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PubMed1997

Transferrin receptor (CD71) expression in peritoneal macrophages from fertile and infertile women with and without endometriosis.

PROBLEM: Hyperactivated macrophages are implicated in the pathophysiology of endometriosis-associated infertility. This study investigates transferrin receptor expression (CD71) as a marker of hyperactivity in peritoneal macrophages of infertile patients with minimal to mild endometriosis (group 1, n = 25). METHOD OF STUDY: Expression of the activation antigen CD71 on peritoneal fluid macrophages was determined by a specific monoclonal anti-CD71 antibody using indirect immunofluorescence technique and was analyzed by flow cytometry. Three different control groups of women were used: women with unexplained infertility (group 2, n = 25), fertile women with endometriosis (group 3, n = 10), and fertile women without endometriosis (group 4, n = 25). RESULTS: The percentage of CD71 positive cells was significantly increased in infertile women with endometriosis as compared with the three control groups. There were no differences among groups 2, 3, and 4 with respect to the percentage of CD71 positive macrophages. CONCLUSIONS: Our results favor the concept that hyperactivated macrophages play a role in the pathophysiology of endometriosis-associated subfertility, a feature which is lacking in patients with unexplained infertility.

Adult↗

PubMed2001

Correlation between decreased type-II interleukin-1 receptor and increased monocyte chemotactic protein-1 expression in the endometrium of women with endometriosis.

PROBLEM: Monocyte chemotactic protein-1 (MCP-1), a potent inducer of macrophage recruitment and activation, is overexpressed in the eutopic endometrium of women with endometriosis. Eutopic endometrial cells of women with endometriosis secrete higher levels of MCP-1 than those of normal women, following stimulation with interleukin-1 (IL-1). The aim of this study was to examine whether there is any correlation between the expression of IL-1 receptor type II (IL-IRII), a specific downregulator of IL-1 activity, and that of MCP-1 in the eutopic endometrium of women with endometriosis. METHOD OF STUDY: Endometrial biopsies of 46 women with endometriosis and 22 healthy women were evaluated simultaneously for IL-1RII and MCP-1 expression by immunohistochemistry. RESULTS: Our study revealed a highly significant correlation between the decreased expression of IL-1RII and the increased expression of MCP-1 in the endometrial tissue of women with endometriosis (Spearman correlation coefficient r = -0.377, P = 0.002), particularly in the initial stages of the disease (stages I and II; r = - 0.368, P = 0.020 and r = -0.480, P = 0.002, respectively). Furthermore, this correlation was observed in the proliferative (r = -0.366, P = 0.047) and the secretory phases (r = -0.321, P = 0.049) of the menstrual cycle. CONCLUSIONS: These results suggest that the reduced capability of endometrial tissue to downregulate IL-1 proinflammatory effects may be involved in the increased expression of MCP-1 in the endometrium of women with endometriosis and the establishment of an inflammatory state. The results also indicate a sustained process of cell activation throughout the menstrual cycle.

Adult↗

PubMed1999

Immunohistochemical study of angiogenic factors in endometrium and endometriosis.

The proliferative activity and angiogenic factors of pelvic endometriosis and uterine endometrium and their correlation with different pigmented lesions are important throughout the menstrual cycle. The proliferative activity and/or expression of angiogenic factors appears to be different between endometrium and endometriosis, and also different in each pigmented lesion. Immunohistochemical studies using computerized image analysis have shown that in normal endometrium, the PCNA index shows cyclic variation, but no cyclic change is observed in endometriosis. In the pelvic peritoneum, the PCNA index is higher in red lesions compared to black and white lesions. There is no difference in VEGF expression among different pigmented lesions. However, a cyclic variation of VEGF concentration was found in the peritoneal fluid of patients with endometriosis. As a newly determined angiogenic factor, the number of endoglin-positive cells and the mean endothelial area were higher in red lesions than in black or white lesions. These results suggest that the pathogenesis and activity of endometriosis possibly depends on internal angiogenesis. The cellular activity of endometriotic lesions may not necessarily coincide with the regulation of angiogenesis, and may not be synchronized in each pigmented pelvic lesion of endometriosis. Copyrightz1999S.KargerAG, Basel

Adult↗

PubMed2002

The efficacy of medical and surgical treatment of endometriosis-associated infertility and pelvic pain.

