Immunological specificity of the beta subunit of the human chorionic gonadotropin (HCG).
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Binding Sites, Antibody↗
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A linear 23-residue peptide reveals a propensity to form an unusual native-like conformation.
To gain insight into the earliest events of protein folding, a 23-residue peptide with a sequence corresponding to the 38-60 fragment of the beta-subunit of human chorionic gonadotropin (hCG beta) was studied by NMR. In aqueous solution the majority of the peptide residues adopted an extended polyproline II (PII) conformation similar to those in mature, fully folded hCG beta. The finding that the isolated protein fragment may acquire native-like structural motifs, even without alpha-helices or beta-structures, extends the possibility of using free peptides as model systems to better understand the protein folding mechanisms. It was shown that the PII-rich structural motif can be determined efficiently by NMR spectroscopy. The observation that in the absence of extensive medium- and long-range interactions the majority of amino acid residues may adopt the PII conformation suggests that the PII-rich structural motifs may play an important role in early events of protein folding.
Base Sequence↗
Cystic trophoblastic tumor: a nonaggressive lesion in postchemotherapy resections of patients with testicular germ cell tumors.
Cystic trophoblastic tumor (CTT) is an uncommon lesion that is usually seen after chemotherapy in patients with testicular germ cell tumors. Its clinical significance has not been well studied. We identified 17 patients with CTT in retroperitoneal lymph node dissections (RPLNDs) after cisplatin-based chemotherapy for testicular germ cell tumors. None had other forms of persistent germ cell tumor except for teratoma, and no patient received additional chemotherapy after RPLND. At the time of RPLND, 7 patients were known to have had normal serum levels of beta-subunit of human chorionic gonadotropin (beta-hCG), whereas 5 had relatively mild elevations (1.6-165 mIU/mL, median, 8.0 mIU/mL). The CTTs consisted of circumscribed, small cysts, usually multifocal, lined by mostly mononucleated trophoblast cells with abundant eosinophilic cytoplasm, often with smudged nuclei and showing only infrequent mitotic figures. Although the epithelial lining was often stratified to several layers in thickness or formed intracystic papillary tufts, solid proliferations of trophoblast cells within the stroma were absent, as were clearly biphasic admixtures of mononucleated and multinucleated trophoblast cells. The cysts were either empty or contained fibrinoid material and were set in a hypocellular, fibrous stroma with adjacent teratoma. Stains for hCG highlighted rare cells. On follow-up of 15 patients, 11 were disease free (mean, 80 months). Three recurred with serum alpha-fetoprotein elevations at 25, 31, and 107 months, respectively, and one with beta-hCG elevation at 2 months. The latter patient, however, also had unresected mediastinal tumor postchemotherapy. We conclude that the finding of CTT in postchemotherapy resections does not warrant additional chemotherapy. Its clinical significance appears similar to that of residual teratoma.
Adolescent↗
Chemotherapy of extragonadal germ cell tumors.
Forty-nine patients with histologically proven germ cell tumors arising in extragonadal sites were retrospectively reviewed. Included in the review were an additional seven patients with undifferentiated tumors with a pathologic appearance compatible with that of a germ cell tumor and elevated levels of serum biomarkers (beta subunit of human chorionic gonadotropin [beta-HCG] +/- alpha-fetoprotein [AFP]. Nineteen patients had a pure seminoma arising in an extragonadal site, whereas 30 patients had nonseminomatous germ cell tumors. Seven patients had primary undifferentiated tumors with elevated levels of serum biomarkers. Sixteen (84%) of the 19 patients with pure extragonadal seminomas with normal levels of serum AFP are alive and free of disease. Eighteen of these 19 patients received platinum-containing regimens and four had received prior chemotherapy that failed. Of the patients with nonseminomatous germ cell tumors, 12 (40%) of the 30 are alive and free of disease with vinblastine/bleomycin +/- cisplatin (13 patients) or CISCAII (cisplatin, cyclophosphamide, and doxorubicin) (nine patients) alternating CISCAII/VBIV (eight patients) chemotherapy. None of the seven patients with undifferentiated germ cell tumors are alive and free of disease. Three of the five patients with pure anterior mediastinal endodermal sinus tumors treated with chemotherapy remain alive and free of disease. Of the seven patients with choriocarcinomas arising in extragonadal sites, three are alive and free of disease. A classification for patients with extragonadal germ cell tumors incorporating site of origin, histology, and likelihood of being truly extragonadal is proposed. The implications of this classification are discussed.
