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1.
Exp Cell Res ; 383(2): 111513, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31362000

RESUMO

Regulatory B cells (Breg cells) play critical roles in modulating immune responses during autoimmune diseases and infection. Here we explored the participation of two main Breg subsets, including IL-10+ Breg (B10) and IL-35+ Breg cells, in maintaining successful pregnancy. We first observed an elevated percentage of B10 cells in peripheral blood from first-trimester pregnant women compared with non-pregnant controls. Serum from pregnancy induced the augmentation of B10  in peripheral blood mononuclear cells from non-pregnant women. In animal models, we demonstrated that there were significant augmentation of B10 cells and obvious increase of IL-10 level in splenic B cells from normal pregnant mice compared to that in abortion-prone pregnant mice and virgin mice. Further analysis showed that both hCG and IL-35 suppressed the proliferation of mouse splenic B cells. Moreover, IL-35 induced the expansion of both mouse splenic B10 and IL-35+ Breg cells while hCG only mediated the generation of B10 cells. Subsequent study in mice demonstrated that the activation of STAT1 and STAT3 in B cells caused by IL-35 and the activation of STAT3 caused by hCG were the predominant mechanism of IL-35+ Breg and B10 cells augmentation. These findings suggested that hCG and IL-35 induced the amplification of B10 and IL-35+ Breg cells which played a vital peripheral regulatory role during pregnancy.


Assuntos
Linfócitos B Reguladores/fisiologia , Gonadotropina Coriônica/fisiologia , Tolerância Imunológica , Interleucina-10/metabolismo , Interleucinas/fisiologia , Manutenção da Gravidez/imunologia , Aborto Espontâneo/sangue , Aborto Espontâneo/imunologia , Aborto Espontâneo/patologia , Adulto , Animais , Linfócitos B Reguladores/efeitos dos fármacos , Linfócitos B Reguladores/metabolismo , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Gonadotropina Coriônica/sangue , Gonadotropina Coriônica/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Tolerância Imunológica/efeitos dos fármacos , Interleucinas/sangue , Interleucinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Gravidez , Manutenção da Gravidez/efeitos dos fármacos , Primeiro Trimestre da Gravidez/sangue , Primeiro Trimestre da Gravidez/imunologia , Adulto Jovem
2.
Minerva Ginecol ; 70(5): 561-587, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30264954

RESUMO

This review article centers upon family of gonadotropin hormones which consists of two pituitary hormones - follicle-stimulating hormone (FSH) and luteinizing hormone (LH) as well as one non-pituitary hormone - human chorionic gonadotropin (hCG) secreted by placenta, and their receptors. Gonadotropins play an essential role in proper sexual development, puberty, gametogenesis, maintenance of pregnancy and male sexual differentiation during the fetal development. They belong to the family of glycoprotein hormones thus they constitute heterodimeric proteins built of common α subunit and hormone-specific ß-subunit. Hitherto, several mutations in genes encoding both gonadotropins and their receptors have been identified in humans. Their occurrence resulted in a number of different phenotypes including delayed puberty, primary amenorrhea, hermaphroditism, infertility and hypogonadism. In order to understand the effects of mutations on the phenotype observed in affected patients, detailed molecular studies are required to map the relationship between the structure and function of gonadotropins and their receptors. Nonetheless, in vitro assays are often insufficient to understand physiology. Therefore, several animal models have been developed to unravel the physiological roles of gonadotropins and their receptors.


Assuntos
Gonadotropina Coriônica/fisiologia , Hormônio Foliculoestimulante/fisiologia , Hormônio Luteinizante/fisiologia , Animais , Gonadotropina Coriônica/genética , Feminino , Doenças Urogenitais Femininas/genética , Doenças Urogenitais Femininas/fisiopatologia , Hormônio Foliculoestimulante/genética , Humanos , Hormônio Luteinizante/genética , Masculino , Doenças Urogenitais Masculinas/genética , Doenças Urogenitais Masculinas/fisiopatologia , Modelos Animais , Mutação , Fenótipo , Gravidez , Receptores da Gonadotropina/genética , Receptores da Gonadotropina/fisiologia
3.
Biomed Khim ; 63(6): 539-545, 2017 Nov.
Artigo em Russo | MEDLINE | ID: mdl-29251616

RESUMO

The effects of chorionic gonadotropin (hCG) on the expression of the hTERT gene in combination with the conversion of the phenotype of naive T-cells and T-cells of immune memory in vitro were studied. hCG inhibited expression of hTERT mRNA in naive T-cells (CD45RA+) and immune memory T cells (CD45RO+), causing a decrease in the replicative potential of the cells. The presence of hCG in the culture led to the conversion of the phenotype of T-lymphocytes. hCG reduced the number of proliferating T-cells of immune memory, estimated by phenotypic signs by differential gating. hCG (10 IU/ml and 100 IU/ml) inhibited expression of CD25 by the studied populations, but did not modulate expression of the CD71 proliferation marker. Thus, hCG inhibited the functional activity of naive T-cells and T-cells of immune memory, which, in the context of pregnancy, can contribute to the formation of immune tolerance to the semi-allogenic fetus.


