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Human chorionic gonadotrophin is a hormone that maintains the structure and function of the corpus luteum beyond its usual cycle, allowing the continuation of pregnancy. It is a luteotrophic agent, secreted by trophoblastic tissue of the embryo. It has multiple roles, including preventing rejection of the fetus, as well as affecting the hypothalamus to inhibit LH and FSH synthesis.
Recently, it has been found to exist in a hyperglycosylated form and also as the free beta subunit of hyperglycosylated hCG, in addition to the regular form. These variants have different structures and functions. Assays for these hCG variants are being widely used clinically in pregnancy detection, prediction of spontaneously aborting and ectopic pregnancies, and prediction of trisomy pregnancies. Measuring the levels of particular forms has also been found useful in detection and management of a wide range of malignancies, such as choriocarcinoma and placental site trophoblastic tumours.
The biology and uses of hCG
Human chorionic gonadotrophin (hCG) is a glycoprotein hormone which maintains the structure and function of the corpus luteum beyond its usual cycle of 12-14 days. This allows the secretion of progesterone to carry on, which is required for the continuation of pregnancy. However, this only explains the initial function of regular hCG. In recent years, research has explained the many roles of hCG throughout gestation, its different structural forms and its wide variety of clinical applications through new methods of detection (Pocock & Richards, 2006).
Regular hCG is made by fused villous syncytiotrophoblast cells. Its structure is similar to that of anterior pituitary LH but has a longer half-life. Regular hCG has a molecular weight of 36 kDa; it consists of a 145 amino acid Î²-subunit and a 92 amino acid Î±-subunit joined non-covalently (Cole, 2009). Placental hCG is secreted from a very early stage in pregnancy by trophoblastic tissue of the embryo to replace pituitary LH in controlling progesterone production from implantation. It is thought to provide the signal that enables the mother's body to recognise the existence of a fertilised egg. Luteal progesterone is required for the first six to eight weeks of pregnancy and loss of the ovaries during this period will result in miscarriage. Ongoing secretion prevents shedding of the uterine endometrium and spontaneous contractile activity of the myometrium is inhibited (Pocock & Richards, 2006).
During pregnancy, hCG undergoes a specific profile of secretion. It appears in the maternal circulation a few days after fertilisation, and can be detected in the urine by about two weeks after ovulation. Levels of hCG increase steadily up to 10 weeks of gestation, before falling quite sharply over the following few weeks. After six to eight weeks, the placenta is well established and is able to synthesise and secrete enough progesterone to maintain the remaining gestation period. At this point, pregnancy is said to be autonomous. The drop in hCG secretion after about eight weeks is probably due to the diminishing requirement for the hormones of the corpus luteum (Pocock & Richards, 2006).
However, promoting progesterone production is not the sole function of hCG. Research in the past 10 years has shown that a more logical primary function of hCG is maintaining maternal blood supply to support hemochorial placentation and nutritional support of the fetus. hCG maintains angiogenesis in the myometrial spiral arteries through the length of pregnancy, acting on LH/hCG receptors on the spiral arteries. It has also been shown that hCG promotes the fusion of villous cytotrophoblast cells to syncytiotrophoblast (Shi et al., 1993). Both of these biological functions are critical for efficient placentation in humans.
The hormone acts as a powerful luteotrophic agent secreted by the zygote. It is important because of its early appearance in maternal body fluids following fertilisation and can be detected in maternal plasma as early as seven days after ovulation. Its presence in the urine about two weeks after ovulation makes it suitable as a reliable and simple test for pregnancy (Pocock & Richards, 2006). The urine test which detects hCG is simple enough to be carried out by women at home. In the 1980's, two-antibody immunometric assays for hCG arose, closely followed by sensitive antibody enzyme labelling and high sensitivity fluorimetric and chemiluminescent tracers. These are the currently used assay formats in commercial laboratories (Cole, 2009).
More sophisticated assay techniques can be used by clinicians to gain more information about the pregnancy. For example, higher than normal levels of hormone suggests the presence of twins. It is also useful to test early women who are prone to miscarriages due to insensitivity of the corpus luteum to hCG. Detecting the presence of an embryo early on would allow progesterone to be administered exogenously to prevent loss of the pregnancy when the corpus luteum regresses (Pocock & Richards, 2006).
hCG is also thought to play a role in preventing rejection of the fetus by the mother. The hormone has been found to upregulate human trophoblast indoleamine 2,3-dioxygenase, which catalyses the breakdown of tryptophan in villous circulation. This breakdown prevents the activation of lymphocytes which in turn prevents the fetoplacental tissues from being attacked by activated lymphocytes, which would lead to pregnancy loss. Lymphocyte inactivation at the maternal-fetal interface could be a key mechanism in the prevention of fetal rejection. Therapeutic hCG use can therefore prevent spontaneous as well as habitual miscarriages and prematurity (Lei et al., 2007).
