Cole LA

Review Article

Austin J Obstet Gynecol. 2016; 3(2): 1058.

HCG the Master Molecule

Cole LA*

USA hCG Reference Service, 34 Broad moor Way, P.O. Box 950, Angel Fire NM 87710, USA

*Corresponding author: Laurence Anthony Cole, USA HCG Reference Service, 34 Broad moor Way, P.O. Box 950, Angel Fire NM 87710, USA

Received: June 28, 2016; Accepted: July 20, 2016; Published: July 25, 2016

Abstract

HCG is here considered the master molecule. The master molecule because HCG controlled human and the human brain evolution. The master molecule because hCG seemingly controls human pregnancy and whether pregnancy will have a term outcome. The master molecule because hCG drives human cancer, and partly whether a cancer is aggressive an kills a person.

Keywords: HCG; Hypertensive disease; Endocrine receptor; Hyperglycosylated hCG; zygote

Introduction

HCG is called here the master molecule because it controls so many critical events in human life, it even organized the evolution of humans from early primates. Hyperglycosylated hCG a variant of hCG is the guard gate deciding which pregnancy can go term, which pregnancy with lead to hypertensive disease, that drives human cancer and in many ways decides which cancer is terminal.

It is important to understand that hCG is not just one molecule but rather is a group of six independent molecules each sharing the same α-subunit and ß-subunit amino acid sequences or the same genes. A major part of this multi-molecule biochemical oddity is that both subunits of the hCG group of molecules evolved from transforming growth factor-ß2 (TGF-ß2), containing cysteine knot four peptide, and three disulfide bridge structures from TGF-ß2 [1-5].

The hCG group also evolved directly from the pituitary hormone Luteinizing Hormone (LH), making hCG both a hormone and a TGF-ß2 antagonist (Table 1) [3-5]. The six primary hCG molecules are the placental hormone hCG (hCG-1) made by syncytiotrophoblast cells which acts on a placental, uterine and corpus luteal LH/ hCG endocrine receptor (Table 1). The placental autocrine hyper glycosylated hCG (hCG-2) made by cytotrophoblast cells which acts on a cytotrophoblast TGF-ß2 receptor (Table 1). The pituitary hormone sulfated hCG (hCG-3) made by gonadotrope cells which acts on an ovarian theca and granulosa LH/hCG endocrine receptor (Table 1).

Table 1: The 6 primary variants of CG. MW is molecular weight, SO₄ is sulfated sugars.




  
    Parameter
    Hormone hCG
    Hyperglycosylated hCG
    Sulfated 

      hCG
    Hyperglycosylated cancer hCG
    Hyperglycosylated cancer free ß-subunit
    Mutated Fetal 

      hCG
  
  
    New    name
    hCG-1
    hCG-2
    hCG-3
    hCG-4
    hCG-4ß
    hCG-5
  
  
    Source cells 
    Syncytiotrophoblastcells 
    Cytotrophoblast cells 
    Pituitary

      Gonadotrope cells 
    Trophoblastic malignancy cells 
    Non-trophoblastic malignancy cells 
    Fetal kidney & liver cells 
  
  
    Mode of    action
    Endocrine
    Autocrine
    Endocrine
    Autocrine
    Autocrine
    Non-Endocrine
  
  
    Total    MW
    36,525
    39,149
    35,943
    40,461
    26,271
    Variable
  
  
    Site of    action
    LH/hCG receptor
    TGFß antagonism
    LH/hCG receptor
    TGFß antagonism
    TGFß antagonism
    Fetal organ
  
  
    Amino    acids α-subunit
    92
    92
    92
    92
    -
    Variable
  
  
    Amino    acids ß-subunit
    145
    145
    145
    145
    145
    Variable
  
  
    Peptide    MW
    25,813
    25,813
    25,813
    25,813
    15,543
    Variable
  
  
    O-linked    sugar units
    4
    4
    4
    4
    4
    Not determined
  
  
    Type    O-linked sugars sugars
    Type 1
    Type 2
    Type 1 + SO₄
    Type 2
    Type 2
    Not determined
  
  
    N-linked    sugar units
    4
    4
    4
    4
    2
    Not determined
  
  
    Type    N-linked sugars
    Biantennary
    Biantennary
    Biantennary + SO₄
    Triantennary ß
    Triantennary
    Not determined
  
  
    Sugar    side chain MW
    10,712
    13,336
    10,130
    14,648
    10,728
    Not determined
  
  
    Percentage    sugars
    29%
    34%
    28%
    36%
    41%
    Not determined
  
  
    Isoelectric    point (pI)
    3.5
    4.5
    3.2
    3.1
    Not determined
    Not determined
  
  
    Clearance    ½-life
    36 hours
    36 hours
    18 hours
    Not determined
    Not determined
    Not determined



Table 1:  The 6 primary variants of CG. MW is molecular weight, SO₄ is sulfated sugars.

Then there is cancer hyper glycosylated hCG (hCG-4), an autocrine produced by all human trophoblastic cancers that binds a TGF-ß2 receptor on the cancer cells (Table 1). Then there are all other cancers, non-trophoblastic cancers. They lack a critical component for hCG α-subunit -ß-subunit combination and produce a cancer hyperglycosylated hCG free ß-subunit (hCG-4ß). This cancer hyper glycosylated hCG free ß-subunit also binds the TGF-ß2 receptor on cancer cells. Finally there is a fetal hCG produced during pregnancy (hCG-5) [6-8]. This drives fetal organ growth and development during pregnancy. While it has been demonstrated that this molecules is produced by fetal liver and kidney, there is insufficient data to determine the structure of this primary form of hCG (Table 1) [6-8].

