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PubMed1996

Nicked free beta-subunit of human chorionic gonadotropin: a potential new marker for Down syndrome screening.

OBJECTIVE: Our purpose was to investigate maternal serum levels of nicked free beta-subunit in normal and Down syndrome pregnancies. STUDY DESIGN: Serum specimens were obtained from 64 karyotypically normal and 6 Down syndrome pregnancies before amniocentesis. Two immunoenzymometric assays for the beta- subunit of human chorionic gonadotropin were used to determine the level of free beta-subunits with peptide linkage breaks ("nicks") between residues 43 to 48. RESULTS: The mean level of nicked free beta-subunit in Down syndrome was 4.76 multiples of the median, which was significantly elevated compared with normal controls (1.07 multiples of the median, p<0.05). In 5 of 6 cases levels were > or = 2 multiples of the median, with a range of 1.96 to 15.43 multiples of the median, which was 2- to 3-fold higher than the regular free beta-subunit assay (mean level 1.53 multiples of the median, range 0.70 to 3.10 multiples of the median). In one case no nicked free-beta subunits were detectable. CONCLUSION: Our preliminary data indicate that nicked free beta-subunit of human chorionic gonadotropin might be a sensitive marker for Down syndrome screening.

Biomarkers↗

PubMed1992

Extraplacental human fetal tissues express mRNA transcripts encoding the human chorionic gonadotropin-beta subunit protein.

The glycoprotein hormone human chorionic gonadotropin (hCG) is synthesized in large quantities by the developing placenta, reaching peak concentrations in maternal blood during the late first trimester and early midtrimester of pregnancy. In general it is believed that the alpha-subunit of this dimeric hormone is expressed in pituitary gonadotropes, thyrotropes, and trophoblasts, while the beta-subunit is expressed exclusively by trophoblasts. Studies from our laboratory and other laboratories have shown that some midtrimester human fetal tissues, in addition to the placenta, can synthesize proteins that appear to be very similar to the beta-subunit of hCG. To define precisely the nature of this putative hCG-beta-subunit in extraplacental fetal tissues, we have examined the mRNA from a variety of human fetal and adult tissues using nucleic acid hybridization and reverse transcription-polymerase chain reaction (PCR) methods. Our results demonstrate that midtrimester fetal kidney and adrenal tissues contain hCG-beta mRNA transcripts at concentrations comparable to that of placenta, while fetal lung, brain, muscle, and adult adrenal contain only trace to undetectable levels of hCG-beta mRNA. By restriction endonuclease mapping of PCR fragments from fetal tissue cDNAs, we show that the hCG-beta transcript expressed in midtrimester human fetal organs is a bone fide copy of hCG-beta gene No. 5 of the beta-subunit gene family located on chromosome 19.

Base Sequence↗

PubMed1994

Bacterial expression and in vitro folding of the beta-subunit of human chorionic gonadotropin (hCG beta) and functional assembly of recombinant hCG beta with hCG alpha.

A bacterial expression system for the beta-subunit of hCG (hCG beta) has been developed to produce suitable amounts of this protein for structural and biological studies. To produce hCG beta in Escherichia coli, the nucleotide sequence that encodes the amino acid leader sequence was removed from the hCG beta complementary DNA, and the gene was cloned into a pET expression vector. After induction of protein synthesis in host bacteria, recombinant hCG beta (rhCG beta) accumulated in inclusion bodies in an unfolded state. The inclusion bodies were purified from induced cultures of E. coli, solubilized in urea, and fractionated by reverse phase HPLC. In this way, 6-7 mg unfolded hCG beta were recovered from 1 liter culture, rhCG beta was folded in the presence of 6.4 mM cysteamine and 3.6 mM cystamine at pH 8.7 at a final concentration of 0.02 mg/ml protein. The folded protein assembled with urinary hCG alpha and the purified rhCG beta/urinary alpha dimer bound to and activated the human LH/CG receptor permanently expressed in a cell line, indicating that it was a functional hormone. The rhCG beta/urinary alpha dimer also stimulated in vivo ovulation in rats, thus confirming the biological activity of bacterially expressed hCG beta. Because E. coli lacks the ability to glycosylate proteins, these activity results indicate that the N-linked and O-linked oligosaccharides of hCG beta are not required for protein folding, subunit assembly, or full biological activity. The success of producing hCG beta in bacteria and of folding it in vitro implies that the beta-subunits of the other members of the glycoprotein hormone family, LH, FSH, and TSH, can also be produced in this manner. This may facilitate structural studies of these hormones as well as lead to the production of recombinant hormones for biological studies and clinical use.

