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Biomedical subjects

A Arici

Publications and source records attributed to A Arici.

At least 37 records · Page 2Linked to original sources
PubMed2000

Implantation defect in endometriosis: endometrium or peritoneal fluid.

Clinical observations indicate that an implantation defect occurs in women with endometriosis. Despite intense research, the role of alterations in endometrial receptivity and the peritoneal fluid microenvironment in the derangement of implantation in endometriosis remains controversial. In this review, the evidence for the altered endometrial receptivity and peritoneal environment are summarized, and their effects on the implantation defect in women with endometriosis are discussed. Recent studies on cell adhesion molecules and their ligands, apoptosis, homeobox genes and the direct action of gonadotrophin-releasing hormone analogues are reviewed with respect to their contribution to endometrial receptivity in endometriosis. The possible mechanisms by which an altered peritoneal environment of endometriosis may affect implantation, including cytokine concentrations, iron metabolism, biochemical factors and embryotoxicity are discussed.

Apoptosis↗
PubMed1999

Prospective, randomized, crossover study to evaluate the benefit of human chorionic gonadotropin-timed versus urinary luteinizing hormone-timed intrauterine inseminations in clomiphene citrate-stimulated treatment cycles.

OBJECTIVE: To compare two methods of timing IUI, urinary LH monitoring and transvaginal ultrasonography/ hCG timing of ovulation, in patients receiving clomiphene citrate. DESIGN: Prospective, randomized, crossover study. SETTING: Yale University Reproductive Medicine Center. PATIENT(S): Infertile couples undergoing IUI because of unexplained infertility, anovulation, or male factor infertility. INTERVENTION(S): Patients received clomiphene citrate on days 3-7 of the menstrual cycle and were randomized initially to one of two monitoring protocols. In protocol A, urinary LH monitoring was used to time IUI. Urinary LH levels were determined daily with the use of commercial kits, starting on day 10 of the cycle. When urinary LH was detected, IUIs were performed daily for the next 2 days. In protocol B, ultrasound monitoring of folliculogenesis was performed until a leading follicle of > or = 18 mm was noted, at which time hCG (10,000 IU) was given intramuscularly and IUIs were performed daily for the next 2 days. If no pregnancy occurred, the couple crossed over to the alternate protocol for the next cycle and continued this alternating therapy for a total of four cycles. MAIN OUTCOME MEASURE(S): Pregnancy rate per cycle. RESULT(S): One hundred forty-one cycles were completed. In these cycles, six pregnancies occurred, for an overall pregnancy rate of 4.26% per cycle. The pregnancy rate with LH-timed IUI was 4.29% (3/70) and that with hCG-induced ovulation was 4.23% (3/71); the difference was not statistically significant. CONCLUSION(S): Timing IUI with the use of a relatively expensive and time-consuming method such as ultrasound monitoring of folliculogenesis and hCG induction of ovulation does not appear to produce an increased pregnancy rate over urinary LH monitoring of ovulation.

Adult↗
PubMed1999

Chemokines and human reproduction.

OBJECTIVE: To review the available information regarding chemotactic cytokines and their possible implications in human reproduction. DESIGN: A thorough literature and MEDLINE search was conducted to identify studies relating to the role of chemokines in ovulation, menstruation, implantation, cervical ripening and preterm labor, and endometriosis. RESULT(S): Chemokines mediate leukocyte traffic through their specific receptors in various tissues. Although four families have been described to date, two remain the major subfamilies: alpha-chemokines (with interleukin-8 as representative for this group), and beta-chemokines (with monocyte chemotactic protein-1 as representative). Interleukin-8, monocyte chemotactic protein-1, and growth-regulated oncogene-alpha are involved in follicular development and atresia, ovulation, steroidogenesis, and corpus luteum function. Interleukin-8 showed cycle-dependent expression in human endometrium, and at the same time, stimulated endometrial stromal cell growth, acting as an autocrine growth factor. Interleukin-8 has been identified in human amnion, chorion, decidua, and villous placenta, and its level increases during labor. Levels of interleukin-8 correlate with the release of collagenases, a crucial step that regulates the process of cervical extracellular matrix remodeling. The levels of monocyte chemotactic protein-1; regulated on activation, normal T-expressed and secreted (RANTES); interleukin-8; and growth-regulated oncogene-alpha are elevated in the peritoneal fluid of women with endometriosis, and they correlate with the stage of the disease. CONCLUSION(S): Chemokines play a relevant role in many physiologic and pathologic situations, such as ovulation, menstruation, implantation, cervical ripening and preterm labor, and endometriosis. Their regulation soon may provide new therapeutic strategies.

