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1.
Eur J Clin Invest ; 37(9): 700-8, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17696959

RESUMO

BACKGROUND: Endothelial cells of human blood vessels (arteries and veins) show high levels of somatostatin subtype-1 receptor (sst(1)). The aim of the present study is to investigate the inhibitory effects of novel somatostatin analogs, highly selective for human sst(1), on in vitro angiogenesis and their modulation of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) expression. MATERIALS AND METHODS: Somatostatin analogs BIM-23745 and BIM-23926 were tested for their ability to prevent proliferation and migration of human endothelial HMEC-1 cells, to modulate VEGF and VEGFR-2 expression and to inhibit sprouting of microvessels from cultured human placental vessel explants in fibrin matrix for 28 days. RESULTS: The somatostatin sst(1 )receptor-selective agonists, BIM-23745 and BIM-23926 showed a suppression of endothelial proliferation (e.g. 10(-6) M BIM-23475, 40.0 +/- 2.1% vs. 100% of controls; 10(-7) M BIM-23926, 55.3 +/- 3.3% vs. 100% of controls), migration (e.g. 10(-7) M BIM-23475, 35.0 +/- 1.56% vs. 100% of controls; 10(-7) M BIM-23926, 53.7 +/- 1.77% vs. 100% of controls) and microvessel sprouting (e.g. 10(-8) M BIM-23475, 42.8 +/- 5.6% vs. 100% of controls; 10(-7) M BIM-23926, 17.2 +/- 11.8% vs. 100% of controls). A small but significant percentage of cells exposed to BIM-23745 and BIM-23926 for 24 h and for 72 h presented typical apoptotic morphology. Moreover, both the analogs significantly inhibit VEGF and VEGFR-2 gene expression in endothelial cells grown for 144 h in a fibrin matrix and the VEGF secretion in conditioned media. CONCLUSIONS: The inhibition of endothelial activities suggests potential therapeutic utility for administration of somatostatin sst(1 )receptor-selective agonists in the proliferative diseases involving angiogenesis.


Assuntos
Receptores de Fatores de Crescimento do Endotélio Vascular/agonistas , Somatostatina/análogos & derivados , Inibidores da Angiogênese/metabolismo , Expressão Gênica , Humanos , Receptores de Somatostatina/agonistas , Receptores de Somatostatina/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Somatostatina/agonistas
2.
J Exp Clin Cancer Res ; 21(1): 37-43, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12071527

RESUMO

The aim of this study was to indicate the patients treated with tamoxifen for breast cancer in which hysteroscopy with biopsy should be considered mandatory. 414 breast cancer patients who underwent hysteroscopy with bioptic evaluation were enrolled in the study. 334 subjects were treated with 20 mg of tamoxifen daily as adjuvant therapy for six up to a hundred months. Of the remaining 80 control patients, which had not received tamoxifen, 30 were in premenopause (Group IA) and 50, in postmenopause (Group IIA). The tamoxifen-treated patients were subdivided in premenopausal (Group IB = 72 patients) and in postmenopausal (Group IIB = 262 patients) groups. All patients were further classified in asymptomatic or symptomatic groups considering whether uterine bleeding was absent or present. The evaluation of the endometrial mucosa was performed by office hysteroscopy. In group IIB patients presenting uterine bleeding, malignant lesions were found in 7.8% of the cases. The incidence of premalignant and malignant lesions in IIB patients treated for longer than 3 years (11.7%) was higher than that observed in IIB patients treated for less than 3 years (1.3%). There was a significant difference in terms of endometrial pathology between Group IIB (32.8%) and Group IIA (8%) (p < 0.001); and between Group IIB (32.8%) and Group IB (13.9%) women (p = 0.003). Among IA and IIA patients there were no cases of endometrial hyperplasia or cancer; on the contrary, in IB and IIB women, 2 and 22 cases of atypical hyperplasia were observed, respectively. All cases of endometrial cancer were observed in Group IIB and had a diagnosis of poor prognosis. In conclusion the hysteroscopy with biopsy should be considered the first diagnostic procedure to perform in tamoxifen-treated postmenopausal patients presenting uterine bleeding and in postmenopausal women treated for longer than 3 years. In premenopause, hysteroscopy should be proposed to women with ultrasonographic abnormalities and/or with uterine bleeding to patients at high risk for endometrial cancer.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Hiperplasia Endometrial/diagnóstico , Neoplasias do Endométrio/diagnóstico , Endométrio/efeitos dos fármacos , Histeroscopia/métodos , Tamoxifeno/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Biópsia , Hiperplasia Endometrial/induzido quimicamente , Neoplasias do Endométrio/induzido quimicamente , Endométrio/patologia , Feminino , Seguimentos , Humanos , Incidência , Programas de Rastreamento , Pessoa de Meia-Idade , Pós-Menopausa , Pré-Menopausa , Fatores de Risco , Tamoxifeno/efeitos adversos
3.
Eur J Obstet Gynecol Reprod Biol ; 101(2): 169-74, 2002 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-11858893

