Expression of several components of the plasminogen activator and matrix metalloproteinase systems in endometriosis

BACKGROUND: Endometriosis is considered a benign disease that has the ability to invade normal tissue. As in neoplastic growth, local extracellular proteolysis may take place. The aim of this study is to analyse several components of the plasminogen activator (PA) pathway and the matrix metalloproteinase (MMP) system in endometriotic tissue, endometrium and peritoneal fluid from women with and without endometriosis (controls). METHODS AND RESULTS: Thirty-nine women with endometriosis and 35 controls were studied. In eutopic endometrium of women with endometriosis, the antigenic levels of urokinase-type PA (uPA) and MMP-3 were elevated when compared with endometrium from controls. Ovarian endometriotic tissues had higher antigenic levels of PA inhibitor type 1 (PAI-1) and tissue inhibitor of metalloproteinases type 1 (TIMP-1) than endometrium. The peritoneal fluid from women with endometriosis showed a significant increase in uPA levels compared with controls. CONCLUSIONS: The increase in antigenic levels of uPA and MMP-3 in endometrium of women with endometriosis might contribute to the invasive potential of endometrial cells. Once the ovarian endometriotic cyst is developed, an increase in PAI-1 and TIMP-1 is detected and significant proteolytic activity is no longer observed. This increase in inhibitors and decrease in proteolytic activity could explain the frequent clinical finding of isolated endometriotic cyst without invasion of the surrounding ovarian tissue.     

Survivin, MMP-2, MT1-MMP, and TIMP-2: their impact on survival, implantation, and proliferation of endometriotic tissues

In order to study survivin, matrix metalloproteinases (MMP-2), membranous type 1 matrix metalloproteinase (MT1-MMP), and tissue inhibitor metalloproteinase-2 (TIMP-2) expression immunohistochemically in endometriotic tissues and normal endometrium, our retrospective study considered 194 patients affected by endometriosis and 71 patients with normal endometrium. Tissue microarrays were created from paraffin-embedded blocks; immunohistochemistry was used to assess protein expression. In endometriotic tissues, survivin was expressed at a higher level than in normal endometrium; its glandular expression level was higher in non-ovarian than in ovarian endometriotic tissues and lower in stromal components. Endometrial tissues from women without endometriosis and endometriotic tissues had different matrix metalloproteinase expression profiles. MMP-2 and MT1-MMP correlated with TIMP-2 in endometriotic tissues. Furthermore, in endometriotic tissues, expression of survivin, aurora B kinase, and Ki-67 showed a significant positive correlation, which indicates a role in cellular proliferation that could be closely linked to its anti-apoptotic activity in endometriosis development. Our results imply a role for matrix metalloproteinases in endometriosis invasiveness; correlation of their expression with that of TIMP-2 underscores its possible key regulatory role.     

mRNA analysis of several components of the plasminogen activator and matrix metalloproteinase systems in endometriosis using a real-time quantitative RT-PCR assay

BACKGROUND: The plasminogen activator (PA) and matrix metalloproteinase (MMP) systems are implicated in the establishment of endometriosis. The mechanisms by which these systems are involved in the pathogenesis of this disease are not well defined and controversial results have been published. The aim of this study was to analyse mRNA and protein levels of several components of the PA and MMP systems in endometriotic tissue and endometrium from women with and without endometriosis. METHODS and RESULTS: Real-time quantitative RT-PCR assays were developed to quantify mRNA levels of these components in 57 women with endometriosis and 32 controls. Endometrium of women with endometriosis showed higher mRNA and antigenic levels of urokinase type-PA (uPA) and MMP-3 than endometrium from controls. In these patients, ovarian endometriotic tissue had higher mRNA and antigenic levels of PA inhibitor type 1 (PAI-1) and MMP inhibitor type 1 (TIMP-1) than endometrium. CONCLUSIONS: The increase in mRNA and protein levels of uPA and MMP-3 observed in endometrium of women with endometriosis may facilitate the attachment of endometrial tissue to the peritoneum and ovarian surface, as well as the invasion of the extracellular matrix. This process would lead to the formation of early endometriotic lesions. Once the ovarian endometriotic cyst is developed, PAI-1 and TIMP-1 would increase which could explain the frequent clinical finding of an endometrioma without invasion of the adjacent ovarian tissue.     

