Title: Human chorionic gonadotropin (hCG) and hyperglycosylated hCG: the mediators that control human pregnancy Author(s):

Laurence A Cole Source: Expert Review of Obstetrics & Gynecology. 6.3 (May 2011): p273. Document Type: Report DOI: http://dx.doi.org.ez27.periodicos.capes.gov.br/10.1586/eog.11.16 Author(s): Laurence A Cole 1 Keywords : hCG; hemochorial placentation; hyperglycosylated hCG; placenta; pregnancy; trophoblast cells It is unclear who specifically discovered the molecule called human chorionic gonadotropin (hCG). In 1912, Aschner stimulated the genital tract of guinea pigs with injections of water-soluble extracts of human placenta [1] . In 1913, Fellner stimulated ovulation in immature rabbits with saline extracts of human placenta [2] . In 1919, Hirose induced ovulation and normal luteal function in immature rabbits by repeated injections of human placental tissue [3] . All of these studies demonstrated that there was a clear link between the placenta and the uterus [1-3] . In 1927, Aschheim and Zondek demonstrated that pregnant women produce a gonadstimulating molecule [4] . They showed that injecting this hormone into intact immature female mice led to follicular maturation, ovulation and hemorrhaging into the ovarian stroma. The realization around this time that the placenta was producing a molecule that promoted ovarian progesterone production led researchers to coin the name human chorionic gonadotropin: chorion, from the Latin chordata , meaning afterbirth; gonadotropin because the hormone is a gonad-tropic molecule, or a stimulator of gonad (or ovary) steroid production. As we know today, hCG is a hormone comprising an [alpha]-subunit and a [beta]-subunit, which are held together by noncovalent hydrophobic and ionic interactions. hCG is an unusual molecule in that 2540% of the molecular weight is derived from sugar side chains. Today, the function of hCG is still marked as being the production of ovarian progesterone in most obstetric, gynecology and medical student text books, but we now know that hCG forms have numerous more critical placental, uterine and fetal functions in pregnancy [5-65,201] . Research over the last 20 years demonstrates that there are at least two independent forms of hCG active in pregnancy: regular hCG and hyperglycosylated hCG. Both molecules share a common 92-amino acid hCG [alpha]-subunit and a 145-amino acid [beta]-subunit amino acid sequence [54,55] . While regular hCG has four biantennary N-linked sugar chains at [alpha]52 and [alpha]78, and [beta]13 and [beta]30, and four trisaccharide O-linked sugar chains at [beta]121, [beta]127, [beta]132 and [beta]138, hyperglycosylated hCG has a larger triantennary sugar chain at the same N-linked site, and a hexasaccharide sugar chain at the same O-linked sites, that are double the size [54,55] . The molecular weight of regular hCG is 36,700, and the molecular weight of hyperglycosylated hCG is 40,500. Interestingly, the regular hCG hormone is only made by differentiated syncytiotrophoblast cells, while the autocrine hyperglycosylated hCG is only made by root cytotrophoblast cells [56,57] , which appears to have completely independent and separate biological functions to regular hCG [58-65] . In this article, we consider all prior publications dealing with the biological functions of regular hCG and hyperglycosylated hCG [1-101,201] , and compile all established functions for regular hCG, for hyperglycosylated hCG, and for the two variants together. It is