RESUMO

BACKGROUND: The pathogenesis of ovarian hyperstimulation syndrome (OHSS) is not completely understood. OBJECTIVE: To investigate the presence of VEGF, IL-6 and IL-2, in serum and follicular fluid, in patients developing severe OHSS. STUDY DESIGN: We enrolled 101 women undergoing in vitro fertilization. Eight patients developing severe OHSS were compared with 43 high risk patients and 50 controls. We analyzed VEGF and IL-6 in serum collected before hCG administration, and in both serum and follicular fluid on the day of oocyte retrieval. RESULTS: OHSS patients presented follicular fluid IL-6 levels higher than both the patients at risk and controls (P<0.05). On the day of the oocyte retrieval the patients developing OHSS showed serum and follicular VEGF values higher than the ones of the patients at risk (P<0.05). Serum and follicular fluid IL-2 levels showed no differences between the examined groups. IL-2, IL-6 and VEGF values were not correlated with each other. CONCLUSIONS: Angiogenesis and inflammation processes are both present in severe OHSS.


Assuntos
Fatores de Crescimento Endotelial/metabolismo , Líquido Folicular/metabolismo , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Linfocinas/metabolismo , Síndrome de Hiperestimulação Ovariana/metabolismo , Adulto , Estudos de Casos e Controles , Gonadotropina Coriônica/uso terapêutico , Fatores de Crescimento Endotelial/sangue , Feminino , Humanos , Interleucina-2/sangue , Interleucina-6/sangue , Linfocinas/sangue , Oócitos , Síndrome de Hiperestimulação Ovariana/sangue , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
4.
Mol Hum Reprod ; 7(8): 771-7, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11470865

RESUMO

Vascular endothelial growth factor (VEGF), a highly specific mitogen for vascular endothelial cells, is involved in placental vascular growth and remodelling. The aim of this study was to investigate whether placental endothelial cells secrete VEGF in an autocrine manner and if this secretion is correlated with endothelial cell growth. Blood vessels, excised from the apical surface of three human placentae, were sectioned into 40 fragments per placenta and cultured in fibrin gel matrix for 27 days. Immunohistochemical detection of placental endothelial cells was performed by positive staining with anti-human factor VIII-associated antigen and negative staining with anti-human alpha-actin and desmin. To investigate the production and autocrine action of VEGF, VEGF concentrations in culture media were measured and the effect of an anti-VEGF neutralizing antibody on endothelial cell growth was observed. The results demonstrate that soluble VEGF is secreted by placental endothelial cells reaching a plateau from day 24 (68.74 +/- 7.52 pg/ml) to day 27 (67.20 +/- 6.28 pg/ml). Furthermore, VEGF concentrations in media collected on days 6, 12, 18, 21 and 27 of culture were found to be directly correlated to the sprouting parameter of endothelial cells, as calculated by image analysis on the same day ( P < 0.001, r (2) = 0.95 ). The use of 10 and 100 ng/ml of a neutralizing antibody against human VEGF suppressed cell proliferation, compared to that observed in the untreated controls, by 74.8 +/- 7.3 and 89.4 +/- 3.9% respectively. In conclusion, this study reports the first evidence of autocrine secretion of VEGF by human placental endothelial cells and demonstrates the involvement of VEGF in endothelial cell growth within a fibrin gel culture.


Assuntos
Comunicação Autócrina/fisiologia , Fatores de Crescimento Endotelial/metabolismo , Endotélio Vascular/metabolismo , Linfocinas/metabolismo , Placenta/irrigação sanguínea , Técnicas de Cultura , Endotélio Vascular/citologia , Endotélio Vascular/crescimento & desenvolvimento , Feminino , Humanos , Microcirculação/citologia , Microcirculação/crescimento & desenvolvimento , Microcirculação/metabolismo , Gravidez , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
5.
Fertil Steril ; 75(6): 1218-21, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11384653

