No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Hyperglycosylated hCG the source of pregnancy failures
... Pregnancy Hyperglycosylated hCG has critical functions in pregnancy driving blastocyst implantation [14,15], and in deep implanting hemochorial placentation [16], and in promoting growth of the placenta as pregnancy advances [17]. It also has critical functions as cancer hyperglycosylated hCG and cancer hyperglycosylated hCG free ß-subnit in human cancers, where it uses a mechanisms parallel to blastocyst implantation to drive malignancy or viciousness of cancer [18,19]. ...
... Other functions of the placental hormone hCG include tempering of blastocyst implantation, the first function in pregnancy [14,15]. Promoting ovarian luteal cells to produce progesterone at 4 to 7 weeks gestation, when menstrual cycle pituitary LH is depleted [37]. ...
... The placental autocrine hyperglycosylated hCG is seemingly the first hCG molecule functioning during pregnancy, driving implantation of the blastocyst of pregnancy. The placental autocrine hyperglycosylated hCG can be detected in serum and urine as early as two days before pregnancy implantation [14,15]. In driving implantation of the blastocyst ( Figure 4) cytotrophoblast cells of the blastocyst produce hyperglycosylated hCG, which acts through a TGF-ß-II receptor to promote metalloproteinase and collagenase secretion by the blastocyst cells. ...
... Scientist show that most biochemical pregnancies and spontaneous abortion pregnancies, approximately two-thirds, are due incomplete implantation of pregnancy [97,98]. As shown by us in two studies examining 62 pregnancies and 127 pregnancies [15,99], all (100%) of normal term pregnancies (81 and 42 total) produced greater than 40% hyperglycosylated hCG (% of total hCG) on the day of implantation. In contrast, only 8 of 36 and 7 of 20 biochemical and spontaneous aborting pregnancies produced greater than 40% hyperglycosylated hCG on the day of implantation. ...
... As discussed in Section hCG, Hyperglycosylated hCG, Hemochorial Placentation and Evolution, and Section hCG, Hyperglycosylated hCG and pregnancy, human hyperglycosylated hCG is the extreme end product of evolution that drives pregnancy implantation to it extreme, and drives production of hemochorial placentation to the extreme. Humans having an extreme molecule to drive implantation are faced with the intricacies and demands of an extreme molecule, so have to face a high proportion of rejected pregnancies, this is miscarriage or spontaneous abortions (17% failure rate) and biochemical pregnancies (25% failure rate) or 25% + 17% or 42% pregnancy failure rate [15,96]. Simian primates only have an 8% failure rate since they do not have to cope with human hyperglycosylated hCG. ...
... It is assumed that the failures exceeding 40% hyperglycosylated hCG are the rare genetic abnormalities and that the bulk, 28 of 36 and 13 of 20 pregnancies are pregnancy failures due to improper implantation. It is concluded that hyperglycosylated hCG is an absolute marker of biochemical pregnancy and spontaneous abortion, and that deficiency of hyperglycosylated hCG (< 50% hyperglycosylated hCG) is the actual cause of human pregnancy failures [15,99]. ...
hCG is a wonder. Firstly, because hCG is such an extreme molecule. hCG is the most acidic glycoprotein containing the highest proportion of sugars. Secondly, hCG exists in 5 common forms. Finally, it has so many functions ranging from control of human pregnancy to human cancer. This review examines these molecules in detail.
These 5 molecules, hCG, sulfated hCG, hyperglycosylated hCG, hCG free beta and hyperglycosylated free beta are produced by placental syncytiotrophoblast cells and pituitary gonadotrope cells (group 1), and by placental cytotrophoblast cells and human malignancies (group 2). Group 1 molecules are both hormones that act on the hCG/LH receptor. These molecules are central to human menstrual cycle and human pregnancy. Group 2 molecules are autocrines, that act by antagonizing a TGF beta receptor. These molecules are critical to all advanced malignancies.
The hCG groups are molecules critical to both the molecules of pregnancy or human life, and to the advancement of cancer, or human death.
... The regular hCG and hyperglycosylated hCG degradation pathways involve elastase and other proteases secreted by Hyperglycosylated hCG is the extravillous invasion cytotrophoblast cell invasion signal [40][41][42][43][44], and is produced in states characterized by cytotrophoblast cells or invasion (Table 1). It is the principal or sole form of hCG produced in the first week of pregnancy, following implantation of the fetus (Table 2) [43,[45][46][47]. ...
... The regular hCG and hyperglycosylated hCG degradation pathways involve elastase and other proteases secreted by Hyperglycosylated hCG is the extravillous invasion cytotrophoblast cell invasion signal [40][41][42][43][44], and is produced in states characterized by cytotrophoblast cells or invasion (Table 1). It is the principal or sole form of hCG produced in the first week of pregnancy, following implantation of the fetus (Table 2) [43,[45][46][47]. Unduly low levels of hyperglycosylated hCG clearly mark failing pregnancies, whether a biochemical pregnancy or early pregnancy loss, spontaneous abortion or ectopic pregnancy [43,[45][46][47]. ...
... It is the principal or sole form of hCG produced in the first week of pregnancy, following implantation of the fetus (Table 2) [43,[45][46][47]. Unduly low levels of hyperglycosylated hCG clearly mark failing pregnancies, whether a biochemical pregnancy or early pregnancy loss, spontaneous abortion or ectopic pregnancy [43,[45][46][47]. While minimally present in hydatidiform mole cases, rising proportions of hyperglycosylated hCG mark invasive hydatidiform mole (invasive mole) and development and advancement of choriocarcinoma (Table 1) [41][42][43][44][48][49][50]. ...
Human chorionic gonadotropin (hCG) is a glycoprotein hormone comprising 2 subunits, alpha and beta joined non covalently. While similar in structure to luteinizing hormone (LH), hCG exists in multiple hormonal and non-endocrine agents, rather than as a single molecule like LH and the other glycoprotein hormones. These are regular hCG, hyperglycosylated hCG and the free beta-subunit of hyperglycosylated hCG.
For 88 years regular hCG has been known as a promoter of corpus luteal progesterone production, even though this function only explains 3 weeks of a full gestations production of regular hCG. Research in recent years has explained the full gestational production by demonstration of critical functions in trophoblast differentiation and in fetal nutrition through myometrial spiral artery angiogenesis.
While regular hCG is made by fused villous syncytiotrophoblast cells, extravillous invasive cytotrophoblast cells make the variant hyperglycosylated hCG. This variant is an autocrine factor, acting on extravillous invasive cytotrophoblast cells to initiate and control invasion as occurs at implantation of pregnancy and the establishment of hemochorial placentation, and malignancy as occurs in invasive hydatidiform mole and choriocarcinoma. Hyperglycosylated hCG inhibits apoptosis in extravillous invasive cytotrophoblast cells promoting cell invasion, growth and malignancy. Other non-trophoblastic malignancies retro-differentiate and produce a hyperglycosylated free beta-subunit of hCG (hCG free beta). This has been shown to be an autocrine factor antagonizing apoptosis furthering cancer cell growth and malignancy.
New applications have been demonstrated for total hCG measurements and detection of the 3 hCG variants in pregnancy detection, monitoring pregnancy outcome, determining risk for Down syndrome fetus, predicting preeclampsia, detecting pituitary hCG, detecting and managing gestational trophoblastic diseases, diagnosing quiescent gestational trophoblastic disease, diagnosing placental site trophoblastic tumor, managing testicular germ cell malignancies, and monitoring other human malignancies. There are very few molecules with such wide and varying functions as regular hCG and its variants, and very few tests with such a wide spectrum of clinical applications as total hCG.
