Erkut Attar

Istanbul University, İstanbul, Istanbul, Turkey

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Publications (34)79.65 Total impact

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    ABSTRACT: Endometriosis is an estrogen-dependent disease. The biologically active estrogen, estradiol, aggravates the pathological processes (e.g., inflammation and growth) and the symptoms (e.g., pain) associated with endometriosis. Abundant quantities of estradiol are available for endometriotic tissue via several mechanisms including local aromatase expression. The question remains, then, what mediates estradiol action. Because estrogen receptor (ER)β levels in endometriosis are >100 times higher than those in endometrial tissue, this review focuses on this nuclear receptor. Deficient methylation of the ERβ promoter results in pathological overexpression of ERβ in endometriotic stromal cells. High levels of ERβ suppress ERα expression. A severely high ERβ-to-ERα ratio in endometriotic stromal cells is associated with suppressed progesterone receptor and increased cyclo-oxygenase-2 levels contributing to progesterone resistance and inflammation. ERβ-selective estradiol antagonists may serve as novel therapeutics of endometriosis in the future.
    Seminars in Reproductive Medicine 01/2012; 30(1):39-45. · 3.21 Impact Factor
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    ABSTRACT: To evaluate maternal and fetal outcomes among women with hyperemesis gravidarum (HG). In a university hospital and a research and training hospital, a retrospective cohort study was conducted among women with singleton deliveries between 2003 and 2011. Maternal outcomes evaluated included gestational diabetes, pregnancy-induced hypertension, cesarean delivery. Neonatal outcomes also determined were 5-min Apgar score of less than 7, low birth weight, small for gestational age (SGA), preterm delivery, fetal sex, and stillbirth. There were no statistical differences in the mean of age, parity, the number of artificial pregnancy, and smoking between two groups. Infants from HG pregnancies manifested similar birth weight (3,121.5 ± 595.4 vs. 3,164 ± 664.5 g) and gestational age (38.1 ± 2.3 vs. 38.1 ± 2.6 weeks), relative to infants from the control group (p = 0.67 and 0.91, respectively). In addition, no statistical significant differences were found in the rates of SGA birth, preterm birth, gestational diabetes, pregnancy-induced hypertension, and adverse fetal outcome between two groups (p > 0.05). Cesarean delivery rates were similar in two groups (31.9% in hyperemesis group vs. 27% in control group, p = 0.49). Comparing the gender of the newborn baby and Apgar scores less than 7 at 5 min, there were no statistically significant differences between two groups (p = 0.16 and 0.42, respectively). Hyperemesis gravidarum is not associated with adverse pregnancy outcomes.
    Archives of Gynecology 12/2011; 285(6):1517-21. · 0.91 Impact Factor
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    ABSTRACT: In this study, we aimed to investigate a possible association of the COX-2 polymorphisms (-765G→C and -1195A→G) and with the risk of developing epithelial ovarian carcinoma (EOC). COX-2 gene polymorphisms was investigated in 111 healthy women and 57 patients with EOC. Individuals who had -765 CG, -1195 AA genotype, and -765 C allele had increased risk for ovarian carcinoma (P < 0.01) and individuals with -765 GG, -1195 AG genotypes and -1195 G allele seem to be protected from ovarian carcinoma (P < 0.01). Haplotype analysis confirmed the association of COX-2 gene variants with ovarian carcinoma and revealed that the frequencies of -765C: -1195A haplotype frequencies was significantly higher in patients as compared with those of controls (P = 0.048). We state that there appears to be a modulating role for the COX-2 -1195A→G and -765G→C polymorphisms in the development of EOC. To the best of our knowledge, this is the first study to show such an association.
    Molecular Biology Reports 11/2010; 38(5):3481-6. · 2.51 Impact Factor
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    ABSTRACT: Loss of progesterone signaling in the endometrium may be a causal factor in the development of endometriosis, and progesterone resistance is commonly observed in women with this disease. In endometriotic stromal cells, the levels of progesterone receptor (PR), particularly the PR-B isoform, are significantly decreased, leading to a loss of paracrine signaling. PR deficiency likely underlies the development of progesterone resistance in women with endometriosis who no longer respond to progestin therapy. Here we review the complex epigenetic and transcriptional mechanisms leading to PR deficiency. The initial event may involve deficient methylation of the estrogen receptor (ER)beta promoter resulting in pathologic overexpression of ERbeta in endometriotic stromal cells. We speculate that alterations in the relative levels of ERbeta and ERalpha in endometrial tissue dictate E2-regulated PR expression, such that a decreased ERalpha-tauomicron-ERbeta ratio may result in suppression of PR. In this review, we propose a molecular model that may be responsible for changes in ERbeta and ERalpha leading to PR loss and progesterone resistance in endometriosis.