It has been suggested that hCG may exert a direct effect on the maternal hypothalamus to inhibit the synthesis of FSH and LH. If so, this might contribute to the suppression of ovulation during pregnancy. It may also have an opposite effect in non pregnant women, during LH peaks or during menopause. Regular hCG may supplement the promotion of ovulation by extending the LH peak range, suggesting that it may also have a function in boosting the rise in progesterone levels during the beginning of the luteal phase of the cycle. In this circumstance the hormone is of pituitary origin, acting as a functional hormone during the menstrual cycle; it promotes either ovulation or progesterone production. Distinguishing the forms of hCG from differing sources is also important, as an hCG test would give a false positive by detecting pituitary hormone, erroneously indicating pregnancy (Pocock & Richards, 2006).
In recent years, hCG has been found not only to exist in its regular form, but also as a hyperglycosylated hCG (H-hCG) form and as the free beta-subunit of hyperglycosylated hCG. The structural differences allow a range of functions and uses of these variants. H-hCG is the principal form of hCG produced in the first weeks of gestation (Cole, 2003) and is an essential component for successful human implantation to prevent early pregnancy loss and spontaneous abortion. It is an autocrine hormone made by undifferentiated cytotrophoblast cells, and acts on these same cells to promote trophoblast invasion, as in implantation of pregnancy and malignancy in gestational trophoblastic diseases (Hamada et al., 2005). It is critical for promoting the mid-trimester hemochorial implantation, and for preventing preeclampsia (Cole, 2007). The hormone is also a biological tumour marker as it acts as a signal for choriocarcinoma cell invasion (Cole, 2006).
The structure of H-hCG includes a double size hexasaccharide, O-linked oligosaccharides and larger N-linked oligosaccharides. There is no difference in the hCG peptide sequence, only in the oligosaccharide side chains. The differences in hCG Î²-subunit O-glycosylation at serine positions 127, 132 and 138, are the main discriminator of regular and hyperglycosylated hCG (Cole, 2009).
A hyperglycosylated free beta-subunit also exists, produced by a high proportion of all malignancies. This also functions as an autocrine hormone by promoting the growth and invasion of the malignancy (Cole, 2009). The Î²-subunit is larger than in the regular hCG dimer, due to larger oligosaccharide side chains. The Î²-subunit has been detected in the urine of choriocarcinoma patients and individuals with non-trophoblastic neoplasm. The molecules have a high proportion of fucosylated trianntenary N-linked oligosaccharide structures and hexasaccharide O-linked oligosaccharides, comparable to hyperglycosylated hCG (Valmu et al., 2006). Many studies indicate that expression of free Î² can either directly or indirectly invoke a negative outcome in human malignancies. Both H-hCG and the Î²-subunit promote cancer cell growth, invasion and malignancy. They function by blocking or antagonising apoptosis, which consequently causes cell growth. The mode of action of both of these forms involves the use of the TGFÎ² receptor (Cole, 2009).
In early pregnancy, following implantation of the fetus, hCG is primarily the hyperglycosylated form. It would be beneficial for a pregnancy test to detect regular hCG and hyperglycosylated hCG equally. The nature of hCG changes as pregnancy progresses, becoming primarily regular hCG with up to 2% hyperglycosylated hCG in the second and third trimesters of pregnancy. Free Î²-subunit is also most evident in early pregnancy becoming an extremely minor component of total hCG during the latter stages of pregnancy (Cole, 2009).
Normal hCG is present at reduced levels during spontaneous aborting and ectopic pregnancies (Cole, 2007) while particularly low levels of H-hCG clearly mark failing pregnancies. Effective proportions of H-hCG (over 50%) are required for successful growth and invasion by cytotrophoblasts at the time of implantation. Below 50% H-hCG measured on the day of implantation absolutely indicates a failing pregnancy (Sasaki, 2008). The hCG doubling test has been widely used as an indication of pregnancy failure, miscarriage, or ectopic pregnancy between four and seven weeks of gestation, but it is only a very vague indication. Multiple studies suggest that measuring free Î²-subunit alone and H-hCG alone are much more accurate predictions to test for pregnancy failures. H-hCG can be used on the day of implantation to identify a term pregnancy versus failing pregnancy with 100% accuracy. H-hCG is also an outstanding marker for predicting third trimester hypertensive disorders and second trimester preeclampsia (Bahado-Singh et al., 2002).
