-
[show abstract]
[hide abstract]
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. · 3.80 Impact Factor
-
[show abstract]
[hide abstract]
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
-
[show abstract]
[hide abstract]
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. · 2.93 Impact Factor
-
Serdar E Bulun,
You-Hong Cheng,
Mary Ellen Pavone,
Qing Xue, Erkut Attar,
Elena Trukhacheva,
Hideki Tokunaga,
Hiroki Utsunomiya,
Ping Yin,
Xia Luo,
Zhihong Lin,
Gonca Imir,
Stephen Thung,
Emily J Su,
J Julie Kim
[show abstract]
[hide abstract]
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. · 3.80 Impact Factor
-
[show abstract]
[hide abstract]
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. · 2.04 Impact Factor
-
[show abstract]
[hide abstract]
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. · 2.93 Impact Factor
-
Erkut Attar,
Hideki Tokunaga,
Gonca Imir,
M Bertan Yilmaz,
David Redwine,
Michael Putman,
Bilgin Gurates,
Rukset Attar,
Nobuo Yaegashi,
Dale B Hales,
Serdar E Bulun
Molecular Endocrinology 02/2009; 23(1):125. · 4.54 Impact Factor
-
Serdar E Bulun,
Hiroki Utsunomiya,
Zhihong Lin,
Ping Yin,
You-Hong Cheng,
Mary E Pavone,
Hideki Tokunaga,
Elena Trukhacheva, Erkut Attar,
Bilgin Gurates,
Magdy P Milad,
Edmond Confino,
Emily Su,
Scott Reierstad,
Qing Xue
[show abstract]
[hide abstract]
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. · 4.19 Impact Factor
-
[show abstract]
[hide abstract]
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. · 1.25 Impact Factor
-
Hiroki Utsunomiya,
You-Hong Cheng,
Zhihong Lin,
Scott Reierstad,
Ping Yin, Erkut Attar,
Qing Xue,
Gonca Imir,
Steven Thung,
Elena Trukhacheva,
Takashi Suzuki,
Hironobu Sasano,
J Julie Kim,
Nobuo Yaegashi,
Serdar E Bulun
[show abstract]
[hide abstract]
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. · 4.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This pilot study was conducted to compare the results of intrauterine insemination (IUI) under ovarian stimulation with either letrozole (Femara) or human menopausal gonadotrophin (HMG). A randomized controlled trial was conducted. Eighty women aged 20-35 years with unexplained infertility of at least 2 years' duration were randomized according to a computer-generated randomization list into the letrozole group and the HMG group. Letrozole was administered at 5 mg/day from day 3 to day 7 of the IUI cycle. HMG injections were started on day 3 at a dose of 75 IU for women under 30 years old and 150 IU for women over 30 years old and monitored periodically by vaginal ultrasound and oestradiol concentrations. The variables selected for analysis were clinical pregnancy rate, endometrial thickness, length of follicular phase and number of preovulatory follicles. No statistically significant difference in clinical pregnancy rates per cycle was found for patients in the letrozole or HMG group (18.4 versus 15.7%). Cost was significantly higher in the HMG stimulation cases (P < 0.001) and no injections were required in the letrozole group. In conclusion, letrozole offers a new treatment regimen in ovarian stimulation regimens for IUI that is cost effective, simple and convenient for the patients.
Reproductive biomedicine online 08/2006; 13(2):208-12. · 2.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE AND DESIGN: To review the role of aromatase inhibitors (AIs) in the treatment of endometriosis. CONCLUSION(S): Endometriosis is a common estrogen-dependent disorder that can result in substantial morbidity, including pelvic pain, multiple operations, and infertility. Approximately only half of women with endometriosis get pain relief from existing medical or surgical treatments. Medical treatments usually are directed at inhibiting estrogen action or its production from the ovaries and do not address local estrogen biosynthesis by the aromatase enzyme in endometriotic lesions. A single gene encodes aromatase, which is the final enzyme in the estrogen biosynthesis pathway, and its inhibition effectively eliminates estrogen production. The recently introduced highly specific AIs have successfully treated pelvic pain and significantly reduced the lesion size. In premenopausal women, an AI alone may induce ovarian folliculogenesis, and thus AIs are combined with a progestin, a combination oral contraceptive, or a GnRH analogue. The side-effect profile of AIs administered in combination with an oral contraceptive or a progestin is remarkably benign. We review herein the published clinical evidence for the use of AIs in the treatment of endometriosis.
