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PubMed1987

Cyclic AMP regulates transcription of the genes encoding human chorionic gonadotropin with different kinetics.

Choriocarcinoma cell lines characteristically synthesize and secrete the alpha- and beta-subunits of human chorionic gonadotropin (hCG), as well as the intact heterodimer. Treatment of one such cell line, BeWo, with 8-bromo-adenosine 3':5'-cyclic monophosphate (8-Br-cAMP) causes at least a 10-fold increase in the concentration of the mRNA encoding each subunit. Changes in mRNA concentrations are associated with similar changes in transcription rates of both the CG alpha and CG beta genes, although the kinetics of their transcriptional responses are different. Transcription of the alpha-subunit gene increases rapidly and becomes maximal within 1 hr after addition of 8-Br-cAMP. By contrast, transcription of the CG beta gene increases slowly and progressively for at least 8 hr after treatment with 8-Br-cAMP. The slow transcriptional response of the CG beta gene(s) appears to be unique compared to that of other cAMP-responsive genes, and suggests that the cyclic nucleotide may regulate transcription of the CG genes by different mechanisms.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1995

The effect of thermal instability of intact human chorionic gonadotropin (ihCG) on the application of its free beta-subunit (free beta hCG) as a serum marker in Down syndrome screening.

The kinetics of free beta hCG concentrations were measured in 30 maternal whole blood samples from second-trimester pregnancies during 72 h incubation at 3, 20, and 30 degrees C. Dissociation of intact hCG (ihCG) was undetectable at 3 degrees C and produced a more than 20 per cent increase of free beta hCG at 20 degrees C and a more than 100 per cent increase at 30 degrees C. hCG dissociation at 30 degrees C was not reduced by a protease inhibitor (sodium iodoacetate) and also occurred in purified hCG dissolved in a protease-free incubation medium. These results were reproduced under conditions of sample transport by post at different environmental temperatures. In conclusion, reliable free beta hCG assessment requires that the specimen be kept cool from vene puncture until assay or completely other transport strategies have to be considered. Evaluation of free beta hCG as an effective marker in prenatal Down syndrome screening must be reconsidered from this aspect.

Blood Specimen Collection↗

PubMed1997

Disappearance of human chorionic gonadotropin and its alpha- and beta-subunits after term pregnancy.

We have used high-specificity and precision immunofluorometric assays to measure the elimination half-times of human chorionic gonadotropin (hCG), hCG alpha, and hCG beta in serum over 21 days after delivery in six women with term pregnancies. Baseline concentrations and half-times were calculated with the use of a curve-fitting algorithm for multiexponential decay. In contrast to the two-component model, a three-component exponential function with baseline provided a fit for which predicted values could not be distinguished from the observed values by analysis of variance. Median half-times were 3.6, 18.0, and 53.0 h for hCG; 1.0, 23.4, and 194 h for hCG beta; and 0.6, 6.2, and 21.9 h for hCG alpha. The mean ratio of hCG alpha to hCG decreased rapidly from 36.9% to 3.3% on day 3; thereafter it increased to 64.3% 21 days after delivery because of a higher baseline concentration of hCG alpha. hCG beta had the slowest total elimination rate, and the ratio of hCB beta to hCG in serum increased from 0.8% before delivery to 26.7% after 21 days. If the metabolism of hCG and hCG beta is similar in patients with trophoblastic disease, the ratio of hCG beta to hCG must be evaluated with caution in samples taken several days after initiating therapy. We conclude that the disappearance of hCG beta from plasma is slower than previously recognized and that the ratios of hCG beta or hCG alpha to intact hCG vary as a function of postpartum time. Such information may be important in clinical studies of pregnancy disorders.

Adult↗

PubMed1989

Prognostic potential of serum CA125 and pregnant markers in threatened abortion.