These six different primary forms of hCG vary in molecular weight from 26,271 (hCG-4ß) to 40,461 (hCG-4), and in proportion sugar from 28% (CG-3) to 41% (hCG-4ß). HCG is considered the most glycosylated glycoprotein and the most acidic glycoprotein in the human genome.

Intriguingly, the six hCG forms seem to fall into two groups, placental hormone hCG (hCG-1), pituitary sulfated hCG (hCG- 3), and seemingly fetal hCG (hCG-5) are all hormones and act on an LH/hCG joint receptor. Secondly is hyper glycosylated hCG (hCG-2), cancer hyper glycosylated hCG (hCG-4) and cancer hyper glycosylated hCG free ß-subunit (hCG-4ß) which are all antagonists binding a TGF-ß2 receptor. The structural difference between placental hormone hCG (hCG-1) and hyper glycosylated hCG (hCG- 2) is very small. They have the exact same α-subunit and ß-subunit amino acid sequences, and only differ by the O-linked sugar side chains. The placental hormone hCG (hCG-1) has four of three or four sugar residue type one sugar side chains. Hyperglycosylated hCG (hCG-2) has four of five or six sugar residue type two sugar side chains. How, I ask, can just two sugars on 4 sugar side chains change a molecule from being a hormone and acting on a hormone receptor, to being an autocrine and acting on an autocrine receptor?

The three dimensional structure of generic hCG has been carefully investigated [9,10]. Unfortunately, to make hCG crystals all eight sugar side chains on hCG had to be removed, as well as the hCG ß-subunit C-terminal peptide. Crystals were made of 50% of the hCG root structure. I call it the root structure in that it cannot be attributed specifically to any one of the six hCG primaries. Unfortunately this tells you little about the differences between the hormone hCG (hCG- 1) and hyper glycosylated hCG (hCG-2). Stephen Butler PhD took this 50% structure and used sophisticated thermodynamic computer modelling software using Raptor (Bioinformatics Solutions Inc.) computer modelling to complete the 3D models of the hormone hCG (hCG-1) and hyper glycosylated hCG (hCG-2) (Figure 1). The three dimensional models of these complete molecules are shown in Figure 2 (Butler SA, structures not published).

Figure 1: The Stephen Butler models of structure of hormone hCG and hyperglycosylated hCG.

    
    
    Figure 1:  The Stephen Butler models of structure of hormone hCG and
hyperglycosylated hCG.

As illustrated, the principal difference is in the ß-subunit C-terminal peptides, shown in black on the figure from ß-subunit residue (Figure 2, the hormone hCG) 110 to 145. As shown the hormone CG ß-subunit C-terminal, starting at residue 110 first folds over α-subunit loop 40-57, and then over ß-subunit loop 92- 102 coming to ß-subunit sugar attachment site at residue 127. The C-terminal peptide then folds downwards into the center of the molecule folding over ß-subunit loop 40-55, it then fold back on itself and terminates at residue 145.

Figure 2: Nicked hyperglycosylated hCG and the TGF-ß2 receptor.

    
    
    Figure 2:  Nicked hyperglycosylated hCG and the TGF-ß2 receptor.

The ß-subunit C-terminal peptide on hyper glycosylated hCG (Figure 2, hyper glycosylated hCG) is a little simpler. Starting again at residue 110 it again first folds over α-subunit loop 40-57, and then over ß-subunit loops 92-102 coming to ß-subunit sugar attachment site at residue 127. The big difference is that does not fold over ß-subunit loop 40-55. This is what makes the big difference, or separates CG (CG-1) and hyper glycosylated hCG. It then terminates at residue 145.

While hyper glycosylated hCG is rapidly nicked by a leukocyte elastase at residue ß47-48 immediately upon secretion [11], the hormone hCG is blocked from nicking by the C-terminal peptide as it fold over ß-subunit loop ß40-55. The end result is that hyper glycosylated hCG is rapidly nicked, and the hormone hCG is very slowly nicked. As shown in Figure 3, nicking of hyper glycosylated hCG exposes the TGF-ß2 cystine knot on hyperglycosylated hCG, a binding site for antagonizing the TGF-ß2 receptor. Nicking also destroys all hCG/LH hormone receptor activity of hyper glycosylated hCG (hCG-2). The end result is that the hormone hCG acts only on the hCG/LH hormone receptor and hyper glycosylated hCG acts only by antagonizing a TGF-ß2 receptor.

Figure 3: The evolution of hCG and LH from TGF-ß2.

    
    
    Figure 3:  The evolution of hCG and LH from TGF-ß2.

Introducing hCG is not simple. There are two groups of hCG primary molecules. The molecules that are hormones and act on an LH/hCG hormone receptor, and the molecules that TGF-ß2 receptor antagonist. There are six separate hCG primary molecules total. They all use the same α- and ß-subunit amino acid sequence or are seemingly coded for by the same α- and ß-subunit genes. A small structural change in the cancer and pregnancy hyper glycosylated hCG molecules incidentally permits and does not permit nicking of molecules and opening up TGF-ß2 binding sites and closing of hormone binding sites.

HCG Controlled Human Evolution

Amazingly, the evolution of hCG instigated and completely controlled the evolution of humans and the human brain [12-15]. The evolution of hCG started out with the evolution of the primate LH. As illustrated in Figure 3, LH subunits were direct descendants of TGF-ß2 monomer. TGF-ß2 evolved in fish about 500 million years ago to ancestral α-subunit monomer. This then evolved into the α- and ß-subunits of gonadotropin ancestral hormone -I and -II (GAH-I and GAH-II) and Thyroid Stimulating Hormone (TSH) in fish. Over hundreds of millions years the α- and ß-subunits mutated and evolved separately becoming separate molecules. GAH-I was the pituitary ancestral hormone to Follicle Stimulating Hormone (FSH), and GAH-II was the pituitary ancestral hormone to LH [1,2].

