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PubMed2004

First-trimester placentation and the risk of antepartum stillbirth.

CONTEXT: Preterm birth and low birth weight are determined, at least in part, during the first trimester of pregnancy. However, it is unknown whether the risk of stillbirth is also determined during the first trimester. OBJECTIVE: To determine whether the risk of antepartum stillbirth varies in relation to circulating markers of placental function measured during the first trimester of pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, prospective cohort study (conducted in Scotland from 1998 through 2000) of 7934 women who had singleton births at or after 24 weeks' gestation, who had blood taken during the first 10 weeks after conception, and who were entered into national registries of births and perinatal deaths. MAIN OUTCOME MEASURES: Antepartum stillbirths and stillbirths due to specific causes. RESULTS: There were 8 stillbirths among the 400 women with levels of pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile compared with 17 among the remaining 7534 women (incidence rate per 10,000 women per week of gestation: 13.4 vs 1.4, respectively; hazard ratio [HR], 9.2 [95% confidence interval [CI], 4.0-21.4]; P<.001). When analyzed by cause of stillbirth, low level of PAPP-A was strongly associated with stillbirth due to placental dysfunction, defined as abruption or unexplained stillbirth associated with growth restriction (incidence rate: 11.7 vs 0.3, respectively; HR, 46.0 [95% CI, 11.9-178.0]; P<.001), but was not associated with other causes of stillbirth (incidence rate: 1.7 vs 1.1, respectively; HR, 1.4 [95% CI, 0.2-10.6]; P = .75). There was no relationship between having a low level of PAPP-A and maternal age, ethnicity, parity, height, body mass index, race, or marital status. Adjustment for maternal factors did not attenuate the strength of associations observed. There was no association between maternal circulating levels of the free beta subunit of human chorionic gonadotropin and stillbirth risk. CONCLUSION: The risk of stillbirth in late pregnancy may be determined by placental function in the first 10 weeks after conception.

Chorionic Gonadotropin, beta Subunit, Human↗

PubMed1996

Detection of metastatic breast cancer by beta-hCG polymerase chain reaction.

Reverse transcriptase-polymerase chain reaction (RT-PCR) for detection of occult malignancies in breast cancer patients is evolving as a useful diagnostic tool. However, no reliable molecular mRNA markers are available. We developed an RT-PCR plus Southern blot assay using beta-hCG (beta-subunit of human chorionic gonadotropin) gene expression as a tumor marker for detection of breast malignancies metastatic to tumor-draining lymph nodes and blood. Breast carcinoma cell lines, primary breast malignancies and human placenta were used as positive controls for establishing the beta-hCG RT-PCR assay. Peripheral blood leukocytes (PBL) from normal volunteer donors, normal breast tissue and lymph nodes from cancer-free patients were used as negative controls. beta-hCG RT-PCR was used to assess tumor cell presence in PBL and tumor-draining axillary nodes from patients with AJCC stage I-IV breast cancer. The assay sensitivity and specificity were enhanced by restriction endonuclease digestion of an Sty I site of the RT-PCR cDNA product followed by Southern blot analysis. beta-hCG mRNA was expressed in all breast cancer cell lines and 80% of primary breast cancers; it was not expressed in negative controls. The assay reliably detected one cancer cell in > 10(7) PBL, with a sensitivity of 10(-5) microgram RNA. Eighty percent of PBL and 61% of tumor-draining axillary nodes from breast cancer patients expressed beta-hCG mRNA. The assay is a sensitive and specific method of identifying breast cancer cells in breast tissues, lymph nodes and blood.

Biomarkers, Tumor↗

PubMed1986

Choriocarcinoma associated with undetectable levels of human chorionic gonadotropin.

A case of choriocarcinoma is presented which developed during close follow-up for hydatidiform mole. Serum levels of beta subunits of human chorionic gonadotropin (beta-HCG) were assessed by radioimmunoassay (RIA) before, during, and after diagnosis of choriocarcinoma and remained below the sensitivity level of the assay. To our knowledge, this is the fourth reported case where choriocarcinoma was not associated with the presence of elevated beta-HCG levels.

Adult↗

PubMed1988

Early abortion with a single dose of the antiprogestin RU-486.