To predict the outcome of patients with threatened abortion at an early stage of gestation is clinically important. CA125 and nine hormones associated with pregnancy were measured from 4 to 12 weeks of gestation in 256 pregnant women with threatened abortion. The nine hormones were: serum human chorionic gonadotropin beta-subunit, serum progesterone, serum cortisol, serum human placental lactogen, serum estrone, serum estradiol, serum estriol, urine human chorionic gonadotropin and urine estrogen. Ultrasonographic examination was also performed from 6 to 12 weeks of gestation. Of the 256 patients, 90 aborted and 166 carried to term. We found that changes in CA125 in patients with threatened abortion differed from those of the nine hormones. At 4 to 8 weeks of gestation the mean value for serum CA125 in patients with successful outcome was significantly higher than that in patients who aborted. Although ultrasonographic examination is effective after 8 weeks of gestation, serum CA125 measurement is useful in predicting early abortion.

Abortion, Threatened↗

PubMed2006

Biological properties of a novel follicle-stimulating hormone/human chorionic gonadotropin chimeric gonadotropin.

A chimeric recombinant human gonadotropin, termed C3, demonstrates both follitropic and lutropic bioactivities. The alpha-subunit construct for C3 is comprised of the recombinant wild-type human glycoprotein hormone alpha-subunit. The beta-subunit DNA construct for C3 encodes residues 1-145 from human chorionic gonadotropin (hCG)-beta with the exceptions that FSH beta amino acid 88 (D) is substituted for hCG beta amino acid 94 (R) and FSH beta amino acids 95-108 (TVRGLGPSYCSFGE) are substituted for hCG beta amino acids 101-114 (GGPKDHPLTCDDPR). C3 is a potent FSH and LH agonist able to bind and to signal through FSH and LH receptors in vitro. In in vivo bioassays optimized to quantify each type of activity, C3 was found to have lutropin and follitropin potencies at levels similar to those of recombinant human LH and recombinant human FSH, respectively. In immature rats, C3 was sufficient to support the maturation of normal ovarian follicles. Moreover, a significant portion of follicles matured by C3 ruptured in response to an ovulatory hCG stimulus and gave rise to morphologically normal oocytes. Furthermore, a low dose of C3 promoted weight gain in the rodent uterus, suggesting it also supported preparation for implantation without histological evidence of excessive luteinization of the ovary. In summary, the biological properties of C3 indicate that its chimeric nature has resulted in a fully functional, dual-acting human gonadotropin.

Amino Acid Sequence↗

PubMed1988

Characterization of a cleavage product in the human choriogonadotropin beta-subunit.

The various molecular forms of human chorionic gonadotropin present in a crude preparation of urine from pregnant women were analyzed by two-dimensional gel electrophoresis and immunoblotting with monoclonal antibodies directed to synthetic peptides corresponding to the carboxyl-terminal part of either the alpha or beta-subunit. Under reducing conditions, immunoblotting with antibodies directed to the beta-subunit revealed the presence of a low-molecular-weight material of 22 kDa. This molecular form had large heterogeneity, as analyzed by isoelectrofocusing; it was immunoreactive with antibodies directed to the 111-145 region. Using microsequencing techniques, we found that the fragment had a NH2 terminal portion corresponding to the sequence of the beta-subunit appearing from residue 48. Thus, the 22-kDa fragment comprises the 48-145 portion of the beta-subunit and is probably a cleavage product of the native protein with intrachain nicking.

Amino Acid Sequence↗

PubMed1998

hCG and the free beta-subunit as screening tests for Down syndrome.

Published studies have reached varying conclusions as to the benefit of replacing human chorionic gonadotropin (hCG) measurements with the free beta-subunit of hCG (the free beta-subunit) for Down syndrome screening. One study reports 14 per cent higher detection for the free beta-subunit, while another finds an actual loss in detection. To explore this issue further, we directly compared the screening performance of hCG and the free beta-subunit, alone and in combination with other serum markers, using banked sera obtained prior to amniocentesis and karyotyping. Altogether, 52 Down syndrome and 5065 unaffected pregnancies were studied. Sera were thawed and assayed for hCG and the free beta-subunit over 1 year. At a 5 per cent false-positive rate, the detection rate for hCG in combination with maternal age and alpha-fetoprotein was higher than when the free beta-subunit was substituted (62 versus 57 per cent). Ultrasound dating and adding unconjugated oestriol both increased detection. The present findings, along with those from six case control studies (our re-analysis), indicate that the screening performances of hCG and the free beta-subunit are similar (median change in detection 0, range -8 to +3 per cent). Under optimal sample collection and transportation conditions, laboratories can expect to achieve similar screening performance using either hCG or the free beta-subunit measurements.