... The international Trophoblastic Disease Service at Charing Cross Hospital in London has always considered urine testing a critical component of gestational trophoblastic disease (GTD) and other cancer case management [9,10]. Quantitative urine hCG measurements, which bypass the need for phlebotomy, are useful in pregnancy testing, cancer screenings [7,[10][11][12][13][14][15][16], and in clarifying false positive serum hCG test results that lead to clinical mishandlings [18][19][20][21][22]. The interfering heterophilic and animal antibodies which cause false positive hCG results do not enter urine so that false positive results can be quickly identified by urine hCG testing [18][19][20][21][22]. ...
... Urine hCG tests are currently limited by the FDA to qualitative determinations and to a sensitivity of 20 IU/L for both automated and point-of-care (POC) assays. This indicator concept has been discredited in other countries [1][2][3][4][5][6][7][8][9][10] and discredited now in the USA [11][12][13][14][15][16]. Quantitative urine hCG, while varying in concentration with diuresis can be as useful as serum hCG as an absolute pregnancy discriminator [2,3,6,[12][13][14]16]. ...
... This indicator concept has been discredited in other countries [1][2][3][4][5][6][7][8][9][10] and discredited now in the USA [11][12][13][14][15][16]. Quantitative urine hCG, while varying in concentration with diuresis can be as useful as serum hCG as an absolute pregnancy discriminator [2,3,6,[12][13][14]16]. A quantitative urine assay removes sample collection barriers in the absence of phlebotomy in addition to providing invaluable diagnostic information. ...
The USA uniquely does not use quantitative urine human chorionic gonadotropin (hCG) tests despite being invaluable in pregnancy testing and in monitoring cancer patients. We look at current hCG tests and their detection of the degraded forms of hCG predominant in urine. We examine levels of urinary hCG, its usefulness in pregnancy testing, and advantages of urine testing in false positive hCG cases and cancer cases.
hCG assays were blindly evaluated at 10 laboratories running different methodologies. Daily urine samples from 164 women were collected through 5 menstrual cycles or until pregnancy was achieved. Urines were assayed for total hCG. We also examined the use of quantitative urine hCG in confirming false positive serum hCG results in 80 clinical cases.
Only the Siemens Immulite test was shown to detect the degraded forms of hCG present in urine. This test equally recognized urine and serum hCG. We investigated background hCG in 9026 urines, the mean hCG level was 0.04 IU/L, and the 99th centile was 1.4 IU/L. In cycles where pregnancy was achieved, hCG could be detected in urine at 24.6 days of a 28.7 day menstrual cycle. At this time, the average hCG was 6.02 IU/L, setting a sensitivity level for quantitative urine hCG tests to detect pregnancy. Quantitative urinary hCG proved critical in detecting cancer in 3 of 80 cases complicated by false positive serum hCG.
The need for a quantitative urine hCG assay is undeniable and we invite manufacturers to produce a quantitative urine hCG test.
... 35,36 Using these tests it has been shown that human CG-H is not only the predominant form of CG produced in choriocarcinoma (Table II) but also the predominant form detected in serum and urine samples in early human pregnancy during the weeks of implantation. [36][37][38][39][40] CG-H has been shown to account for 92% (mean) of total CG in the third complete week of human gestation or the week that immediately follows implantation. In the fourth week of gestation, 73% of the total hCG is hyperglycosylated. ...
... In all of these 42 women the proportion of CG-H on the day of implantation was >50%. 39 Twenty additional women achieved pregnancy but miscarried in the first or second trimesters of pregnancy. In these women, the proportion of CG-H at the time of blastocyst implantation was significantly lower than in those with normal outcome pregnancies, 44±41% (p= 0.00000001). ...
... Pregnancy failures, miscarriages and early pregnancy losses, account for 40% of gestations in humans compared to rodents (10%) and all other species. 7,39,55 Shallow implantation or ineffective invasion leads to human pregnancy failures. 7,25 Approximately two thirds of human pregnancy failures can be attributed to inappropriate placentation 7 and are associated with unduly low human CG-H concentrations. ...
Hyperglycosylated chorionic gonadotropin (CG-H) signals placental cytotrophoblast cell growth and invasion, and chorionic gonadotropin (CG) promotes uterine vascularization. A hypothesis is presented relating the evolution of these molecules to the evolution of human hemochorial implantation and that of the human brain. Deep placental invasion, vascularization and hemochorial placentation, under the influence of CG and CG-H, are a critical part of the nutrition and energy-generating mechanisms needed for human brain development and thus for the evolution of humans. Insufficient CG-H production and the resulting inappropriate implantation is associated with an unduly high incidence of pregnancy failures in humans. Low levels of CG-H and inappropriate hemochorial placentation also appear to be associated with subsequent preeclampsia. It is also of note that human CG-H drives invasion by gestational trophoblastic neoplasms that have been described only in humans.
... Hyperglycosylated hCG is an autocrine binding a TGF-β-II receptor [16][17][18], and not acting at all on an hCG/luteinizing hormone (LH) receptor like the hormone hCG ( Figure 1). Hyperglycosylated hCG is made by invasive cytotrophoblast cells during pregnancy, while the hormone hCG is made by fused syncytiotrophoblast cells during pregnancy [19,20]. Hyperglycosylated hCG acts on the autocrine cytotrophoblast cell TGF-β-II receptor driving implantation of the blastocyst in the beginning of pregnancy [20,21], and deep implantation of hemochorial placentation at 10 weeks gestation [22,23], and during the menstrual cycle finalizes ovulation [24]. ...
... Hyperglycosylated hCG is made by invasive cytotrophoblast cells during pregnancy, while the hormone hCG is made by fused syncytiotrophoblast cells during pregnancy [19,20]. Hyperglycosylated hCG acts on the autocrine cytotrophoblast cell TGF-β-II receptor driving implantation of the blastocyst in the beginning of pregnancy [20,21], and deep implantation of hemochorial placentation at 10 weeks gestation [22,23], and during the menstrual cycle finalizes ovulation [24]. In all three processes, the autocrine TGF-β-II receptor drives invasive metalloproteinase and collagenase production [12,19], cell growth [19,25] and blocks cell apoptosis [26][27][28], three malignancy-like steps. ...
... As established, syncytiotrophoblast cell produce the hormone hCG which acts on an LH/hCG receptor[1][2][3][4][5][6][24][25][26]. Pregnancy cytotrophoblast cells, produce a hyperglycosylated variant of hCG, which controls growth and promotion of cytotrophoblast cells, and invasion by cytotrophoblast cells[2,6,24,25]. ...
... As established, syncytiotrophoblast cell produce the hormone hCG which acts on an LH/hCG receptor[1][2][3][4][5][6][24][25][26]. Pregnancy cytotrophoblast cells, produce a hyperglycosylated variant of hCG, which controls growth and promotion of cytotrophoblast cells, and invasion by cytotrophoblast cells[2,6,24,25]. Hyperglycosylated hCG is seemingly an autocrine, which apparently antagonizes TGF beta activity[2,6,9]. ...
Objective: Hyperglycosylated human chorionic gonadotropin (hCG) is a variant of hCG made by cytotrophoblast cell. Here we examine the role of hyperglycosylated hCG in placenta growth and invasion. Methods: JEG-3 choriocarcinoma cells and term cytotrophoblast monolayer culture were prepared. The effect of supplemental hyperglycosylated hCG and hCG was investigated. Growth of these cells was examined by increase in cell number. Invasion was investigated using Matrigel basement membrane cells. The proportion of cell invading Matrigel was determined. Results: Term cytotrophoblast cell and JEG-3 choriocarcinoma cells grew to 5 427±834 cells (109%) and 7 114±553 cells (142%). With the supplementation of hyperglycosylated hCG, they grew significantly wider to 7 633±177 cells (142%) and 10 315±1 477 cells (206%). With the supplementation of hCG they diminished to 4 227±769 cells (78%) and 5 620±657 cells (79%). Term cytotrophoblast cell and JEG-3 choriocarcinoma cells penetrated Matigel membranes to (40.0±10.0)% and (46.0±9.8)%. Hyperglycosylated hCG significantly enhanced penetration to (76.0±13.0)% and (84.0±6.6)%. hCG diminished penetration to (32.0±9.1)% and (32.0±4.5)%. Conclusions: Hyperglycosylated hCG enhances both cytotrophoblast growth and cytotrophoblast cell invasion. hCG minimally suppresses growth and invasion.
