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PubMed1976

Isoimmunization against human chorionic gonadotropin with conjugates of processed beta-subunit of the hormone and tetanus toxoid.

The immunogenicity of the conjugate prepared from "processed" beta-subunit of human chorionic gonadotropin (choriogonadotropin, HCG) and tetanus toxoid has been studied in animals and a human subject. The conjugate elicited the formation of high-affinity (Ka = 10(9)-10(11) M-1) anti-HCG and anti-tetanus antibodies. On primary immunization, the antibody, response lasted for several months. Repeat injection of the conjugate in the declining phase of antibody titers produced a booster response without a lag period. The antibodies reacted with the beta-subunit of HCG and the complete HCG molecule but were devois of significant crossreactivity with human growth hormone, placental lactogen, follicle-stimulating hormone, thyroid-stimulating hormone, and luteinizing hormone at tonic and surge levels. The antibodies were competent for neutralizing the biological activity of HCG in the mouse uterine weight gain assay, the ventral prostate weight gain assay, and the radioligand assay for binding of 125I-labeled HCG to receptors on corpus luteum. HCG (5000 international units) administered to an immunized subject was completely bound by circulating antibodies. Administration of HCG (in contrast to conjugate) was without booster effect on anti-HCG titers.

Animals↗

PubMed1995

Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors.

Hypersecretion of luteinizing hormone (LH) is implicated in infertility and miscarriages in women. A lack of animal models has limited progress in determining the mechanisms of LH toxicity. We have recently generated transgenic mice expressing a chimeric LH beta subunit (LH beta) in gonadotropes. The LH beta chimera contains the C-terminal peptide of the human chorionic gonadotropin beta subunit. Addition of this peptide to bovine LH beta resulted in a hormone with a longer half-life. Furthermore, targeted expression of the LH beta chimera led to elevated LH levels and infertility in female transgenics. These mice ovulated infrequently, maintained a prolonged luteal phase, and developed pathologic ovarian changes such as cyst formation, marked enlargement of ovaries, and granulosa cell tumors. Testosterone and estradiol levels were increased compared to nontransgenic littermates. An unusual extragonadal phenotype was also observed: transgenic females developed hydronephropathy and pyelonephritis. The pathology observed demonstrates a direct association between abnormal secretion of LH and infertility and underscores the utility of the transgenic model for studying how excess LH leads to cyst formation, ovarian tumorigenesis, and infertility.

Animals↗

PubMed1985

Hydatidiform moles.

This gestational neoplasm arises from the trophoblast, the ectodermal layer of a fertilized ovum. Although benign, hydatidiform moles have the potential to progress to malignant trophoblastic disease. Molar pregnancy must be recognized promptly. The clinical presentation is usually vaginal bleeding, which may contain characteristic tissues. Diagnosis is confirmed by identification of hydropic avascular villi obtained by evacuation of uterine contents. The beta subunit of human chorionic gonadotropin is a valuable tumor marker.

Adolescent↗

PubMed1995

Bronchogenic carcinoma presenting as a pseudopregnancy.

A young woman with an occult bronchogenic carcinoma presented with secondary amenorrhea and an elevated beta subunit of human chorionic gonadotropin that was mistakenly attributed to pregnancy. Physicians should be aware that this carcinoma may present solely with an elevated beta human chorionic gonadotropin value, and the potential exists for confusion with a pregnancy state in women of childbearing age.

Adult↗

PubMed1983

The human genome contains seven genes for the beta-subunit of chorionic gonadotropin but only one gene for the beta-subunit of luteinizing hormone.

We have used restriction enzyme analysis to sample similarities and differences among eight cloned genes, isolated from two independent libraries, which hybridize to a cDNA for the beta subunit of human chorionic gonadotropin (hCG). We find that one of the cloned genes encodes the beta-subunit of the closely related hormone, human luteinizing hormone (hLH). Using differential hybridization of human DNA with beta hCG- and beta hLH-specific probes, we show that there are seven beta hCG genes but only a single beta hLH gene in the human genome. This single beta hLH gene is linked to at least three beta hCG genes. Our restriction analysis reveals that the seven beta hCG genes are extremely similar but not identical, and that there are no obvious structural rearrangements to indicate which, if any, are pseudogenes. These data also reveal that the beta hLH gene is far more homologous to the seven beta hCG genes than the beta hCG:beta hLH protein sequence homology of 82% might predict. We propose that the beta hCG gene arose by a duplication of an ancestral beta hLH gene and that, once the beta hCG function was established, the ancestral beta hCG gene itself duplicated and rearranged, creating the present organization of multiple beta hCG genes.