Abdominal Neoplasms↗
Maternal serum invasive trophoblast antigen and first-trimester Down syndrome screening.
BACKGROUND: In the United States, Down syndrome screening is still performed mainly in the second trimester, using 3 or 4 markers. Moving screening into the first trimester has the advantage of earlier diagnosis. Currently, first-trimester screening typically includes maternal serum pregnancy-associated plasma protein-A (PAPP-A), the free beta-subunit of human chorionic gonadotropin (free beta), and ultrasound measurement of nuchal translucency thickness (NT). The current report describes a case-control study of serum invasive trophoblast antigen (ITA) and its possible inclusion in first-trimester screening for Down syndrome. METHODS: As part of an earlier observational study, serum samples from 54 Down syndrome and 276 matched unaffected pregnancies were collected between 9 and 15 weeks of gestation. Samples had been aliquoted and stored at -20 degrees C for 8 years. ITA was measured and converted to weight-adjusted multiples of the median (MoM). The distributions of other first-trimester markers are from a single published study. RESULTS: Median ITA MoM in Down syndrome pregnancies increase as gestational age increases (2.02 MoM at 11 and 2.44 MoM at 13 completed weeks). At 75% detection, maternal age in combination with ITA and PAPP-A measurements have an 8.0% false-positive rate, slightly lower than the 8.8% found for the free beta and PAPP-A combination; adding NT measurements reduces false positives for the 2 combinations to 2.0% and 1.8%, respectively. CONCLUSION: Serum ITA appears to be a useful first-trimester Down syndrome marker that could replace free beta measurements while maintaining performance.
Autoanalysis↗
The unrecognized extragonadal germ cell cancer syndrome.
Within 3 years we saw 12 patients diagnosed initially as having poorly differentiated or undifferentiated carcinomas who, we believe, actually had extragonadal germinal cancers. Serum levels of the beta subunit of human chorionic gonadotropin (beta-HCG) or alpha-fetoprotein were useful in suggesting and supporting the diagnosis: Levels of one or the other were elevated in six of 10 patients in whom they were measured but levels of both, in only one patient. Staining of histologic specimens for beta-HCG or alpha-fetoprotein showed intracellular localization of one of these markers in the cancer cells of all four patients studied. All patients responded to therapy (11 treated with chemotherapy with or without radiotherapy, one with excision and radiotherapy only), with complete remissions in seven of 12. Two of the patients who had a complete remission have experienced relapse, and five have continued in disease-free remission from more than 8 to more than 56 months. Histologically atypical extragonadal germ cell neoplasms may be commoner than previously supposed. Physicians should consider this treatable and potentially curable cancer in selected patients having poorly differentiated or undifferentiated carcinomas.
Adult↗
Serum tumor markers.
Monoclonal antibodies are used to detect serum antigens associated with specific malignancies. These tumor markers are most useful for monitoring response to therapy and detecting early relapse. With the exception of prostate-specific antigen (PSA), tumor markers do not have sufficient sensitivity or specificity for use in screening. Cancer antigen (CA) 27.29 most frequently is used to follow response to therapy in patients with metastatic breast cancer. Carcinoembryonic antigen is used to detect relapse of colorectal cancer, and CA 19-9 may be helpful in establishing the nature of pancreatic masses. CA 125 is useful for evaluating pelvic masses in postmenopausal women, monitoring response to therapy in women with ovarian cancer, and detecting recurrence of this malignancy. Alpha-fetoprotein (AFP), a marker for hepatocellular carcinoma, sometimes is used to screen highly selected populations and to assess hepatic masses in patients at particular risk for developing hepatic malignancy. Testing for the beta subunit of human chorionic gonadotropin (beta-hCG) is an integral part of the diagnosis and management of gestational trophoblastic disease. Combined AFP and beta-hCG testing is an essential adjunct in the evaluation and treatment of nonseminomatous germ cell tumors, and in monitoring the response to therapy. AFP and beta-hCG also may be useful in evaluating potential origins of poorly differentiated metastatic cancer. PSA is used to screen for prostate cancer, detect recurrence of the malignancy, and evaluate specific syndromes of adenocarcinoma of unknown primary.