All of these evolutionary molecules and subunits each carried a key structural remnant of TGF-ß2 called the cysteine knot structure (Figure 4) [1,2]. This was a four peptide three disulfide bridge structural element, found in LH, FSH, TSH and hCG subunits (the evolutionary descendants of LH) today. These four hormones that evolved together from TGF-ß2 are called the glycoprotein hormones.

Figure 4: The cysteine knot structure, structure of cysteine knot on hCG ß-subunit.

    
    
    Figure 4:  The cysteine knot structure, structure of cysteine knot on hCG
ß-subunit.

More recently, approximately 37 million years ago with the evolution of Aotus, Anthropoid Platyrrhine primates, CG (no h since not human) evolved. A deletion mutation occurred in the ß-subunit of LH (Figure 5) [16,17]. The deletions of a single base cause a frame-shift in subsequent nucleotide triplet codons. This included a termination codon following LH ß-subunit amino acid codon 121. The LH ß-subunit gene was read through the termination codon to residue 145 where a further termination codon was located (Figure 5). This generated the new CG ß-subunit molecule. This combined with the common α-subunit to make CG dimer.

Figure 5: The deletion mutation in LH ß-subunit gene.

    
    
    Figure 5:  The deletion mutation in LH ß-subunit gene.

CG was primarily expressed by pituitary gonadotrope cell, in response to hypothalamic gonadotropin releasing hormone (GnRH) initiation. GnRH is the initiation signal for LH, hCG and FSH. For unclear reason GnRH is also produced by trophoblast cells during pregnancy [18,19]. This is how cytotrophoblast cells started secondarily producing hyper glycosylated CG, and syncytiotrophoblast cells or fused cytotrophoblast cells started secondarily producing the hormone hCG in Aotus.

Aotus placenta upon producing the hormone CG and the cytotrophoblast autocrine hyper glycosylated CG started feeding the fetus by more efficient hemochorial placentation, and ceased feeding by epitheliochorial placentation the inefficient method used by mammals and earlier primates. As illustrated in Figure 6, the mechanics of hemochorial placentation were built by the hormone hCG and hyper glycosylated hCG. Briefly, hyper glycosylated hCG promoted cytotrophoblast cell growth out from columns in the implanted blastocyst. This grew as a tree shaped pattern forming the villous trophoblast or root of hemochorial placentation. The hormone hCG then promoted fusing or differentiation of the villous cells to form a skin of syncytiotrophoblast which surrounds the villous core [20]. The hormone hCG then promotes the extension of uterine spiral arteries to reach the hemochorial placentation apparatus [21,22]. The hormone hCG also builds an umbilical circulation to link the villous core with the fetal circulation [23,24].

Figure 6: Hemochorial placentation in Aotus, Orangutan and Humans.

    
    
    Figure 6:  Hemochorial placentation in Aotus, Orangutan and Humans.

Briefly (Figure 6), maternal blood fills the chamber surrounding the villous core. Nutrients, oxygen and glucose filters through the single layer of syncytiotrophoblast cells surrounding the villous core and enter the villous structure, where nutrients enter the fetal umbilical circulation and enter the fetus (Figure 6).

Aotus CG ß-subunit had just three acidic sugar side chains. While human CG ß-subunit had six acidic side chains. Aotus CG ß-subunit C-terminal peptide had to undergo 17 amino acid changes or point mutations in order to be converted to human CG. Aotus CG was a minimal or starting form of CG, Isoelectric point (pI) 6.3 and circulating ½-life 2.4 hours. Human CG was a super-potent molecule, pI = 3.5 and circulating ½-life 36 hours. Aotus CG came about 37 million year ago, and it took the 37 million years to evolve the human molecule. As indicated in Table 2, it took 37 million years and evolution through at least 32 species to generate the super-potent human molecule. We have information on Langur and Baboon Catarrhines, Orangutan Hominidae, and Homo Habilis, Hominin as intermittent steps in order to trace this evolution [17,25].

Table 2: Laboratory values at hospital admission.




  
    Species 
    Evolved ya 
    Placentation 
    Sugar side chains 
      on hCG ß-subunit 
    Pi / Clearance rate 
    Depth of implantation 
    Brain mass 
      %body weight 
       
    Bipedalism 
    Hand/Tools 
  
  
    Homo sapiens 
    200,000 ya
    Hemochorial
    6 sugar side chains
    pI=3.5 / 36 h
    30%
    2.4% (34X)
     
     
  
  
    Homo heidelbergensis,    Hominin
    400,000 ya
     
     
     
     
     
     
     
  
  
    Homo    erectus, Hominin
    1,000,000 ya
     
     
  
  
    Homo    ergaster, Hominin
    1,800,000 ya
     
     
  
  
    Homo    Habilis, Hominin 
    2,000,000 ya
    Hemochorial
    5 sugar side chains
    Extinct ?
    Extinct ?
    1.2% (17X)
     
     
  
  
    Australopihecus    garni, Hominin
    2,500,000 ya
     
     
     
     
     
     
     
  
  
    Australopihecus    africus, Hominin
    2,700,000 ya
     
     
  
  
    Australopihecus    afarensis, Hominin
    3,500,000 ya
     
       
     
       
  
  
    Australopihecus    anamensis, Hominin
    4,000,000 ya
     
       
     
       
  
  
    Ardipithecus    ramidus, Hominin
    4,300,000 ya
     
       
     
       
  
  
    Orrorin    tugensis, Hominin
    6,000,000 ya
     
     
  
  
    Sahelanthropus    tchadensis, Hominin
    7,000,000 ya
     
     
  
  
    Hominidae or    great apes
    4-12,000,000 ya
     
     
  