Status of HER1 and HER2 in peritoneal,ovarian and colorectal endometriosis and ovarian endometrioid adenocarcinoma

A role for the EGF system, in particular HER1 and 2, in growth of the endometrium has been suggested but HER1 and 2 have not been studied in all locations of endometriosis and in ovarian endometrioid adenocarcinoma (OEC) which is a rare form of malignant transformation of endometriosis. Immunohistochemistry (IHC) was used for studying HER1 and HER2 in ovarian (n = 10), peritoneal (n = 10), colorectal endometriosis (n = 20) and OEC (n = 10). Fluorescent in situ hybridisation (FISH) was used for analysing the status of HER2 gene in colorectal endometriosis and OEC. All samples were negative for HER2 in both glandular and stromal cells and in glandular cells for HER1 by IHC. In 15 out of 20 colorectal endometriosis, there was a weak expression in stromal cells. Following FISH, two colorectal samples had a partial 17 aneusomy and three OEC, a 17 polysomy. The other samples were 17 disomic without HER2 amplification; HER1 and 2 do not seem to have a role in endometriosis physiopathology.     

MMP-2、bFGF在子宫内膜异位症和子宫腺肌病中的表达及意义

目的：探讨基质金属蛋白酶－2（MMP－2）和碱性成纤维生长因子（bFGF)在子宫内膜异位症发生发展中的作用。方法：应用免疫组织化学法（SABC法），检测70例异位内膜组织和30例正常子宫内膜组织（对照组）中MMP－2和bFGF的表达。结果：在异位内膜组和对照组中，MMP－2的阳性表达率分别为71．43％和40．00％，强阳性表达率分别为40．00％和6．67％（P＜0．01）；bFGF的阳性表达率分别为65．71％和40．00％，强阳性表达率别为20．0％和0％（P＜0．01）。而MMP－2和bFGF在卵巢子宫内膜异位症和子宫腺肌症中的肌性表达率，两组间差异均无显著性（P＞0．05）。结论：异位内膜组织中MMP－2的过度表达与异位内膜组织的侵袭力有关，bFGF与子宫内膜异位症的血管生成密切相关，提示MMP－2和bFGF在子宫内膜异位症的发生发展中发挥作用。     

Interleukin 1alpha and tissue-lytic matrix metalloproteinase-1 are elevated in ectopic endometrium of patients with endometriosis

BACKGROUND: Matrix metalloproteinases (MMP) play an essential role in tissue remodelling and menstruation and appear to be regulated by cytokines such as interleukin-1alpha (IL-1alpha). In order to investigate their role in the pathogenesis of endometriosis, the aim of the present study was to compare the protein localization of matrix metalloproteinase-1 (MMP-1) and of its main stimulatory cytokine IL-1alpha in eutopic and dystopic endometrium of patients with endometriosis. METHODS: MMP-1 and IL-1alpha protein localization was analysed retrospectively in paired paraffin-embedded tissue biopsies obtained simultaneously from the endometrial cavity and from endometrial lesions of 37 patients with peritoneal or ovarian endometriosis and in cycling endometria from 37 women without endometriosis. Protein localization was demonstrated by immunohistochemistry; antibody specificity was confirmed by western blot analysis. RESULTS: MMP-1 and IL-1alpha protein staining in women suffering from endometriosis was significantly more pronounced in endometriotic lesions than in eutopic endometrium. This held true for both epithelial MMP-1 and IL-1alpha staining (P < 0.006 and P < 0.001), and for stromal MMP-1 and IL-1alpha staining (P < 0.001 and P < 0.001). Furthermore, stromal MMP-1 and IL-1alpha were significantly co-expressed in dystopic endometriotic tissue (P = 0.045). Endometrial MMP-1 and IL-1alpha protein expression pattern in eutopic endometrium from women suffering from endometriosis, however, did not differ significantly from the pattern seen in healthy women. CONCLUSIONS: The increased expression of both matrix-degrading MMP-1 and its major stimulatory cytokine IL-1alpha in endometriotic lesions and the selective co-expression in the stroma of endometriotic foci clearly suggests their involvement in the pathogenic mechanisms leading to local invasion and tissue destruction.     