Chemokines↗
PubMed1999

Interleukin-8 stimulates the adhesion of endometrial stromal cells to fibronectin.

OBJECTIVE: To study the effect of interleukin-8 (IL-8) and mouse anti-human IL-8 monoclonal antibody on endometrial stromal cell adhesion to fibronectin. DESIGN: Prospective, controlled in vitro study. SETTING: Academic research laboratory. PATIENT(S): Women undergoing benign gynecologic surgery for indications other than endometrial disease. INTERVENTION(S): Endometrial stromal cells were treated with IL-8 and mouse anti-human IL-8 monoclonal antibody at different concentrations and adhesion assays were performed by labeling the cells with calcein. MAIN OUTCOME MEASURE(S): Fluorescence in calcein-labeled endometrial stromal cells. RESULT(S): IL-8 induced a concentration-dependent increase of cell adhesion to fibronectin matrix (twofold at 10 ng/mL; P = .006). Treatment of endometrial stromal cells with anti-IL-8 neutralizing antibody inhibited partially the cell adhesion. CONCLUSION(S): IL-8 stimulates the adhesion of endometrial stromal cells to fibronectin in a concentration-dependent manner. IL-8 may thus be relevant for the attachment of endometrial implants in the pathogenesis of endometriosis.

Animals↗
PubMed1999

Progesterone metabolism in human endometrial stromal and gland cells in culture.

Metabolism of progesterone by human endometrium has been described, but the rapidity and extent of progesterone metabolism is incompletely documented in cellular fractions of normal endometrium. Therefore, we evaluated progesterone metabolism in separated stromal and gland cells in culture obtained from normal human endometrium by thin-layer chromatography. We find that in both cell types, the most abundant metabolite is 3beta-hydroxy-5alpha-pregnan-20-one (70%), followed by 5alpha-pregnane-3,20-dione (15%), and 3alpha-hydroxy-5alpha-pregnan-20-one (10%). A small amount is metabolized to 5alpha-pregnane-3alpha/3beta,20alpha-diols and to 3beta,6alpha-dihydroxy-5alpha-pregnan-20-one. The metabolism of progesterone in cultured endometrial cells occurs rapidly; 70% of progesterone is metabolised in 8 h, and 90% by 24 h. We conclude that when in vitro experiments are conducted utilizing progesterone treatment, the rapidity and the extent of the metabolism of this steroid should be taken into account.

20-alpha-Dihydroprogesterone↗
PubMed1999

HOX gene expression is altered in the endometrium of women with endometriosis.

HOXA10 and HOXA11 are homeobox genes that function as transcription factors essential to embryonic development. We have recently described a role for each of these two genes in regulating endometrial development in the adult during the course of a menstrual cycle. Both Hoxa10 and Hoxa11 are essential for implantation in the mouse and appear to play a similar role in women. To investigate the role of HOX genes in the endometrium of women with endometriosis, quantitative Northern blot analysis was performed on the endometrium of 40 normal cycling controls and 40 patients with documented endometriosis. Patients with endometriosis failed to show the expected mid-luteal rise in HOX gene expression as demonstrated in the controls. Aberrant HOX gene expression suggests that altered development of the endometrium at the molecular level may contribute to the aetiology of infertility in patients with endometriosis.

Adult↗
PubMed1999

The relevance of the peritoneal fluid in endometriosis-associated infertility.

Endometriosis, one of the most prevalent gynaecological disorders, may affect fertility. Extensive research has been done in an attempt to understand the pathogenesis of endometriosis and its association with reproductive failure. It has been suggested that the disease affects almost any step of reproduction, but data are mostly controversial so it is difficult to draw clear conclusions from studies that have been done so far. Not only is peritoneal fluid in close proximity to endometriotic lesions, but it is also the environment in which early reproductive events take place. Studies on the peritoneal fluid in endometriosis have provided significant data towards an understanding of this disease. Immunological factors play a key role in determining the occurrence of endometriosis as well as its heterogenous symptoms. Since data also indicate that there are immunological differences between infertile and fertile women with endometriosis, recent studies have been designed to take these differences into consideration. This review will discuss the mechanisms by which endometriosis may affect fertility, and an emphasis will be placed on the relevance of the peritoneal fluid.

Ascitic Fluid↗
PubMed1999

Is the endometrium or oocyte/embryo affected in endometriosis?