  
    Chimpanzee,    Hominidae
    6,000,000 ya
     
     
  
  
    Orangutan,    Hominidae 
    12,000,000 ya
    Hemochorial
    4 sugar side chains
    pI =4.9 / 6.0 h
    10%
    0.74%(11X)
     
     
  
  
    Hominidae or    great apes
    4-12,000,000 ya
     
     
     
     
     
     
     
  
  
    Hominidae or    great apes
    4-12,000,000 ya
     
     
  
  
    Bonobo,    Hominidae
    4-12,000,000 ya
     
     
  
  
    Hominidae or    great apes
    4-12,000,000 ya
     
     
  
  
    Hominidae or    great apes
    4-22,000,000 ya
     
       
     
  
  
    Gibbon,    Hylobatidae
    16,800,000 ya
     
     
  
  
    Hominoidea,    Africa and Southeast Asia
    12-22,000,000 ya
     
     
  
  
    Hominoidea,    Africa and Southeast Asia
    12-22,000,000 ya
     
     
  
  
    Hominoidea,    Africa and Southeast Asia
    12-22,000,000 ya
     
     
  
  
    Hominoidea,    Africa and Southeast Asia
    12-22,000,000 ya
     
     
  
  
    Hominoidea,    Africa and Southeast Asia
    12-22,000,000 ya
     
     
  
  
    Platyrrhine,    new world primates
    19-40,000,000 ya
     
     
     
     
     
     
     
  
  
    Platyrrhine,    new world primates
    19-40,000,000 ya
     
     
  
  
    Platyrrhine,    new world primates
    19-40,000,000 ya
     
     
  
  
    Platyrrhine,    new world primates
    19-40,000,000 ya
     
     
  
  
    Platyrrhine,    new world primates
    19-40,000,000 ya
     
     
  
  
    Aotus,    Anthropoid primate 
    37,000,000 ya
    Hemochorial
    3 sugar side chains
    pI=6.3 / 2.4 h
    1%
    0.17% (2.4X)
     
     
  
  
    Tarsier, Haplorrhine
    65-25,000,000 ya
     
     
     
     
     
     
     
  
  
    Haplorrhine    monkeys 
    65-25,000,000 ya
     
     
  
  
    Haplorrhine monkeys 
    65-25,000,000 ya
     
     
  
  
    Haplorrhine monkeys 
    65-25,000,000 ya
     
     
  
  
    Strepsirrhine monkeys 
    65-25,000,000 ya
     
     
  
  
    Lemur,    Strepsirrhine primate 
    55,000,000 ya 
    Epitheliochorial
    LH: 1 sugar side chain
    LH: pI=8 / 0.33 h
    No implantation
    0.07%



Table 2:  Laboratory values at hospital admission.

Aotus with the first CG had pI = 6.3 and a circulating ½-life of 2.4 hours. This CG ß-subunit had 3 sugar side chains. We know that Langur and Baboon Catarrhines that evolved 20 million year ago produced a more acidic CG with a ß-subunit with four sugar side chains [17,25]. That the four sugar side chains remained on Orangutan that evolved 10,000,000 years ago. We know that Orangutan CG had a pI = 4.9 and a longer circulating ½-life of 6.0 hours, a half way species. We also know that human CG had a pI = 3.5 and a circulating ½-life of 36 hours. We know that over these 37 million years that Aotus implanted in the uterus minimally by 1% of uterine thickness, that Orangutan implanted by 10% of uterine thickness, and that humans implanted by 30% of uterine thickness. That overall efficiency of hemochorial placentation, pictured in Figure 6, advanced from 1X in Aotus to 10X in Orangutan to 30X in humans. Overall, over the 37 million years of evolution CG became increasing more acidic and increasing with a longer circulating ½-live and more and more efficient. Parallel to this increasing potency, hemochorial placentation and implantation, functions promoted by CG, became increasingly more efficient.

The brain in mammals and early primates was generally very small or about 0.10% of total body weight. This was largely due to inefficient epitheliochorial placentation, a fetal feeding system that worked poorly, not efficiently enough to support brain growth. In primates, 7 brain growth genes are present, MCPH1 gene [26], WDR62 gene and CDK5RAP2 gene [27], CEP152 gene [28], ASPM gene [29], CENPJ gene [27] and STIL gene [30]. All, however, were dependent on the efficiency of placentation in order to allow brain growth [31-33]. When placentation was improved by hemochorial placentation in Aotus brain growth advanced. As CG advanced hemochorial placentation from Aotus to human brain growth advanced in parallel. So that prior to Aotus in Lemur brain size was 0.07% of body weight. In Aotus brain size was 0.17% of body weight (2.4X over Lemur), in Langur and Baboon brain size was 0.47% of body weight (6.7X over Lemur), in Orangutan brain size was 0.74% of body weight (11X over Lemur), in Homo habilis brain size was 1.2% of body weight (17X over Lemur), and in humans was 2.4% of body weight (34X over Lemur) (Table 2).

It is through this series of evolutionary pathways that over 37 million years that hCG became a super and super-duper molecule that the human brain developed. Following species with efficient and super-efficient hemochorial placentation bipedalism developed and became super-efficient, hand and use tool developed and became super-efficient or that human evolved. It would be fair to say that with the evolution of CG and super-potent CG, and the resulting efficient and super-efficient hemochorial placentation that the human and human brain completely developed.

I call CG a master molecule in the title of this review. How CG developed super-efficient hemochorial placentation leading to the development of humans can be considered a major part of why it is master molecule, along with CG’s critical roles in pregnancy, the pituitary and cancer as described hereafter.