This article is a review of the efficacy of medical and surgical treatment of endometriosis-associated infertility and pelvic pain. Endometriosis is the cause of pelvic pain (dysmenorrhea, dyspareunia) and infertility in more than 35% of women of reproductive age. Complete resolution of endometriosis is not yet possible but therapy has essentially three main objectives: (1) to reduce pain; (2) to increase the possibility of pregnancy; (3) to delay recurrence for as long as possible. It could be concluded that a consensus will probably never be reached on minimal and mild endometriosis. Nevertheless, because the Canadian study reported a large number of cases, we strongly support the view that visible endometriosis must be removed at the time of surgery. In cases of moderate and severe endometriosis-associated infertility, the combined approach (operative laparoscopy with GnRH-a) must be considered as 'first-line' treatment. The mean pregnancy rate of 50% reported in the literature following surgery provides scientific proof that operative treatment should be undertaken first to give our patients the best chance of conceiving naturally.

Endometriosis↗

PubMed2007

Two unsuccessful clinical trials on endometriosis and a few lessons learned.

In 1999, a phase II clinical trial on the use of fulvestrant to treat endometriosis was launched; yet after 7 years there is still no report on its outcome. In 2005, another trial on the use of raloxifene to treat endometriosis was terminated early due to unfavorable outcome. The two apparently unsuccessful clinical trials on endometriosis have taught us a few important lessons. First, we need to understand endometriosis through more basic research. We have also been reminded that human endometriosis trials differ from animal studies; anatomy and physiology are often divergent, and outcome measures are certainly different. Ectopic endometrium can differ significantly from eutopic tissue, and this issue needs to be more thoroughly explored. We believe human cell lines will prove to be an inexpensive and valuable tool for future preliminary evaluation of medical therapies as well as discerning pathophysiologic processes of the disease. Based on our current understanding of endometriosis, some concrete benchmarks can be established for testing or screening potential compounds in vitro. Finally, estrogen receptor modulators are often tissue-, cell-, and context-specific in their actions; they should not be simplistically grouped together nor should extrapolations from one compound to another be undertaken in a cavalier manner.

Adult↗

PubMed1996

Effect of culture supernatants of endometriotic lesions, uterine endometrium and peritoneum from rats with experimental endometriosis on the natural killer activity of spleen cells.

Experimental endometriosis in rats was induced by autotransplanting the uterine endometrium to the peritoneum. In all rats, endometrial implants developed into endometriotic tissues similar to those in humans about 2 weeks after transplantation. Natural killer (NK) activity of spleen cells in the endometriosis model rats was significantly (p < 0.05) lower than that in the sham-operated intact rats. The inhibited NK activity in the endometriosis rats recovered to the level in intact rats with danazol (but not buserelin). The supernatant after 24-hour culture of endometrial tissues from both intact and model rats seemed to have significant inhibitory effects on NK activity. The supernatant from endometrial grafts showed significantly (p < 0.05) higher inhibitory effects than that from the endometrial tissues. The inhibitory effects were significantly (p < 0.05) reduced by treatment with danazol or buserelin to the untreated level. In addition, supernatants of unaffected peritoneal tissues from the endometriosis rats had significantly (p < 0.01) higher inhibitory effects on NK activity than those from the intact rats. Even when uterine serosa or silicone was implanted to the peritoneum, the supernatants of the contralateral peritoneal tissues showed significantly (p < 0.05) higher inhibitory effects than those from the intact rats, while having significantly (p < 0.05) lower inhibitory effects than those from the endometriosis rats. These results suggest that this marked inhibitory effect on NK activity by the peritoneum may be associated with the development and progression of endometriosis.