concluded that hCG-related molecules seemingly mediate most aspects of pregnancy, and that hCG-related molecules could be correctly considered as the general pregnancy modulators, and not simply as a progesterone-promoting gonadotropin. Regular hCG Regular hCG only promotes ovarian corpus luteal progesterone production for 3-4 weeks following pregnancy implantation. This function is active for just 10% of the length of pregnancy. Regular hCG is produced throughout the length of pregnancy, with a peak at 10-weeks gestation (Figure 1 & Table 1). Support of ovarian corpus luteum progesterone production surely cannot be the principal function of regular hCG. It is, however, a proven secondary function of regular hCG [1-11] . Box 1 lists all of the established functions of regular hCG. Regular hCG has been demonstrated in recent years to have numerous major functions in the placenta, uterus and fetus during pregnancy. The research groups of Rao et al. , Zygmunt et al. and Berndt et al. have each demonstrated that regular hCG functions to promote angiogenesis in the uterine arteries during pregnancy. Regular hCG assures optimal blood supply to the invading placenta and maximal nutrition to the fetus (Box 1) [12-18] . The hCG/LH receptor gene is expressed by uterine vessels, and regular hCG acts on them to promote growth and spiral artery expansion. This is seemingly a major function of regular hCG during the course of pregnancy, assuring adequate arterial supply or nutrition to the placenta. Regular hCG also has an important function in the placental trophoblast tissue, promoting the fusion of cytotrophoblast cells and their differentiation to syncytiotrophoblast cells (Box 1) [19,20] . As discussed later, it is the combination of hyperglycosylated hCG-promoted growth of cytotrophoblast cells and regular hCGpromoted differentiation of cytotrophoblast cells that leads to placental growth and villus trophoblast formation [19,20,58-65] . There are four separate research groups that have demonstrated that regular hCG promotes an antimacrophage inhibitory factor or a macrophage migration inhibitory factor, a cytokine that modulates the immune response during pregnancy, which reduces macrophage phagocytosis activity at the placenta-uterine interface, preventing destruction of feto-placental tissue, which is always immunologically foreign to the mother (Box 1) [21-24] . Three groups have also demonstrated that regular hCG may directly suppress any immune action against the invading foreign tissue [24-26] . In all, regular hCG appears to be a key factor in preventing rejection of the feto-placental tissue. Most observations suggest that regular hCG has an inhibitory or suppressive function on macrophage activity. One group, Wan et al. demonstrated that regular hCG can directly enhance immunity by stimulating macrophage function [23] . Protecting a blastocyst or placenta from immune or macrophage destruction has to be considered a major responsibility of regular hCG. Multiple groups have found the hCG/LH receptor expressed in the myometrium of the uterus. It has been demonstrated by two of the groups that uterine growth in line with fetal growth is seemingly controlled by regular hCG, so that the uterus expands according to fetal size during pregnancy (Box 1) [27,28] . Four groups have demonstrated that regular hCG relaxes myometrial contractions during the course of pregnancy. Regular hCG acts on a BKCa calcium-activated channel to relax the myometrium during the course of pregnancy [27,29-31] . Regular hCG levels drop during the final weeks of pregnancy and it has been suggested that this drop may be the cause of Braxton Hicks contraction or increased incidence of contraction in the weeks prior to delivery [102] . New research is finding hCG/LH receptors in fetal organs. Goldsmith et al. have found hCG/LH receptors in