... As published by multiple authors, hyperglycosylated hCG is a variant of regular hCG with double size O-linked sugar units and larger triantennary N-linked sugar units boosting the size of hCG from 36,700 to N40,000 molecular weight. It acts as an autocrine growth factor or cytokine to promote cytotrophoblast cell invasion and malignancy as occurs in implantation of pregnancy and in all invasion cases by trophoblast cells [8][9][10][11][12][13]. Quiescent disease arises from highly differentiated trophoblast cells. ...
... It should be considered as the chemotherapy of choice once hCG exceeded 3,000 mIU/ml and hyperglycosylated hCG increased accordingly. This approach was proven in 10 (Table 1B) all showed a complete response of hCG to undetectable hCG levels in response to EMA-CO or EMA-EP. ...
Introduction:
The literature shows that hyperglycosylated hCG is the invasion stimulus in malignant gestational trophoblastic diseases. The USA hCG Reference Service has characterized 2 gestational trophoblastic disease conditions marked by low proportion of hyperglycosylated hCG. These are quiescent gestational trophoblastic disease, defined as inactive or benign invasive disease, and minimally invasive gestational trophoblastic disease, defined as slow growing or chemorefractory disease with hCG increasing very slowly (doubling rate 2-6 weeks). Here we examine the USA hCG Reference Service experience with both diseases.
Methods:
Patient were referred to the USA hCG Reference Service, 133 cases shown to have quiescent gestational trophoblastic disease, 35 cases with aggressive and 30 with minimally invasive gestational trophoblastic disease.
Results:
Quiescent or inactive gestational trophoblastic disease was demonstrated in 133 women. In 127 of these cases, no hyperglycosylated hCG was detected, and in 6 cases 4-27% hyperglycosylated hCG was detected. This is quiescent or inactive disease. Only 1 of 35 cases with aggressive gestational trophoblastic disease (>40% hyperglycosylated hCG) was chemorefractory. In contrast, 30 of 30 minimally invasive cases (<40% hyperglycosylated hCG) were chemorefractory. In chemorefractory cases hyperglycosylated hCG ranged from <1% to 39% of total hCG. The USA hCG Reference Service showed that proportions hyperglycosylated hCG significantly increases as total hCG rises. They recommended in minimally invasive cases to wait to hCG was >3000 IU/L before commencing chemotherapy. This was successful in 10 of 10 minimally invasive cases.
Discussion:
Measurement of hyperglycosylated hCG or invasiveness is a critical step in management of invasive gestational trophoblastic disease. Quiescent of inactive gestational trophoblastic disease requires no therapy. Minimally invasive disease in chemorefractory. The USA hCG Reference Service experience suggests waiting until hCG exceeds 3000 IU/L before commencing any chemotherapy.
... Recently, we investigated this hCG-Hefailing pregnancy relationship [23]. We monitored hCG and hCG-H and the proportion of hCG due to hCG-H daily in 110 women through multiple menstrual cycles until they achieved pregnancy [23]. ...
... Recently, we investigated this hCG-Hefailing pregnancy relationship [23]. We monitored hCG and hCG-H and the proportion of hCG due to hCG-H daily in 110 women through multiple menstrual cycles until they achieved pregnancy [23]. As indicated by Wilcox et al. [86] [87], the day of first detection of hCG (hCG >1 mIU/ml) was assumed as the day of implantation. ...
Hyperglycosylated hCG (hCG-H) is a glycosylation variant of the hormone hCG. Here we review all that is known about this independently functioning molecule. As discussed, it is a very different molecule to the hormone hCG. First, hCG-H is produced by cytotrophoblast cells while regular hCG is made in syncytiotrophoblast cell. Second, it is an autocrine acting directly on the cells which produce it, while regular hCG is an endocrine acting on maternal corpus luteal cells. Third, hCG-H has minimal biological activity in promoting progesterone production compared to regular hCG. Fourth, hCG-H functions unlike regular hCG as an invasion promoter, whether invasion as in choriocarcinoma and testicular germ cell malignancies, or as in implantation of pregnancy. These functions seemingly occur through action on cytotrophoblast cell TGFbeta receptors. Fifth, hCG-H is an essential component for successful human implantation to prevent early pregnancy loss and spontaneous abortion. Sixth, hCG-H is critical for promoting the midtrimester hemochorial implantation, and for preventing preeclampsia. Seventh, measurements of hCG-H have advantages over measurements of regular hCG or total hCG, in detecting pregnancy, pregnancy outcome (failing or term pregnancy), predicting preeclampsia in pregnancy, or as a tumor marker for gestational trophoblastic diseases.
... All examined purified pregnancy hCG, hydatidiform mole hCG and choriocarcinoma hCG, and not the proven components of hCG, the hormone hCG, the autocrine hyperglycosylated hCG, and the invasive cell hyperglycosylated hCG. Unfortunately, all 3 separate hCG forms, while having separate functions [5][6][7][8], are all approximately the same size, molecular weight 36500, 37400, 38800 respectively and the same charge making them un-separable. ...
... The autocrine hyperglycosylated hCG controls pregnancy implantation at the start of gestation [20,21]. It controls deep implantation of hemochorial placentation at the end of the first trimester of pregnancy [22], controls placenta growth during pregnancy [23] and controls malignancy by all human cancer cells [24,25]. ...
Introduction: In 1997 I discovered hyperglycosylated hCG, a separate and independent molecule to the hormone hCG. The structure of hyperglycosylated hCG was also examined, it was a molecule varying from hCG by just 3 or 4 small sugar side chains, or 2.8% of molecular weight. While the hormone hCG binds a luteinizing hormone (LH)/hCG hormone receptor, hyperglycosylated hCG and its β-subunit are autocrines binding and antagonizing a TGF-β-II receptor. Here structural differences between the two molecules are investigated. Methods: Nicking or cleavage of the hormone hCG and the autocrine hyperglycosylated hCG, and dissociation of subunits were carefully investigated using sequence analysis. Results: Research showed that hyperglycosylated hCG was much more rapidly nicked or cleaved at β47-48 than the hormone hCG. And that nicked hCG was much more rapidly dissociated into subunits than non-nicked hCG. Discussion: A model was generated. As proposed, hyperglycosylated hCG is first rapidly nicked or cleaved at β47-48 and then rapidly dissociated. The nicked hyperglycosylated hCG β-subunit antagonizes the TGF-β-ll receptor. In contrast, the endocrine hCG is blocked from nicking, which limits dissociation, only intact hCG binds the LH/hCG hormone receptor.
... Moreover, it is estimated that nearly 41% of pregnancies in humans lead to miscarriages, early pregnancy losses and biochemical pregnancies, while this percentage declines to lower than 10% in most mammalian species [46]. Sasaki et al., suggested that most pregnancy failures are due to inadequate hyperglycosylated hCG production on the day of implantation of the blastocyst [47]. Researchers have also demonstrated that pregnancy-induced hypertension, preeclampsia and eclampsia are complications of incomplete hemochorial placentation mechanisms, which usually take place at the end of the first trimester of pregnancy [48,49]. ...
