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Biomedical subjects

Stephen A Butler

Publications and source records attributed to Stephen A Butler.

11 recordsLinked to original sources
PubMed2006

Follicular fluid levels of inhibin A, inhibin B, and activin A levels reflect changes in follicle size but are not independent markers of the oocyte's ability to fertilize.

OBJECTIVE: To investigate the biochemical relationship between follicular/oocyte maturity and follicular inhibins and activin levels. DESIGN: Prospective study. SETTING: Research laboratory in university hospital. PATIENT(S): Thirty-five women undertook IVF/ICSI program. INTERVENTION(S): Individual follicular fluid aspirations, oocyte isolation, follicular fluid storage. MAIN OUTCOME MEASURE(S): Inhibin A, inhibin B, and activin A concentrations, oocyte retrieval, and fertility outcome. RESULT(S): Inhibin A, inhibin B, and activin A concentrations varied from 7.9 to 436 ng/mL, 9.7 to 786 ng/mL, and 1.7 to 267.9 ng/mL, respectively. There was no change of inhibin A concentrations, whereas inhibin B and activin A concentrations dropped dramatically as the follicles enlarged. Total follicular content of inhibin A and activin A increased, and inhibin B remained constant. Both inhibin A and inhibin B levels were significantly higher in those follicles from which an oocyte could be recovered, but they did not differ with respect to subsequent oocyte fertilization. CONCLUSION(S): Inhibin A is actively produced throughout follicular growth to retain a set concentration. In contrast, inhibin B appears not to be actively produced, and the concentration drops as follicles enlarge. Activin A concentrations also decrease, but there is some extra synthesis. Higher levels of inhibin A and B are associated with oocyte presence but not with fertilization rates.

Activins↗
PubMed2006

Gestational trophoblastic diseases: 2. Hyperglycosylated hCG as a reliable marker of active neoplasia.

OBJECTIVES: To determine whether circulating hyperglycosylated human chorionic gonadotropin (hCG-H), a promoter of choriocarcinoma growth and tumorigenesis, is a reliable marker of active gestational trophoblastic neoplasia (GTN) or choriocarcinoma, and whether hCG-H can consistently discriminate quiescent gestational trophoblastic disease (GTD) from neoplasia. METHODS: Patients were those referred to the USA hCG Reference Service for consultation. These included a total of 82 women with GTN, including 30 with histologic choriocarcinoma. They were compared with 26 patients with resolving hydatidiform mole and 69 with quiescent GTD (persistent positive low value of real hCG but no clinical evidence of disease). All were tested for total hCG and hCG-H. hCG-H was calculated as the percentage of total hCG (hCG-H(%)). RESULTS: We compared the utility of total hCG and hCG-H(%) in detecting active GTN and quiescent GTD. There was no significant difference when measuring total hCG (includes regular and hyperglycosylated hCG), between women with quiescent GTD and self-resolving hydatidiform mole compared to choriocarcinoma/GTN cases (P > 0.05 and P > 0.05). In contrast, hCG-H(%) was significantly higher in choriocarcinoma/GTN cases (P < 0.000001, and P < 0.000001). The usefulness of hCG and hCG-H(%) testing was assessed for discriminating between the 69 quiescent GTD cases, which required no therapy, and choriocarcinoma/GTN which need treatment. While hCG would detect 62% and 24% of malignancies at a 5% false positive rate, hCG-H(%) would detect 100% and 84% of malignancies at this same false positive rate. Follow-up data were received and repeat consultations were performed in 23 cases in which active disease was subsequently demonstrated. In 12 of 23 cases, hCG-H(%) results were able to first identify active disease 0.5 to 11 months prior to rapidly rising hCG or detection of clinically active neoplasia. In the remaining 11 cases, hCG-H(%) active disease appeared at the same time as rising hCG or demonstrable clinical tumor. DISCUSSION AND CONCLUSION: hCG-H(%) appears to reliably identify active trophoblastic malignancy. It is a 100% sensitive marker for discriminating quiescent GTD from active GTN/choriocarcinoma. It is also a marker for the early detection of new or recurrent GTN/choriocarcinoma. The data presented appear sufficient to encourage the adoption of hCG-H as a tumor marker in trophoblastic disease. Further studies are now urgently required to confirm and extend our findings.

