Current TopicHyperglycosylated hCG, a review
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)
- et al.
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) - et al.
The structures of the serine-linked sugar chains on human chorionic gonadotropin
Biochem Biophys Res Comm
(1985) - et al.
Hyperglycosylated human chorionic gonadotropin and the source of pregnancy failure
Fert Steril
(2008) - et al.
Hyperglycosylated hCG (Invasive trophoblast antigen, ITA) a Key antigen for early pregnancy detection
Clin Biochem
(2003) - et al.
hCG in the management of quiescent and chemorefractory gestational trophoblastic diseases
Gyn Oncol
(2010) - et al.
Trophoblast origin of hCG isoforms: Cytotrophoblasts are the primary source of choriocarcinoma hCG
Mol Cell Endocrinol
(2002) hCG and hyperglycosylated hCG in the establishment and evolution of hemochorial placentation
J Reprod Immunol
(2009)- et al.
Human chorionic gonadotropin promotes tumorigenesis of choriocarcinoma JAR cells
Troph Res
(1999) - et al.
Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver regulation by TNF-alpha and TGF-beta1
J Hepatol
(1999) - et al.
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)
The quagmire of hCG and hCG testing in gynecologic oncology
Gynecol Oncol
Persistent low-level “real” human chorionic gonadotropin: a clinical challenge and a therapeutic dilemma
Gynecol Oncol
Survival rates of patients with choriocarcinoma treated with chemotherapy without hysterectomy: effects of anticancer agents on subsequent births
Gynecol Oncol
A single serum test for measuring early pregnancy outcome with high predictive value
Clin Biochem
Preeclampsia and human reproduction. An essay of a long term reflection
J Reprod Immunol
An overview of the past, present and future of nongonadal LH/hCG actions in reproductive biology and medicine
Sem Reprod Endocrinol
The presence of gonadotropin receptors in nonpregnant human uterus, human placenta, fetal membranes, and decidua
J Clin Endocrinol Metab
Gestational trophoblastic diseases: 1. Pathophysiology of hyperglycosylated hCG-regulated neoplasia
Gynecol Oncol
Hyperglycosylated hCG in gestational implantation and in choriocarcinoma and testicular germ cell malignancy tumorigenesis
J Reprod Med
The effects of β-human chorionic gonadotropin on the in vitro growth of bladder cancer cell lines
Br J Cancer
Metastatic phenotype correlates with high expression of membrane-associated complete β-human chorionic gonadotropin in vivo
Cancer
The O-linked oligosaccharides are strikingly different on pregnancy and choriocarcinoma hCG
J Clin Endocrinol Metab
Site-specific glycan analysis of human chorionic gonadotropin β-subunit from malignancies and pregnancy by liquid chromatography - electrospray mass spectrometry
Glycobiol
Carbohydrate and peptide structure of the alpha- and beta-subunits of human chorionic gonadotropin from normal and aberrant pregnancy and choriocarcinoma
Endocrine
Structure, pathology and function of the N-linked sugar chains of human chorionic gonadotropin
Biochim Biophy Acta
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
Hyperglycosylated human chorionic gonadotropin (invasive trophoblast antigen) immunoassay: a new basis for gestational Down syndrome screening
Clin Chem
Differential urinary gonadotropin profiles in early pregnancy and early pregnancy loss
Prenat Diagn
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
Transfection of antisense chorionic gonadotropin β gene into choriocarcinoma cells suppresses the cell proliferation and induces apoptosis
J Clin Endocrinol Metab
Crystal structure of human chorionic gonadotropin
Nature
The heterogeneity of hCG: III. The occurrence, biological and immunological activities of nicked hCG
Endocrinology
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
Cited by (85)
The association between human chorionic gonadotropin and adverse pregnancy outcomes: a systematic review and meta-analysis
2024, American Journal of Obstetrics and GynecologyThe effect of intrauterine hCG injection before embryo transfer on pregnancy rate in frozen embryo transfer cycles
2022, Annals of Medicine and SurgeryHuman chorionic gonadotrophin assays to monitor GTD
2021, Best Practice and Research: Clinical Obstetrics and GynaecologyCore 2 β1,6-N-acetylglucosaminyltransferases accelerate the escape of choriocarcinoma from natural killer cell immunity
2021, Biochemistry and Biophysics ReportsDeimmunization of protein therapeutics – Recent advances in experimental and computational epitope prediction and deletion
2021, Computational and Structural Biotechnology Journal