To thoroughly review the uses of human chorionic gonadotropin (hCG) related to the process of reproduction and also assess new, non-traditional theories. Review of the international literature and research studies. hCG and its receptor, LH/CGR, are expressed in numerous sites of the reproductive tract, both in gonadal and extra-goanadal tissues, promoting oocyte maturation, fertilization, implantation and early embryo development. Moreover, hCG seems to have a potential role as an anti-rejection agent in solid organ transplantation. Future research needs to focus extensively on the functions of hCG and its receptor LH/CGR, in an effort to reveal known, as well as unknown clinical potentials.
... Hyperglycosylated hCG, the second molecule is an autocrine acting on TGFß-II receptor [9,10]. This controls invasion of the uterus during implantation of the blastocyst in pregnancy, growth of cytotrophoblast cells and villous trophoblast tissue during pregnancy [11][12][13][14]. The problem is that the hormone hCG and the autocrine hyperglycosylated hCG are not readily separable by gel filtration methods, ion exchange chromatography methods, reverse phase methods or other HPLC methods. ...
Multiple articles have been published describing the N-linked and O-linked oligosaccharide structures of hCG. All, however, have used purified preparation from pregnancy urine and from choriocarcinoma patient urine. This has told the scientific community that pregnancy and choriocarcinoma hCG-related molecules contain Type 1 and Type 2 O-linked oligosaccharides and biantennary and triantennary N-linked oligosaccharide. Recent years have seen the demonstration of two completely independent hCG molecules, hCG and hyperglycosylated hCG. hCG is a pregnancy hormone made by syncytiotrophoblast cell. Hyperglycosylated hCG is a TGFß receptor binding autocrine produced by cytotrophoblast cells. The two independent share a common amino acid sequence and just vary in carbohydrate structure. Unfortunately, all the carbohydrate structure reports are on a mixture of hCG and hyperglycosylated hCG, as present in pregnancy and choriocarcinoma. This does not all anyone to clearly see the carbohydrate structural differences between the two molecules. Here we carefully examine the carbohydrate structural differences between hCG and hyperglycosylated hCG using the B152 hyperglycosylated hCG-specific immunoassay. It is shown that hCG has only Type 1 O-linked oligosaccharides, while hyperglycosylated hCG only has Type 2 O-linked oligosaccharides. Type of O-linked oligosaccharide structure completely distinguishes hCG and hyperglycosylated hCG.
... hCG reaches a peak at 10 weeks of gestation, then continues to be produced throughout the length of pregnancy. Humans having an extreme molecule to drive implantation are faced with the intricacies and demands of an extreme molecule, so have to face a high proportion of rejected pregnancies, this is miscarriage or spontaneous abortion (17% failure rate) and biochemical pregnancies (25% failure rate) or 25 + 17% or a 42% pregnancy failure rate (10,11). In several studies, the prognostic value of b-hCG in threatened abortion was studied (12)(13)(14). ...
Objectives: To evaluate different biochemical and ultrasonographic markers as predictors of outcome in cases with threatened abortion.
Study design: A prospective observational study involving 250 women in their 1st trimester was divided into three groups: group I (65 women) in whom threatened abortion ended in abortion, group II (85 women) with threatened abortion who completed their pregnancy and group III (100 women) with normal pregnancy. Biochemical markers studied included CA 125, beta human chorionic gonadotropin (β HCG), progesterone, Estradiol (E2), Lactate dehydrogenase (LDH), and Total leucocytic count (TLC) and ultrasonographic markers included Embryonic/Fetal heart rate (E/FHR), Gestational sac diameter (GSD), Crownrump length (CRL) and Yolk sac diameter (YSD). Comparison between markers was done using sensitivity, specificity, PPV and NPV.
Results: There was a statistically significant difference between GI and the other two groups regarding CA 125 β HCG, progesterone, FHR and CRL.
There was no significant difference between the three study groups regarding E2 level, LDH, TLC, GSD or yolk sac diameter.
The sensitivity, specificity, PPV and NPV of CA 125 at 80 IU/ml were 80.2, 78.3, 69.6 and 82.4, respectively, for β HCG at 19887 mIU/ml were 88.6, 81.1, 45,6 and 96.8, respectively, for Progesterone at 25 ng/ml were 90.1, 87.2, 51,2 and 97, respectively, for FHR at 110 bpm were 98.1, 99.1, 89,2 and 91.4, respectively and for CRL at 21 mm were 46.4, 40.1, 35,5 and 33.7, respectively.
Conclusion: CA125, β HCG and progesterone are good biochemical markers and FHR and CRL are good ultrasonographic markers for the prediction of outcome in women with threatened abortion. FHR at 110 bpm gives the best predictivity followed by serum P at 25 ng/ml, β HCG at 19887 mIU/ml, CA 125 at 80 IU/ml and CRL at 21 mm with the least predictive accuracy among studied markers. Adding serum progesterone to FHR gave a sensitivity and specificity of 100%.
... [7][8][9] In addition, a variant of hCG, hyperglycosylated hCG, also detected by total hCG assays promotes placental invasion and implantation of pregnancy. [10][11][12][13] It is hard to conceive with such widely deviating hCG levels how all these pregnancies yielded normal term parturition, whether hCG was 20 mIU/ml at 5 weeks' gestation or 8900 mIU/mL (Table 1). This is explained by the spare receptor phenomenon, or spare hCG/luteinizing hormone (LH) receptors. ...
Serum and urine human chorionic gonadotropin (hCG) vary greatly during the course of pregnancy. We investigated the cause of this variation.
Eighty-two women provided daily urine samples during the first 6 weeks of gestation. First-void urine samples were monitored for luteinizing hormone (LH) and hCG.
Variation was wide when pregnancy hCG anchoring to the last menstrual period (variation 677 ± 786-fold) or to LH peak (variation 810 ± 936-fold). When pregnancy was anchored to the day of implantation (variation 187 ± 123-fold) variation was significantly reduced (P < .00005). Individual differences in the rate of hCG production were examined. hCG production ranged from 1.52-fold to 2.92-fold per day. Rate differences in hCG were also a major source of hCG variation.
Two factors are responsible for the wide fluctuation in hCG concentrations, first dating pregnancies to the start of the last menstrual period rather than the timing of implantation and second, individual pregnancy differences in the rate of hCG production.
When bulky fibroids are discovered during pregnancy, they can become acutely complicated. The question of their resection thus arises. The authors report a case of a woman who was diagnosed at eight weeks' gestation by ultrasound and then by MRI, with a uterine fibroma measuring 22x12x15 cm.
Purpose:
The aim of the study was to assess the eftect ot the addition or iow-cose numan cnononic gonauoiropm (hCG) to ovarian stimulation with recombinant follicle stimulating hormone (rFSH) on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcome.
Materials and methods:
This retrospective clinical study was conducted on 141 women undergoing ICSI through a short GnRH-agonist protocol with rFSH and the addition of low-dose (100 IU/day) hCG. The control group consisted of 124 women undergoing ovarian stimulation with a similar protocol devoid of hCG. Statistical analysis in the study population along with a subgroup analysis for age 35 years and 36 years was performed.
Results:
Women in hCG group were statistically significant older and with higher basal FSH compared to control group. This can be attributed to the Centre's latent tendency to add hCG in the stimulation protocol in poor prognosis patients. Despite this fact and the fact that several ovarian stimulation parameters, such as peak estradiol levels, number of oocytes retrieved, number of mature oocytes, and fertilization rates were in favor of the control group, the quality of transferred embryos and pregnancy rates were in favor of hCG group. Similar results were obtained in the subgroup analyses apart from peak estradiol levels, which did not differ among the study groups.