Animals↗

PubMed1994

Beta-subunit of human chorionic gonadotropin hormone and firefly luciferase simultaneously synthesized in insect cells using a recombinant baculovirus are differentially expressed and transported.

A recombinant baculovirus vAc beta hCG-luc was constructed that carried the cDNAs encoding firefly luciferase (luc) and beta-subunit of human chorionic gonadotropin (beta hCG) placed under the transcriptional control of individual copies of the baculovirus polyhedrin gene promoter. The simple, rapid, and sensitive detection of LUC expression was used for selecting recombinant viruses that simultaneously expressed beta hCG, which was identical in all respects to that synthesized using a recombinant baculovirus carrying the beta hCG gene alone. Immunofluorescence staining of virus-infected cells using anti-LUC antibodies revealed that LUC, a nonglycosylated, intracellular protein was retained within the cells whereas beta hCG, an extensively glycosylated, secretory protein, was processed and secreted into the culture medium. LUC and beta hCG were both immunoreactive on Western blot. beta hCG was bioactive, as evident from its ability to associate with alpha hCG and bind with the receptor and produce testosterone in an in vitro mouse Leydig cell assay system. Comparison of recombinant LUC and beta hCG synthesized by the virus-infected insect cells surprisingly revealed that the level of the former was quantitatively higher by at least 10-fold than the latter. A blot of total RNA isolated from vAc beta hCG-luc-infected insect cells, when probed with probes corresponding to the 3' region of the beta hCG or luc genes, indicated differential transcription of the two genes. Computer-aided sequence analysis indicated extensive secondary structure and stem-loop complex-forming potential of the beta hCG gene, which could be responsible for the transcriptional difference observed.

Amino Acid Sequence↗

PubMed1987

A potential anti-pregnancy vaccine built by conjugation of the beta-subunit of human chorionic gonadotropin to adjuvant-active muramyl peptide.

The beta-subunit of human chorionic gonadotropin (hCG) conjugated to tetanus toxoid is being investigated as a vaccine for human fertility control. Initial clinical trials indicated that the level of antibody response induced by such an immunogen was not always sufficient to prevent pregnancy. Therefore, efforts are being made to evaluate new carriers for the beta-subunit and to select adjuvants to yield a more efficient vaccine. In the present report, we demonstrate that conjugates of the beta-subunit of hCG with muramyl dipeptide (MDP), or its nonpyrogenic derivative murabutide, may have potential as an effective antipregnancy vaccine. The copolymer of beta hCG and MDP administered with Al(OH)3 to mice induced a high anti-beta hCG response, better than that induced by the conjugate of beta hCG to tetanus toxoid given with Al(OH)3. Moreover, the antibodies induced by such an immunogen were competent for neutralizing the biological activity of hCG in vivo. Even more interesting, a copolymer of beta hCG and of murabutide induced high levels of biologically active antibodies. This immunogen may represent a promising candidate for the development of an efficient vaccine for human fertility control.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1997

The role of carboxy-terminal portion of beta subunit of human chorionic gonadotropin in human immunodeficiency virus infection.

Human chorionic gonadotropin (hCG) and the beta subunit of this dimer glycoprotein hormone (beta hCG) have been reported by us to inhibit HIV replication. In order to identify the active site responsible for the antiviral activity, twelve overlapping peptides spanning across beta hCG were examined for their effect against HIV-caused cell death. Although the NH2-terminus of beta hCG appeared to contribute to activity, the core region was biologically inert. The most potent activity was observed with the fragment representing the carboxy-terminus of beta hCG. The dose response curve to serial dilutions of the peptide, containing amino acid residues 106-145, had a bell-shaped appearance - characteristic of hCG and beta hCG. The peak of activity corresponded to 100 ng/ml - the dose at which two thirds of virus-exposed MT-4 T lymphocytes survived. None of the tested peptides were toxic to MT-4. While the mechanism of action remains unclear, the results suggest that the COOH-terminal portion, unique to beta hCG, confers anti-HIV activity.