RESUMO

OBJECTIVE: To determine the levels of the angiogenic factors vascular endothelial growth factor (VEGF) and interleukin (IL-8) in ovarian cysts. DESIGN: Prospective descriptive study. SETTING: University hospital. PATIENT(S): One hundred women, of whom 9 had ovarian carcinomas, 38 had ovarian endometriomata, 43 had serous ovarian cysts, and 10 had follicular ovarian cysts. INTERVENTION(S): Sampling of serum and ovarian cystic fluid before and during surgery. MAIN OUTCOME MEASURE: Levels of VEGF and IL-8 in cystic fluid and serum. RESULT(S): Levels of both VEGF and IL-8 were found to be significantly higher in the cystic fluid of ovarian carcinomas and endometriomata than in serous and follicular cysts. In endometriomata fluid, levels of VEGF and IL-8 were found to be directly correlated (r = 0.68; P=.0074). Serum levels of VEGF were significantly higher in women with ovarian carcinomas and endometriomata than in those with serous and follicular cysts. Ovarian cancers and endometriomata were similar in terms of cystic concentrations of VEGF and IL-8 and in serum levels of VEGF. CONCLUSION(S): An increase in angiogenic factors that differentiate ovarian carcinomas and endometriomata from other kinds of ovarian pathology is demonstrated.


Assuntos
Carcinoma/metabolismo , Endometriose/metabolismo , Fatores de Crescimento Endotelial/metabolismo , Cisto Folicular/metabolismo , Interleucina-8/metabolismo , Linfocinas/metabolismo , Cistos Ovarianos/metabolismo , Doenças Ovarianas/metabolismo , Neoplasias Ovarianas/metabolismo , Fatores de Crescimento Endotelial/sangue , Feminino , Humanos , Interleucina-8/sangue , Linfocinas/sangue , Concentração Osmolar , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
6.
Hematol J ; 2(3): 161-71, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11920241

RESUMO

INTRODUCTION: Naturally occurring antibodies (auto-Abs) recognizing human granulocyte-colony stimulating factor were detected with high frequency in serum samples obtained from umbilical cord blood of newborns (12 of 65 samples screened) and maternal peripheral blood serum samples from women at the end of gestation (seven of 56 cases tested). The aim of this paper was to demonstrate that auto-Abs anti-G-CSF revealed in the blood of newborns were produced during foetal life. MATERIALS AND METHODS: Mononuclear cells from cord blood samples of different newborns containing high titer anti-G-CSF Abs were infected with Epstein-Barr virus in vitro, and EBV-immortalized B-cell lines were isolated and characterized for specific anti-G-CSF Ab production. RESULTS: Six different, unrelated cell lines of male origin which showed the presence of EBNA-2 antigen in the nucleus, displayed a B-cell phenotype (CD30+, CD5-, CD10-, HLA-DR+, CD19+, CD20+, CD23+, CD38+, CD25+), coexpressed low intensity sIgM and sIgD, and produced only IgM with prevailing lambda clonal restriction and anti-rhG-CSF Ab reactivity. The Ab specificity was proven against either glycosylated or unglycosylated G-CSF by saturable binding in direct enzyme-linked immunosorbent assays, by competition binding and Western immunoblotting assays. CONCLUSION: The secreted Abs did not affect the in vitro generation of granulocyte colonies by human normal adult haemopoietic progenitor cells in soft agar clonogenic assays, suggesting that these Abs were not neutralizing.


Assuntos
Autoanticorpos/biossíntese , Linfócitos B/imunologia , Sangue Fetal/imunologia , Fator Estimulador de Colônias de Granulócitos/imunologia , Terceiro Trimestre da Gravidez/imunologia , Adulto , Autoanticorpos/imunologia , Linfócitos B/virologia , Western Blotting , Linhagem Celular Transformada , Transformação Celular Viral , Ensaio de Unidades Formadoras de Colônias , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Feminino , Sangue Fetal/citologia , Glicosilação , Fator Estimulador de Colônias de Granulócitos/química , Granulócitos/citologia , Herpesvirus Humano 4/fisiologia , Humanos , Imunidade Inata , Imunoglobulina D/biossíntese , Imunoglobulina D/imunologia , Imunoglobulina M/biossíntese , Imunoglobulina M/imunologia , Imunofenotipagem , Recém-Nascido , Lenograstim , Masculino , Testes de Neutralização , Gravidez , Terceiro Trimestre da Gravidez/sangue , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia
7.
Mol Hum Reprod ; 6(1): 50-4, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10611260