    Seminars in Reproductive Medicine 01/2010; 28(1):36-43. · 3.21 Impact Factor
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    ABSTRACT: Several polymorphisms in the DNA repair gene are thought to have significant effects on cancer risk. We investigated the association of polymorphisms in the DNA repair genes XRCC1 Arg399Gln, XRCC3 Thr241Met, XPD Lys751Gln, XPG Asp1104His, APE1 Asp148Glu, and HOGG1 Ser326Cys with endometriosis risk. Genotypes were determined by PCR-RFLP assays in 52 patients with endometriosis and 101 age-matched healthy controls. Although there were no significant (P > 0.05) differences in the frequencies of genotypes or alleles of APE1, XRCC1, XPD, XPG, and HOGG1 genes between patients and controls, the frequency of the XRCC3 Thr/Thr genotype was significantly greater in endometriosis patients compared with controls (P = 0.005). XRCC3 Thr/Met genotypes (P = 0.022), and the Met allele (P = 0.005) seem to have a protective role against endometriosis. The distributions of genotypes and alleles of the genes APE1, XRCC1, XRCC3, XPD, XPG, and HOGG1 were not significantly associated with the different stages of endometriosis (P > 0.05). We conclude that the XRCC3 Thr/Thr genotype is associated with endometriosis in Turkish women.
    Genetics and molecular research: GMR 01/2010; 9(2):629-36. · 0.99 Impact Factor
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    ABSTRACT: Endometriosis is regarded as a complex disese, in which genetic and environmental factors contribute to the disease phenotype. Whether vascular endothelial growth factor (VEGF) -460 C/T and +405 G/C polymorphisms are associated with susceptibility to endometriosis was investigated. Diagnosis of endometriosis was made on the basis of laparoscopic findings. Stage of endometriosis was determined according to the Revised American Fertility Society classification. Sixty out of the 112 women enrolled had no endometriosis, 11 had mild or early-stage endometriosis and 41 had severe endometriosis. Polymerase chain reaction (PCR), restriction fragment length polymorphism and agarose gel electrophoresis techniques were used to determine the -460 C/T and +405 G/C genotypes. The VEGF +405 G/C genotype frequencies among the cases and controls were CC 55.8% and 35%; GC 30.8% and 50.0%; GG 13.5% and 15.0%, respectively. The allelic frequencies were C 71.15% (cases) and 60.0% (controls) and G 28.8% (cases) and 40% (controls). Patients with endometriosis had a higher incidence of the VEGF +405 CC genotype compared with the controls (p=0.027). Women with VEGF +405 CC genotype had 2.3-fold higher risk for endometriosis. VEGF +405 GC genotype and G allele in the control group was higher than the endometriosis group (p=0.039, p=0.027 respectively). The VEGF -460 C/T genotype frequencies among the cases were CC 21.2%, CT 26.9% and TT 51.9%; the C and T allelic frequencies were 34.6% and 65.3%, respectively. The VEGF -460 genotype frequencies among the controls were CC 31.70%, CT 18.3% and TT 50.0%; the C and T allelic frequencies were 40.8% and 59.1%, respectively (p>0.05). There was linkage disequilibrium between VEGF -460 C/T and +405 G/C polymorphisms (D': 0.197, r(2)=0.013). We observed that the VEGF 460T/405C haplotype frequency was significantly higher in patients compared to controls (p=0.011). Our data suggest that the CC genotype of VEGF +405 and 460T/405C haplotypes of VEGF may be associated with the risk of endometriosis, but the G allele of VEGF +405 appears to be protective against endometriosis.
    In vivo (Athens, Greece) 01/2010; 24(3):297-301. · 1.22 Impact Factor
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    In Vivo. 01/2010;
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    ABSTRACT: Vascular endothelial growth factor (VEGF) and its receptors are present in both male and female reproductive systems. In this experimental study, the effect of different concentrations of VEGF on sperm motility and survival in vitro was investigated. Human spermatozoa, collected from voluntary, proven fertile donors, were incubated in sperm washing medium containing different concentrations of VEGF (5, 10, 15, 20 ng/ml) for 24 h in a university reproductive endocrinology laboratory setting. Assessment of VEGF action on sperm motion characteristics was evaluated using a computer-assisted semen analyser. Sperm survival was determined by hypo-osmotic swelling and eosin-Y dye tests. VEGF had a positive effect on some parameters of sperm motility in a concentration-dependent manner. Maximal effect was observed at a concentration of 15 ng/ml; motility, progression, straight-line velocity and curvilinear velocity of VEGF-exposed spermatozoa were significantly increased (P < 0.05) at this concentration. However, sperm viability was not prolonged at any concentration of VEGF as shown by hypo-osmotic swelling and eosin-Y dye tests. VEGF may increase some sperm motility parameters, but not survival, in a concentration-dependent manner in vitro.