Anti-HIV Agents↗

PubMed1984

A contemporary approach to suspected ectopic pregnancy with use of quantitative and qualitative assays for the beta-subunit of human chorionic gonadotropin and sonography.

Although assays for the beta-subunit of human chorionic gonadotropin (beta-hCG) and ultrasonography have become popular diagnostic aids in the approach to patients with a suspected ectopic pregnancy, their true utility has not been clearly defined; in fact, the beta-hCG assay is so sensitive that proper clinical interpretation is sometimes difficult. A recent study describing a "discriminatory zone" (beta-hCG level of 6000 to 6500 mIU/ml), which correlates beta-hCG levels with appearance of a gestational sac on ultrasound scans, has been reported to be of diagnostic benefit. A prospective study of 103 women with suspected ectopic pregnancy was undertaken utilizing an algorithm which included beta-hCG assays (quantitative as well as qualitative) and ultrasonography. Seventy-three patients were found not to be pregnant, and seven had a normal pregnancy, 14 patients ultimately had a spontaneous abortion, and seven ectopic pregnancies were identified. The following conclusions were drawn: (1) a qualitative beta-hCG assay with a sensitivity of 25 mIU/ml is an effective test in screening for ectopic pregnancies; (2) the concept of a "discriminatory zone" is valid but not of frequent clinical utility, since most patients suspected of having an ectopic gestation have beta-hCG levels below this zone; (3) serial monitoring of beta-hCG values is an important diagnostic aid; (4) culdocentesis is still an important contemporary diagnostic test for the patient suspected of ectopic pregnancy.

Abortion, Spontaneous↗

PubMed1987

Declining serum concentrations of the beta-subunit of human chorionic gonadotropin and ruptured ectopic pregnancy.

Declining values of the beta-subunit of human chorionic gonadotropin may be associated with ectopic pregnancy or missed abortion. Sonography may not always establish a definitive diagnosis. A case is presented where expectant management of declining levels resulted in rupture of an ectopic pregnancy. Declining values of the beta-subunit of human chorionic gonadotropin should not give the clinician a false sense of security in managing first-trimester pregnancy disorders.

Adult↗

PubMed1992

Simultaneous synthesis of enzymatically active luciferase and biologically active beta subunit of human chorionic gonadotropin in caterpillars infected with a recombinant baculovirus.

The beta subunit of human chorionic gonadotropin (beta hCG), a secretory and extensively glycosylated hormone, and firefly luciferase, a non-secretory enzyme, were simultaneously synthesized in Spodoptera larvae upon infection with a dual expression recombinant baculovirus, vAc beta hCG-luc. Luciferase was retained predominantly in the body tissue while beta hCG was secreted into the hemolymph of infected larvae. Both the proteins were similar to their authentic counterparts in terms of immunoreactivity and bioactivity. The caterpillar-derived recombinant hCG exhibited reduced electrophoretic mobility on SDS-PAGE and increased biological activity as compared to the hCG expressed in insect cells in culture. The implications of using the larval system for expressing an extensively glycosylated protein are discussed.

Animals↗

PubMed2002

The free beta-subunit of human chorionic gonadotropin as a prognostic factor in renal cell carcinoma.

