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Total adiponectin concentrations have been shown to increase in serum of preeclamptic women. However, variance of concentrations of different isoforms has not been studied, despite the emerging notion that high, medium and low molecular weight adiponectin exert different functions. We have determined serum concentrations of each adiponectin isoform using a newly developed enzyme immunosorbent assay. High molecular weight (HMW) adiponectin concentrations were significantly higher in women with preeclampsia ( n =14; median, 11.2μg/ml; interquartile range, 9.2–15.8) compared to normal pregnant women ( n =14; 6.8μg/ml, 5.4–10.7; P =0.04). In contrast, medium molecular weight and low molecular weight adiponectin concentrations were substantially equal between the groups. The ratio of HMW adiponectin to total adiponectin was also markedly higher in preeclamptic women (52.3%, 49.5–58.7) than control women (43.0%; 39.8–48.0; P =0.004). Taken together with other reports our findings imply a physiological feedback response to minimize endothelial damage in preeclamptic women.

Adiponectin is a novel adipocytokine of extreme importance for the metabolism. Recent studies have indicated that adiponectin suppresses inflammation, angiogenesis, and fibrosis, which are central pathogenic factors for endometriosis. We addressed the possibility that adiponectin is implicated in endometriosis.We measured concentrations of adiponectin in peritoneal fluid (PF) of women with (n = 54) or without (n = 26) endometriosis using specific enzyme-linked immunosorbent assay.Adiponectin concentrations in PF of women with endometriosis were significantly lower than those of women without endometriosis. With respect to the stages of the disease, the concentrations of adiponectin in women with stage III/IV endometriosis were significantly lower compared to those in women without endometriosis and with stage I/II endometriosis. Body mass index were comparable among the groups.These findings imply that adiponectin may be an anti-endometriotic factor, possibly due to its anti-inflammatory, anti-angiogenic, and anti-fibrotic properties.

Background Adiponectin is a pleiotropic cytokine originally discovered as an adipocyte-specific gene product. Serum adiponectin concentrations have been reported to be low in women with endometrial cancer, breast cancer and uterine leiomyoma, suggesting possible involvement of adiponectin in these estrogen-related diseases. We thus addressed the relevance of adiponectin to endometriosis, an estrogen-dependent disease, in the present study. Methods Women with (n = 48) and without (n = 30) endometriosis undergoing laparoscopy were recruited in this study. Blood samples were collected, and serum adiponectin concentrations were measured using a specific enzyme-linked immunosorbent assay. The relationship between laparoscopic findings and serum adiponectin concentrations was analysed. Results The adiponectin concentrations in the serum of the women with endometriosis (median, 13.1 microg/ml; interquartile range, 10.2 - 16.7) were significantly lower than those of the women without endometriosis (15.9 microg/ml, 13.5 - 19.5; P = 0.008). A significant negative correlation was found between serum adiponectin concentrations and both endometriosis scores (R = - 0.307, P = 0.006) and adhesion scores (R = - 0.254, P = 0.026) of the revised American Society for Reproductive Medicine classification of endometriosis. Conclusions The present findings suggest that adiponectin is implicated in the pathophysiology of endometriosis.