Assuntos
Diferenciação Celular , Gonadotropina Coriônica/fisiologia , Linfócitos T/citologia , Telomerase/metabolismo , Células Cultivadas , Feminino , Humanos , Antígenos Comuns de Leucócito/metabolismo , Fenótipo , Gravidez , Telomerase/genética
4.
Int J Mol Sci ; 18(6)2017 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-28629172

RESUMO

Embryo implantation is a complex process involving continuous molecular cross-talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, a brief overview of the molecular mechanisms regulated by HCG is presented. Furthermore, we summarize the existing evidence regarding the clinical impact on reproductive outcomes after endometrial priming with HCG prior to embryo transfer. Although promising, further evidence is needed to clarify the protocol that would lead to beneficial outcomes.


Assuntos
Gonadotropina Coriônica/fisiologia , Gonadotropina Coriônica/uso terapêutico , Implantação do Embrião , Transferência Embrionária/métodos , Gonadotropina Coriônica/administração & dosagem , Decídua/metabolismo , Endométrio/metabolismo , Feminino , Fertilização In Vitro/métodos , Humanos , Infertilidade , Gravidez , Taxa de Gravidez , Resultado do Tratamento
5.
Int J Mol Sci ; 18(5)2017 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-28513550

RESUMO

Human chorionic gonadotropin (hCG) is no longer a single, omnipotent ovulation triggering option. Gonadotropin releasing hormone (GnRH) agonist, initially presented as a substitute for hCG, has led to a new era of administering GnRH agonist followed by hCG triggering. According to this new concept, GnRH agonist enables successful ovum maturation, while hCG supports the luteal phase and pregnancy until placental shift.


Assuntos
Gonadotropina Coriônica/fisiologia , Fenômenos Reprodutivos Fisiológicos , Técnicas Reprodutivas , Evolução Biológica , Gonadotropina Coriônica/farmacologia , Feminino , Fertilização In Vitro , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Recombinantes , Transdução de Sinais/efeitos dos fármacos
6.
Fiziol Cheloveka ; 43(1): 97-110, 2017 Jan.
Artigo em Inglês, Russo | MEDLINE | ID: mdl-29509368

RESUMO

The last two decade discoveries shift the accent from consideration of human chorionic gonadotripin (hCG) as a hormone, that controls progesterone production by corpus luteum cells, to a powerful paracrine regulator which'in the tandem with its hyperglycozilated analog (hCG-H) induces successful implantation and coordinated dialog between blastocyst and uterus tissues. Ability of hCG to interact with TSH receptor and hCG-H with TGF-beta-RII extend significantly the spectrum of processes controlled by these molecules. Differences between intracellular pathways of signal transduction between hCG and LH mediated by the same receptor (LH/hCG-R) impugn unity of their effector mechanisms previously considered as obvious. Paracine properties-of hCG comprise control of fusing of trophoblasts into syncytiotrophoblasts, angiogenesis, immunity regulation and endometrium predisposition to implantation. Angiogenesis is associated with LH/hCG-R expressed on mural cells of uterine spiral arteries as well as induced secretion of soluble VEGF type by endometrial cells. hCG.regulates ratio between different forms of T-helper cells in maternal organism on the initial gestation stage determining high level of Th2 cells. hCG supports local immunotolerance acting as chemoattractant for T-suppressors (T-Treg) and apoptotic factor for T-lymphocytes. Endometrial susceptibility arises from activation of osteopantin secretion and decline of mucin secretion by epithelial cells. hCG-H acts on the same tissues as hCG as a paracrine agent regulating multiple cascades of cytokines. hCG-H plays the key role in trophoblast invasion into,uterine decidua as a result of gelatinase secretion by these cells.The degree of angiogenic effect of hCG-H is compatiblewith hCG but its signal transduction is mediated by TGF-beta signal transduction pathway that stimulates mural cell proliferation. hCG-H acts as mitogen on NK-cells and is able to activate them and direct to angiogenesis maintenance. In this article the attempt was made to elucidate the most important discoveries about the role of hCG and its hyperglycosylated analog yet accomplished and still upcoming.