Ovarian steroid receptor expression in endometriosis and in two potential parent epithelia: endometrium and peritoneal mesothelium.

Endometriosis is an oestrogen dependent condition and it is expected that the tissue of origin of endometriosis will express receptors for the ovarian steroids. Two epithelia, endometrium and peritoneal mesothelium, are the potential parent epithelium. Oestrogen and progesterone receptor expression has been studied immunohistochemically in (i) timed endometrial biopsies from 25 normal subjects and 27 patients with endometriosis, (ii) 25 endometriotic biopsies and (iii) 42 peritoneal biopsies. Endometrium but not peritoneal mesothelium expresses both oestrogen and progesterone receptors. No difference in the intensity of staining between endometria of normal subjects compared with the endometria of patients with endometriosis was noted. In paired endometrial and endometriotic biopsies, the intensity of staining for the oestrogen receptor in stromal cells and for the progesterone receptor in both glandular and stromal cells was less in the endometriotic biopsies. These data provide circumstantial evidence for an endometrial origin for endometriosis although quantitative differences exist in receptor expression between endometrium and endometriosis.     

Vascular endothelial growth factor A and C gene expression in endometriosis

Angiogenesis is essential for the pathogenesis of endometriosis. Gene expression levels of vascular endothelial growth factor (VEGF) A and C in 10 eutopic endometrial, 23 normal peritoneal, and 62 endometriotic tissues surgically obtained from 47 women with endometriosis (group 2) were compared with those in 12 control eutopic endometrial and 9 normal peritoneal tissues from 15 women without endometriosis (group 1). VEGF-A mRNA expression levels in eutopic endometrium of group 2 were higher than those of group 1 throughout the menstrual cycle (P <0.01) and increased in the secretory phase. VEGF-A gene expression in peritoneal endometriotic lesion was statistically higher than that in normal peritoneum (P <0.01) and similar to that in eutopic endometrium of group 2. In contrast, gene expression levels of VEGF-C were relatively lower than those of VEGF-A in each lesion, and no cyclic variation was found. VEGF-A and C mRNA expression levels were significantly higher in ovarian endometriomas >6 cm in size than in those <6 cm in size. Immunohistochemical expression of VEGF-A and C was detected in the cytoplasm of glandular epithelial and stromal cells of ovarian endometrioma. These results suggest that endometriosis may arise from eutopic endometrium with higher levels of angiogenic activity possibly induced by VEGF-A in women with endometriosis. Moreover, VEGF-C as well as VEGF-A may be involved in the pathogenesis of ovarian endometrioma.     

Hyperalgesia,nerve infiltration and nerve growth factor expression in deep adenomyotic nodules,peritoneal and ovarian endometriosis