the fetal kidney and liver [32] . Rao et al. have located hCG/LH receptors in the lung, liver, kidneys, spleen and small and large intestines (Box 1) [33-37] . This hCG/LH receptor is present in the fetal organs but completely absent in the adult organs, indicating a fetus-specific receptor. Data indicate that regular hCG may be the promoter of fetal organ growth or differentiation. Interestingly, the human fetus produces its own regular hCG in the kidneys and liver [32,38] . The concentrations of this regular hCG in the fetal circulation are much lower than maternal concentrations, suggesting that placental regular hCG secretion is directed towards the maternal circulation and it is prevented from entering into fetal circulation [38] . While the hCG/LH receptor has been demonstrated to be present in fetal organs, no function has been directly demonstrated (no regular hCG has been directly administered to a human fetus and demonstrated to promote growth). As such, all the findings regarding the fetus should be considered only as indications at this time. Regular hCG is a hormone unique to humans (advanced primates produce a variant of regular hCG and that is much less potent than regular hCG, lacking many of the regular hCG functions), thus this finding can only be confirmed in humans. The necessary research to directly confirm the role of regular hCG could never be permitted in humans, therefore the research remains speculative. Regular hCG also functions in umbilical cord growth and development (Box 1) [39-41] . It is interesting that regular hCG and hyperglycosylated hCG work together to promote the growth (hyperglycosylated hCGpromoted growth of root cytotrophoblast cells) and differentiation (promoted by regular hCG) of the placenta, and promotion of the uterine blood supply to meet the invading placenta (promoted by regular hCG). The next step is the development of the umbilical cord and circulation. This is also seemingly promoted by regular hCG. Regular hCG has also been shown to promote uterine growth and silence uterine contraction during pregnancy, suggesting regular and hyperglycosylated hCG involvement in multiple steps of placentation, uterine growth and fetal development [32-41,58-65] . Multiple publications suggest that signaling occurs between the unimplanted blastocyst and the decidua tissue [42-45] . Four independent reports show that blastocyst preimplantation secretes regular hCG into the uterine space, which is taken up by hCG/LH receptors on the endometrial surface (Box 1). In response, the endometrium is prepared for an impending implantation [54-57] . These nonvascular communications by regular hCG are a critical part of successful pregnancy. Recent studies show the importance of a receptive endometrium and regular hCG preimplantation signaling in a successful pregnancy [58-60] . Regular hCG signaling directly causes immunotolerance and angiogenesis at the maternal-fetal interface. Regular hCG increases the number of uterine natural killer cells, which play a key role in the establishment of pregnancy [47,48,201] . Other data indicate other preimplantation functions of regular hCG. Publications from Rao et al. [49,50] and Gawronska et al. [51] show the presence of an hCG/LH receptor in human sperm and in the Fallopian tubes (Box 1). The function of the hCG/LH receptor in sperm is unclear - it possibly has some relationship to fertility. The hCG/LH receptor in the Fallopian tubes may be acted on by LH, which relaxes the Fallopian tube, allowing fertilization to take place. Finally, the hCG/LH receptor has been demonstrated in brains of adult women. CNS receptors are present in several areas of the brain such as the hippocampus, hypothalamus and brain stem (Box 1) [52,53] . The presences of an hCG/LH receptor in these parts of the brain may explain the hyperemesis gravidarum or nausea and vomiting that occurs during normal pregnancy. Bringing all research on regular hCG over the past 30 years together [5-53,201] , regular hCG can be seen to have a very wide range of actions by means of the hCG/LH receptor. Regular hCG has a number of major

functions during pregnancy, promoting uterine vasculature to support the implanting placenta, differentiation of cytotrophoblast cells to form placenta villi, suppression of contraction in the myometrium, growth of the umbilical cord or fetal circulation, prevention of maternal immunorejection of the implanting placenta, and the promotion of growth of fetal organs. All of this considered, regular hCG appears to be the hormone that seemingly modulates many, if not most, aspects of pregnancy. Hyperglycosylated hCG Hyperglycosylated hCG is an autocrine hormone produced by root trophoblast cells or cytotrophoblast cells. It both is produced by cytotrophoblast cells and acts on cytotrophoblast cells to promote cell growth and cell invasion [58-63] . During early pregnancy, hyperglycosylated hCG is the principal form of hCG produced, accounting for as much as 100% of total hCG production, from 3 to 5 weeks of gestation, which is the time of blastocyst implantation (Figure 1 & Table 1) [58,61,66,67] . Hyperglycosylated hCG concentrations then follow the general pattern of regular hCG concentrations peaking at 10 weeks of gestation, yet continually decreasing in proportion to total hCG. Hyperglycosylated hCG accounts for an average of 90% of total hCG at 3 weeks gestation, 54% at 4 weeks, 29% at 6 weeks, 5.1% at 9 weeks, 2.4% at 12 weeks, 0.65% at 18 weeks and 0.36% at 30 weeks (Figure 1 & Table 1). Clearly, the prime role of hyperglycosylated hCG is at the time of implantation. Hyperglycosylated hCG has been demonstrated to specifically promote trophoblast invasion at pregnancy implantation [58,60,61,63,67] . As stated in the published literature, hyperglycosylated hCG is produced by invasive cytotrophoblast cells or extravillous cytotrophoblast cells [62] . Implantation of pregnancy is driven by proteases, both metalloproteinases and collagenases [68-75] . These degrade adjacent tissue, burning the uterine space needed by the trophoblast villous structures. TGF-[beta] receptors are found on extravillous cytotrophoblast cells [76-92] . It is well established that TGF-[beta] receptors 'turn on' apoptosis and 'turn off' collagenase and metalloproteinase production in cytotrophoblast cells [76-88] . During implantation of pregnancy, the TGF-[beta]-receptor is antagonized and literally turned off. As a result, apoptosis is turned off in pregnancy, and collagenases and metalloproteinases are very much turned on [76-92] . Interestingly, hyperglycosylated hCG fits exactly into this picture. It promotes invasion enzymes (collagenases and metalloproteinases) and specifically inhibits apoptosis [93] . Piecing these findings together strongly suggests that hyperglycosylated hCG, the proven promoter of invasion and blocker of apoptosis [58-65,67,93] , is the antagonist of the TGF-[beta] receptor. Could hyperglycosylated hCG be a TGF-[beta] antagonist as suggested? Recently, the 3D structure of hCG was determined. Found hidden within the [beta]-subunit of hCG is a unique TGF-[beta]-like structure, a cysteine knot structure. This is a knot formed by the overlap and linkage of four short peptide sequences [94,95] . TGF-[beta] and hCG apparently share a common evolutionary origin and inter-related sequences [95-97] . As such, it is feasible that hyperglycosylation of hCG opens the hCG molecule, exposing the TGF-[beta] common sequence so that hyperglycosylated hCG may be a TGF-[beta] antagonist, inhibiting apoptosis and promoting invasion enzymes in cytotrophoblast cells. In support of this hypothesis, studies by Khoo et al. demonstrate that a molecule, which is the electrophoretic molecular size of hyperglycosylated hCG binds the TGF-[beta]-receptor, promoting invasion [98] . Interestingly, the similarly hyperglycosylated free [beta]-subunit of hCG produced in nontrophoblastic cancers has been shown to bind and antagonize the TGF-[beta] receptor [99,100] , inhibiting apoptosis and promoting invasion [99,100] . Research suggests that hyperglycosylation of hCG limits [alpha]-[beta] subunit folding (hyperglycosylated hCG is bound by certain free [beta]-subunit-specific antibodies [101] ). Hyperglycosylated hCG is structurally a free [beta]-subunit with a loosely hanging [alpha]-subunit [103] .