Amniocentesis↗

PubMed1986

Divergent metabolism of human chorionic gonadotropin subunits within rat ovarian lysosomes.

Pseudopregnant rats were injected with either native human chorionic gonadotropin or with (125I)-human chorionic gonadotropin and their ovarian homogenates fractionated on Percoll density gradients. The levels of alpha and beta subunits within subcellular fractions were measured using radioimmunoassays specific for each subunit. Radioactivity measurements of fractions obtained from rats injected with (125I)-human chorionic gonadotropin were used as a separate index of alpha subunit distribution. The alpha subunit was primarily restricted to a combined plasma membrane/prelysosomal vesicle fraction. Immunoreactive beta subunit was present at high concentrations within both this plasma membrane/prelysosomal vesicle fraction and within lysosomes. The striking difference in alpha and beta subcellular distribution may arise from differential sensitivities to lysosomal enzymes.

Animals↗

PubMed1995

Complete sequence of the gene encoding a chorionic gonadotropin-like protein from Xanthomonas maltophilia.

Our laboratory has previously reported that: (i) Xanthomonas maltophilia (Xm) produces a protein which has immunological resemblance to the beta-subunit of human chorionic gonadotropin (hCG) and (ii) possesses a high-affinity receptor which binds holo hCG, and the endogenous ligand, Xm chorionic gonadotropin (xCG), but does not bind human luteinizing hormone (hLH). We have also previously published a 492-bp partial nucleotide sequence of the gene (xcg) coding for xCG. We report herein the entire xcg sequence of 1362 bp, which codes for a 48-kDa protein. This sequence confirmed the 492-bp sequence, as well as two partial amino acid (aa) sequences which we have previously reported. The sequence has a region which is homologous to aa 56-139 of the beta-subunit of hCG, and a second region homologous to the C-terminal tail of hCG. This is the first report of a prokaryotic gene homologous to the hCG beta-subunit-encoding gene.

Amino Acid Sequence↗

PubMed2006

Increased plasma mRNAs of placenta-specific 1 (PLAC1) and glial cells-missing 1 (GCM1) in mothers with pre-eclampsia.

In this study we have investigated whether quantitative analysis of placental mRNAs in maternal plasma provides a way to monitor placental status. We measured plasma concentrations of human chorionic gonadotropin beta-subunit (betahCG) and human placental lactogen (hPL) mRNAs as previously reported mRNAs and pregnancy associated plasma protein A (PAPP-A), placenta-specific 1 (PLAC1) and glial cells-missing 1 (GCM1) mRNAs, which have not been measured during the course of normal pregnancy. Firstly, peripheral blood was obtained at various times from healthy pregnant women to clarify the time course of placental mRNAs. Secondly, blood was obtained from women with pre-eclampsia and gestational age-matched controls to examine whether placental mRNAs change in pre-eclampsia. Plasma was separated from these samples for extraction of RNA, followed by reverse transcription polymerse chain reaction analysis. Median concentrations of PLAC1 and GCM1 mRNA in plasma of pre-eclamptic subjects respectively were 1625 and 2141 copies/ml, significantly higher than 195 and 881 copies/ml, the values for controls (Mann-Whitney test, p<0.001). No significant difference was seen in hPL, betahCG, or PAPP-A mRNA concentration between pre-eclamptic and control groups. Plasma PLAC1 and GCM1 mRNAs appear promising as noninvasively measurable molecular markers for pre-eclampsia.

Adult↗

PubMed2006

[A non-seminomatous extra-gonadal germ cell tumor responding to intensive treatment: a case report].