BACKGROUND: The aim of this study was to investigate a possible role for nerve growth factor (NGF) in the mechanism of pain and hyperalgesia induced by deep adenomyotic nodules and other forms of endometriosis and to clarify the relationship between endometriotic lesions and the surrounding nerves. METHODS: Endometriotic lesions (deep adenomyotic nodules, peritoneal endometriosis, ovarian endometriosis) and eutopic endometrium were obtained from 51 patients presenting with pain. Patients were allocated to two groups (group 1: patients with a deep adenomyotic nodule (n = 23); group 2: patients with peritoneal and/or ovarian endometriosis but without deep adenomyotic nodule (n = 28). Immunohistochemistry with antibodies against NGF, NGF specific tyrosine-kinase receptor (Trk-A) and S-100 protein was performed. Results were expressed as mean H-scores +/- SD, and correlated with the presence of hyperalgesia. RESULTS: The percentage of patients presenting hyperalgesia at physical examination was significantly higher in group 1 (96%) than in group 2 (11%) (P < 0.001). NGF expression was significantly stronger in deep adenomyotic nodules (DAN) than in ovarian (OE) and peritoneal endometriosis (PE), both in the proliferative phase in the glands [DAN: 226 +/- 18; OE: 140 +/- 9 (P < 0.001); PE: 110 +/- 7 (P < 0.001)] and in the stroma [(DAN: 204 +/- 21; OE: 125 +/- 15 (P < 0.001); PE: 100 +/- 9 (P < 0.01)]. NGF expression in DAN is also significantly stronger than in OE and PE in the secretory phase in the glands [DAN:181 +/- 32; OE: 85 +/- 3.3 (P < 0.001); PE: 65 +/- 9 (P < 0.001)] and in the stroma [DAN: 173 +/- 28; OE: 85 +/- 3.7 (P < 0.001); PE: 35 +/- 13 (P < 0.001)]. Perineurial and intraneurial invasion by endometriotic lesions were found only in deep adenomyotic nodules and not in the other forms of endometriosis. The specific receptor for NGF (Trk-A) is expressed in all the nerves that were included in the biopsies. CONCLUSIONS: These results suggest a role of NGF in endometriotic pain and hyperalgesia in deep adenomyotic nodules. The strong expression of the NGF-TrkA pathway in deep adenomyotic nodules could explain why this type of lesion infiltrates in richly innervated anatomical sites.     

基质金属蛋白酶-2、3及其组织抑制剂TIMP-1在子宫内膜异位症中的表达

目的探讨基质金属蛋白酶(MMP-2、MMP-3)及其抑制剂(TIMP-1)在子宫内膜异位症发生及发展中的作用.方法采用免疫组化SP法分别测定MMP-2、MMP-3 、TIMP-1在卵巢子宫内膜异位症异位内膜60例(A组),子宫腺肌症异位内膜40例(B组),子宫肌瘤子宫内膜30例(对照组C)的表达强度.结果 A、B组中MMP-2、MMP-3的表达强度明显高于对照组(P<0.05)而TIMP-1的表达明显低于对照组(P<0.05);A、B组间MMP-2、MMP-3 、TIMP-1 的表达无明显差异(P>0.05).结论在子宫内膜异位症中MMP-2、MMP-3的过度表达及TIMP-1的低表达可能与内异症的发生与发展有关.     

Matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1: a possible role in the pathogenesis of endometriosis

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of endopeptidases which play a role in the degradation and turnover of extracellular matrix proteins. Their action is regulated by specific tissue inhibitors called tissue inhibitors of metalloproteinases (TIMPs). METHODS: We measured the concentrations of total and active MMP-9 in peritoneal fluid of infertile women with mild or moderate endometriosis (n = 22) and compared them with those in a control group of infertile patients (n = 21). RESULTS: We found that the mean (+/-SD) total concentrations of MMP-9 in the peritoneal fluid of patients with endometriosis was 6.2 +/- 1.8 ng/ml, in comparison with 2.9 +/- 2.6 ng/ml in the control group (P = 0.001). Concentrations of active MMP-9 did not differ significantly between the groups. The concentrations of TIMP-1, after logarithmic transformation, were significantly lower (P = 0.017) in endometriotic peritoneal fluids than in peritoneal fluid of control women, 1.02 +/- 0.21 ng/ml and 1.16 +/- 0.18 ng/ml respectively. No correlation between stage of disease, steroid hormone concentration, MMP-9 (total and active) and TIMP-1 was found. CONCLUSIONS: These results suggest that a disturbed equilibrium exists between MMP-9 and TIMP-1 in peritoneal fluid of women with endometriosis. This may play an important role in the pathogenesis of the disease.     