Assuntos
Doenças Autoimunes/terapia , Gonadotropina Coriônica/fisiologia , Gonadotropina Coriônica/uso terapêutico , Gonadotropina Coriônica/química , Gonadotropina Coriônica/metabolismo , Corpo Lúteo/metabolismo , Endométrio/fisiologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Mitógenos/imunologia , Mucina-1/metabolismo , Placenta/fisiologia , Placentação , Gravidez , Progesterona/metabolismo , Transdução de Sinais
7.
Ann Endocrinol (Paris) ; 77(2): 75-81, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27177499

RESUMO

Human chorionic gonadotropin (hCG) is the first hormonal message from the placenta to the mother. It is detectable in maternal blood two days after implantation and behaves like a super LH agonist stimulating progesterone secretion by the corpus luteum. In addition to maintaining the production of progesterone until the placenta itself produces it, hCG also has a role in myometrial quiescence and local immune tolerance. Specific to humans, hCG is a complex glycoprotein composed of two highly glycosylated subunits. The α-subunit is identical to the pituitary gonadotropin hormones (LH, FSH, TSH), contains two N-glycosylation sites, and is encoded by a single gene (CGA). By contrast, the ß-subunits are distinct for each hormones and confer both receptor and biological specificity, although LH and hCG bind to the same receptor (LH/CG-R). The hCG ß-subunit is encoded by a cluster of genes (CGB) and contains two sites of N-glycosylation and four sites of O-glycosylation. The hCG glycosylation state varies with the stage of pregnancy, its source of production and in the pathology. It is well established that hCG is mainly secreted into maternal blood, where it peaks at 8-10weeks of gestation (WG), by the syncytiotrophoblast (ST), which represents the endocrine tissue of the human placenta. The invasive extravillous trophoblast (iEVT) also secretes hCG, and in particular hyperglycosylated forms of hCG (hCG-H) also produced by choriocarcinoma cells. In maternal blood, hCG-H is elevated during early first trimester corresponding to the trophoblastic cell invasion process and then decreases. In addition to its endocrine role, hCG has autocrine and paracrine roles. It promotes formation of the ST and angiogenesis through LH/CG-R but has no effect on trophoblast invasion in vitro. By contrast, hCG-H stimulates trophoblast invasion and angiogenesis by interacting with the TGFß receptor in a LH/CG-R independent signalling pathway. hCG is largely used in antenatal screening and hCG-H might represent a serum marker of implantation and early trophoblast invasion. In conclusion, hCG is the major pregnancy glycoprotein hormone, whose maternal concentration and glycan structure change all along pregnancy. Depending on its source of production, glycoforms of hCG display different biological activities and functions that are essential for pregnancy outcome.


Assuntos
Gonadotropina Coriônica/química , Gonadotropina Coriônica/fisiologia , Placenta/metabolismo , Gonadotropina Coriônica/metabolismo , Feminino , Humanos , Gravidez , Isoformas de Proteínas , Relação Estrutura-Atividade , Trofoblastos/fisiologia
8.
Breast ; 26: 135-40, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27017252

RESUMO

INTRODUCTION: Breast cancer is the most often diagnosed tumor of women and one of the leading cause of cancer related death. Due to different known risk factors there are epidemiological differences. Beside genetic disorders and patient's age it is especially the age of the first full-term pregnancy and in this context the pregnancy hormone human chorionic gonadotropin that seems to play an important role. METHODS: This review is based on a PubMed research in publications of the last 20 years. Only articles in English language were considered. RESULTS: The effect of human chorionic gonadotropin on development of cancer is controversial. In fact, for breast cancer there is evidence that this hormone has a protective effect against tumorigenesis due the differentiation of the mammary tissue after a full term pregnancy through the downregulation of estrogen receptors. CONCLUSION: Human chorionic gonadotropin has among promoting pregnancy important controversial functions especially in tumor development. The mechanisms that explain the pro- and anti-carcinogenic effects are not fully understood yet. It seems to have a protective effect on breast cancer through increasing differentiation and hereby decreasing susceptibility of the mammary tissue for toxicants. This knowledge might help developing a preventive agent in the next future that uses the anti-carcinogenic effect of human chorionic gonadotropin and thereby decrease the mortality out of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Gonadotropina Coriônica/fisiologia , Anticarcinógenos/uso terapêutico , Neoplasias da Mama/etiologia , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Gravidez
9.
Kaohsiung J Med Sci ; 32(1): 1-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26853168