One of the most puzzling problems of endometriosis is determining which mechanisms link this spectrum of conditions to infertility. There is conflicting evidence about the effect of endometriosis on the endometrium and on oocyte/embryo quality. Clinical studies reveal that implantation rates seem to be lower in women with endometriosis, while spontaneous abortion rates show variable results which are difficult to interpret due to the design of the studies. Biochemical markers (integrins and other cell adhesion molecules), morphological markers (pinopodes), apoptosis and ultrasound studies confirm that not only does the endometrium from women with endometriosis behave differently from the endometrium of women without endometriosis, but ectopic endometrium also behaves differently from eutopic endometrium. Data from oocyte donation programmes suggest that oocyte quality may be hampered in women with endometriosis. Recent reports have focused on the molecular mechanisms that may be altered, such as ovarian steroid production, or inadequate luteal function. In this review, we analyse the most recent literature dealing with the different mechanisms which affect the endometrium and oocyte/embryo quality and which thereby might cause infertility.

Abortion, Spontaneous↗
PubMed1999

Interleukin-8 expression in endometrial stromal cells is regulated by integrin-dependent cell adhesion.

Concentrations of interleukin (IL)-8, a potent chemotactic factor produced by many cell types, are elevated in the peritoneal fluid of women with endometriosis. We investigated whether endometrial stromal cell (ESC) adhesion induces the expression of IL-8 and if this process is integrin-mediated. ESCs were plated onto culture dishes coated with various extracellular matrix (ECM) substrates, such as fibronectin, laminin, collagen IV, and poly-L-lysine, or mouse anti-human integrin beta(1,) and beta(2) monoclonal antibodies. IL-8 expression was induced by adherence of ESCs to fibronectin or collagen IV, but not to poly-L-lysine, a non-integrin-dependent adhesion matrix. Engagement of beta(1)-containing integrins was associated with ESC adhesion and resulted in up-regulation of IL-8 mRNA expression and protein secretion. Disruption of the actin cytoskeleton by treating ESC with cytochalasin D completely blocked the increase of IL-8 that was induced in response to integrin activation. These findings indicate a novel mechanism of IL-8 regulation; cell adhesion to ECM is an important event that leads to stimulation of IL-8 expression, and this process is mediated by integrins.

Animals↗
PubMed1999

Macrophage derived growth factors modulate Fas ligand expression in cultured endometrial stromal cells: a role in endometriosis.

Fas-Fas ligand (FasL) interactions play a significant role in the immune privilege status of certain cell populations, and several cytokines and growth factors can modulate their expression. When a FasL-expressing cell binds a Fas-bearing immune cell, it triggers its death by apoptosis. In this study, we demonstrate that normal human endometrial epithelial but not stromal cells express FasL. Moreover, we showed that macrophage-conditioned media induced FasL expression by endometrial stromal cells in a dose-dependent manner. To elucidate which macrophage product was responsible for the up-regulation of FasL, endometrial stromal cell cultures were treated with the macrophage products platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta1, and basic fibroblast growth factor (bFGF). The first two (which are known to be elevated in the peritoneal fluid of women with endometriosis) induced a dose-dependent up-regulation of FasL expression, which was specifically inhibited by the antibody. Interestingly, bFGF (which is not elevated in peritoneal fluid of women with endometriosis) did not induce any response. These results suggest that the pro-inflammatory nature of the peritoneal fluid of women with endometriosis induces the FasL expression by regurgitated endometrial cells, and signals Fas-mediated cell death of activated immune cells. This could be a mechanism for endometrial cells to escape immune surveillance, implant and grow.

Cell Differentiation↗
PubMed1999

Monocyte chemotactic protein-1 expression in human corpus luteum.

Invasion of the corpus luteum by macrophages is a characteristic of luteal regression. Monocyte chemotactic protein-1 (MCP-1), a chemokine that recruits macrophages, is expressed in the rat corpus luteum where it increases in amount during luteolysis. In this study we examined the temporal and spatial expression of MCP-1 and changes in macrophage concentration in the human corpus luteum. Corpora lutea (n = 39) were grouped according to menstrual cycle phase and were examined by immunohistochemistry for MCP-1 and macrophages, and by Northern blot for MCP-1 mRNA. We found increasing amounts of macrophages with progressing luteolysis (P < 0.001). Staining for MCP-1 was stronger in the regressing corpora lutea compared with the staining in corpora lutea of early luteal phase (P < 0.05). MCP-1 was more prominent in blood vessel walls surrounding the corpus luteum than in vessels located far from it. The mean MCP-1 mRNA expression in regressing corpora lutea was higher than that observed in corpora lutea of the early and mid-luteal phase (P = 0.003). In conclusion, we found that MCP-1 expression and the number of macrophages increase with regression of the corpus luteum. MCP-1 is mostly expressed in blood vessel walls surrounding the corpus luteum and may play a role in the recruitment of macrophages to the corpus luteum during its regression.