Antibodies, Monoclonal↗
[Analysis of death causes of gestational trophoblastic neoplasia patients].
OBJECTIVE: To analyze retrospectively the causes of death in gestational trophoblastic neoplasia (GTN) patients. The prognostic risk factors were also discussed. METHODS: One thousand one hundred and thirty GTN patients were hospitalized and treated at Peking Union Medical College Hospital from 1985 to 2004. Sixty-four of them died later and retrospective analyses were carried out on these patients. RESULTS: Fifty-eight out of the 64 patients died during initial treatment. The other six died from disease relapse and progression of the disease (PD). The major causes of death were multi-organ failure, intracranial haemorrhage, cerebral herniation, side-effects of chemotherapy, and PD after relapse. The result of multivariate analysis indicated the adverse prognostic factors included the interval between antecedent pregnancy and chemotherapy treatment (OR = 2.857, P < 0.01), the titer of beta subunit of human chorionic gonadotropin (beta-hCG, P < 0.05), the diagnosis of choriocarcinoma (OR = 3.635, P < 0.05), clinical stage (P < 0.05), multiple metastases (OR = 2.201, P < 0.01) and drug resistance (OR = 0.181, P < 0.01). CONCLUSIONS: A proper evaluation of a GTN patient before initial treatment is important. More attention should be paid to the death-related prognostic risk factors to improve the prognosis of high risk GTN patients.
Adult↗
Metastatic choroidal choriocarcinoma: a clinicopathological study.
A previously healthy 33-year-old woman presented with decreased vision and pain in her left eye. Funduscopic examination revealed a mass in the posterior pole of the eye, and chest radiography showed a lesion in the lower lobe of her left lung. The eye became painful and blind over 12 days and was enucleated. The tumour had the typical histopathological and immunohistochemical features of choriocarcinoma: sheets of cytotrophoblasts with pleomorphic nuclei and lacy cytoplasm intermingled with multinucleated syncytiotrophoblasts. The neoplastic cells stained positively for cytokeratin and the beta subunit of human chorionic gonadotropin (beta-HCG). The serum beta-HCG level was markedly elevated, at 82,000 (normally less than 5) IU/L. The patient was treated with combination chemotherapy, and normal serum beta-HCG levels were obtained. Thirty months after presentation the serum beta-HCG level was normal and there had been no clinical evidence of recurrence. To our knowledge this is the second case of metastatic choriocarcinoma in the eye in which the ocular tumour caused the presenting symptom.
Adult↗
beta-hCG as a diagnostic aid for suspected ectopic pregnancy.
During 13 months from November 1, 1977, through November 30, 1978, 283 patients underwent radioimmunoassay (RIA) for determination of serum beta-subunit of human chorionic gonadotropin (beta-hCG) to rule out ectopic pregnancy. The records of 234 patients were available for statistical analysis and of these, 188 (80%) had negative results, defined as less than 1 ng/ml. The ectopic group comprised 22 patients, all of whom had elevated beta-hCG levels. There were no false-negative results in either group. Patients with suspected ectopic pregnancy had symptoms similar to patients previously reported in the literature with proved ectopic pregnancies. The most common presenting symptoms of those with suspected ectopic pregnancy were abdominal pain (91%), amenorrhea (76%), irregular bleeding (68%), and andexal mass (55%). Seventy-three patients presented with the classic triad of pain, uterine bleeding, and adnexal mass. Only 10 (14%) had ectopic pregnancies. Urine pregnancy tests were found to be of no benefit in diagnosing ectopic pregnancy and confused the clinicians in some instances. In patients with suspected ectopic pregnancy, a negative beta-hCG, by the RIA technique ruled out ectopic pregnancy in 100% of the cases.
Adolescent↗
False-positive human chorionic gonadotropin levels caused by a heterophile antibody with the immunoradiometric assay.
A case of a false-positive test for the beta-subunit of human chorionic gonadotropin as performed by the immunoradiometric assay is described. Further studies revealed that this problem was secondary to a cross-reacting heterophile antibody.
Antibodies, Heterophile↗
Fetal tissue can synthesize a placental hormone. Evidence for chorionic gonadotropin beta-subunit synthesis by human fetal kidney.
