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  • 1. +Model JRI 1820 1–7 ARTICLE IN PRESS Journal of Reproductive Immunology xxx (2009) xxx–xxx Research article 1 hCG and hyperglycosylated hCG in the establishment and F 2 evolution of hemochorial placentation OO 3 Laurence A. Cole ∗ 4 USA hCG Reference Service Reference Service, Women’s Health Research, Department of Obstetrics and Gynecology, 5 University of New Mexico, Albuquerque, NM 87131, USA Received 17 December 2008; received in revised form 17 April 2009; accepted 20 April 2009 PR 6 7 Abstract 8 The evolution of regular chorionic gonadotropin (CG) and hyperglycosylated CG are linked with the evolution of hemochorial 9 placentation in primates. Recent research with humans shows that regular CG promotes spiral artery angiogenesis and hyperglyco- 10 sylated CG controls invasion by implanting trophoblast cells. It is inferred that the evolution of regular CG and hyperglycosylated ED 11 CG in early simian primates, the first species to produce these CG forms, established hemochorial placentation in this species. 12 The circulating half-lives, and thus the circulating concentrations, of regular CG and hyperglycosylated CG increased in advanced 13 simian primates and increased further in humans, seemingly causing greater myometrial invasion and superior angiogenesis in 14 hemochorial placentation in advanced primates and humans. Advanced hemochorial placentation is associated with relatively high 15 proportions of pregnancy failures in humans. This can be explained by considering human implantation inadequate in terms of 16 invasion requirements. The demanding implantation required by the human embryo is seemingly dependent on adequate produc- CT 17 tion of hyperglycosylated CG. Failures in hemochorial placentation invasion lead to anoxia and cause preeclampsia and eclampsia 18 uniquely in humans, which can also be attributed to inadequate hyperglycosylated CG signaling. We propose here that inadequate 19 regular CG and hyperglycosylated CG molecules are the evolutionary causes of these obstetric complications in humans. 20 © 2009 Published by Elsevier Ireland Ltd. E 21 Keywords: hCG; Regular CG; Hyperglycosylated CG; Hemochorial placentation; Brain; Evolution pregnancy failure; Preeclampsia 22 RR 23 1. Introduction Gibbons, 1998). It has also been known for 28 years that 34 chorionic gonadotropin (CG) forms arose in the lower 35 24 The human hemochorial placentation process has simian primates, around the same time as the appear- 36 25 Q1 been recognized for over 30 years (Lockett, 1974). It ance of hemochorial placentation (Fiddes and Goodman, 37 26 is widely believed that human hemochorial placentation 1980; Maston and Ruvolo, 2002; Burton, 2006; Luckett, 38 27 evolved from the more primitive hemochorial placen- 1974; Martin, 1996). We examine here the parallel evo- 39 CO 28 tation seen in advanced and lower simian primates lution of chorionic gonadotropin forms and hemochorial 40 29 (Lockett, 1974), and that the ultra-efficient hemochorial placentation, and their key roles in the nutritional evolu- 41 30 placentation system in humans and advanced primates tion of the brain. 42 31 is essential for the nutritional and energy requirements 32 needed for the development of larger brains in these 2. Chorionic gonadotropin and hemochorial 43 UN 33 species (Martin, 1981, 1996; Cunnane et al., 1993; placentation 44 ∗ Tel.: +1 5052726137; fax: +1 5052723903. In recent years, research has focused on exposing 45 E-mail address: larry@hcglab.com. the chemistry and physiology of regular CG. It is 46 0165-0378/$ – see front matter © 2009 Published by Elsevier Ireland Ltd. doi:10.1016/j.jri.2009.04.007 Please cite this article in press as: Cole, L.A., hCG and hyperglycosylated hCG in the establishment and evolution of hemochorial placentation. J. Reprod. Immunol. (2009), doi:10.1016/j.jri.2009.04.007