Abnormal regulation of chemokine TECK and its receptor CCR9 in the endometriotic milieu is involved in pathogenesis of endometriosis by way of enhancing invasiveness of endometrial stromal cells

The chemokine thymus-expressed chemokine (TECK), which regulates T-cell development and tissue-specific homing, has been identified as a potential contributor to the pathogenesis and progression of endometriosis. Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD), an air pollutant, and estrogen also appear to be involved in endometriosis. Both endometrial stromal cells (ESCs) and the combination of 17β-estradiol and TCDD increase the secretion of TECK in the endometriosis-associated cells and promote the invasiveness of ESCs by increasing expression of matrix metalloproteinase (MMP)-2 and MMP-9. Anti-TECK neutralizing antibodies can effectively inhibit the invasiveness of ESCs and the expression of MMP-2 and MMP-9 in the cells. Interestingly, the expression of chemokine C receptor 9 (CCR9) and its ligand TECK increases significantly in the endometriotic milieu of patients with endometriosis. Therefore, the over-expressed TECK interacts with CCR9 on the ESCs in the endometriotic milieu, which may contribute to the onset and progression of endometriosis.     

Endometriosis: Immunohistochemical study of c-erb B-2 protein expression in endometriosis

Using immunohistochemical techniques, we studied the expressionof c-erb B-2 in normal human endometrial tissue (n = 8), endometriosisinterna (adenomyosis) (n = 8) and endometriosis externa (endometrioticcyst of the ovary) (n = 6). The glandular epithelium of normalendometrial tissue specimens in the proliferative phase stainedpositively. Most of the cases of endometriosis studied showedno expression of c-erb B-2 in glandular epithelium. No expressionwas detected in either the normal or endometriotic stromal cells.Results suggest that c-erb B-2 is not significantly involvedin the pathogenesis of endometriosis.     

Investigation of Matrix Metalloproteinase -1, 2 and tissue inhibitor of matrix metalloproteinases-1 in Endometriosis

Objective: To explore the role of matrix metalloproteinase-1,2 (MMP-1, MMP-2) and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in endometriosis. Methods: The eutopic and ectopic endometria from 40 subjects suffering from endometriosis and regular.endometria from 40 subjects (excluding endometriosis) were collected and examined by in situ hybridization technology and western blot assay. Results: Both expressions of MMP-1 and -2 were stronger in ectopic endometrium and eutopic endometrium than in normal endometrium. On the contrary, the expression of TIMP-1 in ectopic endometrium and eutopic endometrium was lower. The differences were significant (P ＜ 0.01). Moreover, there was no relationship among the expressions of MMP-1, 2 and TIMP-1 in ectopic endometrium. Conclusion: The expressions of MMP-1, 2 and TIMP-1 lose balance and lack of periodic changes in ectopic endometrium , which explains the biological invasive behavior of endometriosis. It was suggested that regulating the balance between the MMPs and TIMP-1 should be an ideal therapeutic target to endometriosis.     

Transcriptional expression of survivin and its splice variants in endometriosis

Survivin is a novel inhibitor of apoptosis (IAP), and the two splice variants of survivin (survivin-2B and survivin-EX3) have been identified. Gene expression levels of survivin, survivin-2B and survivin-EX3 in 56 ectopic (16 peritoneal red and 16 peritoneal black lesions and 24 ovarian endometriomata) and 13 eutopic endometrial tissues surgically obtained from 42 women with endometriosis (group A) were compared with those in 16 control eutopic endometrium from 16 women without endometriosis (group B) by quantitative RT-PCR analysis. Survivin mRNA expression levels in ectopic endometriotic tissues were significantly higher than those in eutopic endometrium of groups A and B over the whole cycle. Red peritoneal lesions had higher gene expression levels of survivin than black lesions. In contrast, all tissue samples examined showed relatively lower gene expression levels of survivin-2B and survivin-EX3. No cyclic variation was found in survivin and the two splice variants, both in ectopic and in eutopic endometrium. Although there was no significant difference in the ratio of survivin-2B/survivin between ectopic and eutopic endometrium, the ratio of survivin-EX3/survivin in peritoneal endometriotic lesions was significantly higher than that of eutopic endometrium of groups A and B. These results suggest that survivin and survivin-EX3 may be closely linked to escape from apoptosis and the development of endometriosis.     