Chorionic Gonadotropin↗

PubMed1986

Evolution of different transcriptional start sites in the human luteinizing hormone and chorionic gonadotropin beta-subunit genes.

To investigate the mechanisms related to the tissue-specific expression of luteinizing hormone (LH) in the pituitary and chorionic gonadotropin (CG) in the placenta, we compared the transcriptional start sites of the common alpha-subunit and structurally related beta-subunit genes encoding human LH and CG. The transcriptional start site of the alpha-subunit gene expressed in human pituitary and placenta is identical, encoding a mRNA with a 5'-untranslated tract of 100 bases. In contrast, the lengths of the 5'-untranslated tracts for human LH beta and CG beta mRNA are different. The human LH beta gene, like the LH beta gene in rat and cattle, transcribes a mRNA with a short 5' untranslated tract of 9 bases. Although the human CG beta gene has a TATAAA box sequence in the same location as the LH beta gene, it is not used for initiation of transcription. Instead, the promoter for the CG beta gene is located at an upstream site resulting in an extended 5' untranslated tract for CG beta mRNA of 366 bases. These results indicate that recognition of the upstream promoter site in the CG beta gene is tissue specific rather than species specific and suggest that the LH beta and CG beta genes evolved distinct regulatory regions which respond differently to intracellular signals in the pituitary and placenta.

Animals↗

PubMed1992

Immunoreactive human chorionic gonadotropin and its free beta subunit in serum and ascites of patients with malignant tumors.

Human chorionic gonadotropin (hCG) is a clinically relevant marker of trophoblastic and nontrophoblastic malignancies. In the present studies, in addition to determining serum hCG, we investigated the presence and properties of hCG immunoreactivity in ascites of patients with nontrophoblastic malignant tumors and, for comparison, in ascites caused by cirrhotic liver disease. Total hCG immunoreactivity [hCG (+hCG-beta)] was found to be elevated above the reference value (greater than 5 IU/liter) in the serum of 2 of 20 patients with cirrhosis and 11 of 20 patients with malignant tumors. For comparison, in ascites, hCG (+hCG-beta) concentrations were frequently higher than in the corresponding serum samples and exceeded 10 IU/liter in 0 of 20 cirrhotic samples and in 16 of 20 malignant samples. In order to elucidate the nature of the hCG immunoreactive material, all samples were then assessed by immunoradiometric assays specific for the intact hCG molecule (holo-hCG) and the free hCG-beta subunit, respectively. In the holo-hCG assay, elevated values were detected in 0 of 20 (0 of 20) cirrhotic ascites (serum) samples and 0 of 20 (1 of 20) malignant ascites (serum) samples. In the free hCG-beta assay, on the other hand, no positive results were obtained in the ascites or serum of 20 patients with liver cirrhosis; however, 8 of 20 serum samples and 16 of 20 ascites samples derived from tumor patients were positive. In accord with the immunological data, gel chromatographical studies of malignant ascites revealed the abundance of free hCG-beta subunit rather than that of holo-hCG. In contrast to malignancy-related ascites, in ascites of patients receiving hCG injections for treatment of infertility, holo-hCG was more abundant than free hCG-beta immunoreactivity. Incubation experiments of purified holo-hCG in ascites for 24 h at -20, 20, or 37 degrees C showed no substantial dissociation of the hCG molecule and release of free hCG-beta immunoreactivity, thus arguing against production of free hCG-beta by degradation of holo-hCG and in favor of its tumor-related secretion. In conclusion, hCG-beta immunoreactivity is frequently elevated in malignancy-related ascites and appears to be related to the presence of free beta subunit of hCG rather than that of the intact hCG molecule. Interestingly, hCG-beta determination in ascites proved to be clearly superior to serum measurement in discriminating between tumor and cirrhosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1981

Estrogen production as a tumor marker in patients with gonadotropin-producing neoplasms.