  • 2. +Model JRI 1820 1–7 ARTICLE IN PRESS 2 L.A. Cole / Journal of Reproductive Immunology xxx (2009) xxx–xxx 47 increasingly clear that regular CG is not just a hormone, 48 as determined in 1920, for promoting corpus luteal 49 progesterone production (Hirose, 1920). Multiple 50 centres have shown luteinising hormone (LH)/regular 51 CG receptors on spiral arteries in the myometrium 52 and decidua, the arteries of hemochorial placentation, 53 and demonstrated a role for CG in the angiogenesis 54 of these spiral arteries as the hemochorial placentation F 55 system is established during pregnancy (Lei et al., 1992; 56 Rao and Alsip, 2001; Herr et al., 2007; Zygmunt et OO 57 al., 2002, 2003; Toth et al., 2001). Recently, studies 58 of human isolated artery segments following in vivo 59 human CG (hCG) injections show that hCG decreases 60 vascular resistance in the artery, dilating the arteries 61 and promoting blood flow (Toth et al., 2001). Functions 62 have also been proposed for regular CG in the fusion or PR 63 differentiation of trophoblast cells, promoting the con- 64 version of cytotrophoblast to syncytiotrophoblast cells 65 (Shi et al., 1993). Functional LH/regular CG receptors 66 have also been located at other sites, like the decidual 67 and fetal membranes in pregnancy (Lei and Rao, 1992), Fig. 1. A schematic diagram illustrating invading villus trophoblast 68 and in the brain (Lei et al., 1993). Exact roles for at 4–6 weeks of gestation. VSyn is villous intermediate syncytiotro- ED 69 these receptors are yet to be established. Regular CG phoblast cells, VCyto is villous cytotrophoblast cells and EVCyto is extravillous cytotrophoblast cells. The schematic shows anchoring vil- 70 is produced by differentiated syncytiotrophoblast cells, lus with EVCyto and floating villus components. Hyperglycosylated 71 the so-called functional placental cells (Jameson and hCG from ECyto is shown in the invading myometrium, while regular 72 Hollenberg, 1993; Kovalevskaya et al., 2002; Cole et hCG from VSyn acts in spiral artery angiogenesis and fusion of VCyto 73 al., 2006b, 2006c). Hyperglycosylated CG, a variant to VSyn. The figure is based on previous publications (Handschuh et CT 74 of regular CG, is made by the invasive cytotrophoblast al., 2007a; Kennedy et al., 2007; Tarrade et al., 2001). 75 cells of the placenta in humans (Kovalevskaya et al., 76 2002; Cole et al., 2006b, 2006c; Handschuh et al., and hyperglycosylated CG evolved parallel to hemocho- 99 77 2007a). Hyperglycosylated CG is notably larger than rial placentation because they played central roles in 100 78 regular CG (41,000 da versus 37,000 da), with four establishing the key invasive and vascular placentation 101 E 79 double size O-linked oligosaccharides and four larger modes that characterize hemochorial placentation. We 102 80 N-linked sugar side chains defining a structurally propose that hyperglycosylated CG drives extravillous 103 cytotrophoblast cells to invade the uterus and implant as RR 81 separate molecule to regular CG (Cole, 1987; Elliott et 104 82 al., 1997; Amano et al., 1988; Cole et al., 2006b, 2006c). deep as possible in the myometrium, and that regular CG 105 83 Hyperglycosylated CG has been proposed to be a promotes spiral artery growth and multiplicity to meet 106 84 major cytotrophoblast invasion signal in hemochorial and provide nutrition to the invading villi. 107 85 placentation (Cole et al., 2006b, 2006c; Lei et al., 1999; Fig. 1 illustrates a placental villus with the anchoring 108 Handschuh et al., 2007a; Hamade et al., 2005; Sasaki et and floating components at 4–6 weeks gestation, with 109 CO 86 87 Q2 al., 2008). Hyperglycosylated hCG is produced specif- the extravillous cytotrophoblast cells on the anchoring 110 88 ically by extravillous cytotrophoblast cells (Handschuh villus producing hyperglycosylated CG to drive deeper 111 89 et al., 2007a, 2007b), where it is thought to have a role in invasion, and the regular CG produced by syncytiotro- 112 90 promoting invasion during placentation (Handschuh et phoblast cells driving spiral artery angiogenesis and the 113 91 al., 2007a; Cole et al., 2006b). While it has been shown fusion of cytotrophoblast cells. 