Biomarkers, Tumor↗
PubMed2006

Gestational trophoblastic diseases: 1. Pathophysiology of hyperglycosylated hCG.

OBJECTIVE: Hyperglycosylated hCG (hCG-H) is a glycosylation variant of hCG produced by cytotrophoblast cells at implantation of pregnancy and in choriocarcinoma. We investigated the biological function of hCG-H in invasion in vitro and in vivo and the use of hCG-H antibodies in blocking tumorigenesis and cancer growth in vivo. METHODS AND RESULTS: hCG-H accounts for 43% to 100% of total hCG immunoreactivity in the culture fluid of choriocarcinoma cell lines and 100% in primary cultures of pregnancy cytotrophoblast cells. We investigated the action of hCG and hCG-H on isolated cytotrophoblast cell primary cultures and on 3 different lines of choriocarcinoma cells cultured on Matrigel basement membrane inserts (culture models for assessing tumor invasion). The addition of hCG-H to medium significantly promoted invasion of membranes with both pregnancy and cancer cell line sources, while regular hCG had no significant effect. JEG-3 human choriocarcinoma cells were transplanted subcutaneously into athymic nude mice. Tumors rapidly formed. B152, mouse monoclonal antibody against hCG-H, and non-specific mouse IgG (control) were administered twice weekly once tumors were clearly visible. While a correlation between time and growth was observed with the control group (r(2)=0.97), no correlation was observed with the B152-treated mice (r(2)=0.15). B152 blocked tumor growth (t test, IgG vs. B152, P=0.003). In a second experiment, antibody B152 or IgG was administered to mice at the time of choriocarcinoma transplantation. B152 significantly inhibited tumorigenesis (t test P=0.0071). CONCLUSIONS: hCG-H is a critical promoter in human cytotrophoblast and human choriocarcinoma cell invasion in vivo and in vitro, promoting tumor growth and invasion through an autocrine mechanism. hCG-H is a signal for choriocarcinoma cell invasion, making it a biological tumor marker. Antibodies against hCG-H block tumor formation and growth. Human or humanized antibodies against hCG-H may be useful in treating and managing choriocarcinoma and other gestational trophoblastic malignancies.

Animals↗
PubMed2006

Gestational trophoblastic diseases: 4. Presentation with persistent low positive human chorionic gonadotropin test results.

OBJECTIVES: A high proportion of women with persistent low levels of hCG, in the absence of pregnancy or any evidence of tumor, have received chemotherapy and hysterectomy for assumed malignancy. Such chemotherapy and surgery were ineffective and unwarranted. This study identifies the causes of persistent low level of hCG and provides guidelines for the management of these patients, preventing unnecessary treatment in the future. METHODS: The USA hCG Reference Service has consulted on 170 women with low levels of hCG persisting for 3 months or longer. Serum total hCG was measured in the Diagnostic Products Corporation (DPC) Immulite assay and hyperglycosylated hCG in the Nichols Advantage test. RESULTS: Among these 170 patients, the average persistent hCG result was 102 +/- 152 mIU/ml, with a range of 6.1-900 mIU/ml. Thirteen (7.6%) of the 170 patients had true malignancy, 5 had placental site trophoblastic tumor, 3 had other gestational trophoblastic neoplasms (GTN), and 5 had non-trophoblastic malignancies. The remaining 157 patients had false-positive hCG, quiescent gestational trophoblastic disease (quiescent GTD), or pituitary hCG (hCG of pituitary origin). Of 71 patients with false-positive hCG, 47 patients received chemotherapy and 9 had surgery that had no effect on the level of hCG. Five of these patients with false-positive hCG were being monitored for hydatidiform mole or GTN. The majority of these cases were first investigated following an incidental pregnancy test. Of 69 patients who had quiescent GTD, 41 received chemotherapy and 9 underwent hysterectomy. All these therapies were unnecessary and ineffective. While 21 patients with quiescent GTD followed incidental pregnancy tests, the majority were discovered while monitoring patients after treatment for hydatidiform mole or GTN/choriocarcinoma (n = 48). Seventeen cases of pituitary hCG were found among those women who were peri- or post-menopause. Two patients also received chemotherapy for assumed malignancy which was not present. CONCLUSION: Clinicians frequently assume that an elevated hCG implies that a patient is pregnant or has GTD or recurrent GTN, even when apart from the pregnancy test, no clinical evidence was found to support such a diagnosis. In most of these cases of persistent low hCG etiologies, all therapies were found unnecessary and ineffective. Guidelines are proposed for managing these patients. It is essential to demonstrate a malignancy clinically and with readily available biochemical tests before initiating therapy. This applies whether the patient is identified by an incidental pregnancy test or is actively being monitored for gestational trophoblastic disease.