A 23-year-old man presented with lumbago as a chief complaint. Computed tomographic (CT) scan revealed multiple lung tumors, multiple liver tumors, bulky retroperitoneal tumors with marked elevation of serum lactic dehydrogenase (LDH), alpha-fetoprotein, and beta subunit of human chorionic gonadotropin (HCG-beta). The patient was referred to our hospital for treatment. Scrotal ultrasonography and physical examination revealed bilateral normal testes. Because of bulky retroperitoneal masses with elevated specific tumor markers as well as bilateral normal testes, our diagnosis led to extra-gonadal germ cell tumor. Because the pulmonary lesion had increased rapidly, chemotherapy was performed without the tumor biopsy. After multiple chemotherapy regimens including BEP (bleomycin, etoposide, cisplatin), high-dose chemotherapy, and TIN (paclitaxel, ifosfamide, nedaplatin), all tumor marker levels fell into within the normal range. The tumor size was decreased remarkably on CT. Then, retroperitoneal lymphadenectomy were performed to confirm whether they still contained viable tumor cells. They contained only necrotic tissues without viable cancer cells by pathological examination. Consequently, the patient has been free of recurrence for 18 months after intensive treatment.

Adult↗

PubMed1982

Production and localization of human prolactin in placenta and decidua in early and at term normal pregnancy.

Prolactin (PRL), a peptide hormone of the anterior pituitary, greatly increases in both plasma and amniotic fluid during pregnancy. The pattern of measurable PRL differs according to gestational stage and between plasma and amniotic fluid levels. This variation has led to several opinions regarding the production site of PRL during pregnancy. In this paper, the authors describe the production and localization of PRL-materializing tissues of human placenta and decidua both in early pregnancy and at term. Immunohistologic investigations with highly purified antiserum obtained by immunization of albino rabbits and reacted with human PRL alone revealed that syncytial trophoblast was a site of PRL production. PRL was also detected in decidual tissue, but the latter did not show a pattern of production. By a method of double staining, the production and localization of either anti-beta-subunit of human chorionic gonadotropin (hCG-beta) or human placental lactogen (hPL) were manifestly differentiated from those of PRL in syncytial trophoblast.

Chorionic Gonadotropin↗

PubMed1994

Extragonadal germ cell tumor of retroperitoneal origin: report of two cases.

Two cases of primary extragonadal germ cell tumor of retroperitoneal origin are reported. One was a 26-year-old man complaining of back pain. He had a large retroperitoneal tumor with lung, liver and supraclavicular lymph node metastases. He was referred to us after being treated for malignant lymphoma. The serum AFP, beta-subunit of human chorionic gonadotropin (hCG-beta), CEA and CA-19-9 were elevated. The retroperitoneal disease was treated surgically and with radiotherapy. The pathological diagnosis was that of embryonal carcinoma and teratoma. The lung, liver and supraclavicular lymph node metastases disappeared completely after two courses of cisplatin-based chemotherapy. While further chemotherapy was postponed due to myelosuppression, the disease relapsed and was resistant to subsequent therapy. The patient died twelve months after he first saw us. The second case was that of a 36-year-old man complaining of edematous legs and external genitalia. He had an extensive retroperitoneal tumor with multiple pulmonary metastases. The serum AFP level was high. Suspected of having an extragonadal germ cell tumor, he was referred to us promptly. Cisplatin-based chemotherapy coupled with resection of residual retroperitoneal and pulmonary disease resulted in complete remission. The pathological diagnosis was that of possible embryonal carcinoma. Further chemotherapy was given as scheduled, using granulocyte colony-stimulating factor. The patient has been in complete remission for two years. The chemotherapeutic regimen and surgical policy in the treatment of the two patients were essentially same. Early diagnosis, adequate initial therapy and the use of granulocyte colony-stimulating factor may be relevant to the favorable prognosis in the latter case.

Adult↗

PubMed1988

Expression of chorionic gonadotropin by schistosomiasis-associated squamous carcinomas of bladder.

Of 22 consecutive cases of squamous cell carcinomas of the urinary bladder, 4 expressed the beta subunit of human chorionic gonadotropin as demonstrated by immunohistochemistry. The significance of this finding is compared to similar observations made in urothelial carcinomas by others and its value as a possible marker in diagnosing and monitoring the progress of these tumors is discussed.

Carcinoma, Squamous Cell↗

PubMed1979

Synthesis and processing of human chorionic gonadotropin subunits in cultured choriocarcinoma cells.