Metabolically active tissues from second trimester human fetuses were examined for their ability to synthesize the placental hormones chorionic gonadotropin and chorionic somatomammotropin. During short-term incubation studies both placenta and fetal kidney were found to synthesize and secrete the beta-subunit of chorionic gonadotropin, whereas its synthesis was not observed in fetal liver, lung or muscle. In addition, chorionic somatomammotropin synthesis and secretion was demonstrated with placental tissue but could not be detected in any of the fetal tissues examined. These observations constitute the first evidence that the genome of a fetal tissue directs the synthesis of what is considered a placental hormone.
Chorionic Gonadotropin↗
Occurrence of molar pregnancy in patients undergoing elective abortion: comparison with other clinical presentations.
Clinical data of molar pregnancies found in women undergoing elective abortion (group 1, n = 39) were compared to those of molar pregnancies in women who experienced spontaneous abortions (group 2, n = 157) and women in whom molar pregnancy was discovered before symptoms of spontaneous abortion were evident (group 3, n = 209). Group 1 women were younger and experienced uterine evacuation at an earlier stage of amenorrhea than groups 2 and 3. Group 3 had larger uteri at evacuation and longer intervals of positive tests for the beta-subunit of human chorionic gonadotropin during the postmolar phase as compared with groups 1 and 2. On the basis of available provincial data for the number of elective abortions, the estimated incidence of molar pregnancies in this population was 1:2,699. The presence of malignant gestational trophoblastic neoplasia was documented in a single patient in group 1. The incidence of malignant gestational trophoblastic neoplasia in this group was not significantly different from that in groups 2 and 3. Routine pathologic examination of the products of conception in women undergoing elective abortion coupled with routine assays of the beta-subunit of human chorionic gonadotropin when molar pregnancy is found can identify both noninvasive and invasive trophoblastic disease in these women.
Abortion, Induced↗
Transvaginal ultrasonography in patients at risk for ectopic pregnancy.
Transvaginal ultrasonography was performed in 139 patients at risk for ectopic pregnancy. Among these patients, 22 ectopic pregnancies and 117 intrauterine pregnancies were eventually confirmed. Transvaginal ultrasonography definitively identified 18 of 22 (82%) ectopic pregnancies at initial evaluation by either direct visualization of an ectopically placed gestational sac (N = 14) or failure to visualize an intrauterine gestational sac combined with a level of the beta-subunit of human chorionic gonadotropin greater than 1300 mIU/ml (First International Reference Preparation) (N = 4). Transvaginal ultrasonography definitively diagnosed 103 of 117 (88%) intrauterine pregnancies at initial evaluation. Eighteen patients could not be definitively diagnosed by transvaginal ultrasonography at initial evaluation because nonvisualization of a gestational sac and a beta-subunit of human chorionic gonadotropin value less than 1300 mIU/ml. Evaluation of this group with serial measurements of beta-subunit of human chorionic gonadotropin, repeat ultrasonography, or both, revealed ectopic gestation (N = 4), early intrauterine pregnancy (N = 4), and complete abortion (N = 10).
Chorionic Gonadotropin↗
Effects of adenine nucleotides on choriogonadotropin alpha and beta subunit synthesis.
The alpha subunit of human chorionic gonadotropin (CG) contains a discrete cAMP response element in the 5' flanking region of the gene. Since cAMP also stimulates the synthesis of the CG beta subunit the presence of a cAMP cis element in the CG beta gene was examined. Deletion mutants bearing various lengths of CG beta 5' region in front of the chloramphenicol acetyl transferase (CAT) gene were transfected in placental tumor cells. No discrete cAMP response element could be identified. Unexpectedly we also observed that AMP and adenosine not only stimulated CAT activity driven by CG beta promoter sequences but also enhanced synthesis of CG alpha and beta subunits in cultured choriocarcinoma cells. GMP, CMP, guanosine, and cytosine were inactive at comparable concentrations. These data suggest that the response of the CG alpha and beta genes to the non-cyclic adenine derivatives occurs by a mechanism that differs from cAMP.
8-Bromo Cyclic Adenosine Monophosphate↗
The identification of peptide sequences of human chorionic gonadotropin containing a conformational epitope.