    Reproductive biomedicine online 12/2009; 19(6):784-8. · 2.68 Impact Factor
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    ABSTRACT: Endometriosis is regarded as a complex trait, in which genetic and environmental factors contribute to the disease phenotype. We investigated whether the interleukin (IL) 1beta (+3953) polymorphism is associated with the severity of endometriosis. Diagnosis of endometriosis was made on the basis of laparoscopic findings. Stage of endometriosis was determined according to the Revised American Fertility Society classification. 118 women were enrolled in the study. 78 women did not have endometriosis, 6 women had stage I, 3 had stage II, 13 had stage III and 18 had stage IV endometriosis. Polymerase Chain Reaction (PCR), Restriction Fragment Length Polymorphism (RFLP), and agarose gel electrophoresis techniques were used to determine the IL 1beta (+3953) genotype. Frequencies of the IL-1beta (+3953) genotypes in the control group were: CC, 0.397; TT, 0.115; CT, 0.487. Frequencies of the IL-1beta (+3953) genotypes in cases were: CC, 0.375; TT, 0.225; CT, 0.400. We found a 2.22 fold increase in TT genotype in the endometriosis group. However, the difference was not statistically significant (P > 0.05). We also observed an increase in the frequency of IL-1beta (+3953) T allele in the endometriosis group. However, the difference was not statistically significant. We also investigated the association between IL-1beta (+3953) polymorphism and the severity of endometriosis. The frequencies of CC+CT genotypes in stage I, III and IV endometriosis patients were 83.3, 84/6 and 72.2%, respectively; and TT genotypes were 16.7, 15.4 and 27.8%, respectively. We observed a statistically insignificant increase in TT genotype in stage IV endometriosis (P > 0.05). We suggest that IL-1beta (+3953) polymorphism is not associated with endometriosis in Turkish women.
    Molecular Biology Reports 09/2009; 37(1):369-74. · 2.51 Impact Factor
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    ABSTRACT: Products of at least five specific steroidogenic genes, including steroidogenic acute regulatory protein (StAR), which facilitates the entry of cytosolic cholesterol into the mitochondrion, side chain cleavage P450 enzyme, 3beta-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, and aromatase, which catalyzes the final step, are necessary for the conversion of cholesterol to estrogen. Expression and biological activity of StAR and aromatase were previously demonstrated in endometriosis but not in normal endometrium. Prostaglandin E2 (PGE2) induces aromatase expression via the transcriptional factor steroidogenic factor-1 (SF1) in endometriosis, which is opposed by chicken-ovalbumin upstream-transcription factor (COUP-TF) and Wilms' tumor-1 (WT1) in endometrium. The aim of the study was to demonstrate a complete steroidogenic pathway leading to estrogen biosynthesis in endometriotic cells and the transcriptional mechanisms that regulate basal and PGE2-stimulated estrogen production in endometriotic cells and endometrium. Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3beta-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues. PGE2 induced the expression of all steroidogenic genes; production of progesterone, estrone, and estradiol; and StAR promoter activity in endometriotic cells. Overexpression of SF1 induced, whereas COUP-TFII or WT1 suppressed, StAR promoter activity. PGE2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells. COUP-TFII or WT1 binding to both promoters was significantly higher in endometrial compared with endometriotic cells. Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE2 via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.
    Molecular Endocrinology 02/2009; 23(1):125. · 4.75 Impact Factor
  • Attar R, Attar E, Arici A.
