Human Chorionic Gonadotropin: Definition, Function, Subunits and Types

HCG is a glycoprotein hormone produced in pregnancy, manufactured by the developing embryo shortly after conception and later by the synciothiotrophoblast.

HCG subunits

HCG is a hormone that comprises an α (alpha) subunit and a β (beta) subunit that are held together by non-covalent ionic and hydrophobic interactions. The molecular weight of hCG is approximately 36,000.

It is an unusual molecule in that 25-41% of the molecular weight is derived from sugar side chains (25-30% in regular hCG and 35-41% in hyperglycosylated hCG).

Function of hCG

The role of hCG is still marked as promoting progesterone in most medical textbooks, but it is now known that hCG has other important fetal, uterine, and placental functions during pregnancy.

From the moment of implantation, the hCG produced by trophoblast cells takes up the corpus luteum’s progesterone production of luteinizing hormone (LH), which acts on a hCG / LH receptor in tandem. This continues for about 3 to 4 weeks.

All molecules share a common hCGβ subunit amino acid sequence. There is hCG, produced by differentiated syncytiotrophoblast cells or more specifically villous syncytiotrophoblast cells as the pregnancy progresses.

These are the molecules that promote progesterone production by cells of the corpus luteum ovaries and have multiple other biological functions as described below.

Hyperglycosylated hCG is a sugar variant of hCG produced by root cytotrophoblast cells or extravillous cytotrophoblast cells as pregnancy progresses.

Hyperglycosylated hCG is not a hormone, but is autocrine, and acts on cytotrophoblastic cells to promote cell growth and invasion, as in implantation of pregnancy and invasion by choriocarcinoma cells.

The free β subunit is the alternative glycosylated monomeric variant of hCG produced by all advanced non-trophoblastic malignancies. The free β subunit promotes the growth and malignancy of advanced cancers.

A fourth variant of hCG is pituitary hCG, produced during the female menstrual cycle. These molecules have sulfated oligosaccharides instead of sialylated ones.

Pituitary hCG works in a similar way to LH to promote follicular maturation, stigma formation, and meiosis in the primary follicle, ovulation, luteinization of the follicle, and progesterone production during the menstrual cycle.

The serum and urinary concentration of hCG and hyperglycosylated hCG during pregnancy are investigated in this comprehensive review.

The extreme variations of hCG and the concentration of hyperglycosylated hCG and how the extreme concentrations administered by the hCG / LH receptor are investigated are examined. hCG binds to a common receptor with LH, the LH / hCG receptor.

Biological function of hCG

The hCG hormone comprises an α subunit and a β subunit

The α subunit is common to hCG, hyperglycosylated autocrine / paracrine hCG, pituitary hormone hCG and the hormones LH, follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH), and the common free α-subunit formed in excess.

The β subunit of hCG, although structurally somewhat similar to the β subunit of LH, differentiates hCG, hyperglycosylated hCG, and pituitary hCG from other molecules.

Both hCG and LH bind and function through a common hCG / LH receptor. The biggest difference between LH and hCG is that LH, pI 8.0, has a circulating half-life of only 25-30 minutes, while hCG, pI 3.5, has a circulating half-life of approximately 37 hours, or 80 times longer than the of LH.

In many respects, hCG is super-produced LH in pregnancy, with 80X the biological activity of LH, acting on the receptor in the joint. While LH, FSH, and TSH are formed by the anterior lobe of the pituitary, hCG is produced by fused and differentiated placental syncytiotrophoblast cells.

With pregnancy, hCG takes over from LH in promoting progesterone production by cells of the corpus luteum of the ovary, preventing menstrual bleeding.

As is known today, hCG only promotes progesterone production for 3-4 weeks after pregnancy implantation. This feature is active for about 10% of the duration of pregnancy.

HCG also works to promote angiogenesis and vasculogenesis in the uterine vasculature during pregnancy

This ensures maximum blood supply to the invading placenta and optimal nutrition for the fetus.

The hCG / LH receptor gene is expressed by the uterine spiral arteries, and hCG acts on them to promote angiogenesis. This is probably a main function of hCG during pregnancy in ensuring an adequate supply of blood or nutrition to the placenta.

HCG also plays an important role in the trophoblastic tissue level of the placenta that promotes the fusion of cytotrophoblast cells and their differentiation to syncytiotrophoblast cells. Testicular twin cell cancers take trophoblast cytology.

HCG may function similarly to promote differentiation of testicular cancer cytotrophoblast cells.

HCG has also been shown to promote an anti-macrophage inhibitory factor or a macrophage migration inhibitory factor, a cytokine that modulates the immune response during pregnancy.

This reduces the activity of macrophage phagocytosis at the placenta-uterine interface, preventing destruction of the fetoplacental tissue.

Most observations suggest that hCG has an inhibitory or suppressive role for macrophage activity. HCG can directly enhance innate immunity by stimulating macrophage function.

In some studies hCG / LH receptors have been found in the myometrium of the uterus

It has been suggested that uterine growth in line with fetal growth can be stimulated by hCG, so that the uterus expands with the size of the fetus during pregnancy.

