Inducible nitric oxide synthase expression by peritoneal macrophages in endometriosis-associated infertility.

OBJECTIVE: Determine whether peritoneal macrophages from women with endometriosis-associated infertility express more inducible nitric oxide synthase (NOS2) and produce more NO than fertile controls. DESIGN: Unblinded clinical study. PATIENT(S): Nine infertile women with endometriosis and nine normal fertile women undergoing laparoscopy.Intervention(s): Peritoneal fluid and macrophages were collected. Cells were also cultured with the NOS2 inducers interferon-alpha (IFN-alpha) or IFN-gamma plus lipopolysaccharide (LPS). MAIN OUTCOME MEASURE(S): Peritoneal fluid NO levels, peritoneal macrophage NOS activity, and peritoneal macrophage NOS2 protein expression. RESULT(S): NOS enzyme activity was higher in peritoneal macrophages from endometriosis patients. Immunoblots demonstrated NOS2 protein only in peritoneal macrophages from women with endometriosis. Peritoneal fluid NO concentration was similar in the two groups, but total peritoneal fluid NO content was higher in endometriosis patients. After 3 days' culture, peritoneal macrophages from women with endometriosis produced more NO in response to IFN-alpha or IFN-gamma plus LPS than controls. CONCLUSION(S): Peritoneal macrophages from women with endometriosis-associated infertility express higher levels of NOS2, have higher NOS enzyme activity, and produce more NO in response to immune stimulation in vitro. As high levels of NO adversely affect sperm, embryos, implantation, and oviductal function, reducing peritoneal fluid NO production or blocking NO effects may improve fertility in women with endometriosis.     

Marked elevation of macrophage migration inhibitory factor in the peritoneal fluid of women with endometriosis

OBJECTIVE: To evaluate the presence of macrophage migration inhibitory factor (MIF) in the peritoneal fluid of normal fertile women and patients with endometriosis and its growth-promoting activity toward human endothelial cells. DESIGN: Retrospective study using ELISA to measure peritoneal fluid MIF, and [3H]-thymidine incorporation into the DNA of human endothelial cells to assess its mitogenic activity. SETTING: Gynecology clinic and human reproduction research laboratory. PATIENT(S): Thirty-six healthy women and 57 women with endometriosis. INTERVENTION(S): Peritoneal fluid samples were obtained at laparoscopy. MAIN OUTCOME MEASURE(S): Macrophage migration inhibitory factor concentrations in the peritoneal fluid samples and [3H]-thymidine incorporation into the DNA of human microvascular endothelial cells to assess proliferation. RESULT(S): This study demonstrated the presence of MIF in the peritoneal fluid and a 238% increase of MIF levels in women with endometriosis as compared with healthy women. Both fertile and infertile women with endometriosis had significantly higher MIF concentrations than did fertile women with normal gynecological status, but the difference was more significant in infertile endometriosis patients. Anti-MIF antibody significantly inhibited proliferation of human microvascular endothelial cells in response to peritoneal fluids from healthy women and women with endometriosis stages I-II and III-IV, as assessed by [3H]-thymidine incorporation. CONCLUSION(S): This study revealed the presence of MIF in the peritoneal fluid and its increased levels in endometriosis and suggests that MIF may be involved in endometriosis-associated infertility and angiogenesis.     

Increased nitric oxide in peritoneal fluid from women with idiopathic infertility and endometriosis.

OBJECTIVE: To verify whether nitric oxide in peritoneal fluid is associated with endometriosis and infertility. STUDY DESIGN: Twenty-five women with idiopathic infertility and 38 with endometriosis were recruited, and 18 cases of uterine myomata and 2 cases of ovarian cyst served as controls. Peritoneal fluid samples were aspirated from the pouch of Douglas during laparoscopy or laparotomy. Metabolites of nitric oxide (nitrite and nitrate) in peritoneal fluid were determined by a method using nitrate reductase and the Griess reaction. RESULTS: Peritoneal concentrations of nitrate/nitrite in both infertile women (42.02 +/- 12.98 mmol/L) and patients with endometriosis (41.75 +/- 16.42 mmol/L) were significantly higher than that in controls (33.96 +/- 13.07, P < .05 for both). No significant difference in peritoneal nitrate/nitrite level was found between infertile women and patients with endometriosis (P > .5). Peritoneal levels of nitrate/nitrite were comparable among patients with endometriosis at different stages (P > .5). Patients with endometriosis had more peritoneal fluid than controls and idiopathic infertile women, while controls and idiopathic infertile women had comparable amounts of peritoneal fluid. CONCLUSION: An increased peritoneal level of nitric oxide is a common alteration in endometriosis, endometriosis-associated infertility and idiopathic infertility and may be associated with the pathogenesis of these diseases.     