HCG and Pregnancy

Three primary forms of hCG are critical to pregnancy, the hormone hCG as produced by syncytiotrophoblast cells, the autocrine hyper glycosylated hCG, and fetal hCG will all be dealt with here. Pregnancy is welcomed by the hormone hCG and the autocrine hyper glycosylated hCG (Figure 7).

Figure 7: Production of the hormone hCG (•) and hyperglycosylated hCG (°) during pregnancy.

    
    
    Figure 7:  Production of the hormone hCG (•) and hyperglycosylated hCG (°)
during pregnancy.

As shown, uterine pregnancy starts with implantation at three weeks gestation and the production of hyper glycosylated hCG. Pregnancy commences with the production of the hormone hCG one or two days later [34]. On the day of implantation (first day of hCG detection) the median hyper glycosylated hCG in urine is 0.30 ng/ml, the median hormone hCG is 0.12ng/ml or hyper glycosylated hCG is 79% of total hCG. After 7 days, the median hyper glycosylated hCG is 21ng/ml, the median hormone hCG is 12ng/ml or hyper glycosylated hCG is 61% of total hCG. After 14 days, the median hyper glycosylated hCG 169ng/ml, the median hormone hCG is 161ng/ml or hyper glycosylated hCG is 57% of total hCG. After 21 days, the median hyper glycosylated hCG is 616 ng/ml, the median hormone hCG 1,552ng/ ml or hyper glycosylated hCG is 31% of total hCG. The concentration of the hormone hCG exceeds the concentration of hyper glycosylated hCG in all weeks of pregnancy thereafter (Figure 7) [34].

Pregnancy starts at two weeks gestation with fertilization of the ovum. The zygote quickly divides to two cells, four cell, eight cells and the sixteen cells it then starts to differentiate into placenta cells and fetal cell forming a morula. The morula keeps differentiating as a 32 cell blastocyst is formed. The blastocyst is shelled losing the zona pellucida outer coating. Syncytiotrophoblast microvilli on the blastocyst then link to the glycalyx or the uterine epithelium cytotrophoblast cells, tying the structure together, then blastocyst cytotrophoblast cells secrete hyper glycosylated hCG and the invasion process of implantation starts. Hyperglycosylated hCG acts on the cytotrophoblast cell TGF-ß2 receptor antagonizing it [3-5], and the cytotrophoblast cells secrete metalloproteinases and collagenases [35], which burn an implantation hole in the uterus (Figure 8). The blastocyst firmly buries itself into the uterine stroma [34].

Figure 8: The stages of implantation.

    
    
    Figure 8:  The stages of implantation.

In the second stage of implantation which occurs at the end of the first trimester of pregnancy, hyper glycosylated hCG deeply implants the placenta in the uterus [12]. In human this is at 30% of uterine thickness. One again cytotrophoblast cell hyper glycosylated hCG antagonizes TGF-ß2 receptor leading to metalloproteinases and collagenase production. Interestingly, poor hyper glycosylated hCG production at pregnancy implantation leads to pregnancy failure, spontaneous abortion, biochemical pregnancy and ectopic pregnancy. Poor hyper glycosylated hCG production at the end of the first trimester and inappropriate deep implantation leads to gestational hypertension and preeclampsia.

Norwitz et al. [36] Semprini and Simon [37] and Wilcox et al. [38] all demonstrated that most pregnancy failures were due to inappropriate implantation at three week gestation. As shown my laboratory [39-41], deficiency of hyper glycosylated hCG can large be shown to be responsible (Figure 9). As shown in Figure 9, 191 of 191 term delivery pregnancies produced >40% proportion hyper glycosylated hCG (hyper glycosylated hCG as a percentage of total hCG) on the day of implantation of pregnancy [41]. It is though that >40% may be an essential criterion for normal outcome pregnancy. In contrast, only 13 of 49 spontaneous abortion pregnancies produced >40% hyper glycosylated hCG on the day of implantation, only 11 of 61 biochemical pregnancies produced >40% hyper glycosylated hCG, and none of 18 ectopic pregnancies produce >40% hyper glycosylated hCG on the day of implantation (Figure 9) [41]. The 13 spontaneous abortion and 11 biochemical pregnancies that produced >40% hyper glycosylated hCG were all gross genetic abnormality pregnancies. This figure shows that <40% hyper glycosylated hCG is an absolute marker of failing pregnancy. Supplementation with hyper glycosylated hCG injection on the day of implantation may prevent failing pregnancies.

Figure 9: Hyperglycosylated hCG and pregnancy failures.

    
    
    Figure 9:  Hyperglycosylated hCG and pregnancy failures.

The story does not end with hyper glycosylated hCG on the day of implantation. Examining 3,391 pregnancies during the three trimesters of pregnancy measuring hyper glycosylated hCG 141 cases of preeclampsia/gestational hypertension were identified [12]. As shown, preeclampsia/gestational hypertension can be predicted from 10 weeks to 18 week of gestation, preeclampsia/ gestational hypertension cases present with hyper glycosylated hCG concentrations (ng/mg creatinine) less that the third percentile, <3% (Figure 10). Seemingly, in these cases insufficient hyper glycosylated hCG is produced for deep implantation of the placenta at 30% of the thickness of the uterus. This leads to inefficient hemochorial placentation and to the fetus having to raise the mother’s blood pressure [12,42-45].

Figure 10: Hyperglycosylated hCG through the length of pregnancy, and in preeclampsia cases (large squares).

    
    
    Figure 10:  Hyperglycosylated hCG through the length of pregnancy, and in
preeclampsia cases (large squares).

It appears that hyper glycosylated hCG is that finicky valve produced during pregnancy, that decided which pregnancies fail and which make it to term, and which pregnancies develop deadly preeclampsia or gestational hypertension.