114 UN 92 that hyperglycosylated hCG acts as an autocrine fac- 93 tor blocking cytotrophoblast apoptosis (Hamade et al., 3. Evolution of chorionic gonadotropin 115 94 2005), a receptor through which its invasive action is 95 mediated remains unidentified. Invasion distinguishes Production of the hormone CG evolved in the lower 116 96 hemochorial placentation from more primitive placen- simian primate at about the same time as hemocho- 117 97 tation models. Considering their specific invasion and rial placentation commenced in primates (Fiddes and 118 98 angiogenesis functions, we hypothesised that regular CG Goodman, 1980; Maston and Ruvolo, 2002; Burton, 119 Please cite this article in press as: Cole, L.A., hCG and hyperglycosylated hCG in the establishment and evolution of hemochorial placentation. J. Reprod. Immunol. (2009), doi:10.1016/j.jri.2009.04.007
  • 3. +Model JRI 1820 1–7 ARTICLE IN PRESS L.A. Cole / Journal of Reproductive Immunology xxx (2009) xxx–xxx 3 Table 1 Parallelisms between placental implantation and invasion characteristics, presence and oligosaccharides structures of CG and CG-H, and relative brain masses in primates. Table summarizes published data (Martin, 1996; Cunnane et al., 1993; Gibbons, 1998; Bambra, 1987; Burton, 2006; Luckett, 1974; Nisula and Wehmann, 1980; Maston and Ruvolo, 2002; Crawford et al., 1986; Elliott et al., 1997). Using a logarithmic equation 1/log(1/2time) = 1/pI–11.6 a relationship was observed between known pI and circulating half time of LH and CG. The circulating half times of lower simian CG and advanced simian CG were estimated by this means. Species Implantation Depth of invasion CG/CG-H Circulating Brain mass (%) characteristics oligosaccharides, pI half time F (1) Primates Human Hemochorial Through decidua to 4 O- and 4 N-linked, 2100 min 2.4 1/3rd myometrium pI 3.5 OO Advanced simian Hemochorial Through decidua to 3 O- and 3 N-linked, 240 min 0.74 primate (baboon, 1/10th myometrium pI 4.9 orangutan) Lower simian Hemochorial Through decidua 2 O- and 3 N-linked, 70 min 0.17 primate only pI 6.3 (marmoset, cebus monkey) PR Prosimian Epitheliochorial No invasion No CG forms 0.07 primate (lemur) produced (2) Mammals (examples) Cetacea (whale) Epitheliochorial No invasion No CG forms 0.08 produced Equus (horse) Epitheliochorial No invasion No CG forms 0.11 produced ED Bos taurus (cow) Epitheliochorial No invasion No CG-H produced 0.09 120 2006; Luckett, 1974; Martin, 1996). Placentation in It appears that additional changes in CG occurred with 147 121 primitive prosimian primates such as the lemur is epithe- further species evolution, through advanced simian pri- 148 CT 122 liochorial, and relatively non-invasive. In this form of mates such as the orangutan and baboon, and then with 149 123 placentation, the placenta is loosely attached to the hominids such as humans. The CG molecule underwent 150 124 decidua and nutrients diffuse from the maternal circu- multiple point mutations so that advanced simian CG had 151 125 lation through the decidua into the placenta (Table 1). 3 N-linked oligosaccharides (like lower simian primates) 152 126 Prosimian primates produced no form of CG (Table 1). and 3, rather than 2, O-linked oligosaccharides on the 153 E 127 Lower simian primates such as the marmoset and cebus C-terminal extension (Fig. 2). After multiple mutations, 154 128 monkey evolved with a form of CG. This is thought to human CG evolved with 4 N-linked oligosaccharides and 155 RR 129 have occurred following duplication of the LH -subunit 4 O-linked oligosaccharides on the C-terminal extension 156 130 gene; in the duplicate gene a deletion mutation occurred (Bambra, 1987; Maston and Ruvolo, 2002; Crawford et 157 131 so that the termination codon coded for an amino acid, al., 1986; Elliott et al., 1997). 