As such, hyperglycosylated hCG probably acts in a manner similar to that proven for the hyperglycosylated free [beta]-subunit, antagonizing the TGF-[beta] receptor. Figure 2 illustrates the proposed hyperglycosylated hCG antagonism-TGF-[beta]-invasion/implantation relationship. As demonstrated in Figure 3, autocrine hyperglycosylated hCG controls extravillous cytotrophoblast growth at implantation of pregnancy, seemingly by antagonizing the TGF-[beta] receptor on cytotrophoblast cells. Hyperglycosylated hCG also promotes cytotrophoblast cell growth and invasion during the course of pregnancy. As demonstrated by our laboratory and by two independent laboratories [59,60,67,93,104] , hyperglycosylated hCG is the form of hCG produced by choriocarcinoma cytotrophoblast cells, and it is critical for cell invasion and malignancy in this disease. When this form of hCG is suppressed, either by antibody [59,60] or by the [alpha]- or [beta]-subunit antisense DNA [93,103] , all cancer cell growth stops. Antibodies to hyperglycosylated hCG have been proposed as a cure for choriocarcinoma [67] . Similarly, invasive moles - persistent, partial and complete moles - rely on hyperglycosylated hCG to become invasive [59,66,67] . Hyperglycosylated hCG appears to be the invasion signal or invasion force during implantation of pregnancy, choriocarcinoma and invasive moles. Ongoing research suggests that it is also the invasion signal in testicular germ cell malignancies, as well as some other germ cell malignancies [60,67] . The combination of hCG & hyperglycosylated hCG Hyperglycosylated hCG promotes cytotrophoblast growth during pregnancy. While regular hCG has no growth-promoting action during pregnancy, it does promote the fusion and differentiation of cytotrophoblasts to syncytiotrophoblasts. As such, the two forms of hCG together lead growth in a number of cytotrophoblast and syncytiotrophoblast cells. As illustrated in Figure 4, while columns of cytotrophoblast cells grow, promoted by hyperglycosylated hCG, the peripheral cells are converted into syncytiotrophoblast cells by regular hCG. As a result of these two processes, placental villous structures are performed. This growth and differentiation procedure continues through the first trimester, leading to multiple villous structures. hCG promotes uterine vasculature angiogenesis, so that the vasculature meets the villous tissues and floods the villous tissues with blood. hCG also promotes the formation of the umbilical cord to the fetus. Taken together, these processes lead to active hemochorial placentation or to an efficient maternal-fetal nutrient exchange [61,67] . As demonstrated, chorionic gonadotropin (CG) first evolved with early simian primates [66] . With the evolution of CG evolved a conversion from noninvasive epitheliochorial placentation (present in prosimian primates) to hemochorial placentation, seemingly as a result of regular CG and hyperglycosylated CG action. It is inferred that regular CG and hyperglycosylated CG together cause hemochorial placentation in both primates and humans. Accumulating the published data Considering all the established functions of regular hCG in pregnancy, the separate invasion and growth function of hyperglycosylated hCG, and the joint function in driving hemochorial placentation, it is inferred that both hCG forms drive pregnancy. As illustrated in Figure 5, hCG and hyperglycosylated hCG drive placenta or trophoblast growth and the development of hemochorial placentation, growth of blood supply in the maternal uterus, suppressing contractions in the uterus, growth of the maternal uterus and suppressing immunorejection of the invading placenta. They promote formation and growth of the umbilical cord and growth of fetal organs. In all, based on the 102 publications presented here, it is inferred that hCG seemingly modulates most aspects of pregnancy. hCG and hyperglycosylated hCG should be considered as the