Animals↗

PubMed1994

Lymphokine-activated killer activity in women with endometriosis.

The aim of the present study was to investigate whether women with endometriosis displayed a decreased lymphokine-activated killer (LAK) activity. In 15 women with and 7 women without endometriosis the cytotoxicity against four different tumor cell lines--K562, the endometrium carcinomas AN3CA and RL95, the natural-killer (NK)-resistant Daudi cell line--was investigated, using either freshly isolated peripheral blood mononuclear cells (PBMC) or recombinant interleukin (IL)-2-stimulated PBMC. In 5 additional women collagenase-DNase-digested endometrium was used, to investigate whether recombinant IL-2-activated lymphocytes displayed an increased cytotoxicity against fresh and cultured endometrial cells. The cytotoxicity of unstimulated PBMC toward K562, AN3CA and RL95 target cells was decreased in women with endometriosis compared to women without endometriosis (p < 0.05, for all). After recombinant IL-2 stimulation the cytotoxicity toward the four different target cells increased significantly, both in women with and without endometriosis. There was no difference in LAK-mediated cytotoxicity against the four tumoral cells between women with and without endometriosis. Significant LAK activity was demonstrated against both fresh and cultured (72 h) endometrial cells. The cytotoxicity of autologous lymphocytes against cultured endometrial cells was 31.0 +/- 17 versus 67.4 +/- 5.8%, using lymphocytes cultured in medium without and with recombinant IL-2, respectively (paired t test, p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Effect on ovulation of surgically induced endometriosis in rabbits.

To study the effect of endometriosis on follicular rupture, endometrial tissue was autografted to New Zealand White rabbits. Endometrium was surgically implanted into the peritoneal cavity or into the rectus muscle. Human chorionic gonadotropin was administered to induce ovulation. During three subsequent laparotomies, the number of corpora lutea and stigmata were counted. The viability of the implants was demonstrated histologically. Ovaries were removed during the last laparotomy and ovarian serial sections were examined. In rabbits with peritoneal induced endometriosis, the percentage of stigmata/corpora lutea was significantly decreased. Macroscopic study was confirmed by histological examination. Indeed, a high incidence of entrapped oocytes was found in rabbits with peritoneal endometriosis. Extraperitoneal endometriosis had no effect on ovulation. Our data demonstrated that endometriosis induced a failure of follicular rupture. After endometriumectomy, no failure to ovulate was observed, suggesting that the effect of endometriosis on the ovulation disappeared with excision of endometrial implants.

Animals↗

PubMed1983

Peritoneal fluid volume, 17beta-estradiol and progesterone concentrations in women with endometriosis and/or luteinized unruptured follicle syndrome.

Data on the presence of an ovulation ostium and the volume and the concentrations of estradiol (17 beta-estradiol) and progesterone In women with endometriosis (n = 80) and women with luteinized unruptured follicle (LUF) syndrome (n = 32) are reported and compared with data obtained from normal ovulatory women, previously reported. in women with endometriosis, less ovulation ostia were observed, the difference being significant in moderate and severe endometriosis. During the luteal phase, no statistical difference was found in the amount of peritoneal fluid of women with endometriosis. Estradiol and progesterone levels in the peritoneal fluid of normal women and women with mild endometriosis were not significantly different. Lower steroid concentrations found in peritoneal fluid of women with moderate (phase days 20-22) and severe endometriosis (phase days 14-19 and 20-22) may explain the high incidence of infertility reported in these women (peritoneal steroids deficiency). During the phases days 14-19 and 20-22, very low peritoneal steroid concentrations were found in women with LUF syndrome. It is suggested that progesterone assay in peritoneal fluid is an aid to diagnose the luteinized unruptured syndrome.

Adult↗

PubMed1996

Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids.