158 132 and transcription continued through for a further 24 The mean isoelectric point (pI) of the root molecule 159 133 codons until a further termination codon was reached. LH is 8.1 (Suginami et al., 1985). It has just 3 acidic 160 The result was a CG -subunit which was 145 amino N-linked oligosaccharides. The mean pI of lower simian CO 134 161 135 acids in length, compared with the LH -subunit, 121 CG or the initial CG with 3 acidic N-linked and 2 acidic 162 136 amino acids in length (Fig. 2). The C-terminal extension O-linked sugar structures is 6.3; advanced simian CG 163 137 was mostly a Ser and Pro polymer. Like LH, the first with 3 acidic N-linked and 3 acidic O-linked sugar struc- 164 138 form of CG in lower simian primates had 3 N-linked tures has a mean pI of 4.9; human CG with 4 acidic 165 139 oligosaccharides and in addition 2 O-linked oligosac- N-linked and 4 acidic O-linked sugar structures has a 166 UN 140 charides on the new C-terminal extension (Maston and mean pI of 3.5 (Bambra, 1987; Maston and Ruvolo, 167 141 Ruvolo, 2002; Fiddes and Goodman, 1980). We propose 2002; Crawford et al., 1986; Cole et al., 2004, 2008). 168 142 that hyperglycosylated CG derived from cytotrophoblast Clearly, the acidity of these gonadotropins increased 169 143 cells and regular CG derived from syncytiotrophoblast with evolution as more and more N- and O-linked 170 144 cells started hemochorial placentation, with hyperglyco- oligosaccharides were added as a result of mutations, 171 145 sylated hCG starting placental invasion and regular CG from LH with 3 sugar side chains to human CG with 172 146 starting the needed spiral artery angiogenesis. 8 sugar side chains (Fig. 2). The increasing acidity of 173 Please cite this article in press as: Cole, L.A., hCG and hyperglycosylated hCG in the establishment and evolution of hemochorial placentation. J. Reprod. Immunol. (2009), doi:10.1016/j.jri.2009.04.007
  • 4. +Model JRI 1820 1–7 ARTICLE IN PRESS 4 L.A. Cole / Journal of Reproductive Immunology xxx (2009) xxx–xxx sugar has physiological implications, since increasing 174 acidity repels the kidney glomerular basement mem- 175 brane (which is also acidic), thus preventing excretion. 176 As such, LH has a circulating half-life of 25 min, while 177 hCG has a circulating half time of 2100 min (Nisula and 178 Wehmann, 1980). It is assumed that lower simian CG and 179 advanced simian CG had circulating half times within 180 these extremes, according to their pIs. Using a logarith- 181 F mic equation [1/log(1/2time) = 1/pI–11.6], a relationship 182 was observed between pI and circulating half-life, and 183 OO the half-lives of lower simian CG (70 min) and advanced 184 simian CG (240 min) were estimated (Table 1). It is 185 assumed that the circulating concentrations of CG and 186 CG-H are proportional to their respective circulating 187 half-life values, being extremely small in lower simians, 188 in the middle range in advanced simian and extremely 189 PR high in humans. 190 As published previously (Sutton and Cole, 2004), 191 hyperglycosylated CG and regular CG both have sim- 192 ilar pI isotopes in the range of 2.9–4.1. The mean pI for 193 both molecules is 3.5. While hyperglycosylated CG and 194 regular CG may have similar clearance half-lives, hyper- 195 ED glycosylated hCG has a more rapid subunit dissociation 196 time (4300 min) compared to regular CG (48,000 min) 197 (Cole et al., 2003). Overall therefore, the hyperglyco- 198 sylated CG dimer may disappear from the circulation 199 somewhat faster (circulating half-life of 2100 min, dis- 200 CT sociation half-life of 4300 min) than regular CG. 201 We conclude that as CG evolved and was retained at 202 higher and higher circulating concentrations, hypergly- 203 cosylated hCG promoted increasingly deeper placental 204 invasion through the decidua and into the myometrium. 205 E Higher concentrations of regular CG promoted more 206 and more potent angiogenesis. As reported, CG and tro- 207 RR phoblast villi solely invade the myometrium leading to 208 minimally active hemochorial placentation in the lower 209 simian. Villi invade to one-tenth the thickness of the 210 myometrium in advanced simian primates and to one- 211 third the thickness of the myometrium and to greatest 212 efficiency in humans (Pijnenborg, 1996; Gibbons, 1998; CO 213 Jauniaux et al., 2006). In this respect, the evolution of 214 CG parallels the evolution of hemochorial placentation. 