RESUMO

Infertility due to low testosterone levels has increased in recent years. This has impacted the social well-being of the patients. This study was undertaken to investigate the potential of gonadotropins in facilitating differentiation of human bone marrow mesenchymal stem cells (BMSCs) into Leydig cells in vitro. BMSCs were isolated, cultured, and their biological characteristics were observed. BMSCs were induced with gonadotropins in vitro and their ability to differentiate into Leydig cells was studied. The level of expression of 3-beta hydroxysteroid dehydrogenase (3ß-HSD) and secretion of testosterone were determined using flow cytometry and enzyme-linked immunosorbent assay, respectively, and the results were compared between the experimental and control groups. The cultured BMSCs showed a typical morphology of the fibroblast-like colony. The growth curve of cells formed an S-shape. After inducing the cells for 8-13 days, the cells in the experimental group increased in size and showed typical characteristics of Leydig cells, and the growth occurred in spindle or stellate shapes. Cells from the experimental group highly expressed 3ß-HSD, and there was a gradual increase in the number of Leydig cells. The control group did not express 3ß-HSD. The level of testosterone in the experimental group was higher than the control group (p < 0.05). Additionally, the cells in the experimental group secreted higher levels of testosterone with increased culture time. The expression of Leydig cell-specific markers in the experimental group was significantly higher (p < 0.05). With these findings, BMSCs can be considered a new approach for the treatment of patients with low androgen levels.


Assuntos
Diferenciação Celular , Gonadotropina Coriônica/fisiologia , Células Intersticiais do Testículo/enzimologia , Hormônio Luteinizante/fisiologia , Menotropinas/fisiologia , Células-Tronco Mesenquimais/fisiologia , 3-Hidroxiesteroide Desidrogenases/metabolismo , Adulto , Células da Medula Óssea/fisiologia , Proliferação de Células , Forma Celular , Células Cultivadas , Feminino , Humanos , Células Intersticiais do Testículo/fisiologia , Masculino , Testosterona/biossíntese , Adulto Jovem
10.
Fiziol Cheloveka ; 42(5): 102-107, 2016 09.
Artigo em Russo | MEDLINE | ID: mdl-29932555

RESUMO

The influence of chorionic gonadotropin (CG) and estriol (E3) at concentrations typical of pregnancy on the expression of phenotypic markers and cytokine production by separated NK cells were studied. It is found that these hormones increase the percentage of CD56brightL-selectin+ NK-cells, but also stimulate the expression of the inhibitory molecule NKG2A in the lymphocytes. In addition, E3 and CG stimulate the production of TGF-B, inhibiting the secretion of all other cytokines by separated NK cells. In general, these hor- mones contribute to the formation of the phenotype and cytokine spectrum characteristic of the regulatory NK3 subpopulation of NK cells during pregnancy.


Assuntos
Gonadotropina Coriônica , Estriol , Células Matadoras Naturais , Gonadotropina Coriônica/fisiologia , Estriol/fisiologia , Humanos , Células Matadoras Naturais/fisiologia , Fenótipo
11.
Anim Sci J ; 87(4): 492-502, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26462462

RESUMO

Leydig cells play a key role in synthesizing androgen and regulating spermatogenesis. The dysfunction of Leydig cells may lead to various male diseases. Although primary Leydig cell cultures have been used, their finite lifespan hinders the assessment of long-term effects. In the present study, primary goat Leydig cells (GLCs) were immortalized via the transfection of a plasmid containing the human telomerase reverse transcriptase (hTERT) gene. The expressions of hTERT and telomerase activity were evaluated in transduced GLCs (hTERT-GLCs). These cells steadily expressed the hTERT gene and exhibited longer telomere lengths at passage 55 that were similar to those of HeLa cells. The hTERT-GLCs at passages 30 and 50 expressed genes that encoded key proteins, enzymes and receptors that are inherent to normal Leydig cells, for example, steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and LH-receptor (LH-R). Additionally, the immortalized goat Leydig cells secreted detectable quantities of testosterone in response to hCG stimulation. Furthermore, this cell line appeared to proliferate more quickly than the control cells, although no neoplastic transformation occurred in vitro. We concluded that the GLCs immortalized with hTERT retained their original characteristics and might provide a useful model for the study of Leydig cell function.