RU-486 is a synthetic progesterone antagonist that is abortifacient in early pregnancy. This trial evaluated the effectiveness and safety of a single 600 mg oral dose given to 50 healthy women less than or equal to 49 days from their last menstrual period. Efficacy was inversely related to the initial beta-subunit of human chorionic gonadotropin level, ranging from 100% at less than 5000 mIU/ml to 81% at greater than 20,000 mIU/ml (p less than 0.05). Uterine bleeding was the most serious side effect. However, the mean change in the hemoglobin value 14 days after treatment was -0.4 gm/dl, and no patient required blood transfusion. This regimen appears to be simple, effective, and safe.

Abortifacient Agents↗

PubMed2004

Preoperative hCGbeta and CA 72-4 are prognostic factors in gastric cancer.

In gastric cancer, the role of tumour markers in assessment of prognosis is unconfirmed. In our study, we evaluated the prognostic significance of serum tumour markers carcinoembryonic antigen (CEA), CA 19-9, CA 72-4, CA 242 and free beta subunit of human chorionic gonadotropin (hCGbeta) in gastric cancer. Preoperative serum samples were obtained from 146 patients with gastric cancer, including 29 with stage I, 11 with stage II, 42 with stage III and 64 patients with stage IV cancer. Quantitation of CEA, CA 19-9, CA 72-4 and CA 242 in serum was performed with commercial assays. HCGbeta was measured with an in-house immunofluorometric assay based on monoclonal antibodies specific for the free beta-subunit of hCG. Survival analysis was performed with Kaplan-Meier life-tables and log-rank test, and with multivariate Cox regression analysis. Disease-specific cumulative 2-year survival rate was 40%. Serum levels of CEA, CA 72-4, CA 242 and hCGbeta showed significant correlation with stage (p<0.027); for CA 19-9 the association was of borderline significance (p=0.056). Of the studied markers, CA 19-9, CA 72-4, CA 242 and hCGbeta were found to be prognostic factors in univariate analysis (p< 0.022). In multivariate analysis, stage had the statistically most significant association with prognosis followed by hCGbeta, tumour histology according to the Laurén classification and by CA 72-4. In gastric cancer, tumour markers hCGbeta and CA 72-4 are independent prognostic factors in addition to stage and histological type of the tumour.

Adult↗

PubMed2006

Ectopic hCGbeta expression by epithelial cancer: malignant behaviour, metastasis and inhibition of tumor cell apoptosis.

Ectopic expression of the beta-subunit of human chorionic gonadotropin (hCG) is now a recognized phenomenon in 20-40% of all common epithelial carcinoma arising from mucosal epithelia such as bladder, cervix, lung and naso-pharynx. Recent studies have shown that it acts as an autocrine growth factor by inhibiting apoptosis. Structural homology and in vitro studies suggest that it may achieve this by inhibition of the transforming growth factor beta (TGFbeta) receptor complex. Such a molecular mechanism would go some way to explaining ectopic hCGbeta's association with poor prognosis and tumors that will rapidly progress to metastasis.

Apoptosis↗

PubMed2005

Multiple sites of tumorigenesis in transgenic mice overproducing hCG.

We have produced transgenic (TG) mice expressing under the ubiquitin C promoter either the glycoprotein hormone common alpha-subunit (C(alpha)) or human chorionic gonadotropin (hCG) beta-subunit. C(alpha) overexpression alone had no phenotypic effect, but the hCG(beta) expressing females, presenting with moderately elevated levels of bioactive LH/hCG, due to dimerization of the TG hCG(beta) with endogenous C(alpha), developed multiple gonadal and extragonadal neoplasias. Crosses of the C(alpha) and hCG(beta) mice (hCG(alpha)beta) had >1000-fold elevated hCG levels, due to ubiquitous transgene expression, and presented with more aggressive tumour formation. The ovaries displayed initially strong luteinisation of all somatic cell types, leading to formation of luteomas, and subsequently to germ cell tumours (teratomas). The pituitary glands of TG females were massively enlarged, up to >100 mg, developing macroprolactinomas with very high prolactin (PRL) production. This endocrine response probably induced breast cancers in the mice. In contrast to the females, similar high levels of hCG in male mice had only marginal effects in adulthood, with slight Leydig cell hyperplasia and atrophy in the seminiferous epithelium. However, clear Leydig cell adenomas were observed in postnatal mice, apparently originating from fetal Leydig cells. In conclusion, these studies demonstrate marked tumorigenic effects of supraphysiological hCG levels in female mice, but clear resistance to similar changes in males. The extragonadal tumours were induced by hCG stimulated aberrant ovarian endocrine function, rather than by direct hCG action, because gonadectomy prevented all extragonadal phenotypes despite persistent hCG elevation. The phenotypes of the TG mice apparently represent exaggerated responses to hCG/LH and/or gonadal steroids. It remains to be explored to what extent they simulate respective responses in humans to pathophysiological elevation of the same hormones.