215 4. Chorionic gonadotropin, hemochorial 216 placentation and evolution of the brain 217 UN Humans have evolved with a uniquely large brain 218 to body mass ratio compared with other primates and 219 other mammals (Table 1) (Gibbons, 1998; Martin, 1981, 220 Fig. 2. The structure of LH and CG produced by early and advanced simian primates and humans. The light grey line is a ribbon model of 1996, 2003; Kliman, 2000; Cunnane et al., 1993; Jau- 221 the structure of the -subunit, and the dark grey line is a ribbon model niaux et al., 2000). While data from newborn primates 222 of the structure of the -subunit (Wu et al., 1994; Elliott et al., 1997). is difficult to collect, the human newborn brain repre- 223 Please cite this article in press as: Cole, L.A., hCG and hyperglycosylated hCG in the establishment and evolution of hemochorial placentation. J. Reprod. Immunol. (2009), doi:10.1016/j.jri.2009.04.007
  • 5. +Model JRI 1820 1–7 ARTICLE IN PRESS L.A. Cole / Journal of Reproductive Immunology xxx (2009) xxx–xxx 5 224 sents 11% of body mass (Jordaan, 2005). In humans Considering these data in combination with the 276 225 over 60% of the fetal energy intake is used to sup- evolution of CG forms and hemochorial placentation dis- 277 226 port the developing brain’s nutritional needs compared cussed in the previous sections of this review, we propose 278 227 with 20% in other primates and mammalian species that the appearance and evolution of CG is at the nutri- 279 228 (Gibbons, 1998; Robillard et al., 2003b; Martin, 1981, tional root of evolutionary advancements in primate and 280 229 1996, 2003; Cunnane et al., 1993; Pijnenborg, 1996). human brains. It appears that brain size started grow- 281 230 Brain size is related to the combination of body mass ing relative to body mass with the appearance of CG in 282 231 and the nutritional support of the developing progeny lower simian primates and the initiation of hemochorial 283 F 232 (Martin, 1981). The increase in brain size seen in placentation. With multiple mutations, CG evolved with 284 233 advanced primates and humans correlates with the large more and more oligosaccharides making the molecules 285 OO 234 energy demands of advanced primate and human fetuses more and more acidic. With this, circulating levels of CG 286 235 (Gibbons, 1998; Robillard et al., 2003b; Martin, 1981, forms became higher and higher; in parallel, hemocho- 287 236 1996, 2003; Cunnane et al., 1993; Pijnenborg, 1996). rial placentation become more and more efficient and 288 237 Numerous studies support the concept that advanced invaded more deeply (Lockett, 1974; Pijnenborg, 1996; 289 238 primates, and to an even greater extent humans, have Gibbons, 1998; Jauniaux et al., 2006). In line with these 290 239 evolved unique, deeper and more efficient placental improvements in efficiency of nutrient delivery, species 291 PR 240 invasion mechanisms and hemochorial placentation sys- with larger and larger brain sizes developed (Table 1). 292 241 tems to support the nutritional demands of the larger While it is possible that the evolutionary pathway that 293 242 embryonic brains (Table 1) (Gibbons, 1998; Robillard started primate species on the road to becoming human 294 243 et al., 2003b; Martin, 1981, 1996, 2003; Kliman, 2000; may have started with the evolution of CG, this is just 295 244 Cunnane et al., 1993; Jauniaux et al., 2006). one part of the story. The CG evolution pathway may 296 245 Table 1 shows that advanced primates and humans be the key in explaining how nutrition was delivered 297 ED 246 have a much greater brain to body mass than other to allow the in utero development of a very large brain 298 247 primates and mammals (Gibbons, 1998; Martin, 1981, for body size. That LH/regular hCG receptors are found 299 248 1996, 2003; Robillard et al., 2003a). In primitive in the hypothalami, hippocampi brainstem and cerebel- 300 249 prosimian primates such as lemurs, no placental inva- lum of the brain (Lei et al., 1993), may also suggest 301 250 sion of the uterus occurs at implantation (epitheliochorial a role for regular CG in intelligent brain development. 302 CT 251 implantation); the placenta simply links to the decidua Furthermore, CG must be considered in the context of 303 252 and nutrition transfer is limited to simple diffusion other key evolutionary events and molecules involved in 304 253 from maternal arteries into the placenta. With such pla- the development of superior consciousness, intelligence, 305 254 Q3 centation, lemurs have a 0.07% brain to body mass. communication skills and emotions that define a human. 