Fertility and sterility 06/2006; 85(5):1307-18. · 3.97 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Endometriosis is the most common cause of pelvic pain and affects an estimated 5 million women in the US. The biologically active estrogen estradiol (E2) is the best-defined mitogen for the growth and inflammation processes in the ectopic endometriotic tissue that commonly resides on the pelvic organs. Progesterone and progestins may relieve pain by limiting growth and inflammation in endometriosis but a portion of patients with endometriosis and pelvic pain do not respond to treatment with progestins. Moreover, progesterone-induced molecular changes in the eutopic (intrauterine) endometrial tissue of women with endometriosis are either blunted or undetectable. These in vivo observations are indicative of resistance to progesterone action in endometriosis. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptors (PRs) and the lack of the PR isoform named progesterone receptor B (PR-B). In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factor(s). These unknown factor(s) act on neighboring epithelial cells to induce the expression of the enzyme 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD-2), which metabolizes the biologically active estrogen E2 to estrone (E1). In endometriotic tissue, progesterone does not induce epithelial 17beta-HSD-2 expression due to a defect in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate 17beta-HSD-2 may be due to the lack of PR-B and very low levels of progesterone receptor A (PR-A) observed in vivo in endometriotic tissue. The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this local mitogen. The cellular and molecular mechanisms underlying progesterone resistance and failure to metabolize E2 in endometriosis are reviewed.
Molecular and Cellular Endocrinology 04/2006; 248(1-2):94-103. · 4.19 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cervix uteri is regarded as an infrequent localization for endometriosis. With widespread use of invasive cervical procedures, however, an increased incidence can be expected. Limited awareness of the clinical appearance of the disease may account for its apparent rarity. This presentation aims to refocus attention to the disease by reviewing the case of a woman who presented to us with minimal metrorrhagia, which is a rare symptom of cervical endometriosis.
MedGenMed: Medscape general medicine 02/2005; 7(2):64.
-
Erkut Attar
Obstetrics and Gynecology Clinics of North America 01/2005; 31(4):779-94, x. · 1.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A young nulliparous woman with stage IIIC bilateral borderline micro-papillary serous carcinoma (MPSC) of the ovary underwent conservative surgery with optimal preservation of future fertility. The left ovary and a substantial portion of the right ovary were removed. The patient became pregnant at the first IVF cycle attempted after conservative management. A Cesarean section was performed in the 37th week of pregnancy and combined with very precise exploration; there were multiple non-invasive implants on the peritoneal surface and liver, and contra-lateral ovarian tissue was of normal appearance. Abdominal hysterectomy and right oophorectomy were done as a definitive treatment 3 months after the Caesarean section. The patient showed a rapid progression to invasive ovarian carcinoma in this period of time. MPSC has the greatest risk of malignant transformation among the advanced stage serous borderline tumours. Fertility-sparing surgery is an option for young, childless women who would like to preserve their fertility. However, the treatment must be taken very cautiously and requires rigorous surveillance.
Human Reproduction 07/2004; 19(6):1472-5. · 4.47 Impact Factor
-
Fertility and Sterility 01/2004; 80(6):1518-20. · 3.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We compared the frequency of Hypermobility Syndrome (HS) in 105 patients with urinary stress incontinence (USI) with the frequency of HS in 105 healthy controls that matched for age and parity. A Beighton score (BS) of more than 3 was used to make the clinical diagnosis of HS. Thirty-six patients (34.28%) from the USI group and 28 patients (26.66%) from the control group were diagnosed as HS. The mean BS values were 6.44+/-0.35 and 5.21+/-0.29 respectively. The difference between the two groups was statistically significant ( P<0.05).
Archives of Gynecology and Obstetrics 01/2004; 269(2):89-90. · 1.28 Impact Factor
-
Serdar E Bulun,
Dong Chen,
Meiling Lu,
Hong Zhao,
Youhong Cheng,
Masashi Demura,
Bertan Yilmaz,
Regina Martin,
Hiroki Utsunomiya,
Steven Thung, [......],
Amy Hakim,
Ping Yin,
Hiroshi Ishikawa,
Sanober Amin,
Gonca Imir,
Bilgin Gurates, Erkut Attar,
Scott Reierstad,
Joy Innes,
Zhihong Lin
[show abstract]
[hide abstract]
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 106(1-5):81-96. · 3.05 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Leukaemia inhibitory factor (LIF) is expressed at high constitutive levels in the human Fallopian tubal epithelium. In this study, the effect of human recombinant LIF on sperm motility and survival in vitro was investigated. Human spermatozoa were incubated in sperm washing medium that contained various concentrations of LIF at 37 degrees C and under 5% of CO(2) in air for up to 48 h. Sperm motion characteristics were measured using a sperm motility analyser. Sperm survival was determined by the hypo-osmotic swelling test. The effect of LIF on sperm motility was concentration-dependent and maximal effect was observed at a concentration of 5 ng/ml. Sperm motility was significantly higher after 24 h exposure to LIF compared with control (P < 0.001). Sperm survival was also prolonged in a concentration-dependent manner. LIF significantly enhanced sperm survival at higher concentrations (10 ng/ml) and the result was significant after 48 h exposure (P < 0.05). LIF increased long-term sperm motility and survival in vitro.
Reproductive biomedicine online 7(1):71-4. · 2.04 Impact Factor