Both the classic form of the gonadotropin-releasing hormone receptor, GnRH I, and GnRH agonists reportedly have antiproliferative and apoptotic (programmed cell death) effects on cultured endometriotic cells as well as on some cancer cells from reproductive organs. The second form of GnRH receptors, GnRH II, is widely distributed in the central nervous system as well as in the female reproductive tract. The present investigators set out to learn whether GnRH II affects the proliferation of endometriotic stromal cells (ESCs) and whether it might have a role in the pathogenesis of endometriosis. Forty women with endometriosis who were having gynecologic surgery and 19 others without endometriosis were studied. GnRH II inhibited the incorporation of 5-bromo-2'-deoxyuridine (a reflection of mitosis) into DNA of ESC in a dose-dependent manner. The maximum effect was a 28% decrease of incorporation below control level. Treatment with interleukin-1β (IL-1β) markedly increased levels of mRNA for cyclooxygenase-2 and IL-8 in ESC as well as secretion of IL-8 protein by these cells. Supplemental GnRH II significantly inhibited these effects. Levels of GnRH II mRNA were lower in endometrial and endometriotic tissues from women with endometriosis than in endometrial tissues from unaffected women. Levels in endometriotic tissues were significantly reduced in the proliferative phase and tended to be low in the secretory phase when compared with those in endometrial tissues from women with endometriosis. Levels of mRNA for type I and type II GnRH receptors followed, for the most part, the same pattern as GnRH I. These findings suggest that GnRH II has antiproliferative and antiinflammatory effects on ESC. Observations of lower levels of expression of GnRH II in eutopic and ectopic endometrium from women having endometriosis indicate that, in this disorder, cytostatic mechanisms mediated by GnRH II may be impaired.

Endometriosis is known to be associated with local inflammatory reactions. Given the emerging concept of thrombin and its specific receptor, protease-activated receptor 1 (PAR1), as important players in inflammation and cell proliferation, we investigated whether thrombin and PAR1 might be involved in the pathophysiology of the disease, using a primary cell culture system of endometriotic tissues. PAR1 mRNA was expressed in primary endometriotic stromal cells (ESCs). Thrombin and SFLLRN (Ser-Phe-Leu-Leu-Arg-Asp), a PAR1 agonist peptide, increased the mRNA expression of IL-8, monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) and the protein secretion of IL-8 nd MCP-1 in ESCs. The addition of thrombin inhibitor d-phenylalanyl-l-prolyl-l arginine chloromethyl ketone (PPACK) together with thrombin inhibited the thrombin-induced secretion of IL-8 and MCP-1. Thrombin, but not SFLLRN, activated matrix metalloproteinase-2 in ESCs, and the effect was inhibited by PPACK. Thrombin and SFLLRN increased proliferating cell nuclear antigen-positive ratio of ESCs, indicating their cell proliferation-stimulating effects. The thrombin-induced increase in proliferating cell nuclear antigen-positive ratio was diminished by PPACK. These findings imply that the thrombin system might be involved in the pathophysiology of endometriosis, stimulating inflammatory responses of endometriotic cells and their mitogenic activity.

BACKGROUND: The present study was conducted to assess whether midkine (MK), a multifunctional molecule known to stimulate tumor growth, may be involved in the development of endometriosis. METHODS: The mitogenic activity of MK on cultured endometriotic stromal cells was examined by measuring 5-bromo-2 0 -deoxyuridine (BrdU) incorporation. Concentrations of MK in the peritoneal fluid (PF) of women without or with endometriosis and those under GnRH agonist treatment were measured using a specific enzyme immunoassay. The expression of MK mRNA in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues was evaluated by RT‐ PCR. RESULTS: MK significantly increased BrdU incorporation into the DNA of cultured endometriotic stromal cells. The MK concentrations in the PF of the women with advanced endometriosis (stages II, III and IV) Median: 1.21 ng/ml; interquartile range 0.80‐2.27 were significantly higher than those of the women without endometriosis and with stage I endometriosis (0.06 ng/ml, 0.67‐1.26, P< 0.05). As for the menstrual phase, the MK concentration in PF in the inteal phase (1.32 ng/ml. 0.72‐ 2.21) were significantly higher than those in the follicular phase (0.95 ng/ml, 0.68‐ 1.24, P< 0.05). In addition, women with adnexal adhesions had higher concentrations of MK in PF than those without adhesions ( P< 0.05). The MK concentrations of the women under GnRH agonist treatment were significantly lower than those of the other groups ( P< 0.001). The expression of MK mRNA was detected in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues. CONCLUSIONS: The present findings suggest that MK may play roles, such as stimulation of endometriotic cell proliferation, in the development of endometriosis.