Pulse and pulse-chase experiments have identified the presence of partially glycosylated precursors of the alpha and beta subunits of human chorionic gonadotropin (hCG) in cultured JAR choriocarcinoma cells. The alpha subunit precursor has an apparent molecular weight (by sodium dodecyl sulfate/polyacrylamide gel electrophoresis) of 18,000 (compared to 22,000 for fully processed alpha subunit); the beta subunit precursor has an apparent molecular weight of 24,000 (fully processed, 34,000). Both of these precursors appear to have an intracellular half-life of at least 1 hr and to contain the mannose core but not the terminal carbohydrate sequences. Fully processed alpha and beta subunits do not accumulate intracellularly, indicating that further processing of the precursors is followed by rapid secretion.

Carbohydrate Sequence↗

PubMed1987

Recent developments in immunocontraception.

The possibility of controlling fertility by antibodies inactivating key reproductive hormones has been amply demonstrated by active and passive immunization in primates. Four birth control vaccines directed against human chorionic gonadotropin are currently in early clinical trials. The nature of these vaccines and the underlying principles are described, as are the available results from clinical studies. The alpha- and beta-subunits of human chorionic gonadotropin and the ovine gonadotropins have been cloned by recombinant deoxyribonucleic acid methods. A new breed of vaccines that combines the genes of gonadotropins linked to hepatitis B surface protein has been developed. The next generation of birth control vaccines is likely to be polyvalent and to have the ability to intercept fertility at more than one point. A number of monoclonal antibodies against human sperm have shown the presence of tissue-specific antigens and the possibility of preventing the fertilization of the egg. Inclusion of more than one carrier in the vaccine increases the percentage of high responders and accords immunoprophylactic benefits against more than one disease. Conjugates have also been developed to obtain high titers of antibodies against gonadotropin-releasing hormone with permissible adjuvants. This vaccine may have therapeutic applications in hormone-dependent cancers and precocious puberty.

Chorionic Gonadotropin↗

PubMed2000

Trophoblastic cells expressing human chorionic gonadotropin genes in peripheral blood of patients with trophoblastic disease.

We attempted to identify the cells expressing alpha and beta subunits of human chorionic gonadotropin (hCG) in the peripheral blood of patients with trophoblastic disease and normal pregnant women by using reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blot. By this method, the mRNAs of hCG alpha and hCG beta were detected in the peripheral blood mononulear cells (PBMNC) from 3 of 7 hydatidiform mole (mole) and 1 of 4 choriocarcinoma patients as well as from normal pregnant women during the first trimester. None of the mRNAs of hCG subunits was detected in the PBMNC from healthy male and nonpregnant healthy women examined. The expression of hCG alpha and hCG beta in patients with trophoblastic disease and normal pregnant women almost correlated with their plasma levels of intact hCG. The present study indicates that the cells expressing hCG alpha and hCG beta, which virtually represent trophoblasts, are circulating in the peripheral blood of patients with trophoblastic disease as well as of normal pregnant women.

Blotting, Southern↗

PubMed1985

Return of ovulation after evacuation of hydatidiform moles.

Plasma levels of progesterone, 17 beta-estradiol and prolactin and serum levels of the beta-subunit of human chorionic gonadotropin were measured by radioimmunoassay before evacuation and then weekly after evacuation in 52 patients with complete moles and 15 patients with partial moles. The first menstrual cycle was ovulatory in 20 patients (29.9%) and anovulatory in 36 patients (53.7%). In 11 patients (16.4%) it was uncertain whether they ovulated in the first cycle. There was no difference in the ovulation rate between patients with complete moles and those with partial moles. The ovulation rate in patients with theca-lutein cysts was lower than that in patients without theca-lutein cysts. The preevacuation serum level of the beta-subunit of human chorionic gonadotropin in patients who ovulated in the first cycle was significantly lower than that in patients who did not ovulate, but there was no significant difference in the other hormones. By the sixth week, 12 patients already had the first ovulatory menstrual period and 40% of patients ovulated when the serum level of the beta-subunit of human chorionic gonadotropin was still above 10 mlU/ml. It is recommended that an effective method of contraception be instituted immediately after evacuation of hydatidiform moles.

Abortion, Therapeutic↗