The free beta-subunit of human chorionic gonadotropin beta is expressed in several nontrophoblastic tumours and this is usually associated with aggressive disease. Little is known about human chorionic gonadotropin beta expression in renal cancer. We determined the pretreatment levels of human chorionic gonadotropin beta in serum of patients with renal cell carcinoma, and studied whether elevated levels predicted the clinical outcome. Serum samples were collected before surgery from 177 patients with renal cell carcinoma and from 84 apparently healthy controls. Human chorionic gonadotropin beta in serum was measured by a highly sensitive time-resolved immunofluorometric assay. The prognostic value of human chorionic gonadotropin beta, and of usual clinical and pathological variables was analyzed by the Kaplan-Meier method, the log rank test and Cox multiple hazard regression. The serum concentrations of human chorionic gonadotropin beta were increased in 23% of the renal cell carcinoma patients and they were significantly higher in patients with renal cell carcinoma than in controls (P<0.0001). The concentrations did not correlate with clinical stage and histopathological grade, but patients with increased human chorionic gonadotropin beta levels had significantly shorter survival time than those with levels below the median (cut-off 1.2 pmol l(-1), P=0.0029). In multivariate analysis human chorionic gonadotropin beta, tumour stage and grade were independent prognostic variables. The serum concentration of human chorionic gonadotropin beta is an independent prognostic variable in renal cell carcinoma. The preoperative value of human chorionic gonadotropin beta in serum may be used to identify patents with increased risk of progressive disease.

Adult↗

PubMed1999

Beta-hairpin stabilization in a 28-residue peptide derived from the beta-subunit sequence of human chorionic gonadotropin hormone.

The beta-subunit of the human chorionic gonadotropin (hCG) hormone, which is believed to be related to certain types of cancer, contains three hairpin-like fragments. To investigate the role of beta-hairpin formation in the early stages of the hCGbeta folding, a 28-residue peptide with the sequence RDVRFESIRLPGSPRGVNPVVSYAVALS, corresponding to the H3-beta hairpin fragment (residues 60-87) of the hCGbeta subunit, was studied under various conditions using three optical spectroscopic methods: Fourier transform ir spectroscopy, electronic CD, and vibrational CD. Environmental conditions are critical factors for formation of secondary structure in this peptide. TFE : H(2)O mixed solvents induced helical formation. Formation of beta-structure in this peptide, which may be related to the native beta-hairpin formation in the intact hormone, was found to be induced only under conditions such as high concentration, high temperature, and the presence of nonmicellar sodium dodecyl sulfate concentrations. These findings support a protein folding mechanism for the hCGbeta subunit in which an initial hydrophobic collapse, which increases intermolecular interactions in hCGbeta, is needed to induce the H3-beta hairpin formation.

Amino Acid Sequence↗

PubMed1992

Free alpha-subunit, free beta-subunit of human chorionic gonadotropin (hCG), and intact hCG in sera of healthy individuals and testicular cancer patients.

To determine the serum concentrations of human chorionic gonadotropin (hCG), its free beta-subunit (hCG beta), and the free alpha-subunit (free alpha) common to all human glycoprotein hormones under physiological and pathological conditions, we developed monoclonal antibody-based immunoenzymometric assays. Free alpha-subunit was detected in the sera of all healthy individuals of both sexes; hCG was measurable in sera of 54% of the men, and 46% were positive for free hCG beta; in nonpregnant women, 69.5% were positive for hCG, 68.4% for the free beta-subunit. Pathological conditions, i.e., hCG-producing tumors, were studied in vitro and in vivo. In vitro, the concentrations of hCG, free hCG beta, and free alpha in tissue-culture supernates of a choriocarcinoma cell-line ("JAR") showed a parallel pattern during time-course analysis. In vivo, in long-term follow-up studies of 13 patients with testicular cancer, serum concentrations of the three analytes paralleled each other, whether the disease was in remission or not. Because of a selective increase of free hCG beta and free alpha in 27% of seminomatous tumor patients and in 13% of the nonseminomatous patients, the percentage of tumor-marker-positive sera was increased from 15% to 42% and 57% to 70%, respectively, by the additional measurement of free hCG beta and free alpha. Thus hCG, free hCG beta, and free alpha are physiologically present in a high percentage of the sera from healthy men, and the determination of free hCG beta and free alpha, although not of prognostic value, improves the diagnostic possibilities in patients with testicular cancer.

Choriocarcinoma↗

PubMed1978

Recognition of the beta-subunit of human chorionic gonadotropin and sub-determinants by target tissue receptors.