Conclusions:
The addition of hCG to rFSH may be associated with better quality embryos and higher pregnancy rates, even in women of advanced reproductive age with higher basal FSH levels, which are often considered to have poorer ovarian reserve.
Research strongly indicates that hyperglycosylated human chorionic gonadotrophin (hCG), hCG-2, drives pregnancy implantation. Hyperglycosylated hCG drives cytotrophoblast cell invasion and growth. Inefficient implantation cause miscarriages of pregnancies, biochemical pregnancies, and ectopic pregnancies. Inefficient implantation is due to an inefficient supply of hyperglycosylated hCG. Antibodies to hyperglycosylated hCG blocks implantation. From the findings it is inferred that hyperglycosylated hCG drives implantation. As demonstrated, hyperglycosylated hCG binds and antagonizes a transforming growth factor (TGF)β receptor. As shown, this antagonization of TGFβ promotes metalloproteinases and collagenase production, leading to physical invasion as occurs in implantation.
This book covers human female biology, how the menstrual cycle is controlled, how steroidogenesis is controlled and how the follicle and the egg are formed. This book covers male biology, and how steroid hormones are made, and how sperm are synthesized and matured. Then this book covers sex biology, such as how the brain deals with libido and sexual images, and how the brain controls erection and ejaculation. This book deals with how sperm are matured upon intercourse, how fertilization takes place, and how the fertilized embryo is matured and implants in the uterus. The subjects of sexuality and homosexuality, chromosome disorders and hydatidiform moles are carefully discussed and considered. Sexual maturation of the fetus during pregnancy is carefully considered. This book carefully describes puberty, adrenarche and menarche. The subject of menopause is carefully considered. The subject of major bacterial and viral and sexual diseases is carefully considered as is the subject of reproductive cancers. In writing this book, care has been taken to update everything and check out the information available on medline and on the internet. This is a textbook for undergraduates, medical students and graduates describing all the details of human reproduction. It is also the only up-to-date book on the market. Having examined a total 70 books on human reproduction, obstetrics and gynecology, they all, with no exceptions, include mostly out-of-date science. This is corrected in this book. This book is also a monograph for reproductive biology scientists, covering all the most recent findings in this field. It can also be sold as a general obstetrics and gynecology information source for use by physicians, the general public and in libraries. This is a unique one-of-a-kind reference on human reproduction.
Gynaecologic oncology is an important component of Gynaecology and Oncology. Gynaecologic oncology is one of the most important subject in Gynaecology and a very challenging field. The management of patients with gynaecological cancers is complex as the impact of the outcome of such cancers can be critical. This handbook on gynaecologic oncology is a complete handbook that covers the basics of carcinogenesis and the advances in the prevention and management of all gynaecologic cancers, including breast cancer. Gynaecologic oncology has always been perceived as the most difficult subject in obstetrics and gynaecology, but this handbook will prove it otherwise. The information in the book is given in a systematic and easy-to-understand manner. The references used are up-to-date and from established sources. The book also introduces the readers to the new FIGO staging system, including FIGO staging 2014 for ovarian and fallopian tube carcinoma. The chapters of the book have been contributed by prominent gynaecologic oncologists of the field. As there are only limited textbooks and handbooks available related to the subject, this handbook is suitable for everyone in the medical field, from house officers; pharmacists; doctors; postgraduate students; specialists; fellows in medical oncology, radiation oncology, and gynaecologic oncology; and sub-specialty trainees to lecturers in universities throughout the world. In short, this compact and handy book is a guidebook and reference that should be owned by everyone.
The concept of glycopeptins all started off as part of a bug hunt. It started off with the observation that from 70 recent obstetrics and gynecology and reproductive biology books, they all only cite hCG as just a promoter of corpus luteal progesterone, a 1920s finding, and ignore the hundreds of more recent findings. Confirmed and double confirmed science shows that hCG is a molecule with at least 12 important functions in pregnancy. That hCG is not one molecule but a group of five independent substances. These are hCG, hyperglycosylated hCG, sulfated hCG, hyperglycosylated hCG free â-subunit and fetal hCG. Each being structurally slightly different, and each having separate biological functions. If a single principal function had to be attributed to the hCG group of molecules, it was surely constructing and running placental hemochorial placentation, the process whereby a mother feeds a fetus. And this process has nothing to do with the female gonad or ovary. How 70 major obstetrics and gynecology books and reproductive books all claimed that hCG's sole job was promoting ovarian corpus luteal progesterone production was misinformation, it was a sin. The hCG group of molecules has many critical functions in the placenta, fetus, uterus, gonads and in human cancer cells. Here these 70 books were, wrongly teaching medical students, medical residents, and graduate students, very out of date garbage. What compounded this garbage was the name human chorionic gonadotropin. Chorionic Gonadotropin meaning placenta gonad hormone or placenta gonad promoter. Clearly, gonad stimulation, or promotion of ovarian progesterone production was not the principal function of this hormone. No choice was seen but to give this group of genetically related molecules sharing a common á-subunit a new and more appropriate name. The name glycopeptins was contrived, to cover all eight inter-related molecules. Glycopeptins means "glycosylated peptides" and nothing else, no hormone or autocrine is implied, no gonad or other sites. Here we start this re-naming process by calling this group the glycopeptins. The name glycotropins was considered, but tropin means hormone or nourisher (Mirriam Webster's Dictionary). Maybe, slowly in the future, hCG can be renamed human chorionic glycopeptin, losing that gonadotropin error. This book focuses for the first time on all eight interrelated molecules, on their evolution together, their structures, their detection, their biological functions, and their receptors.
This chapter reviews the potential uses of hCG-H tests in gestational trophoblastic disease management. We examine an inactive form of disease called quiescent gestational trophoblastic disease. This is a relatively common inactive form of gestational trophoblastic disease and is seen all over the world. It is possibly the most common explanation for persistent low levels of hCG outside of pregnancy. This chapter also examines a widespread variant of gestational trophoblastic neoplasm and choriocarcinoma called minimally aggressive gestational trophoblastic neoplasm. New treatment protocols are proposed for this chemorefractory disorder. hCG-H, the promoter of trophoblast disease invasion, is considered as a new alternative marker to grade gestational trophoblastic diseases as opposed to the present World Health Organization (WHO) grading system. It is also noted that hCG-H determines which cases of gestational trophoblastic disease will respond to chemotherapy. In many ways, gestational trophoblastic disease is governed and regulated by the presence and predominance of hyperglycosylated hCG (hCG-H). It is the presence of unregulated hCG-H in humans that drives gestational trophoblastic neoplasms and causes people to get these human-specific diseases. hCG-H drives pregnancy implantation through regulatory mechanisms involving blockage of apoptosis, metalloproteinases, and collagenases. It is these same processes that drive invasion in gestational trophoblastic neoplasms including choriocarcinoma. This disease is the most malignant disease known to humans. It appears to be totally driven by hCG-H produced by cytotrophoblast cells and the pregnancy implantation-like invasion that it drives. If the woman is immediately treated with chemotherapy, this fast-growing disease can respond well and regress completely, with a 90% 5-year survival rate.
It took 23 years to fully resolve the structure of hyperglycosylated hCG (hCG-H). hCG-H is a form of hCG dimer in which larger oligosaccharides predominate, accounting for up to 41% of the molecular weight of hCG (25-30% of regular hCG, and 35-41% of hyperglycosylated hCG); triantennary N-linked oligosaccharides and hexasaccharide/pentasaccharide. O-linked oligosaccharides predominate in early pregnancy and choriocarcinoma cases. Research indicates that the peptide sequence of hCG-H is the same as that of regular hCG. hCG-H is the principal form of hCG made in gestational trophoblastic neoplasms and during implantation of pregnancy. hCG-H has biological functions separate from those of hCG. hCG-H promotes implantation in pregnancy and invasion in gestational trophoblastic neoplasms. Hyperglycosylation seems to affect hCG folding. The β-subunit, for example, is more exposed on hCG-H than on regular hCG. This makes hCG-H more easily recognized by some free β-subunit-specific antibodies. hCG-H is also more readily nicked than regular hCG. It is cleaved at sites α42-43, β43-44, and β44-45, which are not touched on regular hCG. This suggests that the α- and β-subunits are bound together more loosely in hCG-H than in regular hCG. This might expose some receptor-binding sites and lead to the differing biological activities of hCG and hCG-H This chapter examines the peptide and carbohydrate structures of hCG-H.