306 255 In lower simian primates such as the marmoset and E 256 cebus monkey, placental invasion does occur, extend- 5. Evolutionary complications of chorionic 307 257 ing through the thickness of the endometrial decidua. gonadotropin and hemochorial placentation 308 RR 258 This permits an increase to 0.17% brain to body mass. 259 In advanced simian primates such as baboon and the Compared to other primates, multiple obstetric com- 309 260 orangutan, invasion extends through the decidua to one- plications are unique to humans. Humans developed the 310 261 tenth the width of the myometrium, permitting a more most extreme placentation process to permit develop- 311 262 efficient hemochorial implantation. This allows these ment of the resource-demanding human brain (Fig. 1). 312 advanced primates to achieve a 0.74% brain to body While it has been estimated that up to 41% of preg- CO 263 313 264 mass (Gibbons, 1998; Pijnenborg, 1996). Placentation nancies in humans do not succeed (16% miscarriage, 314 265 in humans is unique, with the blastocyst becoming 25% early pregnancy losses or biochemical pregnan- 315 266 completely embedded within the maternal endometrium cies), only ≤10% pregnancy failures are observed in 316 267 (Gibbons, 1998; Jauniaux et al., 2006; Pijnenborg, other primate species and most mammalian species 317 268 1996). Invasion extents to one-third the width of the (Jauniaux et al., 2006; Wilmut et al., 1986). Previous 318 UN 269 myometrium. This provides the most efficient hemo- studies have identified two-thirds of human pregnancy 319 270 chorial implantation, permitting the 2.4% brain to body failures to be due to inappropriate implantation (Jauniaux 320 271 mass. A serial relationship between implantation, inva- et al., 2006). Similarly, two-thirds of pregnancy failures 321 272 sion and brain mass is observed from prosimian primates can be explained by inadequate human hyperglycosy- 322 273 to lower simian primates, to advanced simian primates to lated CG production on the day of implantation of the 323 274 humans (Gibbons, 1998; Robillard et al., 2003b; Martin, blastocyst (Sasaki et al., 2008). It has been recently 324 275 1981, 1996; Cunnane et al., 1993; Pijnenborg, 1996). established that pregnancy induced hypertension (PIH), 325 Please cite this article in press as: Cole, L.A., hCG and hyperglycosylated hCG in the establishment and evolution of hemochorial placentation. J. Reprod. Immunol. (2009), doi:10.1016/j.jri.2009.04.007
  • 6. +Model JRI 1820 1–7 ARTICLE IN PRESS 6 L.A. Cole / Journal of Reproductive Immunology xxx (2009) xxx–xxx 326 preeclampsia and eclampsia are complications of incom- Burton, G.J., 2006. Early placental development. Placenta 27, A2. 377 327 plete hemochorial placentation mechanisms at the end Burton, G.J., 2004. Placental oxidative stress: from miscarriage to 378 328 of the first trimester of pregnancy. These lead to anoxia preeclampsia. J. Soc. Gynecol. Invest. 11, 342–352. 379 Cole, L.A., Butler, S.A., Khanlian, S.A., Giddings, A., Muller, C.Y., 380 329 and to deadly hypertension disorders later in pregnancy Seckl, M.J., Kohorn, E.I., 2006a. Gestational trophoblastic dis- 381 330 (Robillard et al., 2003a; Burton, 2004), complications eases: 2. Hyperglycosylated hCG as a reliable marker of active 382 331 that are unique to humans. This has also now been linked neoplasia. Gynecol. Oncol. 102, 150–158. 383 332 to low human hyperglycosylated hCG production at the Cole, L.A., Khanlian, S.A., Riley, J.M., Butler, S.A., 2006b. Hypergly- 384 cosylated hCG in gestational implantation and in choriocarcinoma 385 333 end of the first trimester of pregnancy (Bahado-Singh et F and testicular germ cell malignancy tumorigenesis. J. Reprod. Med. 386 334 al., 2002). Measurement of hyperglycosylated hCG at 51, 915–919. 387 335 the end of the first trimester of pregnancy can be a sensi- Cole, L.A., Sutton, J.M., Higgins, T.N.H., Cembrowski, G.S., 2004. 