Adult↗
PubMed1999

Proliferation and differentiation of rat theca-interstitial cells: comparison of effects induced by platelet-derived growth factor and insulin-like growth factor-I.

This study was designed to evaluate mechanisms regulating proliferation of steroidogenically active and steroidogenically inactive theca-interstitial (T-I) cells, and, specifically, to evaluate the effects of platelet-derived growth factor (PDGF) and insulin-like growth factor-I (IGF-I). T-I cells obtained from immature Sprague-Dawley rats were cultured in chemically defined media. Proliferation was assayed by thymidine incorporation and cell counting. Steroidogenically active cells were identified by the presence of 3beta-hydroxysteroid dehydrogenase activity. Flow cytometry facilitated separation of dividing cells (in S and G2/M phases of the cell cycle) from nondividing cells (in G0 and G1 phases of the cell cycle). PDGF alone (0.1-1 nM) produced a dose-dependent increase in DNA synthesis by up to 136%. IGF-I alone (10 nM) increased DNA synthesis by 56%. In the presence of both IGF-I (10 nM) and PDGF (0.1-1 nM), DNA synthesis increased by 108-214%. PDGF (1 nM) increased the total number of T-I cells by 43%; this effect was due to an increase in the number of steroidogenically inactive cells (47%). In contrast, the stimulatory effect of IGF-I (10 nM) was predominantly due to an increase in the number of steroidogenically active cells (163%). Separation of dividing cells from nondividing cells was accomplished with the aid of flow cytometry. In the absence of growth factors, the proportion of steroidogenically active cells was 35% lower among proliferating than resting cells. PDGF (1 nM) decreased the proportion of steroidogenically active cells among both proliferating and resting cells (by 43% and 16%, respectively). In contrast, IGF-I (10 nM) increased the proportion of steroidogenically active cells among proliferating cells by 56%. These findings indicate that differentiated/steroidogenically active cells divide; furthermore, PDGF and IGF-I may selectively stimulate proliferation of individual subpopulations of T-I cells, thereby providing a mechanism for development of structural and steroidogenically active components of the T-I compartment.

Animals↗
PubMed1999

Regulation of monocyte chemotactic protein-1 expression in human endometrial stromal cells by estrogen and progesterone.

There is a cyclicity in the number of endometrial macrophages that is most likely secondary to changes in steroid hormone levels. One cytokine that controls macrophage migration is monocyte chemotactic protein-1 (MCP-1). In the endometrium, highest levels of MCP-1 are detected perimenstrually, when estrogen levels are low; however, when estrogen levels are high (around the time of ovulation), MCP-1 levels are lowest. We hypothesized that sex steroids may be involved in the regulation of macrophage migration by regulating MCP-1 expression. We investigated the regulation of MCP-1 expression in human endometrial stromal cells by estradiol 17beta (E2) and progestins. We found that MCP-1 mRNA levels decreased in response to E2 (5 x 10(-8) M), with biphasic nadirs at 8 h and 24 h. MCP-1 protein production was also inhibited by E2 in a concentration-dependent manner. Tamoxifen, an anti-estrogen, alone (10(-7) M) did not affect MCP-1 expression, but it reversed the E2-induced inhibition up to 80%. Progesterone (10(-7) M) alone slightly decreased MCP-1 levels, and the combination of E2 and progesterone further decreased them, but that decrease was not different from that observed using E2 treatment alone. In summary, we found that E2 inhibits MCP-1 expression in endometrial stromal cells, and we speculate that E2 may control endometrial macrophage migration by regulating MCP-1 expression.

Blotting, Northern↗
PubMed1999

Regulation of monocyte chemotactic protein-1 expression in human endometrial stromal cells by integrin-dependent cell adhesion.