Adult↗
PubMed2006

Hyperglycosylated hCG in gestational implantation and in choriocarcinoma and testicular germ cell malignancy tumorigenesis.

OBJECTIVE: Hyperglycosylated human chorionic gonadotropin (hCG-H) is a carbohydrate variant of hCG with double-sized oligosaccharide side chains. While hCG-H is produced exclusively by stem cytotrophoblast cells in gestational choriocarcinoma, by pregnancy cytotrophoblast at implantation and by the cytotrophoblast produced in testicular malignancies, regular hCG is produced only by differentiated syncytiotrophoblast cells. STUDY DESIGN: hCG-H was measured using the Nichols Advantage hCG-H assay (Nichols Institute Diagnostics, San Clemente, California). RESULTS: hCG-H has a function separate from regular hCG. hCG-H, but not regular hCG, acts in vivo and in vitro to promote invasion, whether invasion through membranes or tumor formation. Invasion or tumorigenesis is completely blocked by administration of specific antibody to hCG-H. The same hCG-H-modulated invasion mechanisms are observed in early pregnancy, gestational choriocarcinoma and testicular cancers. CONCLUSION: hCG-H is a cytokinelike molecule, produced by cells different from those that make regular hCG and having a completely separate function. It appears to be the modulator of invasion as in implantation of pregnancy, gestational choriocarcinoma and testicular cancer malignancy.

Animals↗
PubMed2003

Ectopic human chorionic gonadotropin beta secretion by epithelial tumors and human chorionic gonadotropin beta-induced apoptosis in Kaposi's sarcoma: is there a connection?

Since it was first claimed in 1995 that human chorionic gonadotropin (hCG) inhibits HIV-associated Kaposi's sarcoma (KS), focus has been lost on establishing a credible hypothesis to explain a novel action ascribed to hCG, which is, after all, a pregnancy hormone. After 7 years, no real progress has been made, and there remains no consensus as to which component of hCG preparations is responsible for inducing apoptosis of HIV-associated KS. It would certainly seem apparent that many basic experiments on hCG species have been overlooked in the studies that have been published. Furthermore, the much wider literature concerning the association of hCG with promoting oncogenesis has been ignored. This review puts into context the numerous studies on hCG, HIV-associated KS, and oncogenesis.

Animals↗
PubMed2003

Human chorionic gonadotropin isoforms in the diagnosis of ectopic pregnancy.

BACKGROUND: Early diagnosis of ectopic pregnancy uses ultrasound with serial measurements of total human chorionic gonadotropin (hCG). The objective of this study was to explore the possibility that an isolated measurement of hCG isoforms/subunits rather than total hCG could be used as a single test for ectopic pregnancy. METHODS: Total and intact hCG, free hCG beta- and alpha-subunits (hCGbeta and -alpha), and hCG beta-core fragment were measured by RIA and IRMA in the serum and urine of 76 women presenting at outpatient emergency departments with a positive pregnancy test, lower abdominal pain, and/or vaginal bleeding. Final diagnoses were based on outcomes of pregnancies and tissue histology. RESULTS: Twenty-seven of the 76 women were subsequently diagnosed with viable pregnancies, 37 with spontaneous miscarriage, and 12 with ectopic pregnancy. Concentrations of all forms of hCG were lower in cases of ectopic pregnancy and spontaneous miscarriage than in viable pregnancies. Serum samples gave better results than urine samples. The free hCGbeta isoform (P <0.0001) had 100% sensitivity at a specificity of 79% at a 281 pmol/L (6.5 micro g/L) cutoff. Total hCG (P = 0.005) had comparable ROC characteristics with a 100% sensitivity and 68% specificity at a cutoff value of 1053 pmol/L (375 IU/L). Neither hCGbeta (P = 0.7) nor total hCG (P = 0.4) could distinguish ectopic pregnancies from spontaneous miscarriage. CONCLUSION: Measurement of serum free hCGbeta at the time of presentation can identify women with a high probability of ectopic pregnancy who may benefit from closer surveillance, reducing the risk of tubal rupture.