Similarly, hCG has been shown to relax myometrial contractions during the course of pregnancy. HCG acts on a calcium channel activated BK-Ca to relax the myometrium during the course of pregnancy.

HCG levels decrease during the last weeks of pregnancy. It has been suggested that this drop may be the cause of increased contractions in the weeks leading up to delivery.

HCG / LH receptors in the fetal kidney and liver

HCG / LH receptors have been located in the lung, liver, kidneys, spleen, and small and large intestine.

Interestingly, this hCG / LH receptor is present in fetus organs, but is completely absent in adult organs. It is suggested that hCG can promote the growth and differentiation of organs in the fetus.

The human fetus could produce its own hCG from the kidneys and liver.However, the hCG concentrations in the fetal circulation are much lower than the maternal concentrations, suggesting that the placental secretion of hCG is directed into the maternal circulation and its entry into the fetal circulation is prevented.

While the hCG / LH receptor has been shown in fetal organs, no function has been directly demonstrated, simply indicated by the presence of the receptor. As such, all findings regarding the fetus should be considered as suggestions only at this time.

Unfortunately, all animals except advanced primates do not produce a form of hCG, so it is difficult to confirm the role of hCG in the fetus.

 HCG works in the growth and development of the umbilical cord

Interestingly, hCG and hyperglycosylated hCG work together to promote growth (growth of cytotrophoblastic cells in the root, hyperglycosylated hCG) and differentiation (promoted by hCG) of the placenta, and the promotion of uterine blood supply to cover the invasive placenta (promoted by hCG).

The next step is the development of the umbilical cord and circulation. This is also apparently promoted by hCG, suggesting hCG and hypergluosylation of hCG at multiple stages of placentation and fetal development.

Signaling between the non-implanted blastocyst and the decidua tissue

These non-vascular hCG communications are a critical part of a successful pregnancy.

Recent studies show the importance of a receptive endometrium and hCG preimplantation signaling in a successful pregnancy.

HCG signaling directly causes immunotolerance and angiogenesis at the maternal fetal interface. hCG increases the number of uterine natural killer cells that play a key role in establishing pregnancy.

Implantation function of hCG before pregnancy

Various studies show the presence of an hCG / LH receptor (shown by the presence of mRNA and the demonstration of receptor action) in human sperm and fallopian tubes. The function of the hCG / LH receptor in sperm is unclear.

Possibly it has something to do with fertility. The hCG / LH receptor in the fallopian tubes may be the one that acts on LH, which relaxes the fallopian tube for fertilization to occur.

It has long been speculated that hCG may play a role in the implantation of pregnancy. Publications suggest an autocrine or paracrine role for hCG in implantation of pregnancy.

Implantation hCG is apparently produced by cytotroplast cells. However, hCG is an endocrine. We now know from recent research that a variant of hCG, hyperglycosylated hCG, rather than hCG itself, is produced by cytotrophoblast cells.

Hyperglycosylated hCG is either autocrine or paracrine and has been shown to directly promote implantation of pregnancy.

This appears to be what was considered the implantation function of hCG. A recent study suggests a direct role for hCG in cytotrophoblast cell metalloproteinase production, this could be true and needs careful investigation.

The hCG / LH receptor has been shown in the brains of adult women

CNS receptors are present in several areas of the brain such as the hippocampus, hypothalamus, and brain stem. Finding an hCG receptor in these parts of the brain may explain hyperemesis gravidarum or nausea and vomiting that occurs during normal pregnancy.

In total, hCG has a wide range of actions through the hCG / LH receptor. HCG and hyperglycosylated hCG appear to act together to promote the growth and differentiation of trophoblast cells or the formation of the villous structures of the placenta.

They appear to start their action early with the endometrial signaling of the next blastocyst implantation.

Hyperglycosylated hCG promotes implantation and growth of cytotrophoblast cells. HCG promotes the differentiation of cytotrophoblast cells with syncytiotrophoblast cells, and thus villous structures are formed that are a mixture of the two types of cells.

HCG also promotes the uterine vasculature to provide maximum blood to the hemochoric placentation structure. hCG also acts on the fetus to promote growth and differentiation of fetal organs.

During this time, hCG acts on the maternal brain to promote hyperemesis gravidarum. Taking it all together, hCG and hyperglycosylated hCG are the hormone and autocrine that apparently control pregnancy.

Biological function of hyperglycosylated hCG

Hyperglycosylated hCG is a glycosylation variant of hCG produced by root cytotrophoblastic cells and extravillous cytotrophoblast cells. It shares the amino acid sequences of the hCG α and β subunits with 8 oligosaccharide side chains.

HCG has monoantennial N-linked oligosaccharides (8 sugar residues) and biantennials (11 sugar residues), and mainly O-linked trisaccharide oligosaccharides (3 sugar residues).

Hyperglycosylated hCG has mainly fucosylated triantennial oligosaccharides (15 sugars) N-linked and double-size O-linked hexasaccharide oligosaccharides (6 sugar residues).