Angiogenesis is important in the pathophysiology of endometriosis, a condition characterized by implantation of ectopic endometrium in the peritoneal cavity. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor involved in physiological and pathological angiogenesis, and elevated levels of VEGF are found in peritoneal fluid of patients with endometriosis. Our aim was to investigate the site of expression and regulation of VEGF in endometriosis. VEGF immunoreactivity was found in tissue macrophages present in ectopic endometrium and in activated peritoneal fluid macrophages. Macrophage activation was highest in women with endometriosis, and media conditioned by peritoneal fluid macrophages from these women caused a VEGF-dependent increase in endothelial cell proliferation above that seen from normal women. Peritoneal fluid macrophages secreted VEGF in response to ovarian steroids, and this secretion was enhanced after activation with lipopolysaccharide. Peritoneal fluid macrophages expressed receptors for steroid hormones. VEGF receptors flt and KDR (kinase domain receptor) were also detected, suggesting autocrine regulation. During the menstrual cycle, expression of flt was constant but that of KDR was increased in the luteal phase, at which time the cells migrated in response to VEGF. KDR expression and the migratory response were significantly higher in patients with endometriosis. This study demonstrates that activated macrophages are a major source of VEGF in endometriosis and that this expression is regulated directly by ovarian steroids.

Adult↗

PubMed2003

Laparoscopic management of patients with endometriosis and chronic pelvic pain.

Endometriosis has been traditionally included among the most important causes of chronic pelvic pain (CPP) in women of reproductive age. The main clinical manifestations of endometriosis are dysmenorrhea, dyspareunia, and chronic nonmenstrual pain. Despite the high prevalence of endometriosis in women suffering from CPP, controversy still exists regarding the true association between the stage and extent of this peculiar disease and the severity of pain. Over the last decade, advances in endoscopic technology have enabled gynecologic surgeons to recognize many atypical appearances of the endometriotic implants not known to exist before, thus allowing their complete excision or destruction. Laparoscopic surgery may offer considerable relief in patients with endometriosis and CPP. Although cases with advanced endometriosis seem to benefit the most, we also support surgical treatment in patients with early endometriosis diagnosed using laparoscopy, as many will experience improvement in their symptoms.

Adult↗

PubMed2004

Future directions in endometriosis research.

Endometriosis is an important gynecological disease, pathologically defined by the ectopic presence of both endometrial glands and stroma, and clinically associated with pelvic pain and infertility. Our current knowledge of the pathogenesis, pathophysiology of related infertility, and spontaneous evolution is still limited, although endometriosis has been described for many years. Future research in endometriosis needs to focus on pathogenesis studies in the baboon model and on the early interactions between endometrial and peritoneal cells in the pelvic cavity at the time of menstruation. Proteomic and genomic approaches are needed to detect potential differences between eutopic endometrium and myometrium in women with and without endometriosis. Immunomodulatory drugs inhibiting endometriosis-associated pelvic inflammation may offer new medical treatment for endometriosis in the future.

Animals↗

PubMed2004

EMX2 gene expression in the female reproductive tract and aberrant expression in the endometrium of patients with endometriosis.

EMX2 is a transcription factor necessary for reproductive tract development. Sex steroids regulate endometrial HOXA10 expression, which in turn negatively regulates EMX2. In this study, we characterize menstrual cycle-dependent expression of EMX2 in endometrium from women with and without endometriosis. In the absence of endometriosis, EMX2 mRNA levels declined 50% in periimplantation endometrium compared with levels in the proliferative phase. To determine whether the decrease in endometrial EMX2 expression was regulated by endogenous endometrial HOXA10, primary endometrial stromal cells were transfected with an EMX2-reporter construct containing a HOXA10 binding site. Acting via this site, we observed HOXA10-mediated repression of reporter expression. In the endometrium of patients with endometriosis, unlike normal endometrium, EMX2 levels were not decreased in the periimplantation period. We have previously shown that up-regulation of HOXA10 in periimplantation endometrium fails to occur in women with endometriosis. To determine whether elevated endometrial EMX2 levels were due to failure of HOXA10-mediated transcriptional repression, secondary to low HOXA10 levels in endometriosis, we transfected stromal cells with HOXA10 antisense and an EMX2-reporter construct. Reporter expression was increased, indicating reversal of HOXA10-mediated transcriptional repression. Endometrial EMX2 expression is aberrant in women with endometriosis and is mediated by altered HOXA10 expression.