The beta-subunit of human chorionic gonadotropin, purified immunochemically to eliminate undissociated human chorionic gonadotropin, induced testosterone production by mouse Leydig cells at concentrations 400-fold higher than human chorionic gonadotropin. Steroidogenesis was also stimulated by a synthetic fragment of the beta-subunit of human chorionic gonadotropin conforming to the peptide sequence residues 39--71, whereas peptide sequence residues 39--56 and three C-terminal fragments (residues 115--145, 111--145 and 101--145) failed to cause steroidogenesis. These studies suggest the presence in the beta-subunit of human chorionic gonadotropin of determinants recognized by the tissue receptors, a part of these determinants residing between amino acid residues 57--71.

Animals↗

PubMed1998

Suppression by beta-mercaptoethanol of the intracellular hormonal dynamics of human chorionic gonadotropin-beta subunit (hCG-beta) in BeWo choriocarcinoma cells.

The effects of beta-mercaptoethanol (ME) on the steady-state level of mRNA of the human chorionic gonadotropin-beta subunit (hCG-beta) and the intracellular hormonal dynamics of the product protein were examined in BeWo cells, a choriocarcinoma cell line, using Northern blot analysis and a radioimmunoassay (RIA) specific for hCG-beta. ME reduced both medium and intracellular contents of hCG-beta in a dose-dependent manner, with its minimum effective dose being 0.01 per cent. The highest dose used (0.1 per cent) caused more than 90 per cent inhibition with both parameters, without affecting the cell number and the cell viability as verified by trypan blue exclusion. Significant reductions in both the medium and intracellular contents began to occur 6 h after the onset of incubation with ME. The ME-induced suppressions were reversible. Northern blot analysis showed that ME had no effects on the steady-state level of hCG-beta mRNA. When medium and cell lysates collected from ME-free incubations were incubated with 0.03 per cent ME, there were significant reductions of immunoreactive hCG-beta with both the medium and cell lysates. The magnitude of reduction, however, was much greater with the latter (75 per cent) than with the former (25 per cent). In contrast, the hCG-beta immunoreactivity of the RIA reference preparation was unaffected by incubation with ME. These results suggested that the major target(s) of ME action were the intracellularly located hCG-beta molecule, presumably its intramolecular disulphide bonds. It must also be pointed out that the hCG-beta molecule synthesized and secreted by BeWo cells have some structural deviation from the reference standard molecule of normal trophoblastic origin to explain the differential susceptibility to ME.

Choriocarcinoma↗

PubMed1994

Alpha-subunit and human chorionic gonadotropin-beta immunoreactivity in patients with malignant endocrine gastroenteropancreatic tumours.

In the serum of patients with malignant endocrine gastroenteropancreatic (GEP) tumours, both alpha-subunit (alpha-SU), common to all glycoprotein hormones, as well as free beta-subunit of human chorionic gonadotropin (hCG-beta) have been reported to be elevated in a substantial fraction. Both have been discussed as markers of malignancy in these neoplasms. In the present study we evaluated the diagnostic significance of alpha-SU and hCG-beta as serum markers in patients with malignant endocrine gastroenteropancreatic tumours. The study group consisted of 52 patients with endocrine GEP-malignancies (24 nonfunctioning, 23 carcinoid syndromes, four gastrinoma, one glucagonoma), located in the small intestine (n = 29), pancreas (n = 17), colon or rectum (n = 3), retroperitoneum (n = 2) and stomach (n = 1). alpha-SU and hCG-beta immunoreactivity was also assessed in the serum of patients with benign GEP-tumors (five insulinoma, and three gastrinoma). Concentrations of alpha-SU and hCG-beta were determined using two highly sensitive and specific immunoradiometric assays employing two monoclonal antibodies each. In 19 of 52 patients (37%), either alpha-SU (n = 9), hCG-beta (n = 7) or both subunits (n = 3) were elevated. In the subgroup of 24 patients with nonfunctioning GEP-tumours, increased concentrations of either alpha-SU (n = 6) or hCG-beta(n = 3) or both subunits (n = 1) were found in 10 of 24 patients (42%). In four of 23 patients with carcinoid syndrome (17%), either alpha-SU (n = 2), hCG-beta(n = 1) or both subunits (n = 1) were above the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

Enhancement of antigonadotropin response to the beta-subunit of ovine luteinizing hormone by carrier conjugation and combination with the beta-subunit of human chorionic gonadotropin.

