG levels outside of pregnancy in a woman of menstrual age. As shown in.

Fig. 7 and 62 of these 134 cases of quiescent gestational trophoblastic disease cases followed the

hCG-H in managing minimally aggressive gestational trophoblastic disease

The absence of hCG-H (<1% hCG-H) in choriocarcinoma or gestational trophoblastic neoplasm is indicative of quiescent gestational trophoblastic disease or inactive disease. In contrast, the presence of high proportions of hCG-H of total hCG (>40% hCG-H) seemingly demonstrates a highly aggressive gestational trophoblastic neoplasm [18], [38], [40] (Table 3). Here we consider “borderline” cases; malignancies with low proportions of hCG-H a condition between highly invasive disease and quiescent

hCG-H in predicting down syndrome pregnancies

The first application discovered for hCG-H was in Down syndrome screening [16].

In 1995, I presented the discovery of hyperglycosylated hCG (hCG-H) and the availability of a new assay. I was approached by a member of Maternal Fetal Medicine at Yale University to test a library of second-trimester Down syndrome pregnancy samples and controls. Why should hCG-H be a marker of Down syndrome pregnancy? hCG and hCG-H take on different profiles in Down syndrome pregnancies. The limited fusion of

hCG-H in predicting hypertensive disorders

Hypertensive disorders, pregnancy induced hypertension (PIH), preeclampsia, eclampsia and hemolysis, and low platelet count (HELP syndrome) are the most deadly complication of pregnancy. Each can lead to hemorrhage and death. They are most common in nulliparous or first-time pregnancies. All told, they occur in approximately 7% of all pregnancies.

·Hypertensive disorders can be predicted by testing hCG-H in serum or urines during the first- and second-trimesters of pregnancy [56]. Ray

hCG-H in screening for failing pregnancies

There are two major types of pregnancy failures in humans, spontaneous abortions (SABs) and biochemical pregnancies. SABs (miscarriages) occur within the first or second-trimesters of pregnancy. After the second trimester, they are considered stillborn pregnancies. Worldwide, first and second-trimester miscarriages account for 15-20% of all pregnancies. In the USA, the miscarriage rate accounts for 16% of all pregnancies. Biochemical pregnancies are pregnancies which fail to implant

hCG-H evolution and human evolution

Just as hyperglycosylated chorionic gonadotropin (CG-H) is produced by human cytotrophoblast cells, and chorionic gonadotropin (CG) is made by differentiated synctotropblast it is assumed that the same 2 molecules are made by primate cells. CG and CG-H were first made by early simian primiates (i.e. cybus money, spider monkey). Just as CG and CG-H evolved, hemochorial placentation evolved in early simian primates [23], [61]. Earlier primates like prosimian primates (i.e. lemur) did not produce

hCG-H summary

In summary, hCG-H is an unusual molecule. Differing from hCG just by the presence of large oligosaccharides, and have totally separate biological function. This is the only known example of two independent molecules having the same peptide backbone and only varying in oligosaccharide structure. hCG-H appears to be the molecule that controls implantation and invasion by extravillous cytotrophoblast cells, and invasion in choriocarcinoma. Science also shows CG and CG-H as critical molecules in

References (71)

  • C.Y. Muller et al.

    The quagmire of hCG and hCG testing in gynecologic oncology

    Gynecol Oncol

    (2009)
  • E.I. Kohorn

    Persistent low-level “real” human chorionic gonadotropin: a clinical challenge and a therapeutic dilemma

    Gynecol Oncol

    (2002)
  • S. Goto et al.

    Survival rates of patients with choriocarcinoma treated with chemotherapy without hysterectomy: effects of anticancer agents on subsequent births

    Gynecol Oncol

    (2004)
  • J.M. Sutton-Riley et al.

    A single serum test for measuring early pregnancy outcome with high predictive value

    Clin Biochem

    (2006)
  • P.Y. Robillard et al.

