The hormone hCG comprises an α-subunit and a β-subunit. The α-subunit is common to hCG, to the autocrine/paracrine hyperglycosylated hCG, to the hormone pituitary hCG, and to the hormones LH, follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH), and to the common free α-subunit formed in excess. The β-subunit of hCG, while 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 just 25-30 minutes [15
], while hCG, pI 3.5, has a circulating half-life of approximately 37 hours [16
], or 80-fold longer than that of LH. In many respects hCG is a super LH produced in pregnancy, with 80X the biological activity of LH, yet acting on the joint receptor. While LH, FSH and TSH are made by the anterior lobe of the pituitary, hCG is produced by fused and differentiated placental syncytiotrophoblast cells [6
The original biological activity of hCG was first revealed in the nineteen twenties and confirmed and elaborated in the years that followed [1
]. With pregnancy, hCG takes over from LH in promoting progesterone production by ovarian corpus luteal cells, preventing menstrual bleeding (Table ). As we know today, hCG only promotes progesterone production for 3-4 weeks following pregnancy implantation. This function is active for approximately 10% of the length of pregnancy. As shown in Tables and hCG reaches a peak at 10 weeks of gestation, or almost one month after progesterone promotion is complete, then continues to be produced through the length of pregnancy. Clearly, progesterone production is not the principal purpose of hCG. As illustrated in Table , hCG has been shown in recent years to have numerous functions in the placenta, uterus and possible in the fetus during pregnancy.
The biological functions of the isoforms of hCG.
Concentration of total hCG and hyperglycosylated hCG (hCG-H) in 496 serum samples from 310 women with term pregnancies measured using the Siemens Immulite 1000 total hCG assay.
Concentration of total hCG and in 4246 urine samples from 574 women having term pregnancies measured using the Siemens Immulite 1000 total hCG assay.
The research groups of Rao et al., Zygmunt et al., and Noel et al., have each shown that hCG also functions to promote angiogenesis and vasculogenesis in the uterine vasculature during pregnancy. This insures maximal blood supply to the invading placenta and optimal nutrition to the fetus [24
] (Table ). The hCG/LH receptor gene is expressed by uterine spiral arteries, and hCG acts on them to promote angiogenesis. This is probably a major function of hCG during the course of pregnancy insuring adequate blood supply or nutrition to the placenta. hCG also has an important function at the placenta trophoblast tissue level promoting the fusion of cytotrophoblast cells and their differentiation to syncytiotrophoblast cells [31
] (Table ). Testicular gem cell cancers take on trophoblast cytology. hCG may function similarly to promote differentiation of testicular cancer cytotrophoblast cell.
Four independent research groups showed that hCG promotes an anti-macrophage 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 foreign fetoplacental tissue [33
] (Table ). Three other groups have shown that hCG may directly suppress any immune action against the invading foreign tissue [36
]. All told, hCG appears to be one of the numerous factors acting to prevent rejection of the fetoplacental tissue. Most observations suggest that hCG has an inhibitory or suppressive function on macrophage activity. One group, Wan et al. [35
] demonstrated that hCG can directly enhance innate immunity by stimulating macrophage function.
Multiple groups have found hCG/LH receptor in the myometrium of the uterus. It has been indicated by two groups that uterine growth in line with fetal growth may be stimulated by hCG, so that the uterus expands with fetal size during pregnancy [39
] (Table ). Four groups have shown that hCG relaxes myometrial contractions during the course of pregnancy. hCG acts on a BK-Ca calcium activated channel to relax to myometrium during the course of pregnancy [39
]. hCG levels drop during the final weeks of pregnancy. It has been suggested that this drop may be the cause of increased contractions in the weeks prior to delivery.