Urinary estradiol production rates, plasma estradiol, and peripheral conversion of dehydroepiandrosterone sulfate (DHEAS) to estradiol were explored in patients whose neoplasms made human chorionic gonadotropin and/or human chorionic gonadotropin beta fragments. In five men with choriocarcinoma, estradiol production was elevated, plasma estradiol was high, and DHEAS conversion to estradiol ranged from 0.5 to 11.7%. In six patients with "ectopic" gonadotropin-producing tumors, originating from lung, stomach, and liver, estradiol production was elevated to a lesser degree. Sera from 154 of 864 patients (16.8%) with a wide variety of advanced neoplastic disorders were noted to have minimal elevations of human chorionic gonadotropin beta subunit in their sera but had normal luteinizing hormone assays. Plasma estradiol levels in these patients were not elevated, and in only one of ten patients studied was there slight elevation of the estradiol production rate. Similarly, in only one of ten patients was there measurable conversion of DHEAS to estradiol. We conclude that, in patients whose neoplastic disorders are associated with major elevations of human chorionic gonadotropin, there is concordant extragonadal production of estradiol via DHEAS, presumably representing an associated trophoblastic function. However, estrogen production is not a sensitive tumor marker in those patients whose neoplasms are associated with minimal elevations of human chorionic gonadotropin beta fragments only.

Choriocarcinoma↗

PubMed1984

Paradoxical effect of antibodies against chorionic gonadotropin on BeWo choriocarcinoma cells in vitro and in vivo: evidence for heterogeneity of cell types.

Antisera raised in monkey or baboon against purified beta-subunit of human chorionic gonadotropin (beta-hCG) coupled to tetanus toxoid exert complement-dependent cytotoxic effects on BeWo choriocarcinoma cells maintained in tissue culture. The cytotoxic effect is manifested morphologically as well as by incorporation of radioactive thymidine and leucine. However, in the presence of saturating amounts of anti-beta-hCG antibodies and complement, antibodies failed to kill all of the BeWo choriocarcinoma cells. Evidence is presented to suggest that the partial and not complete cytotoxic effect of antibodies may be due to the heterogeneity of cell types, one sensitive to immune attack by anti-beta-hCG antibodies, the other resistant. Immunoenzymatic localization of hCG revealed its presence on the cell surface of only a fraction of BeWo cells. The antibody-resistant BeWo cell population had no demonstrable hCG on the cell surface. Resistant cells did not secrete hCG into the medium when cultured for up to 4 days. However, the resistant cell population, upon transplantation to the hamster cheek pouch, regained the ability to secrete hCG. Heterogeneity of cell types may explain the refractoriness of the BeWo cells transplanted to the hamster cheek pouch to an inhibitory effect of antibodies at later stages of tumor growth.

Animals↗

PubMed1992

Cross-reactivity of a commercial chemiluminescence immunoassay for human chorionic gonadotropin with the free beta-subunit.

An enhanced chemiluminescence immunoassay for the determination of serum human chorionic gonadotropin (HCG) in specimens from oncology patients has been assessed with respect to its cross-reactivity with the free HCG beta-subunit (HCG-beta). The assay, standardized against the First International Reference Preparation 75/537, had a cross-reactivity with the free beta-subunit of 625% (molar basis). Therefore this assay achieves high sensitivity for the detection of either intact HCG or free HCG-beta in serum of patients with seminomatous or nonseminomatous testicular cancers. Results of both assays, the in-house immunoradiometric assay (+HCG-beta) and the Amerlite HCG-60 assay, showed a close correlation (R = 0.854-0.960) when serum samples from tumour patients were analyzed. Moreover, the content of free beta-subunit determined in a specific HCG-beta assay, could be quantitatively measured in the enhanced chemiluminescence immunoassay. Thus, this assay is suitable for oncology use, but also highlights the limitations of measuring HCG in serum samples.

Antibodies, Monoclonal↗

PubMed2000

Chronic hypersecretion of luteinizing hormone in transgenic mice disrupts both ovarian and pituitary function, with some effects modified by the genetic background.