In 1960, the first antibody-based pregnancy test was formulated. The first antibody-based tests examined hemagglutination inhibition and latex agglutination. These were insensitive slide tests that detected hCG at a concentration of 1000 mIU/ml or greater. Over the next four decades, bioassays like the rabbit test were the only practical way to detect pregnancy or measure hCG. In 1964, the competitive hCG radioimmunoassay (RIA) was invented and revolutionized pregnancy testing. At last a test was available that could measure hCG as low as 5 mIU/ml and measure pregnancy as early as the day of a missed period. The invention of the RIA led to readily available pregnancy testing/hCG measurement at clinical laboratories throughout the world. The initial RIAs were problematic because they used an antibody against hCG dimer and detected both hCG and luteinizing hormone (LH). The problem was that the α-subunit of hCG was identical to the α-subunit of LH, and the α-subunit of hCG was 80% homologous with the α-subunit of LH. Hence, the early hCG dimer RIA detected both hCG and LH and could only show pregnancy hCG and exclude LH by demonstrating a continual increase in hormone levels. This was an important distinction because LH has no relationship to pregnancy and need not be measured when testing for pregnancy. The hCGβ test RIA became the world standard for the next 20 years. Even today, in the age of immunometric assays, both physicians and textbooks still describe hCG tests as hCGβ tests.
This chapter deals with CG evolution, the evolution of humans and human CG, and the complications humans now face because of the tremendous evolution of these molecules. The evolution of chorionic gonadotropin (CG) is a biological marvel in which two separate molecules evolved from a single deletion mutation in early primates. Dozens of incredible changes in amino acid sequences occurred during the development of CG and hyperglycosylated CG (CG-H) in early primates, advanced primates, and humans. These changes took CG and CG-H from nonacidic molecules with minimal activity in early primates to very acidic molecules with a long circulating half-life and maximal activity in humans. In so doing, they made human CG and CG-H ultrapotent. Although CG promotes differentiation of cytotrophoblast cells to syncytiotrophoblast cells, CG-H promotes the formation of cytotrophoblast columns and their extensions into primitive villi in early primates. Together, CG and CG-H drive the formation of trophoblast villi, the root structures of hemochorial placentation. CG drives angiogenesis in uterine vasculature so that invading villi are met with maternal blood. Both CG and CG-H drive the efficient nutrient system that we call hemochorial placentation. Seemingly, it is the evolution of ultraefficient CG and CG-H that drove hemochorial placentation to its maximum potential. In turn, an increasingly efficient transfer of fetal nutrients eventually led to an increased amount of nutrients needed to form the human brain.
This chapter examines the biochemistry of trophoblast cell invasion and implantation and considers the roles of hCG-H in these processes. These findings are logically connected and a model is proposed for hCG-H-regulated invasion and implantation. Hyperglycosylated hCG (hCG-H) is a form of hCG with large oligosaccharides constituting as much as 35-41% of the molecular weight of the molecule. As shown in various papers, hCG-H, rather than hCG, promotes growth and invasion of the uterus during pregnancy implantation. Cytotrophoblast cells also promote growth, invasion, and malignancy throughout the body during choriocarcinoma. hCG-H produced by either choriocarcinoma or normal placenta cytotrophoblast cells promotes invasion of Matrigel membranes (basement membrane on gel). hCG-H promotes choriocarcinoma growth in pregnancy and testicular germ cancer cells. It also promotes JEG-3 choriocarcinoma tissue growth and malignancy in nude mice. Antibodies specific to hCG-H completely stop the growth and spread of choriocarcinoma in a nude mouse, blocking all disease. Thus, it is inferred that hCG-H is essential for choriocarcinoma escalation and malignancy.
Tumor markers are biological substances that are produced/released mainly by malignant tumor cells, enter the circulation in detectable amounts and are potential indicators of the presence of a tumor. The most useful biochemical markers are the tumor-specific molecules, i.e., receptors, enzymes, hormones, growth factors or biological response modifiers that are specifically produced by tumor cells and not, or minimally, by the normal counterpart (Richard et al. Principles and practice of gynecologic oncology. Wolters Kluwer Health, Philadelphia, 2009). Based on their specificity and sensitivity in each malignancy, biomarkers are used for screening, diagnosis, disease monitoring and therapeutic response assessment in clinical management of cancer patients.
Glycoproteins are the proteins to which various sugar chains are covalently linked. Two major types of sugar chains (N- and O-linked) are found in glycoproteins. N-linked sugar chains contain an N-acetylglucosamine (GlcNAc) residue at their reducing termini, which is linked to the amide group of an asparagine (Asn) residue of a polypeptide. O-linked sugar chains contain an N-acetylgalactosamine (GalNAc) residue at their reducing termini, which is linked to a serine (Ser) or threonine (Thr) residue of a polypeptide backbone. Accumulation of the structural data of various glycoproteins revealed that N-linked sugar chains include more structural rules than O-linked sugar chains. All N-linked sugar chains contain the 3 mannose (Man), 2 GlcNAc pentasaccharide: Manα1-6(Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAc as a common core, which will be called trimannosyl core in this chapter. Based on the structures and locations of the extra sugar residues added to the trimannosyl core, N. -linked sugar chains are further classified into three subgroups: complex type, high-mannose type, and hybrid type.
Several articles show that signaling occurs between the unimplanted blastocyst and the decidua tissue [1–4]. Four separate reports show that the blastocyst preimplantation secretes human chorionic gonadotropin (hCG) into the uterine space, which somehow reaches hCG/LH hormone receptors on the endometrial surface. This prepares the endometrium for impending implantation [1–4]. These nonvascular communications by hCG are a critical part of successful pregnancy. Recent studies show the importance of a receptive endometrium and of hCG preimplantation signaling [5–7]. hCG signaling seemingly causes immunotolerance and angiogenesis at the endometrial maternal−fetal interface. hCG has been shown to increase the number of uterine natural killer cells that play a key role in the establishment of pregnancy [5–7].
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.
Introduction:
Hyperglycosylated human chorionic gonadotropin (hCG) is a variant of hCG with large oligosaccharide side chains. Although hCG is produced by syncytiotrophoblast cells, hyperglycosylated hCG marks cytotrophoblast cell. Hyperglycosylated hCG signals placental implantation.
Methods:
Total hCG in serum and urine is measured by the Siemens Immulite hCG pregnancy test; the result is in milli-international unit per milliliter. Hyperglycosylated hCG is determined by the B152 microtiter plate assay; the result is in nanogram per milliliter. Hyperglycosylated hCG results can be converted to milli-international unit per milliliter equivalents by multiplying by 11. The test measures proportion hyperglycosylated hCG, hyperglycosylated hCG / total hCG.
Results:
Proportion hyperglycosylated hCG marks cases intent on developing persistent hydatidiform mole (68% detection at 17% false detection). Proportion hyperglycosylated hCG also marks persistent hydatidiform mole (100% detection at 5.1% false detection). Proportion hyperglycosylated hCG distinguishes choriocarcinoma and gestational trophoblastic neoplasm cases, absolutely discriminating aggressive cases and minimally aggressive cases. Proportion hyperglycosylated hCG identifies quiescent gestational trophoblastic disease cases. It recognizes quiescent cases that become persistent disease (100% detection at 0% false positive).