H-hCG measurements may be more sensitive than regular hCG measurements in detecting pregnancy (Cole, 2003). Multiple studies have suggested that H-hCG may be used as an improved early pregnancy test in IVF settings. During IVF procedures, regular hCG is administered to promote poly-ovulation and it takes two to three weeks after embryo transfer for the administered hCG to leave the system. After the exogenous hCG has departed the system, the endogenous hCG can then be measured to indicate pregnancy. As H-hCG is the principal form of hCG produced in the first weeks of pregnancy, an H-hCG pregnancy test will only detect endogenous H-hCG independent of administered regular hCG. This would allow pregnancy detection as soon as implantation has occurred, or at three to four days after embryo transfer. Therefore H-hCG is a better pregnancy test than regular hCG for assisted reproductive technology applications (Cole, 2009).
H-hCG can also been used as a marker for fetuses with Down's syndrome, during both the first and second trimesters of pregnancy. In addition, H-hCG is a potential replacement for hCG in the antenatal screening of Down's syndrome (Cole, 1998). Poor trophoblast differentiation is a hallmark of Down syndrome pregnancies, so H-hCG measurements and other screening tests are effective markers (Cole & Khanlian, 2007). Immunoassay systems can measure hyperglycosylated forms of hCG using the antibody B152, for early pregnancy, as it is prevalent at this time (Birken, 2001). Down's syndrome pregnancies were associated with double hCG levels in the second trimester of pregnancy, however a triple test is used for predicting those at high risk. This involves a combination of three markers; hCG, Î±-fetoprotein and unconjugated estriol. Inhibin A can be added as a fourth marker for a quadruple test. Currently, the most commonly used predictor for Down's syndrome screening risk is ultrasound nuchal translucency with pregnancy-associated plasma protein-A (PAPP-A) and the Î²-subunit and also with PAPP-A and H-hCG.
Gestational trophoblastic diseases can be detected using total hCG and H-hCG immunoassays. Patients with a hydatidiform mole commonly present with unusually high serum hCG. It is possible for the hydatidiform mole to persist or there may be invasion of the uterus and other organs by extravillous invasive cytotrophoblast cells. Invasive mole is a malignancy comprising differentiated villous trophoblast cells and is marked by the significant presence of H-hCG. When invasive moles are detected, H-hCG comprises about 30-35% of total hCG, making them distinguishable from non-invasive moles (Cole, 2009).
Highly invasive choriocarcinoma is characteristed by nearly 100% of total hCG being present as H-hCG. This sets it apart from all other hCG producing diseases, allowing it to be identified. It is a malignancy of transformed non-villous non-differentiating cytotrophoblast cells. The choriocarcinoma cytotrophoblast cells produce H-hCG which drives growth and invasion. (Cole, 2009). In contrast, quiescent gestational trophoblastic disease is a syndrome involving inactive or benign gestational trophoblastic disease. It comprises primarily highly differentiated syncytiotrophoblast cells, with minimal extravillous villous or cancer cell cytotrophoblast cells so lacks H-hCG as the invasive signal (Cole, 2009).
Free Î²-subunit immunoassays can be used to detect placental site trophoblastic tumours (PSTT). PSTT is a malignancy of intermediate trophoblast cells, and does not produce H-hCG. The free Î²-subunit is primary produced rather than regular hCG or H-hCG, even though these tumours involve syncytiotrophoblast cells. In this case, H-hCG free Î² acts like H-hCG as a promoter of cancer cell growth and invasion (Cole, 2009).
H-hCG free Î² can be used as a marker for cancer, as almost every human malignancy in advanced stages produce the Î²-subunit. However, more recent studies show that while the free Î² is not a reliable diagnostic marker or a good marker in these non-trophoblastic malignancies it has proved to be an excellent marker for poor prognosis. H-hCG free Î² is terminally degraded to generate Î²-subunit core fragment, Î²6- 40 disulfide linked to Î²55-92, with degraded oligosaccharides, a more sensitive tumour marker in urine samples. Serum H-hCG free Î² and urine Î²-subunit core fragment have both proven useful in the detection and management of a wide range of malignancies. The expression of the free Î² or detection of Î²-subunit core fragment in a patient with malignancy correlates with poor grade and stage of tumour, indicating that expression of free Î² is associated with a negative outcome in human malignancies (Cole, 2009).
In conclusion, hCG can now be viewed as 3 independent molecules with different carbohydrate structures and roles; regular hCG, hyperglycosylated hCG and the free Î²-subunit. Not only does it maintain the corpus luteum to allow the continuation of pregnancy, but it also promotes myometrial spiral artery angiogenesis, has a role in preventing rejection of the fetus, as well as affecting the hypothalamus to inhibit LH and FSH synthesis. Assays for these hCG variants are being widely used clinically in pregnancy detection and prediction of spontaneously aborting, ectopic and trisomy pregnancies. The levels of each form can also be indicative of malignancies, such as total hCG and H-hCG detecting gestational trophoblastic diseases and the free Î² subunit being an excellent marker for poor prognosis. There have many advances in the field of hCG, and it is likely there will be more improvements in hCG clinical applications in the future.