Increased expression of matrix metalloproteinase-9 in the eutopic endometrial tissue of women with endometriosis

BACKGROUND: Endometriosis is a disease where endometrial tissue implants in ectopic locations. Remodelling of the extracellular matrix (ECM) is a prerequisite for the implantation of this tissue to be possible. METHODS: In this study, we detected immunoreactive matrix metalloproteinase-9 (MMP-9) throughout endometrial tissue and identified von Willebrand factor (vWF)-positive endothelial cells, CD45-positive leukocytes, CD3-positive T lymphocytes and CD68-positive macrophages as cells expressing MMP-9 in the stroma. RESULTS: We found an increased expression of MMP-9 in the uterine endometrial tissue of women with endometriosis, as assessed by zymography and enzyme-linked immunosorbent assay (ELISA) (P < 0.05). However, RT-PCR did not show a statistically significant increase in MMP-9 mRNA expression in these tissues (P = 0.14). There was no significant difference between women with and without endometriosis in the expression of tissue inhibitor of MMPs (TIMP)-1, a known natural inhibitor of the pro- and active forms of MMP-9, whether tested by ELISA or by RT-PCR (P = 0.46 and 0.37, respectively). Interestingly, the ratio of MMP-9/TIMP-1 expression was significantly higher in women with endometriosis than in normal women both at the protein and the mRNA levels (P < 0.05). CONCLUSION: These findings make plausible the involvement of MMP-9/TIMP-1 imbalance in the invasiveness of the endometrial tissue of patients with endometriosis and the ectopic development of the disease.     

Differential expression and localization of de-novo synthesized endometriotic haptoglobin in endometrium and endometriotic lesions

Endometriosis protein-I (ENDO-I) mRNA expression and protein localization were evaluated using in-situ hybridization and immunohistochemistry in endometriotic lesions and eutopic endometrium from women with endometriosis, and in eutopic endometrium from women without endometriosis (controls). When present, ENDO-I mRNA and protein were observed in the functionalis zone of endometrial stroma and the stroma of endometriotic lesions. Expression and localization differences were scored and statistically analysed. During the secretory stage, ENDO-I mRNA expression by endometriotic lesions and eutopic endometrium from women with disease was significantly greater than ENDO-I mRNA expression by proliferative stage eutopic endometrium from women with disease or eutopic endometrium from controls, regardless of cycle stage (P < 0.001). More ENDO-I protein was localized in endometriotic lesions and eutopic endometrium from women with disease than in eutopic endometrium from controls, regardless of cycle stage (P < 0.001). Differential expression and localization of ENDO-I may help develop minimally invasive diagnostic strategies for endometriosis. Further, as ENDO-I shares nucleotide sequence and amino acid sequence with hepatic haptoglobin-which in certain disease states is immunosuppressive and angiogenic-differences in ENDO-I expression and localization in the peritoneal cavity may contribute to the pathogenesis of endometriosis and/or facilitate development of unprecedented diagnostic or therapeutic approaches for management of this enigmatic disease.     

Expression of angiogenic factors in endometriosis: relationship to fibrinolytic and metalloproteinase systems

BACKGROUND: Endometriosis is a highly prevalent, benign disease in which the angiogenic, fibrinolytic and metalloproteinase (MMP) systems may be implicated. The objective of this study is to analyse mRNA expression and protein levels of several angiogenic factors and to correlate them with several components of the fibrinolytic and MMP systems in samples from 71 women with endometriosis and 50 controls. METHODS AND RESULTS: Eutopic endometrium showed higher mRNA expression of vascular endothelial growth factor (VEGF) in patients than in controls. However, ovarian endometrioma had lower VEGF mRNA levels than did the eutopic endometrium of patients. Similar results were obtained for VEGF protein levels. On the other hand, a significant increase in thrombospondin-1 (TSP-1) levels was observed in ovarian endometrioma than in eutopic endometrium. The peritoneal fluid from women with endometriosis showed a significant increase in VEGF, urokinase-type plasminogen activator (uPA) and MMP-3 levels than that of controls. A significant correlation was observed between the levels of VEGF and uPA in endometrium and in peritoneal fluid. CONCLUSIONS: Endometrium and peritoneal fluid from women with endometriosis have increased levels of VEGF, uPA and MMP-3 levels. Therefore, the development of endometriotic implants at ectopic sites may be facilitated, promoting the progress of the endometriosis.     