mediators pregnancy, and not just as promoters of progesterone production, as indicated in most major reproductive biology and obstetrics and gynecology text books. Text books need to be updated to reflect the complete function of hCG. They need to explain that there are multiple forms of hCG - the hormone hCG produced by syncytiotrophoblast cells, and the autocrine hyperglycosylated hCG produced by cytotrophoblast cells. They need to relay much of the information mentioned in this article, that is: hCG promotes uterine angiogenesis, umbilical cord formation, uterine growth, and inhibits immunosuppression and macrophage activity; that hCG and hyperglycosylated hCG together promote placental growth and differentiation; and that hyperglycosylated hCG promotes implantation and cytotrophoblast cell growth, as well as growth of invasive mole and choriocarcinoma. Most of the research described in this article on the biological functions of hCG and hyperglycosylated hCG has been obtained from in vitro studies. Work with nude mice and choriocarcinoma, and how antibodies and antisense DNA block choriocarcinoma growth and malignancy are also from in vivo studies. Further in vivo studies are planned to investigate the effect of hyperglycosylated hCG administration on the prevention of miscarriages of pregnancy and preeclampsia. Expert commentary As demonstrated by Hussa, the hCG research field has expanded greatly over the last 20 years [105] . Prior to 1887, scientific publication regarding hCG structure and biological activity were limited to <40 each year. During the years 1992-2010 this number grew to 260-400 publications each year. It is good to hear that the hCG field is growing, since research is opening more and more doors, and each door opened in hCG research seems to have a dozen new doors behind it. Before and during the 1970s, hCG was not well studied. It was thought to be only a minor hormone produced during pregnancy that mimicked LH. During pregnancy, hCG maintained progesterone production by the corpus luteum, and maintained progesterone production from the day of implantation to week 7 of gestation (the week since the last menstrual period). It was previously thought that the high concentration of hCG produced throughout the course of the pregnancy was simply a natural waste. Research presented in this article, mostly completed between 1992 and 2010 or in more recent times, shows that hCG is a much larger and more important molecule than originally thought. hCG seemingly controls many, if not most, aspects of human pregnancy. A variant called hyperglycosylated hCG promotes implantation of the blastocyst at the start of pregnancy. As pregnancy advances, growth of the blastocyst is promoted by hyperglycosylated hCG, and the deeper invasion of this embryo into the uterus is promoted by hyperglycosylated hCG. hCG produced by the growing and differentiating (under the influence of hCG) blastocyst promotes angiogenesis in the uterine spiral arteries so that the uterine arteries can grow and meet the invading placenta. Columns of cytotrophoblast cells are formed in the growing embryo, and as these columns grow out of the embryo structure with the promotion of hyperglycosylated hCG, hCG promotes the differentiation of peripheral cells (those best exposed to the blood supply) to become syncytiotrophoblast cells. With this growth outwards and continual differentiation, placental villous structures are synthesized. With the combination of growing villous structures and hCG-promoted spiral artery angiogenesis, hemochorial placentation takes shape and efficient nutrition is passed to the fetus. This is not forgetting the link between the placenta and fetus - the umbilical cord - also originating from and growing with hCG promotion. Next, hCG block macrophage phagocytosis of foreign tissue invading the mother, and hCG suppresses contractions in the uterine myometrium during the course of pregnancy. Last, hCG appears to promote the growth of fetal organs during pregnancy. In simpler terms, hCG and its derivatives are the all-round pregnancy promoters, controlling growth in numerous key aspects of pregnancy.