Exciting new research is finding hCG/LH receptors in fetal organs. Goldsmith et al. [44
], have found hCG/LH receptors in the fetal kidney and liver. Rao et al. [45
], have located hCG/LH receptors in the lung, liver, kidneys, spleen, and small and large intestines. Interestingly, this hCG/LH receptor is present in the fetal organs but completely absent in the adult organs. It is suggested that hCG may promote organ growth and differentiation in the fetus. The human fetus might produce its own hCG from the kidneys and liver [44
]. The concentrations of hCG in the fetal circulation, however, are much lower than maternal concentrations, suggesting that placental hCG secretion is directed towards the maternal circulation and it is prevented from entering into fetal circulation [50
]. While hCG/LH receptor has been shown in fetal organs, no function has been directly demonstrated, just indicated by the presence of receptor. As such, all the findings regarding the fetus have to be considered as just suggestions at this time. Unfortunately, all animals except advanced primates do not make a form of hCG, making the role of hCG in the fetus difficult to confirm.
hCG has also been shown to function in umbilical cord growth and development [51
]. It is interesting that hCG and hyperglycosylated hCG work together to promote the growth (growth of root cytotrophoblast cells, hyperglycosylated hCG) and differentiation (promoted by hCG) of the placenta, and promotion of the uterine blood supply to meet the invading placenta (promoted by hCG). The next step is the development of the umbilical cord and circulation. This is also seemingly promoted by hCG, suggesting hCG and hyperglycosylated hCG involvement in multiple steps of placentation and fetal development [44
Multiple publications suggest a signaling occurs between the unimplanted blastocyst and the decidua tissue [54
]. Four independent reports show that the blastocyst preimplantation secretes hCG into the uterine space which is taken up by hCG/LH receptors on the endometrial surface (Table ). In response, the endometrium is prepared for an impending implantation [54
]. These non-vascular communications by hCG are a critical part of successful pregnancy. Recent studies show the importance of a receptive endometrium and of hCG preimplantation signaling in a successful pregnancy [58
]. 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 the establishment of pregnancy [58
Other new data shows other pre-pregnancy implantation function of hCG. Publications from Rao et al. [61
] and by Gawronska et al. [63
], shows the presence of an hCG/LH receptor (shown by presence of mRNA and demonstration of receptor action) in human sperm and in the fallopian tubes (Table ). 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 that which is acted on by LH, which relaxes the fallopian tube for fertilization to take place.
It has long been speculated that hCG may have a role in implantation of pregnancy [64
]. Publications suggest an autocrine or paracrine function of hCG in implantation of pregnancy. hCG of implantation is seemingly produced by cytotropblast 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 [6
]. Hyperglycosylated hCG is an autocrine or paracrine and has been shown to directly promote implantation of pregnancy [6
]. This is seeming what was considered the hCG implantation function. Hyperglycosylated hCG and its role in implantation of pregnancy are reviewed in Section 3. A recent study by Fluhr and collages [65
], suggest a direct role of hCG in cytotrophoblast cell metalloproteinase production, this could be true and needs careful investigation.
Finally, the hCG/LH receptor has been demonstrated in adult women's brains. CNS receptors are present in several areas of the brain such as the hippocampus, hypothalamus and brain stem [68
] (Table ). The finding of an hCG receptor in these parts of the brain may explain the hyperemesis gravidarum or nausea and vomiting that occurs during normal pregnancy.
All told, hCG has a very wide range of actions through the hCG/LH receptor. hCG and hyperglycosylated hCG seemingly act to together to promote the growth and differentiation of trophoblast cells or formation of the placenta villous structures. They seemingly start their action early with blastocyst signaling of the endometrium of forthcoming implantation. Hyperglycosylated hCG then promotes implantation and growth of cytotrophoblast cells. hCG promotes the differentiation of cytotrophoblast cells to syncytiotrophoblast cells and so the villous structures which are mixture of the two cell types are formed. hCG also promotes the uterine vasculature to maximally provide blood to the hemochorial 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 everything together, hCG and hyperglycosylated hCG are the hormone and autocrine that seemingly control pregnancy.