Assuntos
Células Intersticiais do Testículo , Testosterona/metabolismo , 17-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Linhagem Celular , Proliferação de Células , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Gonadotropina Coriônica/fisiologia , Sistema Enzimático do Citocromo P-450/metabolismo , Cabras , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/enzimologia , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/fisiologia , Masculino , Fosfoproteínas/metabolismo , Receptores do LH/metabolismo , Espermatogênese , Telomerase/genética , Telomerase/metabolismo , Homeostase do Telômero
12.
Reprod Biomed Online ; 32(1): 14-43, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26615903

RESUMO

During pregnancy, several tightly coordinated and regulated processes take place to enable proper fetal development and gestational success. The formation and development of the placenta is one of these critical pregnancy events. This organ plays essential roles during gestation, including fetal nourishment, support and protection, gas exchange and production of several hormones and other mediators. Placental hormones are mainly secreted by the syncytiotrophoblast, in a highly and tightly regulated way. These hormones are important for pregnancy establishment and maintenance, exerting autocrine and paracrine effects that regulate decidualization, placental development, angiogenesis, endometrial receptivity, embryo implantation, immunotolerance and fetal development. In addition, because they are released into maternal circulation, the profile of their blood levels throughout pregnancy has been the target of intense research towards finding potential robust and reliable biomarkers to predict and diagnose pregnancy-associated complications. In fact, altered levels of these hormones have been associated with some pathologies, such as chromosomal anomalies or pre-eclampsia. This review proposes to revise and update the main pregnancy-related hormones, addressing their major characteristics, molecular targets, function throughout pregnancy, regulators of their expression and their potential clinical interest.


Assuntos
Hormônios/metabolismo , Placenta/fisiologia , Animais , Gonadotropina Coriônica/metabolismo , Gonadotropina Coriônica/fisiologia , Feminino , Desenvolvimento Fetal/fisiologia , Humanos , Placenta/metabolismo , Placentação/fisiologia , Pré-Eclâmpsia/metabolismo , Gravidez , Progesterona/metabolismo , Progesterona/fisiologia
13.
BMC Cancer ; 15: 1013, 2015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26704433

RESUMO

BACKGROUND: Treatment possibilities of metastatic renal cell carcinoma (mRCC) have recently changed dramatically prolonging the overall survival of the patients. This kind of development brings new challenges for the care of mRCC. CASE PRESENTATION: A 22 year-old female patient with translocation type mRCC, who previously had been treated for nearly 5 years, became pregnant during the treatment break period. Follow-up examinations revealed a dramatic clinical and radiological progression of mRCC in a few weeks therefore the pregnancy was terminated. A few days after surgical abortion, CT examination showed a significant spontaneous regression of the pulmonary metastases, and the volume of the largest manifestation decreased from ca. 30 to 3.5 cm(3) in a week. To understand the possible mechanism of this spectacular regression, estrogen, progesterone and luteinizing hormone receptors (ER, PGR and LHR, respectively) immuno-histochemistry assays were performed on the original surgery samples. Immuno-histochemistry showed negative ER, PGR and positive LHR status suggesting the possible angiogenic effect of human chorionic gonadotropin hormone (hCG) in the background. CONCLUSION: We hypothesize that pregnancy may play a causal role in the progression of mRCC via the excess amount of hCG, however, more data are necessary to validate the present notions and the predictive role of LHR overexpression.


Assuntos
Aborto Terapêutico , Carcinoma de Células Renais/secundário , Gonadotropina Coriônica/fisiologia , Neoplasias Renais/patologia , Regressão Neoplásica Espontânea , Complicações Neoplásicas na Gravidez/patologia , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Feminino , Humanos , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/metabolismo , Neoplasias Renais/terapia , Neovascularização Patológica , Gravidez , Complicações Neoplásicas na Gravidez/metabolismo , Complicações Neoplásicas na Gravidez/terapia , Adulto Jovem
14.
Adv Exp Med Biol ; 867: 159-76, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26530366