Animals↗

PubMed1990

[Immunometric tests system for glycoprotein hormones and their free subunits].

Highly specific sensitive immunoenzymometric assays were established for human glycoprotein hormones, the common free alpha-subunit of glycoprotein hormones and the free beta-subunit of human chorionic gonadotropin, using a large panel of monoclonal antibodies previously produced in our laboratory. The significance of serum levels of human chorionic gonadotropin and its free subunits under physiological conditions, as well as their prognostic value in human chorionic gonadotropin-producing tumours was determined in vitro and in vivo. These investigations revealed that all three analytes were present in the sera of the majority of normal individuals; moreover, the percentage of positive sera for these tumour markers in patients suffering from seminomatous and non-seminomatous testicular cancers was significantly elevated when two, or even better, all three parameters were determined.

Biomarkers, Tumor↗

PubMed1988

Hormonal evaluation and autoimmune background in pruritic urticarial papules and plaques of pregnancy.

There is little insight into the pathogenesis of most of the dermatoses specifically associated with pregnancy. We evaluated the hormonal profile and the autoimmune background in 11 pregnant women with pruritic urticarial papules and plaques of pregnancy. No statistically significant difference was found between the serum levels of the beta-subunit of human chorionic gonadotropin, estradiol, cortisol, and urinary estriol of the patients and gestational age-matched control subjects. No autoantibodies were found in the patients' group. We conclude that patients with pruritic urticarial papules and plaques of pregnancy have no hormonal alterations when compared with normal pregnant women and that no known major autoimmune background plays a part in the pathogenesis of the disease.

Adult↗

PubMed1999

Spliceosome-mediated RNA trans-splicing as a tool for gene therapy.

We have developed RNA molecules capable of effecting spliceosome-mediated RNA trans-splicing reactions with a target messenger RNA precursor (pre-mRNA). Targeted trans-splicing was demonstrated in a HeLa nuclear extract, cultured human cells, and H1299 human lung cancer tumors in athymic mice. Trans-splicing between a cancer-associated pre-mRNA encoding the beta-subunit of human chorionic gonadotropin gene 6 and pre-trans-splicing molecule (PTM) RNA was accurate both in vitro and in vivo. Comparison of targeted versus nontargeted trans-splicing revealed a moderate level of specificity, which was improved by the addition of an internal inverted repeat encompassing the PTM splice site. Competition between cis- and trans-splicing demonstrated that cis-splicing can be inhibited by trans-splicing. RNA repair in a splicing model of a nonfunctional lacZ transcript was effected in cells by a PTM, which restored significant beta-galactosidase activity. These observations suggest that spliceosome-mediated RNA trans-splicing may represent a general approach for reprogramming the sequence of targeted transcripts, providing a novel approach to gene therapy.

Animals↗

PubMed2001

Defect of syncytiotrophoblast formation and human chorionic gonadotropin expression in Down's syndrome.

The syncytiotrophoblast (ST) is a major component of the human placenta as it is involved in feto-maternal exchanges and the secretion of pregnancy-specific hormones. We have studied the formation and function of the ST in normal and trisomy 21 (T21)-affected placenta using the in vitro model of cytotrophoblast differentiation into ST. Cytotrophoblast cells were isolated from first trimester, second trimester and term placentae. In vitro cytotrophoblast cells isolated from normal placenta fused to form the ST. This was associated with an increase in the transcript levels and the secretion of human chorionic gonadotropin (hCG). However, the secretion of hCG decreased through pregnancy. In T21-affected placentae, we observed a defect (or a delay) in ST formation and a dramatic decrease in the synthesis and secretion of this hormone compared with cultured cells isolated from control age-matched placentae. These results were confirmed by a significant (P < 0.05) decrease in transcript levels of alpha and beta subunits of hCG in total homogenates of T21-affected placentae compared with controls. These results suggest a decrease in functional mass of ST in T21 placenta, and therefore a decrease in production of placental pregnancy-specific polypeptide hormones.