The hormone hCG during pregnancy has multiple critical functions. The primary function appears to be building and maintaining hemochorial placentation, the highly efficient fetal feeding system established by the placenta. Each placenta has 5-7 hemochorial placentation chambers.

Hyperglycosylated hCG promotes cytotrophoblast cell growth out from columns in the implanted blastocyst. This grows a tree shaped pattern of cytotrophoblast cells forming the villous trophoblast or root of hemochorial placentation (Figure 6). The hormone hCG then promotes fusing or differentiation of the villous cells to form a skin of syncytiotrophoblast which surrounds the villous core [20]. This syncytiotrophoblast skin forms the single cell barrier between maternal and fetal circulations (Figure 6). The hormone hCG then promotes the extension of uterine spiral arteries to reach and bleed into the hemochorial placentation chamber [21,22]. The hormone hCG also builds an umbilical circulation to link the villous core with the fetal circulation [23,24].

Briefly (Figure 6), maternal blood fills the chamber surrounded the tree-shaped villous core. Nutrients, oxygen and glucose filters through the single layer of syncytiotrophoblast cells and enters the villous structure, where nutrients enter the fetal umbilical circulation and enter the fetus (Figure 6).

Other critical function of the hormone hCG includes promotion of progesterone production by maternal ovarian corpus luteal cells, from five weeks to eight weeks of gestation [46]. Starting at around 8 weeks of gestation, the placental syncytiotrophoblast cells take over pregnancy progesterone production. The hormone hCG also has clear protective functions. The hormone hCG protect the uterine myometrial muscle from having contractions during the course of pregnancy [47,48]. It is thought that at term hCG levels have to decline significantly for the contraction of labor and delivery to proceed [47,48]. The hormone hCG also acts on maternal macrophages to prevent attack of placenta and fetal tissues as foreign tissues [49,50].

Fetal hCG made by fetal liver and kidney has been shown to promote growth and differentiation of fetal organs during fetal development during pregnancy [6-8]. Fetal hCG has been shown to cease at pregnancy parturition [6-8].

Hyperglycosylated hCG promotes blastocyst implantation in pregnancy [34,39-41]. Hyperglycosylated hCG is also seemingly responsible for deep implantation at the end of the first trimester pregnancy [12]. Among other functions, hyper glycosylated hCG seems to be responsible for placental cell growth during the course of pregnancy [51]. As shown in Figure 7, hyper glycosylated hCG is produced continuously during the course of pregnancy.

I call hCG the master group of molecules at the end of the section on hCG evolution. I also call it again the master molecule when considering the key role played by hCG primary molecules in pregnancy. It runs pregnancies, not only by driving hemochorial placentation but protecting pregnancies in multiple different ways. It decides which pregnancies are successful and makes it to term, and which pregnancies may become terror cases afflicted with preeclampsia. As it happens hCG is seemingly responsible for fetal development and generation of new human organs.

HCG and Pituitary

HCG evolved from LH ß-subunit. Like LH it is primarily a pituitary gland gonadotrope cell hormone and secondarily a placental hormone. We researched 276 sequential menstrual cycles from 111 women who attempted over six menstrual cycles to achieve pregnancy, and eventually became pregnant [52]. Daily hCG and LH was measured was measured over multiple menstrual cycles. In every case and every menstrual cycle the LH mid-cycle peak appeared on the same day as the hCG mid cycle peak. The median LH midcycle peak in the urines was 119mIU/ml, and the median hCG midcycle peak was 1.1mIU/ml, including the 24% hCG peaks that were not detected (<1.0mIU/ml) [52]. LH and hCG biological activities were determined and it was demonstrated that pituitary hCG is the principal luteotrophic activity produced by the pituitary [52]. Pituitary hCG seemingly drives ovulation and seemingly luteogenesis, folliculargenesis and luteotrophic steroidogenesis. While it is now proven that pituitary hCG has the principal ovulation activity, further evidence is needed to confirm that hCG, and not LH has principal luteogenesis, folliculargenesis, steroidogenesis and male activities.

Other publications show that pituitary hCG is sulfated, like LH, it is pulsatile, is controlled by GnRH, and very much mimics LH [53-56]. Pituitary sulfated hCG is the hormone that along with FSH controls the menstrual cycle. It seemingly promotes the conversion of cholesterol to androstenedione in theca cells, the first stage of estrogen synthesis in the follicular phase of the menstrual cycle. It seemingly promotes follicular growth, promotes follicular ovulation, seemingly promotes luteogenesis, and seemingly promotes progesterone synthesis by the corpus luteum in the luteal phase of the menstrual cycle.

In addition 56 women were found unable to get pregnant after 6 menstrual cycles of trying. Investigation of the cases showed that 30 of 56 went through 6 menstrual cycles with no detectable midcycle hCG peak. It was inferred because of this big difference (0 of 6 hCG cycles vs. 76% of all cycle showing a detectable peak) that these women had hCG problems, choriogonadotropinism, this may be a major cause of infertility not previously recognized.

HCG and Human Cancer

Cancer hyper glycosylated hCG and its free ß-subunit drives all or most human cancers, driving cancer cell growth and cancer cell invasion of adjacent cells or malignancy. Trophoblastic cancers, i.e. Choriocarcinoma, testicular germ cell malignancy and ovarian germ cell malignancy produce cancer hyperglycosylated hCG, while all other cancers cannot combine the α-subunit and ß-subunit due to an absence of placental disulfide isomerase critical for the ß-subunit, so produce a cancer hyperglycosylated hCG free ß-subunit [57].

Both cancer hyperglycosylated hCG and cancer hyperglycosylated hCG free ß-subunit are unique forms of the hyperglycosylated hCG molecule in that they have triantennary N-linked oligosaccharides attached to the ß-subunit differing themselves from the pregnancy hyperglycosylated hCG molecules [58-60].