RESUMO

Tumor markers are biological substances that are produced/released mainly by malignant tumor cells, enter the circulation in detectable amounts and are potential indicators of the presence of a tumor. The most useful biochemical markers are the tumor-specific molecules, i.e., receptors, enzymes, hormones, growth factors or biological response modifiers that are specifically produced by tumor cells and not, or minimally, by the normal counterpart (Richard et al. Principles and practice of gynecologic oncology. Wolters Kluwer Health, Philadelphia, 2009). Based on their specificity and sensitivity in each malignancy, biomarkers are used for screening, diagnosis, disease monitoring and therapeutic response assessment in clinical management of cancer patients.This chapter is focused on human chorionic gonadotropin (hCG), a hormone with a variety of functions and widely used as a tumor biomarker in selected tumors. Indeed, hCG is expressed by both trophoblastic and non-trophoblastic human malignancies and plays a role in cell transformation, angiogenesis, metastatization, and immune escape, all process central to cancer progression. Of note, hCG testing is crucial for the clinical management of placental trophoblastic malignancies and germ cell tumors of the testis and the ovary. Furthermore, the production of hCG by tumor cells is accompanied by varying degrees of release of the free subunits into the circulation, and this is relevant for the management of cancer patients (Triozzi PL, Stevens VC, Oncol Rep 6(1):7-17, 1999).The name chorionic gonadotropin was conceived: chorion derives from the latin chordate meaning afterbirth, gonadotropin indicates that the hormone is a gonadotropic molecule, acting on the ovaries and promoting steroid production (Cole LA, Int J Endocrinol Metab 9(2):335-352, 2011). The function, the mechanism of action and the interaction between hCG and its receptor continue to be the subject of intensive investigation, even though many issues about hCG have been well documented (Tegoni M et al., J Mol Biol 289(5):1375-1385, 1999).


Assuntos
Biomarcadores Tumorais/análise , Gonadotropina Coriônica/análise , Neoplasias/diagnóstico , Especificidade de Anticorpos , Gonadotropina Coriônica/imunologia , Gonadotropina Coriônica/fisiologia , Humanos
15.
Oncol Rep ; 34(5): 2395-402, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26479853

RESUMO

We investigated the expression of human chorionic gonadotropin (HCG) and its effects on vasculogenic mimicry (VM) formation in ovarian cancer cells under normoxic and hypoxic conditions in three-dimensional matrices preconditioned by an endothelial-trophoblast cell co-culture system. The co-culture model was established using human umbilical vein endothelial cells (HUVECs) and HTR-8 trophoblast cells in a three-dimensional culture system. The co-cultured cells were removed with NH4OH, and ovarian cancer cells were implanted into the preconditioned matrix. VM was identified morphologically and by detecting vascular markers expressed by cancer cells. The specificity of the effects of exogenous HCG in the microenvironment was assessed by inhibition with a neutralizing anti-HCG antibody. HCG siRNA was used to knock down endogenous HCG expression in OVCAR-3 ovarian cancer cells. HTR-8 cells 'fingerprinted' HUVECs to form capillary-like tube structures in co-cultures. In the preconditioned HCG-rich microenvironment, the number of vessel-like network structures formed by HCG receptor-positive OVCAR-3 cells and the expression levels of CD31, VEGF and factor VIII were significantly increased. The preconditioned HCG-rich microenvironment significantly increased the expression of hypoxia inducible factor-1α (HIF­1α) and VM formation in OVCAR-3 cells under hypoxic conditions. Treatment with a neutralizing anti-HCG antibody but not HCG siRNA significantly inhibited the formation of vessel-like network structures. HCG in the microenvironment contributes to OVCAR-3 differentiation into endothelioid cells in three-dimensional matrices preconditioned with an endothelial-trophoblast cell co-culture system. HCG may synergistically enhance hypoxia-induced vascular markers and HIF-1α expression. These findings would provide perspectives on new therapeutic targets for ovarian cancer.


Assuntos
Gonadotropina Coriônica/fisiologia , Neoplasias Ovarianas/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Técnicas de Cocultura , Feminino , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Patológica/metabolismo , Neoplasias Ovarianas/irrigação sanguínea , Receptores do LH/metabolismo , Microambiente Tumoral
16.
Neuro Endocrinol Lett ; 36(4): 316-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26454486

RESUMO

Human chorionic gonadotropin (hCG) is a polypeptide hormone studied as far as 1912, but researchers has no complete knowledge concerning its biological function. Since 1970' it is known that hCG can be found not only in the urine and serum of pregnant, but in choriocarcinoma and testicular cancer patients. Up-to-date one can distinguish four subtypes of hCG differing in secondary carbohydrate chains configuration as well as it regular and glycosylated forms, but non trophoblastic sources of this hormone, such as pituitary are still not widely known. The article gives an overlook on hCG studies in order to help clinicians in taking wise, evidence based decisions in asymptomatic patients with elevated hCG.