Clearly, hCG and hCG variants are the key pregnancy promoters. With the understanding of biology, in the coming years we will start to learn more about the consequences of hCG biology. We know that hCG serum concentrations vary widely in individual pregnancies. We will start to understand what low and high hCG concentrations represent, and what low and high concentrations of hyperglycosylated hCG signify, and how to prevent any adverse consequences. New doors will be open from this basic research. Five-year view To date, we have found from research that hyperglycosylated hCG is at the root of pregnancy implantation [58,60,62,63] . As established, inappropriate pregnancy implantation explains biochemical pregnancies, which account for 25% of all pregnancies, and most miscarriages of pregnancy (17% of pregnancies) [58] . Inefficient supply of hyperglycosylated hCG, the implantation promoter, has been demonstrated to be the cause of all these pregnancy failures [58] . Clinical trials have been proposed to granting authorities that involve administering hyperglycosylated hCG to pregnant women around the time of implantation of pregnancy in an attempt to eliminate the possibility of biochemical pregnancies and miscarriages in women eager to bear a child. It is hoped that in the next 5 years, we will see the results of these studies and new methods adopted to eliminate most biochemical pregnancies and miscarriages in humans. Similarly, hyperglycosylated hCG seems to have a relationship with onset of hypertension in pregnancy (preeclampsia); hypertension in pregnancy affects 7% of all pregnancies. Hypertension in pregnancy occurs because of ineffective placental invasion during the first trimester of pregnancy (40 publications). This is apparently due to unduly low hyperglycosylated hCG production [103] . Clinical trials are also planned during the next 5 years to administer hyperglycosylated hCG to pregnant women during the course of the first trimester of pregnancy to prevent the fatal occurrence of hypertension in pregnancy. Hopefully these clinical trials will also lead to new treatments. This article demonstrates that hCG is an important molecule during pregnancy, controlling the growth of the placenta and the growth of the fetus, preventing contractions, and preventing macrophage and immune rejection of a pregnancy. Surely new doors will open showing how unduly low hCG serum concentrations and unduly high hCG serum concentrations create pregnancy complications. These complications may range from diabetic pregnancy to placenta accreta to placenta percreta, to intrauterine growth restriction and preterm labor. They all need to be carefully investigated. It is the author's belief that, 5 years from now, hCG will be recognized in a completely new light, as a critical molecule in the management of pregnancy. Table 1. Concentration of human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin (ng/ml) in 287 serum samples from first 10 weeks of gestation. Median Gestation age (weeks since Cases Median total hyperglycosylated start of menstrual period) (n) hCG (ng/ml) hCG (ng/ml) 3-3 weeks and 6 days 4-4 weeks and 6 days 5-5 weeks and 6 days 42 42 67 0.23 3.4 65 0.20 2.5 18.4 Mean proportion hyperglycosylated hCG of total hCG (%) 90 11 54 27 42 27

6-6 weeks and 6 days

29

252

56

29 38

7-7 weeks and 6 days 8-8 weeks and 6 days 9-9 weeks and 6 days 10-10 weeks and 6 days