388 OO 336 tive test for predicting PIH, preeclampsia and eclampsia Between-method variation in hCG test results. Clin. Chem. 50, 389 337 in pregnancy (Bahado-Singh et al., 2002). High cir- 874–882. 390 Cole, L.A., Dai, D., Butler, S.A., Leslie, K.K., Kohorn, E.I., 2006c. 391 338 culating concentrations of hyperglycosylated CG, the Gestational trophoblastic diseases: 1. Pathophysiology of hyper- 392 339 invasion stimulus, are unique to human hyperglycosy- glycosylated hCG-regulated neoplasia. Gynecol. Oncol. 102, 393 340 lated CG. Humans uniquely develop choriocarcinoma 144–149. 394 341 and invasive moles, in which invasion by trophoblast Cole, L.A., 1987. The O-linked oligosaccharide structures are strik- 395 PR 342 cells is not regulated, presumably a complication of ingly different on pregnancy and choriocarcinoma hCG. J. Clin. 396 Endocrinol. Metab. 65, 811–813. 397 343 humans having hyperglycosylated CH as such a potent Cole, L.A., Khanlian, S.A., Kohorn, E.I., 2008. Evolution of the human 398 344 invasion stimulus (Cole et al., 2006a, 2006b, 2006c). brain, chorionic gonadotropin and hemochorial implantation of the 399 345 Here we connect together for the first time the placenta: insights into origins of pregnancy failures, preeclampsia 400 346 evolution of CG forms and hemochorial placentation. and choriocarcinoma. J. Reprod. Med. 53, 449–557. 401 347 Taken together, CG forms may not only be the signal Cole, L.A., Sutton, J.M., Stephens, N.D., 2003. Invasive trophoblast 402 ED antigen (ITA): a new high-sensitivity test for detecting gestational 403 348 for hemochorial placentation and the driving force for Down syndrome. J. Clin. Ligand Assay 26, 23–28. 404 349 the nutrition system needed to support brain growth, Crawford, R.J., Traeger, G.W., Niall, H.D., 1986. The nucleotide 405 350 but also the sources of multiple major obstetrical and sequence of baboon chorionic gonadotropin beta-subunit genes 406 351 malignant diseases in humans. These fertility limitations have diverged from the human. Gene 46, 161–169. 407 352 and diseases may be considered evolutionary limita- Cunnane, S.C., Herbige, L.S., Crawford, M.A., 1993. The importance 408 CT of energy and nutrient supply in human brain evolution. Nutr. 409 353 tions in humans, derived from the extreme demands Health 9, 19–35. 410 354 of human placentation. Identification of an association Elliott, M.M., Kardana, A., Lustbader, J.W., Cole, L.A., 1997. Carbo- 411 355 between the roles of regular CG and hyperglycosy- hydrate and peptide structure of the - and -subunits of human 412 356 lated CG with hemochorial placentation may be the chorionic gonadotropin from normal and aberrant pregnancy and 413 357 first step in finding cures and treatments for the nega- choriocarcinoma. Endocrine 7, 15–32. 414 E Fiddes, J.C., Goodman, H.M., 1980. The cDNA for the -subunit 415 358 tive consequences of such an evolutionary development: of human chorionic gonadotropin suggests evolution of a gene 416 359 pregnancy failure, PIH/preeclampsia/eclampsia and by read through into the 3 -untranslated region. Nature 286, 417 RR 360 choriocarcinoma/invasive mole. It is feasible that preg- 684–687. 418 361 nancy failure and PIH/preeclampsia/eclampsia could be Gibbons, A., 1998. Solving the brain’s energy crisis. Science 280, 419 362 treatable with hyperglycosylated CG administration and 1345–1347. 420 Hamade, A.L., Nakabayashi, K., Sato, A., Kiyoshi, K., Takamatsu, Y., 421 363 that choriocarcinoma and invasive mole may be treatable Laoag-Fernandez, J.B., Ohara, N., Maruo, T., 2005. Transfection 422 364 with human antibodies targeted at or vaccines against of antisense chorionic gonadotropin gene into choriocarcinoma 423 hyperglycosylated CG. CO 365 cells suppresses the cell proliferation and induces apoptosis. J. Clin. 424 Endocrinol. Metab. 90, 4873–4879. 425 Handschuh, K., Guibourdenche, J., Tsatsaris, V., Guesnon, M., Lau- 426 366 References rendeau, I., Evain-Brion, D., Fournier, T., 2007a. Human chorionic 427 gonadotropin produced by the invasive trophoblast but not the vil- 428 367 Amano, J., Nishimura, R., Mochizuki, M., Kobata, A., 1988. 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