Objective To report a case of sciatic endometriosis diagnosed by computerized tomography (CT)–guided biopsy in combination with CD10 immunohistochemical staining. Design Case report. Setting University hospital. Patient(s) A 33-year-old Japanese woman complaining of right-sided sciatica. Intervention(s) Transgluteal computerized tomography (CT)-guided needle biopsy of a mass in the course of the right sciatic nerve was conducted for a histologic diagnosis. Main Outcome Measure(s) Histologic study with hematoxylin and eosin staining and CD10 immunohistochemical staining was performed. Result(s) Computerized tomography-guided biopsy was performed without any complication. CD10 staining distinguished endometrial stromal cells. Conclusion(s) Computerized tomography-guided biopsy followed by CD10 immunohistochemical staining is a minimally invasive procedure for accurate diagnosis of sciatic endometriosis.

Protease-activated receptor 2 (PAR2) is activated by various proteases released from the leukocytes, such as neutrophils and mast cells. Because these leukocytes reside in the endometrium, we speculated that PAR2 might be activated there. In this study, we investigated the presence and possible roles of PAR2 in the endometrium. During the menstrual cycle, the expression of PAR2 mRNA in human endometrial tissues is increased from the late secretory phase to the menstrual phase and in early pregnancy. In vitro, PAR2 agonist peptide (PAR2AP) stimulated IL-8 production in both endometrial epithelial cells (EECs) and stromal cells (ESCs). PAR2AP also stimulated the mRNA expression of stem cell factor, a known activator for mast cells, in ESCs, and activated matrix metalloproteinase-7, an epithelial cell-specific matrix metalloproteinase, in EECs. In addition, PAR2AP significantly increased the 5-bromo-2'-deoxyuridine incorporation in ESCs. PAR2AP induced the phosphorylation of three MAPKs, i.e. p38 MAPK, p42/44 MAPK, and stress-activated protein kinase/c-Jun N-terminal kinase, in ESCs. Inhibitors of all three MAPKs inhibited PAR2AP-induced secretion of IL-8 in both EECs and ESCs. This is the first report demonstrating the presence of PAR2 in the human endometrium. The increased expression of PAR2 around the menstrual period, its up-regulation of molecules important for endometrial remodeling, and its mitogenic effect on endometrial cells raise the expectation of the possible involvement of PAR2 in menstruation and other architectural changes of the endometrium occurring during the menstrual cycle. MAPKs may mediate PAR2 functions in these processes.

Endometriosis accompanies local inflammatory reactions in the peritoneal cavity. We examined the phosphorylation of mitogen-activated protein kinases (MAPKs), i.e. extracellular signal-regulated kinase (ERK), p38 MAPK (p38) and c-Jun N-terminal kinase (JNK) in endometriotic stromal cells, and their possible pathophysiological roles in endometriosis in relation to proinflammatory substances.Endometriotic stromal cells were isolated from endometriomas and were cultured for the experiments. Phosphorylation of MAPKs in endometriotic stromal cells treated with interleukin (IL)-1beta, tumor necrosis factor (TNF)alpha and H(2)O(2) were examined by Western blot analysis. Effects of PD98059, SB202190 and SP600125 (inhibitors of ERK, p38 and JNK, respectively) on IL-1beta-induced secretion of IL-6 and IL-8, and on IL-1beta-induced expression of cyclo-oxygenase-2 (COX-2) in endometriotic cells were studied. In addition, eutopic endometrial tissues were collected, and the phosphorylation rate of p38 in eutopic endometrial tissues and endometriotic tissues were determined.IL-1beta, TNFalpha and H(2)O(2) stimulated the phosphorylation of ERK, p38 and JNK, while the total amounts of proteins of the respective MAPKs were virtually the same compared with those in the unstimulated controls. Both SB202190 and SP600125 suppressed IL-1beta-induced secretion of IL-6 and IL-8, and PD98059 suppressed IL-1beta-induced secretion of IL-8. Both SB202190 and PD98059 suppressed IL-1beta-induced expression of COX-2 in endometriotic cells. The p38 phosphorylation rates in the endometriotic tissues were significantly higher than those in the eutopic endometrial tissues of the same patients.Given the current theory that inflammatory changes are involved in the progression of endometriosis, MAPKs could play as pivotal intracellular signal transducers in endometriotic cells, and thus have a pathophysiological role in the disease.