    01/2009: pages 85-91; , ISBN: 978 1 905740 741
  • R.Attar, E. Attar
    01/2009: pages 107-113; , ISBN: 978-605-88989-0-5
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    ABSTRACT: Endometriosis is a common and chronic disease characterized by persistent pelvic pain and infertility. Estradiol is essential for growth and inflammation in endometriotic tissue. The complete cascade of steroidogenic proteins/enzymes including aromatase is present in endometriosis leading to de novo estradiol synthesis. PGE(2) induces the expression of the genes that encode these enzymes. Upon PGE(2) treatment, coordinate recruitment of the nuclear receptor SF-1 to the promoters of these steroidogenic genes is the key event for estradiol synthesis. SF-1 is the key factor determining that an endometriotic cell will respond to PGE(2) by increased estradiol formation. The presence of SF-1 in endometriosis and its absence in endometrium is determined primarily by the methylation of its promoter. The key steroidogenic enzyme in endometriosis is aromatase encoded by a single gene because its inhibition blocks all estradiol biosynthesis. Aromatase inhibitors diminish endometriotic implants and associated pain refractory to existing treatments in affected women.
    Molecular and Cellular Endocrinology 01/2009; 300(1-2):104-8. · 4.04 Impact Factor
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    Rukset Attar, Erkut Attar
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    ABSTRACT: Stem cells can be used in different areas of obstetrics and gynecology. Adult stem cells are specialized cells found within many tissues of the body where they function in tissue homeostasis and repair. In vitro they have been shown to differentiate into a wide variety of cell types. Hematopoietic stem cells (HSC) have been used to set up therapeutic strategies for the treatment of gynecological solid tumors such as ovarian cancer. Stem cells can be used for prenatal transplantation and in utero gene therapy. Also stem cells can be used in infertility and IVF for research and treatment.
    Transfusion and Apheresis Science 07/2008; 38(3):245-51. · 1.23 Impact Factor
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    ABSTRACT: Local estrogen biosynthesis is a major factor in the pathogenesis of endometriosis. Aberrant expression of steroidogenic acute regulatory protein (StAR) and aromatase in endometriotic tissue leads to an up-regulation of estrogen production. The transcription factor steroidogenic factor-1 (SF-1) activates the promoters of both StAR and aromatase in endometriotic tissue. We investigated differences in SF-1 expression in endometriotic tissue and normally located endometrium to elucidate the mechanism underlying increased StAR and aromatase activities in endometriosis. Serial deletion and site-directed mutants of the SF-1 promoter showed that an E-box sequence was critical for its activity in endometriotic stromal cells. EMSAs showed that the upstream stimulatory factor (USF) 1 and 2 in nuclear extracts from endometrial and endometriotic stromal cells bound to the E-box. Chromatin-immunoprecipitation-PCR assay, however, demonstrated in intact cells that binding activity of USF2 to the SF-1 promoter was strikingly higher than that of USF1 in endometriotic stromal cells and that USF1 or USF2 binding activity was hardly detectable in endometrial stromal cells. Moreover, knockdown of USF2 but not USF1 resulted in robust and consistent down-regulation of SF-1 and its target genes StAR and aromatase in endometriotic stromal cells. USF2 but not USF1 mRNA and protein levels were significantly higher in endometriotic vs. endometrial stromal cells. In vivo, USF2 mRNA and immunoreactive USF2 levels in endometriotic tissues were strikingly higher than those in endometrium. Taken together, the elevated levels of USF2 in endometriosis account for, in part, the aberrant expression of SF-1 and its target gene StAR and aromatase.
    Molecular Endocrinology 05/2008; 22(4):904-14. · 4.75 Impact Factor
  • R.Attar, E. Attar
    01/2008: pages 371-378; , ISBN: 978-9944-341-66-0
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    ABSTRACT: Objective: To evaluate the association between male age and semen parameters and outcome of assisted reproduction techniques. Design: A retrospective study of the patients attending to the IVF laboratory in a university based infertility clinic. Materials and Methods: 645 couples undergoing IVF/ICSI-ET cycles between 1998 and 2005 were included in this retrospective study. Ovulation inductions, oocyte retrievals, embryo cultures and embryo transfers were done by using standard protocols. Fertilization technique was not taken as a separate classification item. The study population was grouped into three depending on the male age such as <30 years old in Group A, >31 and <44 years old in group B and >45 years old in group C. The evaluated outcomes were semen parameters and fertilization, grade I (good quality) embryo development, number of transferred embryo, arrested embryo and pregnancy rates. All of the semen analyses were done within 3-5 days of abstinence period. Since the semen analyses were done as a part of sperm preparation in the assisted reproductive treatment cycle, motility (percent motile) and sperm count were assessed with light microscope according to WHO criteria and performed