Adult↗

PubMed2003

Expression of PEA3/E1AF/ETV4, an Ets-related transcription factor, in breast tumors: positive links to MMP2, NRG1 and CGB expression.

The PEA3/E1AF/ETV4 gene encodes an Ets-related transcription factor that is expressed in the epithelial cells of the mammary gland. Previous reports have shown that PEA3 can up-regulate promoter activities of many genes associated with tumorigenesis. A significant fraction of those encode matrix metalloproteinases (MMP genes) required for degradation of the extracellular matrix. To better obtain a molecular characterization of PEA3 expression in sporadic breast cancer, we quantified PEA3 mRNA by means of real-time reverse transcriptase-polymerase chain reaction assay in a large series of human primary breast tumors. PEA3 expression showed wide variations in tumor tissues, being under-expressed in 30 of 130 (23.1%) and over-expressed in 18 of 130 (13.8%) compared with normal breast tissues. High PEA3 mRNA levels correlated significantly with Scarff-Bloom-Richardson histopathological grade III (P = 0.018) but not with poor prognosis, suggesting that PEA3 is a marker of tumor aggressiveness rather than a prognostic factor in human breast cancer. We also observed positive links between the expression of PEA3 and those of MKI67 and ERBB2 (P = 0.034 and P = 0.045, respectively) and an inverse relationship with ERalpha (P = 0.0016). Our results do not support recent findings suggesting that PEA3 could be a tumor-suppressor gene that can act therapeutically in ERBB2 over-expressed tumors. Our results also suggest major roles of the MMP2, NRG1 and CGB genes (which encode type I gelatinase, heregulin and human chorionic gonadotropin beta subunit, respectively) in the PEA3 pathway dysregulation observed in breast cancer. Taken together, the data confirm the role of the PEA3 gene in breast tumorigenesis, and suggest the existence of numerous other still unknown genes transactivated by the PEA3 transcription factor.

Breast Neoplasms↗

PubMed1984

Spontaneous abortion among insulin-dependent diabetic women.

A prospective study was undertaken to evaluate the frequency of spontaneous abortion in clinically apparent pregnancies among insulin-dependent diabetic women evaluated prior to pregnancy. The study was done in 132 pregnancies occurring in 91 diabetic women. The spontaneous abortion rate was 30%; 70% of the pregnancies progressed beyond 20 weeks. The abortion rates for Classes B, C, D, and F through RT were 0%, 25%, 44%, and 22%, respectively. Initial serum levels of the beta-subunit of human chorionic gonadotropin above 6000 mIU were usually associated with favorable outcome while levels below 6000 mIU were not predictive of outcome. Data from this study suggest that the risk of spontaneous abortion among insulin-dependent diabetic women may be substantially higher than for the general population. Higher abortion rates were generally associated with more advanced White classification of diabetes. Age at diagnosis was the only factor which showed a significant contribution to the risk of abortion.

Abortion, Spontaneous↗

PubMed1987

Clinical evaluation of basic fetoprotein in testicular cancer.

We attempted to determine the efficacy of basic fetoprotein as a marker in testicular cancer. The levels of serum basic fetoprotein were studied in 58 patients (31 with seminoma and 27 with nonseminoma). Elevated levels were observed in 22 seminoma (71 per cent) and 15 nonseminoma (56 per cent) patients, while the levels of other markers (beta-subunit of human chorionic gonadotropin, alpha-fetoprotein and lactic dehydrogenase) remained normal in 6 seminoma (19 per cent) and 2 nonseminoma (7 per cent) patients. The levels of basic fetoprotein changed in relation to the clinical courses and they elevated again in 3 of 4 patients with recurrence. The concentration of basic fetoprotein in testicular cancer tissue was significantly higher than in the normal testis. Histological localization of basic fetoprotein in testicular cancer tissue was demonstrated immunohistochemically. Thus, basic fetoprotein was considered to be a useful serum marker for testicular cancer.

Antigens, Neoplasm↗

PubMed1996

Performance evaluation of automated immunoassays on the Technicon Immuno 1 system.