In the cancer model, cancer hyperglycosylated hCG and hyperglycosylated hCG free ß-subunit are secreted as autocrines and feedback as an antagonist to a TGF-ß2 receptor [3-5]. In response the receptor blocks apoptosis in the cancer cell, promotes growth of the cancer and promotes production of collagenases metalloproteinases invasive enzymes [35,57].

From 1984 to 1992 I carried out extensive tumor marker studies testing 959 serum samples and 1495 urine samples for hCG ß-subunit tumor markers (Table 3) [61-69]. Serum was tested for hCG ß-subunit using an hCG ß immunoassay and urine was tested for ß-core fragment the urine terminal degradation product. Testing a wide variety of cancers of different histologies, in serum I could detect 38% of malignancies (range 17%-100%) and in urine I could detect 52% of malignancies (range 28%-100%) (Table 3) [61-69]. I asked myself why do only 52% of cancers and not 100% of cancers produce this marker?

Table 3: Laboratory values at hospital admission.




  
    Malignancy 
    Serum hCGß
    Urine hCG ß-core    fragment 
  
  
    Sensitivity (3 fmol/ml)
    Sensitivity (3 fmol/ml) 
  
  
    # Cases
    Sensitivity
    # Cases
    Sensitivity
  
  
    Bladder cancer
    170
    35%
    113
    48%
  
  
    Breast cancer
    42
    36%
    37
    57%
  
  
    Cervical cancer
    60
    37%
    410
    48%
  
  
    Choriocarcinoma
    63
    100%
    63
    100%
  
  
    Colorectal cancer
    136
    17%
    80
    36%
  
  
    Endometrial cancer
    55
    33%
    233
    44%
  
  
    Gastric cancer 
     
     
    83
    57%
  
  
    Hepatic cancer
     
     
    14
    50%
  
  
    Lung cancer
    143
    18%
    90
    28%
  
  
    Intestinal cancer
     
     
    17
    47%
  
  
    Lymphoma
     
     
    4
    50%
  
  
    Ovarian germ cell cancer
    30
    100%
    11
    64%
  
  
    Ovarian other cancers
    150
    38%
    207
    70%
  
  
    Pancreatic cancer 
    29
    33%
    29 
    55% 
  
  
    Renal cancer
     
     
    15
    67%
  
  
    Testicular germ cell cancer
    17
    100%
    17
    100%
  
  
    Uterine cancer
     
     
    63
    41%
  
  
    Vulvar cancer



Table 3:  Laboratory values at hospital admission.

In 2000 it was first shown that cancer hyperglycosylated hCG and cancer hyperglycosylated hCG free ß-subunit both functioned through binding a TGF-ß2 receptor [3,4,57]. Two types of autocrines bind TGF-ß2, simple autocrines and complex autocrines act on a TGF-ß2 receptor [70,71]. Complex autocrines are produced at higher concentration, these autocrine circulate the body and return binding the cancer cell TGF-ß2 receptor. Simple autocrines are produced at low concentrations, they only minimally circulate and mostly just act directly after secretion on the TGF-ß2 receptor [70,71].

As shown in Table 3, urine ß-core fragment detects 70% of ovarian cancers. I investigated 24 new cases of ovarian cancer pretherapy. As shown in Table 4, 17 of 24 cases were detected in the ß-core fragment assay with concentration of 3.2 to 58.6 fmol/ml or within the >3.0 fmol.ml cut-off. Seven cases were negative in the assay, cut-off 3 fmol/ml, but contained 0.40 – 2.0 fmol/ml ß-core fragment. It was concluded that 17 cases produced a complex autocrine and were detected by the assay. That the remaining seven cases, while producing a tiny concentration of ß-core fragment, were probably a simple autocrine, yet still produced ß-core fragment. It was concluded that all cancers seemingly produce the tumor markers, but that a significant proportion were simple autocrine cancers producing just tiny barely detectable concentrations.

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Citation: Cole LA. HCG the Master Molecule. Austin J Obstet Gynecol. 2016; 3(2): 1058.

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Species	Evolved ya	Placentation	Sugar side chains on hCG ß-subunit	Pi / Clearance rate	Depth of implantation		Brain mass %body weight	Bipedalism	Hand/Tools
Homo sapiens	200,000 ya	Hemochorial	6 sugar side chains	pI=3.5 / 36 h	30%		2.4% (34X)		
Homo heidelbergensis, Hominin	400,000 ya								
Homo erectus, Hominin	1,000,000 ya								
Homo ergaster, Hominin	1,800,000 ya								
Homo Habilis, Hominin	2,000,000 ya	Hemochorial	5 sugar side chains	Extinct ?	Extinct ?		1.2% (17X)		
Australopihecus garni, Hominin	2,500,000 ya								
Australopihecus africus, Hominin	2,700,000 ya								
Australopihecus afarensis, Hominin	3,500,000 ya								
Australopihecus anamensis, Hominin	4,000,000 ya								
Ardipithecus ramidus, Hominin	4,300,000 ya							 	 
Orrorin tugensis, Hominin	6,000,000 ya								
Sahelanthropus tchadensis, Hominin	7,000,000 ya								
Hominidae or great apes	4-12,000,000 ya
Chimpanzee, Hominidae	6,000,000 ya								
Orangutan, Hominidae	12,000,000 ya	Hemochorial	4 sugar side chains	pI =4.9 / 6.0 h	10%		0.74%(11X)	
Hominidae or great apes	4-12,000,000 ya
Hominidae or great apes	4-12,000,000 ya
Bonobo, Hominidae	4-12,000,000 ya							
Hominidae or great apes	4-12,000,000 ya
Hominidae or great apes	4-22,000,000 ya
Gibbon, Hylobatidae	16,800,000 ya							
Hominoidea, Africa and Southeast Asia	12-22,000,000 ya
Hominoidea, Africa and Southeast Asia	12-22,000,000 ya
Hominoidea, Africa and Southeast Asia	12-22,000,000 ya
Hominoidea, Africa and Southeast Asia	12-22,000,000 ya
Hominoidea, Africa and Southeast Asia	12-22,000,000 ya
Platyrrhine, new world primates	19-40,000,000 ya
Platyrrhine, new world primates	19-40,000,000 ya
Platyrrhine, new world primates	19-40,000,000 ya
Platyrrhine, new world primates	19-40,000,000 ya
Platyrrhine, new world primates	19-40,000,000 ya
Aotus, Anthropoid primate	37,000,000 ya	Hemochorial	3 sugar side chains	pI=6.3 / 2.4 h	1%	0.17% (2.4X)
Tarsier, Haplorrhine	65-25,000,000 ya
Haplorrhine monkeys	65-25,000,000 ya
Haplorrhine monkeys	65-25,000,000 ya
Haplorrhine monkeys	65-25,000,000 ya
Strepsirrhine monkeys	65-25,000,000 ya
Lemur, Strepsirrhine primate	55,000,000 ya	Epitheliochorial	LH: 1 sugar side chain	LH: pI=8 / 0.33 h	No implantation	0.07%