30 33 24 20

3278 4331 5832 10,352

359 386 430 521

16 13 7.0 5.4 5.1 4.4 4.3 3.1

Total hCG is regular hCG plus hyperglycosylated hCG. The total hCG assay used was the Siemen's Immulite 1000, a serum assay that equally detects hCG, nicked hCG, hyperglycosylated hCG, nicked hCG missing the C-terminal peptide and hCG[beta] [105] . Hyperglycosylated hCG was measured with the B152 immunometric assay, an assay that only detects hyperglycosylated hCG and its [beta]-subunit [58,59] . hCG: Human chorionic gonadotropin. Box 1. Biological functions of regular human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin. Regular hCG, a hormone produced by syncytiotrophoblast cells * Promotion of corpus luteal progesterone production [1-11] * Angiogenesis of uterine vasculature [12-18] * Cytotrophoblast differentiation [19,20] * Immunosuppression and blockage of phagocytosis in trophoblast cells [21-26] * Growth of uterus in line with fetal growth [27,28,38] * Quiescence of uterine muscle contraction [27,29-31] * Promotion of growth of fetal organs [32-37] * Umbilical cord growth and development [39-41] * Blastocysts signal endometrium prior to implantation [42-44] * hCG in sperm and receptors found in uterine tissue and Fallopian tubes, suggesting prepregnancy communication [45-51,201] * hCG receptors in adult brain hippocampus, hypothalamus and brain stem; may explain nausea and vomiting during pregnancy [43,52]

Hyperglycosylated hCG, autocrine, produced by cytotrophoblast cells * Stimulates implantation of pregnancy by invasion of cytotrophoblast cells [58-63] * Stimulates growth of cytotrophoblast cells [58-63,67] Regular hCG & hyperglycosylated hCG in unison * Promotes growth and differentiation of villous trophoblast cells [31,57,61,66] hCG: Human chorionic gonadotropin. Key issues * It is important to fully understand the roles of human chorionic gonadotropin (hCG), hyperglycosylated hCG, and hCG together with hyperglycosylated hCG in pregnancy. * hCG promotes corpus luteal progesterone production during the first 3-4 weeks of gestation. * hCG promotes cytotrophoblast differentiation to syncytiotrophoblast cells, and blocks immune or macrophage rejection of the maternally foreign invading trophoblastic tissue. * hCG promotes growth of the uterus in line with growth of the fetus. It also promotes quiescence or quieting of myometrial contraction during the course of pregnancy. * hCG promotes the growth and development of fetal organs, and promotes the formation and growth of the umbilical cord during pregnancy. * Blastocysts use hCG to signal to the endometrium of pending implantation of pregnancy. hCGs also act on the human brain, causing nausea and vomiting during pregnancy. CAPTION(S): Figure 1. Concentration of human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin (ng/ml) in 536 serum samples from length of normal pregnancy. Results show median concentration and range of values by gestational age. The total hCG assay used was the Siemen's Immulite 1000, a serum assay that equally detects hCG, nicked hCG, hyperglycosylated hCG, nicked hCG missing the C-terminal peptide, and hCG[beta] [105] . Hyperglycosylated hCG was measured with the B152 immunometric assay, an assay that only detects hyperglycosylated hCG and its [beta]-subunit [58,59] . hCG: Human chorionic gonadotropin. References 1 Aschner B. Ueber die function der hypophyse. Pflug. Arch. Gest. Physiol. 146, 1-147 (1912). 2 Fellner OO. Experimentelle untersuchungen uber die wirkung von gewebsextrakten aus der plazenta und den weiblichen sexualorganen auf das genital. Arch. Gynakol. 100, 641 (1913). 3 Hirose T. Experimentalle histologische studie zur genese corpus luteum. Mitt. Med. Fakultd. Univ. ZU

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1 USA hCG Reference Service,

Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, MSC10-5580, 333 Cedar Street, NM 87131, USA. larry@hcglab.com Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript. Laurence A Cole Source Citation (MLA 7th Edition) Cole, Laurence A. "Human chorionic gonadotropin (hCG) and hyperglycosylated hCG: the mediators that control human pregnancy." Expert Review of Obstetrics & Gynecology 6.3 (2011): 273+. Academic OneFile. Web. 9 Sep. 2012. Document URL http://go.galegroup.com.ez27.periodicos.capes.gov.br/ps/i.do? id=GALE%7CA257361227&v=2.1&u=capes58&it=r&p=AONE&sw=w Gale Document Number: GALE|A257361227