We performed an immunoassay evaluation for various analytes on a fully automated random-access analyzer, the Technicon Immuno 1 system from Bayer Corp. This system involves latex agglutination, magnetic separation sandwich, and magnetic separation competitive immunoassay configurations. The evaluated analytes were thyrotropin (TSH), triiodothyronine, thyroxine, free thyroxine, follitropin, lutropin, prolactin, beta subunit of human chorionic gonadotropin, cortisol, ferritin, alpha-fetoprotein, carcinoembryonic antigen, and prostate-specific antigen. We tested the assay precision, linearity, and correlation with comparison methods for these analytes. The functional sensitivity of the TSH assay and the sample-to-sample carryover were also studied. Excellent results were obtained for within-run and between-day precision studies, with most assays showing within-run CVs <4% and between-day CVs <6%. The linearity for all assays was acceptable and the correlation between Immuno 1 assays and comparison methods showed satisfactory results. The functional sensitivity of the TSH assay was estimated at 0.04 mU/L. No sample-to-sample carryover was detected.

Autoanalysis↗

PubMed1984

[Human B-HCG and AFP as biological markers in germinal testicular tumors].

Alpha-fetoprotein (AFP) and the beta subunit of human chorionic gonadotropin (BHCG) were determined in 64 cases of testicular germinal tumors. Pure seminomas do not produce either AFP or BHCG, endodermal sinus tumors always produce AFP and never BHCG. Testicular germinal tumors may produce BHCG (44.4 per 100) and AFP (33.3 per 100), one or both at a time. There is a significant correlation between the amount of BHCG and AFP on the one hand, and tumor size and tumor dissemination on the other. When therapy is effective, BHCG and AFP become negative, while they remain positive in case of incomplete tumor removal or turn again to positive in case of relapse.

Adult↗

PubMed1986

Concentration of tumour markers CEA, AFP, alpha and beta subunits of hCG in cerebrospinal fluid in children with inflammatory diseases of the central nervous system.

Carcinoembryonic antigen (CEA), alphafetoprotein (AFP) and alpha-beta subunits of human chorionic gonadotropin (hCG) were determined by radio-immunoassay in CSF of 83 children presenting some central nervous disease and compared to the corresponding values obtained in 88 children without neuroinfection. CEA and alpha hCG were absent in the CSF of children without neuroinfection. CEA and alpha hCG levels in CSF higher than 0.0 ng/ml were regarded as elevated. In patients with inflammatory process of CNS, CEA values were positive in 9% (maximum 8.0 ng/ml) and alpha hCG in 4% (maximum 5.0 ng/ml). AFP in CSF ranged from 15.0 to 49.0 ng/ml in children without neuroinfection, and from 0.0 to 100.0 ng/ml in patients with inflammatory diseases of the CNS. As a normal upper limit of AFP in CSF, 53.2 ng/ml is suggested; in 31% of the patients with inflammatory diseases of CNS the AFP level was elevated. The normal upper limit of beta hCG concentration in CSF was regarded as 0.4 ng/ml; in 12% of the patients with viral meningoencephalitis the beta hCG level in CSF was slightly elevated, it ranged from 0.5 to 3.0 ng/ml.

Adolescent↗

PubMedDate not supplied

Skin metastases of gynecologic adenocarcinomas affect serum levels of hCGbeta but not those of SCC antigen.

Squamous cell carcinoma antigen (SCC-Ag) has been shown to be elevated in patients with epidermoid carcinoma of the cervix but also in patients with benign tumors of epithelial origin and in benign skin disorders. Elevated serum levels of the free beta subunit of human chorionic gonadotropin (hCGbeta) have been observed in patients with cancer of different types, and cancer aggressiveness is related to hCGbeta expression. Therefore, we expected that extensive metastatic skin dissemination of gynecologic malignancies would cause a rise in the serum levels of SCC-Ag and hCGbeta. The serum levels of SCC-Ag, hCGbeta and CA 125 were monitored in 2 patients with extensive skin dissemination of ovarian and endometrial adenocarcinoma. Skin metastases had no effect on serum levels of SCC-Ag but they caused an increase in serum levels of hCGbeta. SCC-Ag is not a marker for metastatic skin lesions of gynecologic carcinomas of nonepidermoid origin. hCGbeta expression is associated with aggressiveness of cancer and may be a useful marker indicating therapy resistance.

Adenocarcinoma↗