Hormones are chemical messengers responsible for the regulation of many body processes. The term hormone is derived from a Greek word meaning "to excite." Hormone molecules diffuse from the blood into the interstitial fluid and then combine with receptor proteins on or in the cells of the target tissue. The metabolic activities of most cells are regulated by several different hormones, so cells must have receptors for each of these hormones. They generally belong to one of four different chemical groups: 1) steroids, 2) amino acid derivatives, 3) peptides or proteins, or 4) fatty acid derivatives. Human chorionic gonadotropin (hCG) is a glycoprotein hormone that was originally identified by virtue of its involvement in reproduction. This hormone and the pituitary hormones lutropin (LH), follitropin (FSH) and thyrotropin (TSH), comprise the glycoprotein hormone family. These hormones are composed of two non-covalently associated dissimilar subunits alpha and beta. The function of each subunit is not known, although it is presumed that since the beta-subunit confers target specificity, it is directly involved in receptor binding, while the common alpha may play the role of the active subunit once binding has occurred.
By considering the fact about the possible association between hCG and some crucial biological functions of the body, research about structure and functions of this hormone will enable scientists to solve more and more medical problems. Many of these problems are related to various human diseases particularly genetic diseases such as Down syndrome. In order to predict or treat these kind of deficiencies many researchers especially biochemists have been conducting numerous scientific experiments to obtain more and more valuable information about this pregnancy hormone. Structural and functional analysis of hCG, regulation and effect of hCG on reproductive organ blood flow, structural analysis of the carboxyl terminal peptide from human chorionic gonadotropin by nuclear magnetic resonance spectoscopy, human chrionic gonadotropin effect on nitric oxide synthase, relationship between hCG and Down syndrome are some of the most recent and most important topics that we will discuss in this paper.
Since the old days of scientific experiments basic structural studies of any organic or inorganic substance has always been considered as the first step to explore and to know that substance. Certainly, there is no exception in the case of human chorionic gonadotrpin (hCG) as well. To obtain some valuable information about the structure of hCG biochemists accomplished some studies on the tryptic core of the hCG beta-subunit and its characterization by immunological, and biological procedures. In that experiment the beta-subunit of hCG was digested with trypsin to produce a disulfide-linked residual core for structure-function studies and characterization of antibody. The beta-core was structurally characterized by isolating peptides, reduction and S-carboxymethylation, by ion exchange chromatography and HPLC procedures to establish the location of bond cleavages in the core. They found that trypsin cleaved hCC-beta between residues 2-3, 43-44, 74-75, 95-96, and 114-115. A comparison of the peptide bonds cleaved in hCG-beta with those in the disulfide-linked native protein, indicates that bonds beta 8-9, beta 20-21, beta 60-61,beta 63-64, and beta 68-69 are not accessible to trypsin in native hCG-beta, and thus, they may represent internal, or at least inaccessible, portions of the molecule. While use of native subunit does not elicit antibodies that will react against isolated peptides, precedents exist indicating that the use of isolated peptides as immunogens may enhance antibody recognition of part of the surface of the native molecule.
In human, hCG is synthesized by the placenta as well as by a variety of tumors. The hCG synthesis starts at a very early stage of pregnancy. The blastocyte secretes hCG on day 7 and, after implantation, the palcenta starts to produce huge amounts of hCG, of which more than 90% is released into the maternal circulation. The hCG biosynthesis reaches a peak between the 10th and 11th week of gestation. The synthesis of hCG starts declining between the 11th and 12th week of gestation and is maintained at a low level throughout the pregnancy, besides the intact hormone , free hCG subunits, enzymatically modified molecules are found in the urine and also in the serum of pregnant women.
The presence of hCG/LH receptors in the uterus and the cyclic nature of the receptor density suggest that, in some species, hCG/LH regulates uterine function. Initial human studies have shown a correlation between hCG level and decreased uterine vascular resistance in pregnancy. Studies in pseudopregnant rats conversely reveal that administration of hCG decreases uterine blood flow. In a scientific experiment, 50 IU of hCG was injected into some female Sprague-Davley rats. The high, 50 IU dose of hCG was based on the dose used for superovulation on rats. A single injection to the rat on each day of the 4-day estrus cycle decreased uterine blood flow by more than 30% within 20 min, but it did not alter uterine blood flow in ovariectomized rats. This dose of hCG also decreased ovarian blood flow and liver flow in estrus rats, but increased liver blood flow in ovariectomized rats. Injection of 0.10 IU hCG did not alter blood flow of reproductive organs in any group, but decreased liver flow in estrus rats. Neither dose of hCG changed cervical, kidney, or skeletal muscle blood flow in any group.
Another aspect of hCG that seems very important to scientists and researchers is its possible effect in creating cancer in different portions of the human body. Many human cancer cell lines of different types and origins have been tested and found to bear cell-surface hCG or its fragments. Vaccines based on hCG have thus been proposed as a means either to control fertility or to prevent cancer. Despite the clear potential of vaccines against hCG, none of the formulations currently under study have yet been shown to fulfill the requirement for their widespread use in humans.
Greater understanding of hCG's three-dimensional structure might yield information that would facilitate improvement of the hCG vaccines engineered thus far. Two crystallographic structures of hCG have recently been solved and they revealed that hCG is a member of the family of cysteine knot growth factors. Other proteins in this group are growth factor (PDGF) and transforming growth factor-beta (TGF_beta). In such proteins, both subunit association and receptor binding are dependent upon a segment of the beta chain being wrapped around the alpha chain linked by the disulfide Cys(26)-Cys(110).