Adult↗

PubMed2000

Increased leptin levels in serum and peritoneal fluid of patients with pelvic endometriosis.

Pelvic endometriosis is an immune-related chronic inflammatory disease, characterized by ectopic implants of endometrium in the peritoneal cavity and associated with increased secretion of proinflammatory cytokines and neoangiogenesis. Leptin, the adipocyte-derived hormone, has been shown to have a role in food intake, basal metabolism, and reproductive function. Leptin levels are dynamically regulated, being elevated by inflammatory mediators and reduced by starvation. Leptin itself can influence the proinflammatory immune responses of CD4+ T lymphocytes, and reports have also shown this hormone to be an angiogenic factor in vitro and in vivo. We investigated whether leptin concentrations in serum and peritoneal fluid (PF) differed between 13 patients with different stages of endometriosis and 15 age- and body mass index-matched controls. We found a statistically significant (P < 0.05) increase in leptin levels in serum (30.3 +/- 14.8 ng/mL) and PF (35.9 +/- 17.4 ng/mL) of patients with endometriosis, compared with our control population (serum, 15.6 +/- 8.4; PF, 17.5 +/- 7.2 ng/mL). Regression equations, relating leptin to body mass index, were also significantly different in endometriosis patients, compared with controls. Higher levels of leptin were observed in the earlier stages of endometriosis than advanced-stage disease. These data suggest that the proinflammatory and neoangiogenic actions of leptin may contribute to the pathogenesis of endometriosis.

Adult↗

PubMed2001

Nuclear peroxisome proliferator-activated receptors alpha and gamma have opposing effects on monocyte chemotaxis in endometriosis.

The peroxisome proliferator-activated receptors (PPARs) alpha and gamma are nuclear receptors that play important roles in inflammatory diseases like ulcerative colitis and arthritis. In this study, we examined the possible role of PPARs in macrophage attraction into the peritoneal cavity of patients with endometriosis. We identified PPAR-alpha and -gamma messenger RNA by RT-PCR and protein by immunoblotting of lysates of peritoneal macrophages and monocytic U937 cells. Using immunocytochemistry, we localized PPAR-alpha and -gamma within the nuclei of both cell types. Monocyte chemotactic activity of peritoneal fluid from patients with endometriosis was quantified in Boyden chambers. Migration of U937 cells was increased by WY 14643 and reduced by rosiglitazone. Peritoneal fluid from patients with endometriosis activated U937 cells transiently transfected with a PPAR-alpha/GAL4 luciferase reporter. By contrast, peritoneal fluid did not cause significant activation of PPAR-gamma/GAL4 constructs. The U937 cells transiently transfected with a PPAR response element luciferase reporter showed disease stage-dependent up-regulation when treated with peritoneal fluid from patients with endometriosis. Treatment with peritoneal fluid from healthy controls down-regulated PPAR response element transactivation. We conclude that peritoneal fluid of endometriosis patients contains activators of PPAR-alpha that stimulate macrophage chemotaxis. Inhibitors of PPAR-alpha or activators of PPAR-gamma could be developed for the treatment of inflammation associated with endometriosis.

Apoptosis↗

PubMed1988

Functional aspects of peritoneal macrophages in endometriosis of women.