As a result, the molecular weight of hCG is 36,000, while the molecular weight of hyperglycosylated hCG is 40,000 to 41,000, depending on the degree of hyperglycosylation.

The additional sugar structures in hyperglycosylated hCG appear to prevent complete folding of the αβ dimer. This exposes another receptor binding site on hyperglycosylated hCG.

The function of hyperglycosylated hCG, the blockade of apoptosis, and a possible promoter activity of metalloproteinase, suggests that hyperglycosylated hCG may be an antagonist of the functions controlled by the TGFβ receptor in cytotrophoblast cells.

Although these pathways appear highly probable from multiple studies of placental implantation, apoptosis of cytotrophoblast cells, cytotrophoblast cells and metalloproteinases, and placental invasion biology, this TGFβ receptor is involved in these actions.

This still needs to be proven by the necessary research. Hyperglycosylated hCG appears to act by antagonizing a cytotrophoblastic receptor for TGFβ, apparently blocking apoptosis and promoting invasion by metalloproteinases.

So hyperglycosylated hCG is the main variant of hCG produced in early pregnancy. Hyperglycosylated hCG comprises an average of 87% of the total hCG produced in the serum during the third week, 51% during the fourth week, and 43% during the fifth week of gestation.

Hyperglycosylated hCG levels decrease to <1% of total hCG during the 2nd and 3rd trimesters of pregnancy. This is consistent with hyperglycosylation of hCG which has a role in promoting implantation in early pregnancy.

Hyperglycosylated hCG acts on choriocarcinoma cells (cytotrophoblastic cell cancer) promoting invasion. Hyperglycosylated hCG is the main hCG variant produced by choriocarcinoma cells.

The role of hyperglycosylated hCG in choriocarcinoma invasion has now been demonstrated by 3 independent groups, each of which shows that this molecule promotes invasion by choriocarcinoma cells into the Matrigel chambers.

Other studies examine the growth of transplanted choriocarcinoma cells in nude mice in vivo.

Blocking hyperglycosylated hCG with an antibody specific for hyperglycosylated hCG, or by blocking the expression of α and β subunit DNA, has been shown to reduce the total growth of choriocarcinoma.

All of these findings suggest the use of a blocking agent, such as an antibody against hyperglycosylated hCG in the treatment of choriocarcinoma.

Some other research has indicated that hyperglycosylated hCG, the promoter of cytotrophoblastic cell invasion in choriocarcinoma, specifically promotes invasion in pregnancy implantation and deep implantation of villous placental structures driven by extravillous cytotrophoblastic cells.

Laboratory experiments show that the hyperglycosylated hCG antibody, antibody B152, blocks the growth of cytotrophoblast cell lines in vitro.

 Hyperglycosylated hCG promotes the growth of cytotrophoblastic cells, during implantation and in choriocarcinoma.

There are publications that explain that two thirds of pregnancy failures, biochemical pregnancies and miscarriages of pregnancy are due to the failure of the blastocysts to implant properly.

The remaining third of failures are due to hydatidiform mole or genetic abnormalities. A total of 62 pregnancies were investigated. On the day of pregnancy implantation, 42 of 42 term pregnancies produced only hyperglycosylated hCG in vivo (26 of 42 cases) or> hyperglycosylated hCG> 50% of total hCG.

Studies conducted and published indicate that two-thirds of failures (13 of 20) produced insufficient hyperglycosylated hCG or <50% hyperglycosylated hCG of total hCG.

It is inferred that pregnancy failures are due to insufficient production of hyperglycosylated hCG leading to failure to implant properly.

Similarly, hypertensive disorders of pregnancy or pre-eclampsia in pregnancy are due to lack of proper connection of the placental implantation of the villous haemochoria with the appropriate uterine blood supply. Studies indicate that this may also be due to a hyperglycosylated hCG deficiency.

In conclusion, hyperglycosylated hCG is the invasive sign of cytotrophoblast invasion of pregnancy implantation and invasion of choriocarcinoma.

Ineffective invasion due to insufficient hyperglycosylated hCG occurs in failed pregnancies, biochemical pregnancies, and miscarriages, and apparently in hypertensive disorders of pregnancy.

Biological function of the free β subunit

The free β-subunit produced is a hyperglycosylated variant of the β-subunit of hCG with triantennial N-linked oligosaccharides and O-linked hexasaccharide oligosaccharides.

Excess β subunit or free β subunit occurs in hydatidiform mole, choriocarcinoma, and almost exclusively all primary non-trophoblastic cancers.

Studies and investigations show the presence of the free β subunit of hCG in the membranes of all cancer cell lines in vitro, and in all histological samples (slides) of malignant tumors.

This information is considered quite controversial. New data, however, apparently confirm these findings in cervical cancer cells.

Other studies indicate a clear association between the detection of the free β-subunit in serum samples or the detection of its degradation product, the central fragment of the β-subunit, in urine samples, with cases of advanced-grade and deficient-stage cancer. poor outcome malignancy.