Discussion:
Proportion hyperglycosylated hCG is an invaluable test for discriminating gestational trophoblastic diseases.
There are two independent variants of human chorionic gonadotropin (hCG) with totally independent functions. Both forms share the 92 amino acid αα-subunit and the 145 amino acid ββ-subunit. Regular hCG is a hormone with eight sugar side chains, four biantennary N-linked sugar structures and four trisaccharide O-linked sugar structures (molecular weight: 36,700). Hyperglycosylated hCG is an autocrine with eight sugar side chains, four triantennary N-linked oligosaccharides and four hexasaccharide O-linked oligosaccharides (molecular weight: 40,500). Hyperglycosylated hCG is produced by cytotrophoblast cells and regular hCG is formed by fused differentiated syncytiotrophoblast cells. These two molecules together coordinate most aspects of pregnancy. Research over the past 40 years has demonstrated that regular hCG promotes progesterone production by the corpus luteum, promotes angiogenesis of uterine spiral arteries, inhibits macrophage rejection of the implanting placenta, promotes growth of the umbilical cord, suppresses contractions in the myometrium during pregnancy, promotes the growth of the uterus in line with the growth of the fetus, promotes differentiation of cytotrophoblast cells to syncytiotrophoblast cells, communicates between blastocyst and the uterus prior to implantation, and promotes growth of fetal organs during pregnancy. Hyperglycosylated hCG is responsible for implantation of the blastocyst or implantation of pregnancy, promotes continued invasion following implantation, and also promotes growth of cytotrophoblast cells. Regular hCG and hyperglycosylated hCG together promote growth and differentiation of the placenta during pregnancy or villous structure formation, leading to hemochorial placentation.
Few molecules have created so much confusion as the hCG series of molecules. Here we present a comprehensive review of hCG as a tumor marker, of hCG and cancer and modern perspectives on the multiplicity of hCG, and its appropriate use in the management of gynecological malignancies and gestational trophoblastic diseases.The complexity of hCG is better understood. There is regular hCG produced by syncytiotrophoblast cells in pregnancy and by hydatidiform moles. This hormone functions to advance uterine angiogenesis and promote progesterone production by corpus luteal cells. Hyperglycosylated hCG is an independent molecule to regular hCG, it varies significantly from hCG in structure and is produced by cytotrophoblast cells. It is an autocrine or cytokine which functions to promote growth, invasion and malignancy. It is an absolute marker of invasive mole and invasive choriocarcinoma. Hyperglycosylated hCG is invaluable in the diagnosis and management of gestational trophoblastic diseases. The free β-subunit of hCG is also an autocrine or cytokine and is produced in most gynecologic malignancies. Serum free β-subunit or its urinary degradation product β-core fragment is produced by 68% of ovarian, 51% of endometrial and 46% of cervical malignancies. Free β-subunit enhances growth and invasion in all these malignancies leading to poor prognosis. Free β-subunit and β-core fragment are good tumor markers for these malignancies.There are few circumstances that create more confusion than the patient presenting with persistent low positive hCG results in the absence of pregnancy and absence of obvious malignancies. The series of hCG molecules as tumor markers will be reviewed to help the clinician best diagnose these often difficult clinical problems.
Considerable evidence indicates that one third of early pregnancy failures, spontaneous abortions and biochemical pregnancies, are due to chromosomal abnormalities, and two thirds are due to inappropriate implantation. These findings led us to investigate the role of hyperglycosylated hCG, an important pregnancy implantation signal, in pregnancy failures. We used urinary hCG determinations to evaluate a total of 127 pregnancies on the day of implantation, as marked by a positive urinary hCG. These included 81 normal term pregnancies, 18 spontaneous abortion pregnancies, and 28 biochemical pregnancies. Of the normal term pregnancies, the mean±standard deviation concentration of hyperglycosylated hCG was 5.4±4.3 mIU/ml equivalents, and the percentage of hyperglycosylated hCG was 88±17%. All term pregnancies produced hyperglycosylated hCG>51%. Of the 18 cases that spontaneously aborted, both the mean hyperglycosylated hCG (1.9±2.0 mIU/ml equivalents) and the percentage of hyperglycosylated hCG (41±33%) were significantly lower than in the normal pregnancy group. Only 4/18 spontaneously aborting pregnancies produced more than 51% hyperglycosylated hCG on the day of implantation. Similarly, of the 28 biochemical pregnancies, both the mean hyperglycosylated hCG (0.63±1.3 mIU/ml equivalents) and the percentage of hyperglycosylated hCG (21±29%) were significantly lower than in the normal pregnancy group. Only 4/28 pregnancies produced more than 51% hyperglycosylated hCG. Low hyperglycosylated hCG concentrations are associated with pregnancy failure. Whether this association is a primary cause of pregnancy failure or is simply a marker for an abnormal conceptus requires further investigation.
This review examines human chorionic gonadotropin (hCG) or pregnancy tests from multiple perspectives. It first investigates the molecule hCG and shows that the term represents five independent molecules differing in carbohydrate and meric structure that share a common amino acid sequence. The review goes on to show that multiple degradation produces also the need to be tested for an hCG or pregnancy test to be optimally efficient. The review then carefully examines the literature showing the sensitivity and specificity of automated laboratory tests. Point-of-care pregnancy tests are then investigated along with over-the-counter pregnancy tests. Appropriate detection of hyperglycosylated hCG, nicked hCG, nicked hCG missing the β-subunit C-terminal peptide and nicked hyperglycosylated hCG is a limitation on all pregnancy tests. In the opinion of the author, just one automated laboratory test, the Siemen’s Immulite, one point-of-care test, the Beckman-Coulter Icon 25, and one brand of over-the-counter device, First Response, are suitable for early pregnancy detection and possibly other applications.
Introduction:
The hCG amino acid sequence supports 5 glycoproteins. All are called hCG forms. This review examines all 5 molecules, the hormone as produced by the placental syncytiotrophoblast cells, the sulfated hormone produced by the pituitary gonadotrope cells, the hyperglycosylated hCG autocrine made by placental cytotrophoblast cells, and the autocrine cancer promoters hyperglycosylated hCG, hCGß and hyperglycosylated hCGß as made by all malignancies. This review examines all the molecules and multiple proven functions, ranging from evolution to cancer promotion to hormone action.
Results and discussion:
hCG forms are critical super-growth factors in humans, with an exceptional wide range of functions.
Background
hCG is a term referring to 4 independent molecules, each produced by separate cells and each having completely separate functions. These are hCG produced by villous syncytiotrophoblast cells, hyperglycosylated hCG produced by cytotrophoblast cells, free beta-subunit made by multiple primary non-trophoblastic malignancies, and pituitary hCG made by the gonadotrope cells of the anterior pituitary.
Results and discussion
hCG has numerous functions. hCG promotes progesterone production by corpus luteal cells; promotes angiogenesis in uterine vasculature; promoted the fusion of cytotrophoblast cell and differentiation to make syncytiotrophoblast cells; causes the blockage of any immune or macrophage action by mother on foreign invading placental cells; causes uterine growth parallel to fetal growth; suppresses any myometrial contractions during the course of pregnancy; causes growth and differentiation of the umbilical cord; signals the endometrium about forthcoming implantation; acts on receptor in mother's brain causing hyperemesis gravidarum, and seemingly promotes growth of fetal organs during pregnancy.