just before the fertilization procedure. Data were analyzed using Pearson correlation test, Chi-Square Tests, one-way analyses of variance (ANOVA), and logistic regression model and the Tukey test was used post-hoc for multiple comparisons. P<0.05 was considered statistically significant. All statistical analyses were performed using Windows SPSS version 10.0 software. Results: The mean of male and female ages were 35.1(5.6) and 32.1 (5.1) respectively. Group C was associated with lower semen volume whereas group B with higher total sperm count. The percentage of the MII oocyte fertilization had no correlation either with the male age or female age. The number of the arrested embryos was negatively correlated only with female age (p=0.006). Male and female ages were both negatively correlated with the number of grade I embryos (p<0.0001) and number of transferred embryos (p<0.0001) on day 3. Although female age showed higher odds ratio for pregnancy outcome in a logistic regression model that investigated the interaction of ages on the pregnancy outcome, there were no statistically significance (p<0.071). Conclusions: Male age has a predictive value in semen quality. Although male age is observed as a confounding factor in good embryo development, female age appears as a dominant determinant factor. Financial Support: None
    Fertility and Sterility 09/2007; 88(Supplement 1):S264. · 4.17 Impact Factor
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    ABSTRACT: Angiogenesis, the development of new blood vessels from preexisting capillaries, is essential for the development, growth and advancement of solid tumours. Angiogenesis is enhanced by prostaglandins (PGs) that are synthesised by the catalysis of cyclooxygenases (COX-1 and COX-2) from arachidonic acid. COX-2 is upregulated in a variety of malignancies and favours the growth of malignant cells by stimulating proliferation and angiogenesis. The aim of this study is to investigate the angiogenetic process by determining the levels of vascular endothelial growth factor (VEGF), monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 in endometrial cancer cells and to study the effect of nimesulide, a selective COX-2 inhibitor, on these mediators using cell culture. Endometrial tissue specimens were obtained from subjects with endometrial cancer and intramural leiomyoma. Cells were incubated with either 10 or 50 microM nimesulide for 24 h. VEGF, MCP-1 and IL-8 concentrations were determined by sandwich quantitative enzyme immunoassay (ELISA). VEGF concentration was significantly higher in cancer cells than normal endometrial cells. VEGF was decreased with 10 microM nimesulide in cancer cells whereas it remained unaltered in normal cells. Both MCP-1 and IL-8 concentrations were lower in cancer cells than normal cells. MCP-1 levels were decreased with both doses of nimesulide in normal cells, whereas IL-8 levels were significantly affected only by 50 microM of nimesulide. These results suggest that COX-2 inhibitors may be effective in the treatment of endometrial cancer via suppression of angiogenesis.
    Clinical and Experimental Medicine 04/2007; 7(1):6-10. · 2.40 Impact Factor
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    ABSTRACT: Pathogenesis and growth of three common women's cancers (breast, endometrium and ovary) are linked to estrogen. A single gene encodes the key enzyme for estrogen biosynthesis named aromatase, inhibition of which effectively eliminates estrogen production in the entire body. Aromatase inhibitors successfully treat breast cancer, whereas their roles in endometrial and ovarian cancers are less clear. Ovary, testis, adipose tissue, skin, hypothalamus and placenta express aromatase normally, whereas breast, endometrial and ovarian cancers overexpress aromatase and produce local estrogen exerting paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kb regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. In cancers of breast, endometrium and ovary, aromatase expression is primarly regulated by increased activity of the proximally located promoter I.3/II region. Promoters I.3 and II lie 215 bp from each other and are coordinately stimulated by PGE(2) via a cAMP-PKA-dependent pathway. In breast adipose fibroblasts exposed to PGE(2) secreted by malignant epithelial cells, PKC is also activated, and this potentiates cAMP-PKA-dependent induction of aromatase. Thus, inflammatory substances such as PGE(2) may play important roles in inducing local production of estrogen that promotes tumor growth.
    The Journal of Steroid Biochemistry and Molecular Biology 01/2007; 106(1-5):81-96. · 3.98 Impact Factor
  • Fertility and Sterility - FERT STERIL. 01/2007; 88.

Publication Stats

534 Citations
79.65 Total Impact Points

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Institutions

  • 2002–2011
    • Istanbul University
      • • Department of Obstetrics and Gynecology
      • • Molecular Medicine
      • • Division of Reproductive Endocrinology and Infertility
      İstanbul, Istanbul, Turkey
  • 2010
    • Istanbul Medical University
      İstanbul, Istanbul, Turkey
  • 2008–2009
    • Yeditepe Üniversitesi Hastanesi
      İstanbul, Istanbul, Turkey
  • 2005–2008
    • Northwestern University
      • • Feinberg School of Medicine
      • • Department of Obstetrics and Gynecology
      Evanston, IL, United States