A series of overlapping peptides were synthesized representing the entire amino acid sequence of the beta-subunit of human chorionic gonadotropin (hCG) and these were reacted with a monoclonal antibody shown to be specific for hCG. One linear peptide (residues 40-52 of the sequence) reacted significantly with the monoclonal antibody but a conjugate of this peptide to diphtheria toxoid (DT) failed to elicit significant levels of antibodies reactive to hCG in rabbits. The subsequent preparation of an extended peptide (residues 38-57) in which the two cysteines were oxidized to form a loop peptide yielded a highly immunogenic antigen when conjugated to DT. Antibody levels reactive with hCG from loop peptide immunizations of rabbits exceeded those found after immunization with a 37 residue peptide representing the carboxyl terminus of the beta-hCG subunit. The antisera did not react with pituitary glycoprotein hormones with similar sequences.
Amino Acid Sequence↗
Abnormal maternal serum levels of human chorionic gonadotropin free subunits in trisomy 18.
We have measured maternal serum levels of free alpha and beta subunits of human chorionic gonadotropin between 8 and 12 weeks of gestation in 704 women at increased risk for trisomy. This group was studied because of advanced maternal age or a previous birth with chromosomal abnormality. All sera had been collected prior to chorion villus biopsy for prenatal diagnosis. Serum levels of free alpha and beta hCG were determined by specific monoclonal antibody-based immunoradiometric assays. Analysis of chorionic tissue showed that in 38 of 704 (5.4%) pregnancies the fetus had a chromosome abnormality. There were 8 fetuses with trisomy 18 (1.1%) and 9 (1.3%) with trisomy 21. In all pregnancies carrying a trisomy 18 fetus, we observed either high levels of free alpha hCG or low levels of free beta hCG or both. More importantly, the calculated ratio of free beta hCG/alpha hCG was less than 0.25 multiples of the median (MoM) in 6 of 8 (75%) trisomy 18 cases. Only 21 of 666 mothers (3.2%) carrying a normal fetus had a ratio less than 0.25 MoM (P less than 0.0001). There was no difference between this ratio in trisomy 21 and normal pregnancy. Thus, when adjusted for gestational age, a low free beta hCG/alpha hCG ratio in maternal serum indicates a pregnancy at high risk [RR = 72 (95% CI 32, 162)] for trisomy 18.
Chorionic Gonadotropin↗
Use of monoclonal antibodies to subunits of human chorionic gonadotropin to examine the orientation of the hormone in its complex with receptor.
Monoclonal antibodies were prepared against the alpha and beta subunits of human chorionic gonadotropin (hCG). Although all were selected on the basis of their ability to bind the intact hormone, each also bound one of the two subunits but not both. Using a solid phase double antibody system to measure the relative binding to sites on the surface of hCG, we observed that four of the five antibodies bound to different sites on the molecule. This information was correlated with the ability of each antibody to inhibit the biological activity of hCG. Of the five antibodies tested for their ability to inhibit hCG-induced stimulation of rat testes steroidogenesis in vitro, two proved to be potent inhibitors, whereas the other three had almost no effect. This inhibition of steroidogenesis was highly correlated with the ability of the antibodies to inhibit hCG binding to testes homogenates. Thus, we have begun to derive a scheme that describes the relative binding positions of individual monoclonal antibodies and receptor on hCG. The purified monoclonal antibodies were iodinated and employed to evaluate which antigenic sites on hCG remained free in hCG-receptor complexes. The data indicated that portions of the beta subunit in hCG-receptor complexes were buried (i.e., failed to bind radiolabeled antibody), whereas other portions remained exposed (i.e., they bound radiolabeled antibody). Those antibodies that interacted with portions of hCG that became inaccessible in the receptor complex also blocked the biological actions of hCG, whereas those that interacted with exposed sites had little or no effect on activity. Although we did not find antibodies to the alpha subunit that would bind to the hormone-receptor complex, we found that one of the two antibodies specific to alpha subunit epitopes blocked the actions of the hormone. Both antigenic determinants on the alpha subunit appeared to be lost after the hCG-receptor complex had formed. These studies suggest that each hCG subunit participates in the hormone-receptor complex and that portions of the beta subunit project from the surface of the receptor.
Animals↗