Hyperglycosylated hCG functions to promote growth of cytotrophoblast cells and invasion by these cells, as occurs in implantation of pregnancy, and growth and invasion by choriocarcinoma cells. hCG free beta-subunit is produced by numerous non-trophoblastic malignancies of different primaries. The detection of free beta-subunit in these malignancies is generally considered a sign of poor prognosis. The free beta-subunit blocks apoptosis in cancer cells and promotes the growth and malignancy of the cancer. Pituitary hCG is a sulfated variant of hCG produced at low levels during the menstrual cycle. Pituitary hCG seems to mimic luteinizing hormone actions during the menstrual cycle.
Human chorionic gonadotropin (hCG) has been used to prevent subsequent miscarriages after previous recurrent miscarriages. In addition to the luteotrophic effects, hCG has uterine immune and autocrine actions. hCG also affects cytokine expression. A Cochrane database systematic review has indicated that hCG seems to prevent further miscarriages, (OR for miscarriage = 0.26, 95% CI 0.14-0.52). However, the trials in the Cochrane database were not matched for the number of miscarriages, 1°, 2° or 3° aborter status, maternal age, etc. and no account was made for chromosomally abnormal pregnancies. All of these impact on the subsequent prognosis and may confound the results. The previous trials in the literature all assessed urinary (u-hCG) rather than recombinant hCG (r-hCG), raising the question whether the effect on pregnancy outcome is due to hCG itself, or other urinary proteins present in u-hCG. A new trial is indicated in which r-hCG is compared to u-hCG and the most effective compared to placebo. Treatment and placebos arms should be stratified for the prognostic factors above and the results corrected for fetal chromosomal aberrations. Until such a trial is carried out, the use of hCG supplementation is empiric.
Human chorionic gonadotropin (hCG) is not a single biological molecule. There is the regular form of hCG produced by differentiated syncytotrophoblast cells (regular hCG). This hormone primarily functions to maintain the myometrial and decidual spiral arteries, or the vascular supply of the placenta during the full course of pregnancy. Hyperglycosylated hCG is made by undifferentiated cytotrophoblast cells, which are extravillous cytotrophoblast cells. This is an autocrine with separate functions, it maintains trophoblast invasion as in implantation of pregnancy and malignancy in gestational trophoblastic diseases. A hyperglycosylated free beta-subunit is produced by a high proportion of all malignancies. This also functions as an autocrine by promoting the growth and invasion of the malignancy. When ordering an hCG test it is important to realize what is being measured and whether the test ordered will detect appropriately these three variants of hCG as well as their degradation products. Most automated commercial laboratory tests, point-of-care tests and over-the-counter tests are limited in what they detect, focusing only on regular hCG. This is in part due to the US FDA, who only consider regular hCG as part of a pregnancy test, and to whom only detection of regular hCG is necessary. This may cause test errors since primarily hyperglycosylated hCG is produced in early pregnancy and in choriocarcinoma and germ cell testicular malignancies. Only free beta-subunits may be produced in other germ cell malignancies (all applications for hCG test). The exceptions are the older style hCGb radioimmunoassay and the Siemens Immulite platform hCG test, which detect all beta-subunit variants of hCG and their degradation product appropriately. Apart from test specificity limitations, assays for hCG and its variants are widely used clinically in pregnancy detection, early pregnancy detection, prediction of spontaneously aborting, and ectopic pregnancies and prediction of trisomy pregnancies. hCG tests are essential in managing gestational trophoblastic diseases, whether hydatidiform mole, invasive mole or choriocarcinoma, and are very useful in management of testicular malignancies and other germ cell malignancies.
The evolution of regular chorionic gonadotropin (CG) and hyperglycosylated CG are linked with the evolution of hemochorial placentation in primates. Recent research with humans shows that regular CG promotes spiral artery angiogenesis and hyperglycosylated CG controls invasion by implanting trophoblast cells. It is inferred that the evolution of regular CG and hyperglycosylated CG in early simian primates, the first species to produce these CG forms, established hemochorial placentation in this species. The circulating half-lives, and thus the circulating concentrations, of regular CG and hyperglycosylated CG increased in advanced simian primates and increased further in humans, seemingly causing greater myometrial invasion and superior angiogenesis in hemochorial placentation in advanced primates and humans. Advanced hemochorial placentation is associated with relatively high proportions of pregnancy failures in humans. This can be explained by considering human implantation inadequate in terms of invasion requirements. The demanding implantation required by the human embryo is seemingly dependent on adequate production of hyperglycosylated CG. Failures in hemochorial placentation invasion lead to anoxia and cause preeclampsia and eclampsia uniquely in humans, which can also be attributed to inadequate hyperglycosylated CG signaling. We propose here that inadequate regular CG and hyperglycosylated CG molecules are the evolutionary causes of these obstetric complications in humans.
When considering human chorionic gonadotropin (hCG) and hCG tests, it is important to realize that it is not a single biological molecule. The regular form of hCG produced by differentiated syncytotrophoblast cells (regular hCG) is a hormone made with the primary function of maintaining the myometrial and decidual spiral arteries and the vascular supply of the placenta during the full course of pregnancy. Hyperglycosylated hCG (hCG with double-size O-linked oligosaccharides) is made by undifferentiated cytotrophoblast cells. This is an autocrine hormone with separate functions, it maintains invasion as in implantation of pregnancy and malignancy in gestational trophoblastic diseases. A hyperglycosylated free beta-subunit is produced by a high proportion of all malignancies. This functions as an autocrine hormone to promote the growth and invasion of the malignancy. It is important to realize when ordering an hCG test what you are measuring and whether the test ordered will detect appropriately these three variant of hCG as well as their degradation products. Most automated commercial laboratory tests, point-of-care test and over-the-counter tests are limited in what is detected, focusing only on regular hCG. This is in part due to the US FDA, who only consider hCG as a pregnancy test, and to whom only detection of regular hCG is critical. This may be a cause of test errors since primarily hyperglycosylated hCG is produced in early pregnancy, choriocarcinoma and germ cell testicular malignancies, and only free beta-subunit may be produced in other germ cell malignancies (all applications for hCG test). The exceptions are the older style hCGbeta radioimmunoassay and the Siemen's Immulite platform hCG test which detect all variant and their degradation product appropriately. Regardless of test specificity limitations, assays for hCG variants are widely used clinically in pregnancy detection, early pregnancy detection, prediction of spontaneously aborting and ectopic pregnancies and prediction of trisomy pregnancies. hCG tests are essential in managing gestational trophoblastic diseases, whether hydatidiform mole, invasive mole or choriocarcinoma, and are very useful in management of testicular malignancies and other germ cell malignancies.
To address conflicts in the normal variabilities of the menstrual cycle using the newest generation test methods and to establish normal ranges for use in clinical practice.
Daily urine samples were collected from 167 women eager to achieve pregnancy. Samples were tested prospectively for LH and total hCG. A total of 458 nongestational and 111 gestational menstrual cycles were evaluated.
Division of Women's Health Research, University of New Mexico.
One hundred sixty-seven women desiring pregnancy.
None.
Levels of hCG and LH.
Menstrual cycles were 27.7 +/- 2.4 days in length. The LH peak indicated the onset of the presumed ovulatory window, which occurs at 14.7 +/- 2.4 days. Implantation (first day of sensitive detection of hCG) occurred in gestational menstrual cycles at 24.6 +/- 3.1 days, or 4.3 +/- 2.2 days before missing the expected onset of menses.
Our data confirm epidemiological studies on menstrual cycle length and variability and hormonal studies on timing of the ovulatory window and its variability. They dispute, however, the published data on the timing and variance of implantation. As shown, implantation is limited to a 10-day interval culminating in the day of the expected onset of menses. Reference range data provide guidelines for differentiating normal and problem menstrual cycles.
ResearchGate has not been able to resolve any references for this publication.