Peritoneal fluid was collected in the periovulatory phase of the cycle from 25 women undergoing laparoscopy. Endometriosis was diagnosed in 13 patients (AFS score 1, N = 9; AFS score 2, N = 4) and 12 patients without endometriosis served as controls. In endometriosis patients the total peritoneal fluid cell number and cell concentration was significantly higher than in controls, indicating peritoneal irritation by endometrial implants. Peritoneal fluid macrophages in patients with endometriosis showed significantly increased erythrophagocytosis and lower chemiluminescence than in controls, suggesting an advanced differentiation of the macrophages in endometriosis patients. The macrophages in this stage of differentiation may interfere with gametes and embryos and thus contribute to endometriosis-associated subfertility.

Cell Count↗

PubMed2001

Measurement of serum and peritoneal fluid LH concentrations as a diagnostic tool for human endometriosis.

A rapid, sensitive enzymeimmunoassay for the measurement of LH concentrations in serum and peritoneal fluid samples of healthy women and women with endometriosis is reported. The ligand (LH) was captured by a readily available, widely used and well-characterized monoclonal antibody (mAb, 518B7) generated against the beta subunit of bovine LH. This mAb, although specific for LH, shows very little species specificity and detects LH by radioimmunoassay in humans. A polyclonal antiserum raised in rabbits against hCG was conjugated to horseradish peroxidase and was used as the second antibody signal. This anti-hCG antiserum crossreacts with LH. The enzymeimmunoassay uses the standard human LH (hLH) preparations (NIADDK-hLH-I-3, AFP-827OB) and results are based on the relative concentrations of LH in serum and peritoneal fluid. Total assay time was < 3 h. The range of the standard curve was 0.002-0.500 ng LH per well and the lowest concentration of hLH that could be distinguished from zero concentration was 0.15 +/- 0.02 ng ml(-1) serum and 0.058 +/- 0.021 ng ml(-1) peritoneal fluid. Clinical diagnostic parameters for the LH enzymeimmunoassay showed a sensitivity of 85.71%, specificity 92.50%, efficiency 88.54%, positive predictive value 94.11% and negative predictive value 82.22%. The study was retrospective. Serum LH concentrations of women with endometriosis were 13.67 +/- 7.21 ng ml(-1), whereas serum LH concentrations of women in the control group were 4.52 +/- 2.03 ng ml(-1). One-way ANOVA showed significant differences (P < 0.001) between women with endometriosis and control groups. Women in the control group had peritoneal fluid LH values of 5.65 +/- 2.43 ng ml(-1), whereas peritoneal fluid LH values of 64.06 +/- 16.44 ng ml(-1) were obtained in women with endometriosis (P < 0.001). A cycle-dependent pattern of serum and peritoneal fluid LH concentration was observed in women in the control group, which was not observed in the peritoneal fluid of the group with endometriosis. The application of this assay to serum or peritoneal fluid samples provides the attractive possibility that it could be included in the panel of markers used for diagnosis of endometriosis.

Adult↗

PubMed2004

[Rectovaginal septum endometriosis: a disease with specific diagnosis and treatment].

BACKGROUND: The involvement of the rectovaginal septum, of rectum and sigmoid by endometriosis leads to intense symptoms as dysmenorrhea, pelvic pain, deep dyspareunia, tenesmus and hematochezia in young and middle aged women during periods. The diagnosis can be made by tipycal history and vaginal examination, rectal examination, barium enema, proctoscopy and so on. The indications of operation include severe clinic symptoms and failed conservative therapy. The treatment of choice for this type of endometriosis is the surgical resection of affected tissue, in order to relieve patient symptoms, and avoid disease progression. The correct assessment as to the presence and extension of the endometriosis-affected sites such as the rectum, uterosacral ligaments and rectovaginal septum is extremely important to provide better results with the surgical treatment of endometriosis. AIM: To describe the main aspects related to rectovaginal septum endometriosis and offer the general surgeon some information about this enigmatic disease. CONCLUSION: Rectovaginal septum endometriosis is a frequent disease, with specific diagnosis and treatment.

Endometriosis↗