Endometriotic disease: the role of peritoneal fluid

Peritoneal fluid and the intraovarian milieu are a specific microenvironment. Peritoneal fluid originates mainly as an ovarian exudation product caused by increased vascular permeability, with cyclic variation in volume and steroid hormones which are always higher than in plasma. It contains large amounts of macrophages and their secretion products, and has a large exchange area with plasma through the peritoneum, which is highly permeable for small molecules. Diffusion becomes virtually zero for molecules with a molecular weight of >100000 Da. In women with the luteinized unruptured follicle (LUF) syndrome, concentrations of oestrogens and progesterone are much lower in the luteal phase. Endometriosis is associated with sterile low-grade inflammation, increased concentrations of activated macrophages and many of their secretions, such as cytokines, growth factors and angiogenic factors. Concentrations of CA-125 and of glycodelins are also increased, secreted locally by the endometrial cells. Natural killer (NK) cell function declines, possibly mediated by glycodelins or local intercellular adhesion molecule (ICAM) -1 shedding. The ovary is also a specific microenvironment, with steroid hormone concentrations 1000-fold higher in follicles than in plasma. Endometrial and superficially implanted cells are influenced by peritoneal fluid concentrations so that local environment, rather than inherent cellular differences could explain differences between superficial endometriosis and eutopic endometrium. Differences between superficial implants and endometriotic disease, deep infiltrating or cystic ovarian endometriosis, may thus arise via different endocrine environments. Superficial endometrial implants are regulated by peritoneal fluid factors, whereas deep endometriosis and cystic ovarian endometriosis are influenced by blood or ovarian factors. The endometriotic disease theory considers superficial endometriotic implants and their remodelling as a physiological process in most women, and concentrates on the causes of severe endometriosis such as differences in the eutopic endometrium from women with and without endometriosis (which may indicate hereditary differences), the invasiveness of some endometriotic cells in vitro, focal 'shielding' of endometriotic foci by adhesions, and inhibition of NK activity by ICAM-1 and glycodelins. Endometriotic disease is thus seen as a benign tumour. The type of cellular lesion, hereditary and immunological environments and local hormone concentrations in the ovary and in peritoneal fluid, will decide expression as cystic ovarian endometriosis, deep endometriosis or adenomyosis externa, and whether the latter is associated with adhesions.     

Analysis of cyclooxygenase-2 (COX-2) expression in different sites of endometriosis and correlation with clinico-pathological parameters

BACKGROUND: Recent studies have demonstrated the overexpression of cyclooxygenase-2 (COX-2) in endometriosis. The aim of this study was to investigate the expression of COX-2 in different anatomical sites of endometriosis and its association with clinico-pathological parameters in a single institutional series of patients undergoing operative treatment. METHODS: COX-2 expression was analysed by immunohistochemistry in 136 samples of endometriotic tissue from 103 patients affected by endometriosis. RESULTS: COX-2 immunoreaction was observed in 78.5% of ovarian endometriotic cysts, in 11.1% of peritoneal implants and 13.3% of recto-vaginal nodules. COX-2 positivity was not distributed differently according to age, pre-operative serum levels of CA125 and AFS score. Moreover, COX-2 positivity did not show any significant variation according to the subjective intensity of pain, as dysmenorrhoea, chronic pelvic pain, lower urinary tract or gastrointestinal symptoms, or according to infertility. CONCLUSIONS: Increased COX-2 expression in the endometriotic ovarian cyst wall was observed with respect to other extraovarian localizations. No relevant correlations between COX-2 positivity and clinico-pathological characteristics and symptoms of patients were observed.