Assuntos
Gonadotropina Coriônica/metabolismo , Gonadotropina Coriônica/fisiologia , Neoplasias Testiculares/diagnóstico , Neoplasias Trofoblásticas/diagnóstico , Neoplasias Uterinas/diagnóstico , Feminino , Humanos , Masculino , Gravidez
17.
Hum Reprod ; 30(5): 1029-38, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25743784

RESUMO

STUDY QUESTION: What is the in situ localization and function of hyperglycosylated hCG (hCG-H) in first trimester pregnancy tissues? SUMMARY ANSWER: HCG-H localizes to the syncytiotrophoblast, cytotrophoblast and invasive extravillous trophoblast within the maternal decidua and promotes invasion during the first trimester of pregnancy. WHAT IS KNOWN ALREADY: Serum levels of hCG-H decline dramatically throughout the first trimester of pregnancy. As hCG-H is produced by choriocarcinoma cells, it is proposed to regulate trophoblast invasion. STUDY DESIGN, SIZE, DURATION: Tissues were collected from elective first trimester pregnancy terminations. Placental villous and decidua basalis were collected from Week 6 to Week 12 of gestation (n = 49). PARTICIPANTS/MATERIALS, SETTING, METHODS: Tissues were collected from elective first trimester surgical pregnancy terminations to determine localization, abundance and function of hCG-H. Placental villous outgrowth studies determined the impact of neutralizing endogenous hCG-H on trophoblast function. Real-time proliferation, migration and invasion assays using JEG-3 choriocarcinoma cells further elucidated the role of hCG-H in trophoblast function. MAIN RESULTS AND THE ROLE OF CHANCE: HCG-H localized to syncytiotrophoblast layer of the placental villous from gestational weeks 6-9; thereafter hCG-H localized as a discrete layer between syncytio- and cyto-trophoblast layers. Immunoreactive hCG-H was also observed within the cytotrophoblast layer in Week 7-8 of gestation. HCG-H abundance decreased within placental villous from Weeks 6-12 of gestation (n = 3 placentas per gestational weeks 6-12). HCG-H also localized to anchoring villi within maternal decidua, extravillous trophoblasts invading into the maternal decidua and endovascular trophoblasts remodeling maternal blood vessels. Treatment of primary first trimester villous explants with hCG-H neutralizing antibody reduced trophoblast outgrowth (n = 3 placentas, P < 0.05). Treatment of a trophoblast cell line with neutralizing antibody reduced trophoblast invasion (n = 4, P < 0.05) but did not affect migration or proliferation. LIMITATIONS, REASONS FOR CAUTION: Functional invasion and migration assays performed using cell lines. Not possible to perform such assays with primary human material. WIDER IMPLICATIONS OF THE FINDINGS: HCG-H is an important autocrine factor facilitating trophoblast invasion in the first trimester of pregnancy. Targeting hCG-H may prove useful in the treatment of pathologic pregnancies, such as ectopic pregnancies, or pregnancy complications including pre-eclampsia and gestational trophoblast diseases. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Victorian Government Operational Infrastructure Support Program. J.E. is supported by NHMRC project grant #1047756, L.A.S. and E.D. by NHMRC Fellowships #1002018 and #550905 respectively and E.M. by an NHMRC Early Career Fellowship #611827. The authors have no conflicts of interest relating to this work.


Assuntos
Gonadotropina Coriônica/fisiologia , Placenta/fisiologia , Placentação/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Coriocarcinoma/metabolismo , Gonadotropina Coriônica/sangue , Vilosidades Coriônicas/fisiologia , Decídua/fisiologia , Feminino , Glicosilação , Humanos , Imuno-Histoquímica , Gravidez , Primeiro Trimestre da Gravidez , Trofoblastos/fisiologia
18.
Fertil Steril ; 103(4): 867-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25712575

RESUMO

A single bolus of human chorionic gonadotropin (hCG) at midcycle has been the gold standard for triggering final oocyte maturation and ovulation in assisted reproductive technology cycles. More recently, gonadotropin-releasing hormone (GnRH)-agonist (GnRH-a) triggering has been introduced. The GnRH-a trigger may allow a more physiologic surge of both luteinizing hormone (LH) and follicle-stimulating hormone, although whether the combined surge will result in improved oocyte and embryo quality remains to be seen. However, the short duration of the LH surge with the GnRH-a trigger (approximately 34 hours) has been shown to be beneficial for preventing ovarian hyperstimulation syndrome in GnRH antagonist in vitro fertilization (IVF) cycles when compared with the prolonged elevation of hCG (≥6 days) after exposure to an hCG bolus. This review discusses the physiologic basis for the use of a GnRH-a trigger in IVF cycles.