Background Failure of apoptosis of refluxed endometrial cells within the peritoneal cavity is a possible etiologic factor for development of endometriosis. Osteoprotegerin (OPG) is a survival factor that exerts its effect by binding to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), thus preventing TRAIL from binding to the apoptosis receptors DR4 and DR5. In the present study, we addressed the possibility that the TRAIL/OPG system is involved in the pathogenesis of endometriosis. Methods Concentrations of OPG and TRAIL in the peritoneal fluid (PF) of women with or without endometriosis were measured using specific enzyme-linked immunoabsorbent assay. The expression of DR4 and DR5 in the endometriotic tissue was examined by reverse transcription-polymerase chain reaction. Results OPG concentrations in PF of women with endometriosis were significantly higher than those of women without endometriosis (P=0.006). With respect to the stages of the disease, the concentrations of OPG in women with stage III/IV endometriosis were significantly higher than in those without endometriosis and those with stage I/II endometriosis. On the other hand, the ratios of TRAIL/OPG concentrations were significantly lower in stage III/IV endometriosis compared to those in non-endometriosis and stage I/II endometriosis. DR5 mRNA expression was clearly detected in all the endometriotic tissues studied. Conclusions These findings suggest that the TRAIL/OPG system is involved in the pathophysiology of endometriosis, possibly affecting the apoptosis of endometriotic cells.

predicted the subsequent pregnancy outcome in the cohort study. On the other hand, and intermediate FXII activity level of 85-101%was predictive of subsequentmiscarriage. Conclusions:TheC/T genotype, but not lowFXII activity was confirmed to be a risk factor for PRL. However, neither the C/T genotype nor low FXII activity had any predictive effect on the for subsequent pregnancy outcome. The CT genotype of the FXII gene was found to be a risk factor for PRL.

Objective To investigate a new role of interleukin (IL)-17A in endometriosis. Design Laboratory study. Setting University hospital. Patient(s) Patients with ovarian endometrioma undergoing laparoscopy or laparotomy. Intervention(s) Primary culture of endometrioma stromal cells (EoSCs) was stimulated with IL-17A. Sections of endometrioma tissue were immunostained with antibodies for IL-17A, growth-regulated oncogene–α (Gro-α), and elastase, a marker of neutrophils. They were also examined with immunofluorescent double staining for IL-17A and myeloperoxidase, another marker of neutrophils. Main Outcome Measure(s) Concentration of Gro-α was measured using a specific ELISA. Neutrophil chemotaxis was measured with Boyden chamber method. Immunostained sections were examined under microscope. Result(s) Interleukin-17A increased the secretion of Gro-α from EoSCs dose-dependently. The conditioned medium of EoSCs stimulated with IL-17A attracted more neutrophils than that of EoSCs stimulated with vehicle, and the increase was inhibited by the addition of Gro-α-neutralizing antibody. On immunostaining, IL-17A and Gro-α were detected in similar areas of the stroma beneath the epithelium, where Gro-α was detected in cells with a stromal cell appearance whereas IL-17A was detected in neutrophils as determined by detection of elastase. Fluorescent immunostaining corroborated that myeloperoxidase-positive neutrophils were also positive for IL-17A. Conclusion(s) It is suggested that IL-17A produced by neutrophils stimulates Gro-α secretion from EoSCs, thereby recruiting more neutrophils and inducing perpetuating inflammation in endometriosis.