Previous studies have demonstrated the control of fertility in monkeys on immunization with the beta subunit of ovine luteinizing hormone (beta-oLH) along with Freund's complete adjuvant (CFA). An eventual birth control vaccine would demand immunization without CFA. Beta-oLH linked to tetanus toxoid (TT) adsorbed on alum-induced antibody response in bonnet monkeys with detoxified sodium phthalyl derivative of Salmonella enteritidis lipopolysaccharide added only in the first injection. The antibodies reacted with both LH and human chorionic gonadotropin (hCG). A higher immune response was obtained with the use of a conjugate of beta-oLH and beta-hCG linked to a common carrier (TT) or with a mixture of beta-hCG/TT and beta-oLH/TT. In both cases, the antibodies were of high affinity with Ka ranging from 5 X 10(9) to 6 X 10(10) M-1. The antibodies were devoid of reactivity with human thyroid-stimulating hormone and human follicle-stimulating hormone. Monkeys with titers above 120 ng/ml hCG binding capacity (greater than 60 ng/ml in most cases) were protected from becoming pregnant during repeated mating with males of proven fertility in ovulatory cycles.

Animals↗

PubMed2004

Processing of O-linked glycosylation in the chimera consisting of alpha-subunit and carboxyl-terminal peptide of the human chorionic gonadotropin beta-subunit is affected by dimer formation with follicle-stimulating hormone beta-subunit.

hCG, LH, FSH, and TSH are a family of heterodimeric glycoprotein hormones that contain a common alpha-subunit, but differ in their hormone-specific beta-subunits. hCGbeta is unique among beta-subunits due to a carboxyl-terminal peptide (CTP) bearing four O-linked oligosaccharides. We previously reported that there were differences in O-glycosylation between two chimeras consisting of alpha-subunit and CTP, i.e. a variant with CTP at the N-terminal region (Calpha) and another analog with CTP at the C-terminus (alphaC) of the alpha-subunit. To address whether O-glycosylation is influenced by the heterodimer formation, Calpha and alphaC were expressed alone or with FSHbeta-subunit in Chinese hamster ovary cells. The O-linked glycosylation was assessed by continuous labeling with [(35)S]methionine/cysteine, immunoprecipitation with anti-alpha or anti-FSH serum, serial digestion with endoglycosidase-F and neuraminidase, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The decrease in molecular weight of dimeric chimeras digested with endoglycosidase-F was greater in Calpha than that in alphaC after treatment with neuraminidase, revealing that both chimeras have different numbers of sialic acids on O-linked carbohydrates. By treating with endoglycosidase-F, the dimeric alphaC migrated faster than its free form, whereas the mobility difference between assembled and unassembled forms of Calpha was very little. These data indicate that processing of O-glycosylation is affected by the backbone polypeptide chain(s).

Animals↗

PubMed1982

Could aspiration of the Graafian follicle cause luteal phase deficiency?

Luteal phase quality was evaluated in 32 patients wih nonstimulated cycles after laparoscopic oocyte recovery for in vitro fertilization. A luteal phase deficiency occurred in two cases (6.2%), the mean duration of the luteal phase was 13.5 +/- 1.3 days in 30 patients, and two patients developed amenorrhea of 23 and 43 days respectively after laparoscopy in spite of normal progesterone values 7 and 9 days after oocyte recovery. Six embryo transfers were performed after fertilization and regular cleavage of the obtained oocytes. No pregnancy resulted from the embryo transfers, although the patients had apparently normal luteal phases. In one patient there was a transient beta-subunit human chorionic gonadotropin (beta-hCG) elevation in serum. Luteal phase deficiency should not be main cause of a nonsuccessful embryo transfer. However, a prophylactic luteal phase support after oocyte recovery and embryo transfer in nonstimulated cycles is proposed.

Chorionic Gonadotropin↗