    Preeclampsia and human reproduction. An essay of a long term reflection

    J Reprod Immunol

    (2003)
  • Rao CV. Paradigm shift on the targets of hCG actions. In: Cole LA, editor. Human chorionic gonadotropin. Oxford:...
  • C.V. Rao

    An overview of the past, present and future of nongonadal LH/hCG actions in reproductive biology and medicine

    Sem Reprod Endocrinol

    (2001)
  • E. Reshef et al.

    The presence of gonadotropin receptors in nonpregnant human uterus, human placenta, fetal membranes, and decidua

    J Clin Endocrinol Metab

    (1990)
  • L.A. Cole et al.

    Gestational trophoblastic diseases: 1. Pathophysiology of hyperglycosylated hCG-regulated neoplasia

    Gynecol Oncol

    (2006)
  • L.A. Cole et al.

    Hyperglycosylated hCG in gestational implantation and in choriocarcinoma and testicular germ cell malignancy tumorigenesis

    J Reprod Med

    (2006)
  • Butler SA, Iles RK. Biological function of the free beta subunit: expression and treatment target in cancer. In: Cole...
  • D.J. Gillott et al.

    The effects of β-human chorionic gonadotropin on the in vitro growth of bladder cancer cell lines

    Br J Cancer

    (1996)
  • H.F. Acevedo et al.

    Metastatic phenotype correlates with high expression of membrane-associated complete β-human chorionic gonadotropin in vivo

    Cancer

    (1996)
  • L.A. Cole

    The O-linked oligosaccharides are strikingly different on pregnancy and choriocarcinoma hCG

    J Clin Endocrinol Metab

    (1987)
  • L. Valmu et al.

    Site-specific glycan analysis of human chorionic gonadotropin β-subunit from malignancies and pregnancy by liquid chromatography - electrospray mass spectrometry

    Glycobiol

    (2006)
  • M.M. Elliott et al.

    Carbohydrate and peptide structure of the alpha- and beta-subunits of human chorionic gonadotropin from normal and aberrant pregnancy and choriocarcinoma

    Endocrine

    (1997)
  • A. Kobata et al.

    Structure, pathology and function of the N-linked sugar chains of human chorionic gonadotropin

    Biochim Biophy Acta

    (1990)
  • S. Birken et al.

    Development and characterization of antibodies to a nicked and hyperglycosylated form of hCG from a choriocarcinoma patient: generation of antibodies that differentiate between pregnancy hCG and choriocarcinoma hCG

    Endocrine

    (1999)
  • L.A. Cole et al.

    Hyperglycosylated human chorionic gonadotropin (invasive trophoblast antigen) immunoassay: a new basis for gestational Down syndrome screening

    Clin Chem

    (1999)
  • J. O’Connor et al.

    Differential urinary gonadotropin profiles in early pregnancy and early pregnancy loss

    Prenat Diagn

    (1999)
  • K. Handshuh 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-a

    Endocrinology

    (2007)
  • A.L. Hamade et al.

    Transfection of antisense chorionic gonadotropin β gene into choriocarcinoma cells suppresses the cell proliferation and induces apoptosis

    J Clin Endocrinol Metab

    (2005)
  • A.J. Lapthorn et al.

    Crystal structure of human chorionic gonadotropin

    Nature

    (1994)
  • L.A. Cole et al.

    The heterogeneity of hCG: III. The occurrence, biological and immunological activities of nicked hCG

    Endocrinology

    (1991)
  • N.K. Khoo et al.

    SV40 Tag transformation of the normal invasive trophoblast results in a premalignant phenotype I Mechanisms responsible for hyperinvasiveness and resistance to anti-invasive action of TGFβ

    Intl J Cancer

    (1998)
  • Cited by (85)

    • Human chorionic gonadotrophin assays to monitor GTD

      2021, Best Practice and Research: Clinical Obstetrics and Gynaecology
    View all citing articles on Scopus
    View full text