When the pituitary or hypothalamus becomes resistant to steroid negative feedback, a vicious cycle ensues, resulting in chronic hypersecretion of luteinizing hormone (LH) from the pituitary and steroids from the ovaries. In women, LH hypersecretion is implicated in infertility, miscarriages, and development of granulosa cell tumors. Progress in defining the underlying mechanisms of LH toxicity, however, has been limited by the lack of well-defined animal models. To that end, we have developed a new transgenic mouse model (alpha-LHbetaCTP) wherein LH hypersecretion occurs chronically and results in several dire pathological outcomes. Chronic hypersecretion of LH was achieved by introducing a transgene containing a bovine alpha subunit promoter fused to the coding region of a chimeric LHbeta subunit. The alpha subunit promoter directs transgene expression only to gonadotropes. The LHbeta chimera contains the carboxyl-terminal peptide (CTP) of the human chorionic gonadotropin beta subunit linked to the carboxyl terminus of bovine LHbeta. This carboxyl extension extends the half-life of LH heterodimers that contain the chimeric beta subunit. In intact alpha-LHbetaCTP females, serum LH is elevated five- to ten-fold in comparison to nontransgenic littermates. Levels of testosterone (T) and estradiol (E2) also are elevated, with an overall increase in the T-to-E2 ratio. These transgenic females enter puberty precociously but are anovulatory and display a prolonged luteal phase. Anovulation reflects the absence of gonadotropin-releasing hormone (GnRH) and the inability to produce a pre-ovulatory surge of LH. The ovaries are enlarged, with reduced numbers of primordial follicles and numerous, giant, hemorrhagic follicles. Despite the pathological appearance of the ovary, females can be superovulated and mated. Although pregnancy occurs, implantation is compromised due to defects in uterine receptivity. In addition, pregnancy fails at midgestation, reflecting a maternal defect presumably due to estrogen toxicity. When the transgene is in a CF-1 background, all females develop granulosa cell tumors and pituitary hyperplasia by five months of age. They die shortly thereafter due to bladder atony and subsequent kidney failure. When the transgene is placed in other strains of mice, their ovaries develop a luteoma rather than a granulosa cell tumor and the pituitary develops pituitary hyperplasia followed by adenoma. In summary, alpha-LHbetaCTP mice provide a direct association between abnormal secretion of LH and development of a number of ovarian and pituitary pathological responses.

Adenoma↗

PubMed1990

Relevance of immuno-contraceptive vaccines for population control. I. Hormonal immunocontraception.

Human chorionic gonadotropin--subunit beta (beta-hCG) has been so far most extensively studied antigen for immuno-contraceptive properties. Studies of vaccination of non-human primates has been so far controversially reported since some antisera obtained from baboons immunized with beta-hCG had shown cross-reactivity to other tissues. Despite these problems and concerns about the complete safety of this first generation vaccine, a decision has been made to proceed with a limited clinical trials with this vaccine. Results from these trials are encouraging and indicate that contraceptive antibody titers can be achieved with permissible adjuvants. Neutralization of LH and/or FSH by circulating antibodies may impede their action and interfere with the maturation of gametes. Gonadotropin releasing hormone can be also a suitable target for immunological attack.

Chorionic Gonadotropin↗

PubMed1997

Screening for Down syndrome using urine hCG free beta-subunit in the second trimester of pregnancy.

Human chorionic gonadotropin (hCG) free beta-subunit levels were determined in 709 control and 13 Down syndrome urine samples from the second trimester of pregnancy. Results were normalized to urine creatinine concentration and converted to multiples of the unaffected pregnancy medium (MOM). The concentration of free beta-subunit in Down syndrome cases was 3.9 MOM. Seven of 13 Down syndrome pregnancies (54 per cent) had free beta-subunit levels at or above the 95th centile of unaffected pregnancies. Urine free beta-subunit may potentially be useful as a screening test for Down syndrome.

Adult↗

PubMed1988

Primary choriocarcinoma of the urinary bladder.

A case of choriocarcinoma of the urinary bladder is presented. A 57-year-old man underwent a cystectomy for transitional cell carcinoma, grade II. Choriocarcinoma was found, in addition to the transitional cell carcinoma, in the removed urinary bladder. After the operation, metastases appeared in both lungs, evolving rapidly despite chemotherapy. The patient died five months after admission. Immunohistochemically, staining for human placental lactogen was strongly positive, and both alpha and beta subunits of human chorionic gonadotropin were weakly positive in the primary site of the removed urinary bladder and in the metastatic foci.

Carcinoma, Transitional Cell↗

PubMed1986

Plasma prolactin, progesterone, estradiol, and human chorionic gonadotropin in complete and partial moles before and after evacuation.

Plasma prolactin, progesterone, and 17 beta-estradiol were measured by radioimmunoassay in 58 patients with complete moles, 17 patients with partial moles, and the same number of maturity-matched pregnant control subjects. In both complete and partial moles in the first trimester, the pre-evacuation plasma levels of these hormones were similar to those of pregnant control subjects, but in the second trimester they were all significantly lower than those of pregnant controls. There was no significant difference in the regression patterns of these hormones between complete and partial moles, but the serum beta-subunit of human chorionic gonadotropin (beta hCG) was higher in complete moles. Patients who subsequently developed persistent gestational trophoblastic tumors had higher plasma estradiol, prolactin, and serum beta hCG than those without persistent gestational trophoblastic tumors both before and after evacuation, but the difference in plasma estradiol and prolactin disappeared by nine weeks after evacuation. The levels of these hormones in patients with theca-lutein cysts were higher than those without theca-lutein cysts in the first few weeks after evacuation. Plasma estradiol, progesterone, and prolactin returned to normal nonpregnant levels before serum beta hCG, and they were not useful as tumor markers.