Assuntos
Fármacos para a Fertilidade Feminina/uso terapêutico , Hormônio Liberador de Gonadotropina/agonistas , Indução da Ovulação/métodos , Gonadotropina Coriônica/fisiologia , Gonadotropina Coriônica/uso terapêutico , Feminino , Fertilização In Vitro/métodos , Humanos , Síndrome de Hiperestimulação Ovariana/etiologia , Gravidez , Taxa de Gravidez
19.
Placenta ; 36 Suppl 1: S60-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25707740

RESUMO

Human chorionic gonadotropin (hCG) is the first hormonal message from the placenta to the mother. It is detectable in maternal blood two days after implantation and behaves like an agonist of LH stimulating progesterone secretion by the corpus luteum. hCG has also a role in quiescence of the myometrium and local immune tolerance. Specific to humans, hCG is a complex glycoprotein composed of two glycosylated subunits. The α-subunit is identical to the pituitary gonadotropin hormones (LH, FSH, TSH), contains two N-glycosylation sites, and is encoded by a single gene (CGA). By contrast the ß-subunits are distinct in each of the hormones and confer receptor and biological specificity. The hCG ß-subunit contains two sites of N-glycosylation and four sites of O-glycosylation and is encoded by a cluster of genes (CGB). In this review, we will stress the importance of hCG glycosylation state, which varies with the stage of pregnancy, its source of production and in the pathology. It is well established that hCG is mainly secreted by the syncytiotrophoblast into maternal blood where it peaks around 8-10 weeks of gestation (WG). The invasive extravillous trophoblast also secretes hCG, and in particular like choriocarcinoma cells, hyperglycosylated forms of hCG (hCG-H). In maternal blood hCG-H is high during early first trimester. In addition to its endocrine role, hCG has autocrine and paracrine roles. It promotes formation of the syncytiotrophoblast and angiogenesis through LHCG receptor. In contrast, hCG-H stimulates trophoblast invasion and angiogenesis by interacting with the TGFß receptor 2. hCG is largely used in antenatal screening and hCG-H represents a serum marker of early trophoblast invasion. Other abnormally glycosylated hCG are described in aneuploidies. In conclusion, hCG is the major pregnancy glycoprotein hormone, whose maternal concentration and glycan structure change all along pregnancy. Depending on its source of production, glycoforms of hCG display different biological activities and functions that are essential for pregnancy outcome.


Assuntos
Gonadotropina Coriônica/metabolismo , Gonadotropina Coriônica/fisiologia , Processamento de Proteína Pós-Traducional , Gonadotropina Coriônica/química , Gonadotropina Coriônica/farmacologia , Feminino , Glicosilação , Humanos , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/metabolismo , Isoformas de Proteínas , Processamento de Proteína Pós-Traducional/fisiologia , Relação Estrutura-Atividade
20.
Reproduction ; 149(2): R71-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25301969

RESUMO

In a developing human corpus luteum, a closely regulated cellular communication system exists between the luteal steroidogenic cells and endothelial cells. This system guaranties the vascularization process during luteal formation. The process is combined with rapid release of large amounts of progesterone into the bloodstream. The regulation of endothelial proliferation and permeability by LH and human chorionic gonadotropin (hCG) is integral to this process. On the cellular level, endothelial permeability is regulated by intercellular junctions, such as adherens junctions (AJ) and tight junctions (TJ), which act as zipper-like structures between interacting endothelial cells. Several cell junctional proteins are localized to the corpus luteum, including Occludin, Nectin 2, Claudin 1, and Claudin 5, as well as, vascular endothelial (VE)-Cadherin. It has been assumed that regulation of AJ- and TJ-proteins is of particular importance for permeability, and accordingly, for the functionality of the corpus luteum in early pregnancy, because treatment with hCG induces downregulation of juntional proteins in the luteal vessels. The effect of hCG on the adhesive molecules is mediated by VE growth factor (VEGF). On a functional level, the hCG-dependent and VEGF-mediated decrease in junctional proteins causes a decrease in the density of cell-cell closure and, accordingly, an increase in endothelial permeability. In doing so, the different junctional proteins are not only directly influenced by VEGF but also interact among themselves and influence each other reciprocally. Disturbances in this strictly, regulated interactions may explain the development of pathologies with increased vascular permeability, such as the ovarian hyperstimulation syndrome.


Assuntos
Permeabilidade Capilar , Corpo Lúteo/metabolismo , Síndrome de Hiperestimulação Ovariana , Junções Aderentes , Comunicação Celular , Gonadotropina Coriônica/fisiologia , Endotélio Vascular/metabolismo , Feminino , Humanos , Junções Intercelulares , Hormônio Luteinizante/fisiologia , Síndrome de Hiperestimulação Ovariana/etiologia , Junções Íntimas , Fator A de Crescimento do Endotélio Vascular/fisiologia
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