A 37-amino acid peptide that constitutes the carboxyl terminus of the beta subunit of hCG is found uniquely in hCG and not in other related glycoproteins. This carboxyl terminal peptide is unusual in that 10 of the 37 amino acid residues are proline, which is known to introduce kinks into secondary structure elements of protein structures due to the constrained peptide chain conformations allowed by proline's ring structure. The carboxyl terminal peptide remains open since this region is disordered in the protein.
Preliminarily to accomplish the experiment mentioned above studies were focused on establishing NMR experiments. A purified sample of carboxyl terminal peptide was analyzed by NMR spectroscopy. Initial attempts to record NMR spectra of the peptide in solution were performed at 35 C with a peptide concentration of 4mM. Selective T1( longitudinal relaxation times) were determined for all resolved residues. To record informative and analyzable spectra, all subsequent experiments were conducted using peptide at a concentration of 8 mM and temperature of 4 C. Therefore, the final results were that double-quantum filtered correlated spectroscopy data on the peptide in water at 4 C reveals 27 multiplets in the peptide fingerprint region as expected. Absence of identifiably clear peaks in the nuclear Overhauser effect spectroscopy (NOESY) spectrum indicate that by itself in water the carboxyl terminal peptide of hCG appears to lack defined structure, and thus is likely a random coil.
The effects of human chorionic gonadotrophin on the production of nitric oxide synthesis is the other interesting aspect of this hormone which has been explored by researches for decades. At present, the physiological role of NO synthesis by hCG is unknown. However, since NO has emerged as an important intracellular and intercellular regulatory molecule having function as diverse as neural communication, cell growth regulation and host defense, it is tempting to hypothesize that this molecule is involved in the local control of the various fundamental processes. Also it has been demonstrated that NO may play a central role in control of the intrafollicular influx of inter- alpha-trypsin inhibitor protein and in the process of ovulation. Nitric oxide (NO) synthesis from L-arginine is generated by a form of nitric oxide synthase (NOS) that is Ca ion dependent.
The effects of human (hCG) on the production of nitric oxide (NO) by mouse peritoneal macrophages was examined. In that experiment TG-elicited macrophages were cultured in medium that contained rIFN_ (5U/ml). Then, cells were stimulated with hCG at various times during 48 hour culture, and NO release was measured. They found that hCG alone did not induce NO synthesis, whereas hCG in combination with rIFN- increased NO synthesis in cultured macrophages. The maximum cooperative effects of hCG for NO release were shown at 6 h after rIFN_ treatment. When hCG was added to rIFN- -treated cells, the synergistic effect was always maximal at 100 U/ml. Concentrations of less than 1 U/ml were considerably less effective. This increase in NO synthesis was reflected as increased amount of inducible NO synthase (iNOS)mRNA. The production of nitrite decreases with inhibition of iNOS by increasing the amount of arginase.
Down syndrome (DS) is one of the genetic diseases that is very closely related to human chorionic gonadotropin. As mentioned earlier, an increase in the knowledge of the structural and functional relationship could be used to predict and cure this genetic deficiency. Earlier screening for Down syndrome with the use of maternal serum markers would be desirable for several reasons because of the benefits to be derived from earlier diagnosis. Several analytes have been shown to be present in abnormally high or low concentration in the serum of pregnant women whose fetuses are affected by Down syndrome. The aim of this study was to examine the value of maternal serum beta-hCG (MS-beta-hCG), and maternal serum alpha-feoprotein MS-AFP levels in biochemical screening for Down syndrome in 19 women carrying a fetus affected by Down syndrom during the first trimester of pregnancy in relation to the normal range.
From 1990 to 1993, maternal serum samples were collected from 1138 women referred to their unit largely for advanced maternal age (94.4 per cent of the pregnant women were more than 35 years old), before undergoing first-trimester chorionic villus sampling (CVS). Gestational dating was performed by ultrasound scan in all women prior to sampling. First-trimester serum samples of 19 pregnancies carrying a fetus with DS were available for assay. For each week of gestation between 10 and 13 weeks, the medians of the serum analyte levels in continuing chromosomally normal pregnancies were determined. The results in DS pregnancies were then compared with this normal range for each gestational week. First-trimester screening with (MS-AFP) levels has been evaluated by some researchers suggesting that the second trimester of pregnancy, but there is little information available on its value in the first trimester. Some studies describe researchers preliminary results with biochemical screening for DS in the first trimester of pregnancy in order to evaluate its efficiency at this time.
Hormones are chemicals that regulate the activities of specific organs or cells. Hormones are produced by the endocrine glands and are transported by the bloodstream to target organs that contain cells that respond specifically to particular hormones. Human chorionic gonadotropin (hCG) which is a pregnancy hormone is a heterodimeric glycoprotein gormone that is involved in activation of the adenylate-cyclase system in luteal cells, which is essential for the maintenance of the corpus luteum in early pregnancy. It includes the pituitary hormones follitropin, lutropin and thyrotropin. The hormone consists of two dissimilar subunits, alpha and beta, which are non-covalently associated.
In the last couple of decades, a tremendous number of scientific experiments have been constantly done by different researchers to increase the human knowledge about this crucial pregnancy hormone. It is proved that hCG has very strong effects on many biological and physiological functions of human body such as blood flow, creation of cancer cells, some genetic diseases like Down syndrome and so on. Therefore, it would be one of the most efficient ways to improve medical science by knowing more about this hormone.
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