Adult↗

PubMed1996

Gonadotropin beta-subunit nicking enzyme (GBNE), a potential marker of early malignancies.

GBNE is an arginine-specific metalloprotease that cleaves human chorionic gonadotropin free beta-subunit in pregnancy serum. We tested GBNE activity in 539 serum samples, from individuals that were healthy, with benign diseases, or with a broad mixture of cancers. The mean GBNE activity in 130 samples from healthy individuals, 151 from those with benign disease, and 258 from cancer patients was 5.4 +/- 0.32, 5.8 +/- 0.20 and 16 +/- 1.2 units, respectively. ROC analysis indicated 86% discrimination between control samples and cancer. A cut-off of 12 units was selected. This was equaled or exceeded by 3.1% of samples from healthy individuals, 3.9% from those with benign disease, and 57% from those with cancer. There was no significant difference in detection of the different cancer primaries, breast (sensitivity 56%), gastrointestinal (53%), genitourinary (62%), gynecological (58%) and lung (55%) cancers. Sensitivity was highest for early stage, and lowest for advanced malignancies, for all cancer primaries. Taken together, sensitivity was 70, 44, 43 and 24%, for stages I, II, III and IV, respectively. GBNE is suggested to be a nonorgan site-restricted tumor marker with high sensitivity for early stage cancers.

Biomarkers, Tumor↗

PubMedDate not supplied

UGP in urogenital disorders: Egyptian experience.

UGP (Urinary gonadotropin peptide) also know as urinary gonadotropin fragment (UGF) or the beta-core of hCG (c beta hCG), was identified as a peptide with a molecular weight of 10.5 kD, having the same amino acid sequence as the core section of the beta-subunit of human chorionic gonadotropin. UGP has been found in normal pregnancy urine as well as in the urine of patients with gestational trophoblastic and non-trophoblastic malignancies. The aim of the present work was to investigate the clinical value of UGP in Egyptian patients with urogenital disorders. The study included 793 cases (462 males and 331 females) classified into 5 groups: 277 with bladder cancer, 121 with benign urinary tract disorders, 27 with different gynecological malignancies, 53 with benign gynecological disease and 315 apparently healthy individuals as a control group. The normal females included 88 premenopausal and 71 postmenopausal women. UGP was determined in 24- hour urine samples from all cases, and in morning urine samples from 151 subjects by ELISA technique using the reagents supplied by Ciba Corning Diagnostics, CA, USA (Triton UGP - EIA). The results of this study revealed significant elevation of UGP in cancer patients when compared to either normal controls or patients with benign diseases. Females in the control and benign diseases groups expressed higher UGP values than males and UGP in postmenopausal women was significantly elevated when compared to premenopausal control females. A a tumor marker, UGP was more sensitive and more specific in bladder than in gynecological cancer. A significant correlation (r = 0.934) was obtained between UGP levels in 24-hr and morning urine samples.

Adult↗

PubMed1989

[Fundamental studies of targeting cancer chemotherapy against choriocarcinoma--application of liposome].

For the fundamental study of the targeting cancer chemotherapy against choriocarcinoma using the anti-human chorionic gonadotropin beta subunit (hCG beta) antibody-conjugated-liposome containing anticancer drugs, we evaluated the specific accumulation of the antibody to the choriocarcinoma tissue and the uptake of liposome by choriocarcinoma cells. In vivo, the mice bearing human choriocarcinoma were injected anti-hCG beta antibody (30 micrograms/body) and the localization of the antibody in the tumor and other mouse organs were investigated by the PAP method. The antibody specifically accumulated to the choriocarcinoma tissue within 4 hours after the injection of the antibody, and gradually increased. In vitro, cultured BeWo cells were exposed to the liposome containing adriamycin, the antibody conjugated liposome containing adriamycin or the adriamycin alone, respectively, for 2 hours. Then the uptake of the adriamycin by the tumor cells was studied under fluorescent microscopy. The nuclear accumulation of adriamycin was clearly observed in the tumor cells exposed to the liposome containing adriamycin or the antibody conjugated liposome containing adriamycin, whereas only faint cytoplasmic accumulation of the adriamycin without any nuclear accumulation was observed in the cells exposed to the adriamycin alone. These results indicate that the liposome is a good carrier of anticancer drugs for immunotargeting chemotherapy.

Animals↗