RESUMO

Patients with endometriosis are characterized by the ability of the endometrium to implant and by the peritoneal response to the tissue; angiogenic factors may play a significant role in the aetiology of endometriosis supporting the implantation of ectopic endometrial cells. Vascular endothelial growth factor (VEGF) is a mitogen, morphogen and chemoactractant for endothelial cells and, in vivo, it is a powerful mediator for vessel permeability. Interleukin-8 (IL-8) is a chemoatractant for neutrophils and is a potent angiogenic factor. Women (n = 20) with ovarian endometriomata and 10 women with follicular cysts were enrolled in this study to investigate the role of VEGF and IL-8 in the development and maintenance of ovarian endometriomata. Cystic fluids were collected by laparoscopy, immediately centrifuged and stored until the enzyme-linked immunosorbent assays were performed. The VEGF and IL-8 concentrations were found to be significantly higher in the fluids of the ovarian endometriomata than in those of the follicular cysts of controls (P < 0.001 and P < 0.001 respectively); in addition, a significant inverse correlation between the VEGF cystic fluid concentrations and the diameter of the endometriotic adnexal masses was found (r = -0.56, P = 0.01). The evidence that the high concentrations of VEGF and IL-8 are present in the ovarian endometriomata indicates that angiogenesis could be a specific event both for the progression and maintenance of such cysts.


Assuntos
Endometriose/metabolismo , Endométrio/metabolismo , Fatores de Crescimento Endotelial/metabolismo , Interleucina-8/metabolismo , Linfocinas/metabolismo , Adulto , Antígeno Ca-125/sangue , Endometriose/patologia , Feminino , Cisto Folicular/metabolismo , Cisto Folicular/patologia , Humanos , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
8.
Gynecol Endocrinol ; 13(5): 311-5, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10599547

RESUMO

The study aims to evaluate whether serum vascular endothelial growth factor (VEGF) levels, before treatment with gonadotropins, may be considered a predictive marker of moderate ovarian hyperstimulation syndrome (OHSS). At the University of Pisa hospital infertility unit we have retrospectively selected 10 patients who developed moderate forms of OHSS and 30 control patients who presented a normal response to ovarian stimulation among 400 women undergoing in vitro fertilization (IVF). Serum samples were collected before starting pFSH administration (150-300 IU/day). VEGF levels in serum were measured. No statistically significant difference was found between the serum VEGF levels of patients who developed moderate forms of OHSS and women without any symptoms of the syndrome. Further, serum VEGF concentrations were not significantly correlated with the age of the patients, the number of international units of FSH administered during the cycle of stimulation, the follicle and oocyte numbers counted on the day of the egg retrieval or estradiol levels detected on the same day. This study demonstrates that serum VEGF levels, before starting gonadotropin treatment, are not predictive of the subsequent development of moderate forms of ovarian hyperstimulation syndrome.


Assuntos
Fatores de Crescimento Endotelial/sangue , Gonadotropinas/efeitos adversos , Linfocinas/sangue , Síndrome de Hiperestimulação Ovariana/diagnóstico , Indução da Ovulação/efeitos adversos , Adulto , Estradiol/sangue , Feminino , Fertilização in vitro , Hormônio Foliculoestimulante/efeitos adversos , Humanos , Técnicas Imunoenzimáticas , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , Síndrome de Hiperestimulação Ovariana/etiologia , Síndrome de Hiperestimulação Ovariana/fisiopatologia , Indução da Ovulação/métodos , Estudos Retrospectivos , Estatísticas não Paramétricas , Pamoato de Triptorrelina/efeitos adversos , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
10.
Gynecol Endocrinol ; 12(4): 243-7, 1998 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9798133

RESUMO

Vascular endothelial growth factor (VEGF) is a powerful mediator for vessel permeability and it is strongly implicated in angiogenesis, stimulating endothelial cell proliferation as well as capillary permeability. We studied 30 women undergoing in vitro fertilization (IVF) programs and evaluated, on the day of oocyte retrieval, VEGF levels in plasma and follicular fluid and related such concentrations to the amount of follicle-stimulating hormone (FSH) administered. Furthermore, the correlation between the number of oocytes retrieved and the VEGF concentrations both in plasma and in follicular fluid were also investigated. Results indicate that follicular fluid VEGF concentrations and the amount of pure FSH administered were directly proportional (p < 0.05). On the day of oocyte retrieval, the VEGF plasma concentrations and the number of oocytes collected were directly proportional (p < 0.05). VEGF plasma levels increased after human chorionic gonadotropin (hCG) administration (30.37 +/- 18.60 pg/ml up to 52.62 +/- 43.63 pg/ml). In conclusion, this study demonstrates that the doses of pure FSH administered to women undergoing IVF cycles have a crucial role in hCG-dependent VEGF production.