Biomarkers↗
PubMed2003

Reduction of bladder cancer cell growth in response to hCGbeta CTP37 vaccinated mouse serum.

The free beta-subunit of human chorionic gonadotrophin (hCGbeta) is well established as an ectopic product of epithelial tumors. Originally explained as an epi-phenomenon, hCGbeta production by many types of carcinoma is increasingly regarded as a significant tumor event. Studies in bladder cancer have shown that hCGbeta production, while not diagnostic, is a very good indicator for poor prognosis through correlations with resistance to radiotherapy and rapid metastasis. These clinical findings led to in vitro studies that have shown a direct response to hCGbeta by bladder carcinoma cell lines. This response is linked by inhibition of apoptosis to an increase in cell population. More recently, studies on hCGbeta as a marker for poor prognosis in other epithelial cancers now suggest that this phenomenon may not be restricted to bladder carcinoma. Thus, ectopic hCGbeta represents an ideal target for immunodepletive therapy. Antisera were generated from mice vaccinated with full-length hCGbeta carboxy terminal peptide (CTP37) and a truncated region comprising 24 of the amino acids of the CTP (CTP24), expressed on the surface of cowpea mosaic virus (CPMV). The effect of the resultant murine antiseras on bladder carcinoma cell growth in vitro was investigated. When CTP37 antisera, at dilutions of 1:50 and 1:100, were incubated with two hCGbeta-producing cell lines, SCaBER and RT112, significant reductions in cell number, up to 43%, were observed. In the bladder cancer cell line T24, which does not produce hCGbeta, CTP37 antisera had no growth effects. CTP24 antiserum, like control sera from mice immunized with wild-type CPMV, had no effects on the in vitro growth of any cell lines. This implies that full-length CTP37, but not CTP24, is involved in the oncogenic inhibition of apoptosis by hCGbeta. hCGbeta CTP37 vaccines are available as well-tested antifertility vaccines in the Third World. They have now been tested on cancer patients. This study is the only in vitro evidence that such a vaccine would have beneficial antitumor effects via immunodepletion mechanisms. We propose that vaccines such as this could be used as an adjuvant therapy in the treatment of hCGbeta-producing bladder cancers.

Adjuvants, Immunologic↗
PubMedDate not supplied

The free monomeric beta subunit of human chorionic gonadotrophin (hCG beta) and the recently identified homodimeric beta-beta subunit (hCG beta beta) both have autocrine growth effects.

The ectopic production of free hCG beta is a common phenomenon in epithelial tumours, a phenomenon originally believed to have no biological significance. However, it is now apparent that hCG beta may significantly effect tumour development by increasing cell populations through inhibition of apoptosis. The recently identified hCG beta beta homodimer, with topological similarities to cystine knot growth factors, has been suggested to be the responsible mediator of these novel tumourigenic responses. In this study we isolated hCG beta monomer from hCG beta beta homodimer using size exclusion chromatography and confirmed the separation by Western blotting. Using a tetrazolium bromide incorporation cell number quantification assay (MTT), we measured the growth effects of separated hCG beta fractions corresponding to monomeric (hCG beta) and dimeric (hCG beta beta) forms on the hCG beta responding cell line T24. Maximal increases in cell number corresponded to the elution peak of dimeric and monomeric hCG beta. In conclusion, it would appear that the recently observed hCG beta beta homodimer is no more bioactive than its monomeric counterpart, in stimulating bladder cancer cell growth. This strengthens the proposition that hCG beta may exert its antiapoptotic effects by antagonistic inhibition of other cystine knot growth factor receptors and not by a specific receptor-mediated homodimeric interaction as seen for its topological counterparts TGF, PDGF-B and NGF.

Apoptosis↗