Shed menstrual endometrium is viable and has the ability to implant and grow in women, who eventually develop endometriosis. Many of the cell-to-cell or cell-to-extracellular matrix (ECM) connections are mediated by integrins. Monocyte chemotactic protein (MCP)-1, a potent chemotactic factor produced in many cell types, is elevated in the peritoneal fluid of women with endometriosis. In this study, we investigated whether endometrial stromal cell (ESC) adhesion itself induces the expression of MCP-1 and whether this process is integrin mediated. ESC were plated on Petri dishes and 24-well plates coated with fibronectin, laminin, collagen IV, poly-L-lysine, or mouse anti-human integrin beta(1) and beta(2) monoclonal antibodies. Adherence of ESC to various ECM substrates, except for poly-L-lysine, a non-integrin-dependent adhesion matrix, induced the expression of MCP-1 at both mRNA and protein levels. Engagement of beta(1)-containing integrins was associated with ESC adhesion and resulted in up-regulation of MCP-1 gene expression and protein secretion. Disruption of the actin cytoskeleton by treating ESC with cytochalasin D completely blocked the increase of MCP-1 induced in response to integrin activation. These findings indicate a novel mechanism of MCP-1 regulation. Cell adhesion to ECM is an important event that leads to stimulation of MCP-1 expression, and this process is mediated by integrins.

Animals↗
PubMed1999

Tumor necrosis factor-alpha stimulates proliferation of rat ovarian theca-interstitial cells.

Tumor necrosis factor-alpha (TNF-alpha) is a potent modulator of ovarian function, affecting steroidogenesis of both granulosa and theca-interstitial (T-I) cells. Women with polycystic ovary syndrome (PCOS) have increased levels of serum TNF-alpha. The present study evaluated the effects of TNF-alpha on T-I cell proliferation. Purified rat T-I cells were cultured for 48 h with or without TNF-alpha (0.001-1 nM), insulin-like growth factor I (IGF-I; 10 nM), and/or insulin (10 nM). Proliferation was measured by [(3)H]thymidine incorporation assay and by counting the steroidogenically active (stained positive for 3beta-hydroxysteroid dehydrogenase; 3beta-HSD) and inactive (3beta-HSD negative) cells. TNF-alpha stimulated thymidine incorporation in a dose-dependent fashion (up to 3.2-fold; P < 0.01). Insulin and IGF-I stimulated T-I proliferation (respectively, by up to 2.4- and 3.1-fold; P < 0.001). TNF-alpha potentiated effects of insulin and IGF-I in a dose-dependent and additive fashion (up to 6.7-fold; P < 0.001). TNF-alpha (1 nM) increased total cell count (by 80%, P < 0.05) and the proportion of 3beta-HSD-positive cells (by 19%, P < 0.05). Flow cytometry DNA analysis revealed that TNF-alpha (1 nM) increased the proliferative index by up to 16% (P = 0.05). The present findings demonstrate that TNF-alpha stimulates mitotic activity of T-I cells by increasing the proportion of actively dividing cells and preferentially increasing the number of steroidogenically active cells. The effects of TNF-alpha appear to be independent of those induced by insulin and IGF-I. We postulate that TNF-alpha may play a pathophysiologic role in disorders of the T-I compartment, such as PCOS.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

Sex steroids mediate HOXA11 expression in the human peri-implantation endometrium.

Under the influence of sex steroids, human endometrium undergoes sequential development in preparation for implantation. Hoxa11 is essential for implantation in the mouse. Here we describe a potential role for HOXA11 in human endometrial development and implantation. Northern analysis demonstrates that HOXA11 is expressed in a menstrual cycle phase-dependent fashion in adult human endometrium. HOXA11 messenger RNA levels dramatically increase at the time of implantation and remain increased in pregnancy. In vitro, HOXA11 expression is increased in response to estrogen or progesterone. There is a dose-responsive increase over the physiologic range of progesterone concentration. Pretreatment with Cyclohexamide does not decrease the response to estrogen. Steroids are novel regulators HOX gene expression. The spatial and temporal pattern of HOXA11 expression in the human endometrium suggests a role in endometrial development, implantation, and maintenance of pregnancy.

Embryo Implantation↗
PubMed1998

HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium.

Hox genes are well-known transcriptional regulators that play an essential role in directing embryonic development. Mice that are homozygous for a targeted disruption of the Hoxa10 gene exhibit uterine factor infertility. We have recently demonstrated that HOXA10 is expressed in the adult human uterus. To examine expression of HOXA10 during the menstrual cycle, Northern blot analysis and in situ hybridization were performed. Expression of HOXA10 dramatically increased during the midsecretory phase of the menstrual cycle, corresponding to the time of implantation and increase in circulating progesterone. Expression of HOXA10 in cultured endometrial cells was stimulated by estrogen or progesterone. Stimulation of HOXA10 by progesterone was concentration-dependent within the physiologic range, and the effect of estrogen was inhibited by cycloheximide. These results identify sex steroids as novel regulators of HOX gene expression. HOXA10 may have an important function in regulating endometrial development during the menstrual cycle and in establishing conditions necessary for implantation in the human.

Cells, Cultured↗