Assuntos
Fatores de Crescimento Endotelial/sangue , Fatores de Crescimento Endotelial/metabolismo , Fertilização in vitro , Hormônio Foliculoestimulante/administração & dosagem , Líquido Folicular/metabolismo , Linfocinas/sangue , Linfocinas/metabolismo , Gonadotropina Coriônica/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Oócitos , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
11.
Fertil Steril ; 70(3): 560-4, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9757891

RESUMO

OBJECTIVE: To evaluate plasma and follicular fluid levels of vascular endothelial growth factor (VEGF) in women undergoing controlled ovarian hyperstimulation to establish the possible role of this growth factor as a predictive marker of ovarian hyperstimulation syndrome (OHSS). DESIGN: Prospective observational study. SETTING: University hospital infertility unit. PATIENT(S): Fifteen women at risk of OHSS and 15 controls. INTERVENTION(S): An IM injection of hCG was administered; plasma and follicular fluid samples were collected 34-38 hours after administration of hCG. MAIN OUTCOME MEASURE(S): VEGF levels in plasma and in follicular fluid. RESULT(S): VEGF levels increased after hCG administration in the patients at risk of developing OHSS and in those who developed OHSS. Further, on the day of the oocyte retrieval the increase in the VEGF levels in the plasma of the patients who developed OHSS was statistically significant compared with the increase in the levels in the women who did not. On the same day, the levels of VEGF in follicular fluid were 10 times greater than those in plasma. CONCLUSION(S): Plasma levels of VEGF peak after hCG administration and are related to the risk of developing OHSS.


Assuntos
Fatores de Crescimento Endotelial/metabolismo , Fertilização in vitro , Líquido Folicular/metabolismo , Linfocinas/metabolismo , Síndrome de Hiperestimulação Ovariana/metabolismo , Adulto , Estudos de Casos e Controles , Gonadotropina Coriônica/uso terapêutico , Fatores de Crescimento Endotelial/sangue , Feminino , Humanos , Linfocinas/sangue , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
12.
Mol Hum Reprod ; 4(2): 139-45, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9542971

RESUMO

One of the major morphological anomalies observed in many human pre-embryos is extensive cellular fragmentation. Previously we confirmed that embryo fragmentation seemed to be associated with the activation of programmed cell death (PCD). The purpose of our experiments was to establish a rate for murine embryo fragmentation in vivo after hormonal stimulation in young versus older females and to compare it with the rate of embryo fragmentation during in-vitro fertilization (IVF). While murine maternal age beyond 40 weeks increased the rate of embryo fragmentation following in-vivo fertilization (P = 0.001), oocytes from females of all ages had a uniformly high rate of fragmentation when fertilized in vitro (33%). None of the fragmented murine embryos proceeded further in development. In the mouse, fragmentation occurs exclusively during the first cell cycle. Furthermore, IVF significantly reduced the rate of blastocyst formation (P = 0.0001) and decreased the mean cell number at the blastocyst stage in comparison with embryos produced in vivo (P < 0.0001). The cell death index was significantly affected by both maternal age (P = 0.005) and IVF (P = 0.0001). Identification of specific factors which trigger PCD, especially those associated with IVF, may enable us to lower the rates of fragmentation in preimplantation embryos and thereby increase pregnancy rates after human IVF.


Assuntos
Apoptose , Desenvolvimento Embrionário , Desenvolvimento Embrionário e Fetal , Fertilização in vitro , Idade Materna , Animais , Blastocisto/fisiologia , Feminino , Humanos , Camundongos , Gravidez
13.
Gynecol Endocrinol ; 11(1): 59-68, 1997 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9086341

RESUMO

Recent case reports of ovarian cancer associated with infertility treatment raise the question of a possible etiopathogenetic role of fertility drugs in ovarian cancer. In this paper, the possible relationship between infertility treatment and ovarian cancer is reviewed with respect to the epidemiological and pathogenetic profiles of ovarian cancer and the potential risk factors associated with fertility drugs; a case report review and a critical reappraisal are also provided within this article. Currently available data in the literature, from epidemiological studies and case reports, suggest that a direct causal effect of infertility treatment on ovarian cancer seems unlikely. Since infertile women are likely to have a higher risk for the development of ovarian cancer, and the role of fertility drugs in the etiopathogenesis of ovarian carcinoma is not established, a close clinical examination of infertile patients before, during and after infertility treatment is recommended. Moreover, further investigation is required to resolve the question of the possible association between fertility drugs and ovarian cancer through large prospective epidemiological or retrospective case-control studies.


Assuntos
Fármacos para a Fertilidade Feminina/efeitos adversos , Neoplasias Ovarianas/induzido quimicamente , Adulto , Feminino , Humanos , Neoplasias Ovarianas/epidemiologia , Indução da Ovulação
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