Pathologic Diagnosis	Stage	Status	hCG ß-core fragment fmol/ml	CA-125 U/ml)
Ovarian Serous cystadenocarcinoma	IV	Recurrent	0.40	60
Ovarian Serous cystadenocarcinoma	IIIc	New	0.70	271
Ovarian Brenner tumor	Ia	New	0.88	2.0
Ovarian Serous cystadenocarcinoma	IIIc	Recurrent	1.20	237
Ovarian Mucinous cystadenocarcinoma	Ia	New	2.0	4.0
Ovarian Endometrioid carcinoma	I	New	2.0	5.0
Ovarian Serous cystadenocarcinoma	II	New	2.0	7.0
Ovarian Clear cell carcinoma	IIIc	Recurrent	3.20	33
Ovarian Serous cystadenocarcinoma	IIIc	New	3.30	1253
Ovarian Mixed epithelial tumor	IIIc	New	3.51	4.0
Ovarian Serous cystadenocarcinoma	IIIc	New	3.70	531
Ovarian Serous cystadenocarcinoma	IIIc	New	5.10	1010
Ovarian Mixed epithelial tumor	IIc	New	5.26	54
Ovarian Serous cystadenocarcinoma	IV	Recurrent	6.30	4537
Ovarian Serous cystadenocarcinoma	IIIc	Recurrent	6.90	1520
Ovarian Endometrioid carcinoma	IIc	New	7.60	880
Mixed mesodermal	III	Recurrent	11.30	156
Ovarian Serous cystadenocarcinoma	IV	Recurrent	11.90	1090
Ovarian Serous cystadenocarcinoma	IIIc	New	12.05	4834
Ovarian Mixed epithelial tumor	IIIc	Recurrent	17.90	1600
Ovarian Serous cystadenocarcinoma	IV	New	20.40	2420
Serous cystadenocarcinoma	IIb	New	28.00	109
Clear cell carcinoma	III	Persistent	48.78	78
Squamous carcinoma in teratoma	II	New	58.60	22

Case	Total hCG, Immulite 2000 assay mIU/ml	Total hCG, Other assay mIU/ml	Other assay, % Immulite result	Other assay used
1	441,624	292,136	66%	Siemens Dimension
2	16,621	9,358	56%	Siemens Dimension
3	7,370	5,743	78%	Siemens Dimension
4	6,464	6,717	104%	Siemens Dimension
5	444	103	23%	Siemens Centaur
6	275	263	96%	Siemens Dimension
7	235	48	20%	Abbott Architect
8	206	87	42%	Siemens Dimension
9	168	50	30%	Siemens Dimension
10	156	103	66%	Siemens Centaur
11	148	38	26%	Siemens Centaur
12	148	38	26%	Siemens Dimension
13	140	66	47%	Ortho Vitros Eci
14	140	66	47%	Siemens Centaur
15	138	120	87%	Siemens Dimension
16	137	93	68%	Tosoh A1A
17	127	97	76%	Siemens Dimension
18	118	70	59%	Abbott AxSym
19	118	66	56%	Beckman Access 2
20	110	74	67%	Siemens Centaur
21	106	111	105%	Siemens Dimension
22	88	61	69%	Siemens Centaur
23	82	66	80%	Siemens Centaur
24	47	38	81%	Siemens Dimension
25	46	38	83%	Siemens Dimension
26	32	14	44%	Siemens Dimension
27	32	17	53%	Abbott Axsym
28	32	7	22%	Siemens Centaur
29	31	28	90%	Siemens Dimension
30	19	14	74%	Siemens Dimension
31	18	4.5	25%	Roche Elecsys hCG+ß
32	17	<2.0	<12%	Siemens Centaur
33	16	8.0	50%	Siemens Centaur
34	15	9.0	60%	Siemens Dimension
35	13	9.0	69%	Siemens Centaur
36	12	10	83%	Beckman DxI
37	11	11	100%	Siemens Dimension
38	9.2	7.1	77%	Roche Elecsys hCG+ß
39	8.0	8.0	100%	Siemens Centaur
40	6.0	5.0	83%	Siemens Dimension
41	5.9	4.6	78%	Siemens ACS180
43	3.0	<1.0	<33%	Siemens Dimension
44	2.8	<1.0	<36%	Siemens Dimension
45	2.4	<2.0	<83%	Beckman Access 2
46	2.0	1.0	50%	Siemens Dimension
	Median 65	Median 38