子宫内膜异位症患者腹腔液白细胞介素17水平的变化及其意义

目的探讨白细胞介素17(IL17)与子宫内膜异位症(内异症)发病的关系。方法应用酶联免疫吸附(ELISA)法检测36例不同期别内异症患者(内异症组)和26例非内异症患者(对照组)腹腔液中的IL17水平。结果内异症组和对照组腹腔液IL17水平分别为(5.7±1.9)ng/L和(5.3±1.4)ng/L,两组比较,差异无统计学意义(P>0.05)。按1985年美国生育学会内异症分期标准(rAFS)进行分期,Ⅰ～Ⅱ期内异症患者(16例)腹腔液IL17水平为(6.4±1.7)ng/L,Ⅲ～Ⅳ期内异症患者(20例)为(5.1±1.8)ng/L,两者比较,差异有统计学意义(P<0.05)。卵泡期和黄体期腹腔液IL17水平在两组间比较,差异均无统计学意义(P>0.05)。内异症不孕患者腹腔液IL17水平为(6.4±1.8)ng/L,内异症未合并不孕患者为(5.1±1.8)ng/L,两者比较,差异有统计学意义(P<0.05)。结论IL17水平变化可能与早期内异症及内异症不孕的发病有关。     

Elevations in peritoneal fluid macrophage migration inhibitory factor are independent of the depth of invasion or stage of endometriosis

OBJECTIVE: To quantify levels of macrophage migration inhibitory factor (MIF) in the peritoneal fluid (PF) of women with endometriosis, and to correlate these levels with the extent of disease. DESIGN: Controlled clinical study. SETTING: Academic medical center. PATIENT(S): Peritoneal fluid samples were collected during laparoscopic surgery in 60 women with endometriosis and 16 controls undergoing tubal ligation; 52 of the women with endometriosis had received no hormonal treatment in the 6 months prior to surgery, while 8 were using gonadotropin-releasing hormone (GnRH) agonists. MAIN OUTCOME MEASURE(S): Peritoneal fluid migration inhibitory factor (PF MIF) levels. RESULT(S): Women with endometriosis had significantly higher PF MIF levels (10.8 +/- 0.9 ng/mL) than controls (3.0 +/- 0.7 ng/mL). However, no correlation existed between MIF levels and the stage of disease (r = 0.05) or the depth of endometriotic invasion (r = 0.08). Moreover, treatment with a GnRH agonist did not suppress PF MIF levels. Peritoneal fluid MIF levels did not vary significantly between the proliferative and secretory phases of the cycle, and did not distinguish women with endometriosis-associated infertility from women with endometriosis-associated pain. CONCLUSION(S): Peritoneal fluid migration inhibitory factor levels are markedly elevated in women with endometriosis but are independent of the extent of disease.     

Peritoneal fluid concentrations of interleukin-17 correlate with the severity of endometriosis and infertility of this disorder

This prospective study aimed to determine whether patients with endometriosis are having different level of interlukin-17 (IL-17) in peritoneal fluid when compared with patients without endometriosis. The patients with minimal/mild endometriosis had a significantly higher level of IL-17 in peritoneal fluid compared with those with moderate/severe endometriosis or without endometriosis. The concentration of IL-17 in peritoneal fluid was significantly higher when endometriosis and infertility coexist. However, the concentration of IL-17 in peritoneal fluid did not correlate with the phase of the menstrual cycle in the patients with or without endometriosis. Our study suggested that IL-17 might play an important role in the pathogenesis of early endometriosis and endometriosis-associated infertility.     

Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase,and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium

OBJECTIVE: To investigate expression of matrix metalloproteinase-2 (MMP-2), membranous type 1 matrix metalloproteinase (MT1-MMP), and tissue inhibitor of metalloproteinase-2 (TIMP-2) in ectopic and eutopic endometrium from women with and without endometriosis throughout the menstrual cycle. DESIGN: Molecular studies in human tissue. SETTING: Reproductive immunology laboratory of a university medical center. PATIENT(S): Fifty-three premenopausal woman (23 with endometriosis and 30 without endometriosis) undergoing laparoscopic surgery. Endometrium and ectopic endometriosis tissue were obtained at the time of surgery. MAIN OUTCOME MEASURE(S): Messenger RNA and protein expression from eutopic and ectopic endometrium was analyzed by using quantitative competitive polymerase chain reaction, zymography, and Western blot assay. RESULT(S): Uterine endometrium from women with endometriosis expressed higher levels of MMP-2 and MT1-MMP and lower levels of TIMP-2 than did endometrium from normal women. CONCLUSION(S): Eutopic endometrium from patients with endometriosis may be more invasive and prone to peritoneal implantation because of greater expression of MMP-2 and MT1-MMP and lower expression of TIMP-2 messenger RNA, compared with endometrium from women without endometriosis. Thus, increased proteolytic activity may help to explain the invasive factors that result in endometriosis.     

Matrix metalloproteinase-13 and membrane type-1 matrix metalloproteinase in peritoneal fluid of women with endometriosis.

OBJECTIVE: It is becoming more and more evident that different types of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in the pathogenesis of endometriosis. The aim of the present study was to measure levels of the active forms of MMP-13 and membrane type-1 matrix metalloproteinase (MT1-MMP)/MMP-14 as well as TIMP-2 in the peritoneal fluid of women with endometriosis. STUDY DESIGN: We determined the levels of the active forms MMP-13 and MT1-MMP/MMP-14 as well as TIMP-2 in the peritoneal fluid of 20 women with endometriosis and 18 controls by different types of enzyme-linked immunosorbent assay. RESULTS: We found that the concentrations (mean +/- standard deviation) of total active MMP-13 and endogenous active MT1-MMP/MMP-14 in the peritoneal fluid of patients with endometriosis were 1.69 +/- 0.67 and 3.12 +/- 1.07 ng/ml, respectively. In control women the corresponding values were 3.02 +/- 0.43 and 4.45 +/- 1.03 ng/ml. The differences were statistically significant (p < 0.0001 and p < 0.0004 for MMP-13 and MMP-14, respectively). Levels of TIMP-2 did not differ significantly. CONCLUSIONS: Decreased concentrations of active MMP-13 and MT1-MMP/MMP-14 may imply that the proteolytic activity of the peritoneal milieu of women with endometriosis is disturbed, which may have implications in the pathogenesis of the disease.     

Oxidative stress may be a piece in the endometriosis puzzle

OBJECTIVE: To assess the total antioxidant potential of women with endometriosis-associated infertility, women with idiopathic infertility, and fertile controls. DESIGN: Retrospective study. SETTING: University medical hospital. PATIENT(S): Sixty-five women admitted for diagnostic laparoscopy. MAIN OUTCOME MEASURES: Peritoneal fluid samples were analyzed for superoxide dismutase activity and total antioxidant status on spectrophotometry, glutathione peroxidase activity on enzyme-linked immunosorbent assay, and lipid peroxides levels on colorimetry. RESULT(S): Mean activity of superoxide dismutase, glutathione peroxidase, and total antioxidant status was lowest and lipid peroxide level was highest among infertile patients with endometriosis. Women with idiopathic infertility, in contrast, had the highest superoxide dismutase, glutathione peroxidase, and total antioxidant status activity and the lowest lipid peroxide level. CONCLUSION(S): High antioxidant potential is not a contributing factor in women with idiopathic infertility. Low total antioxidant status and low activity of antioxidant enzymes in the peritoneal fluid of infertile women with endometriosis probably do not influence fertility in these women, but these factors may play a role in the development of the disease.     

Antizona and antisperm antibodies in women with endometriosis and/or infertility

OBJECTIVE: To measure the levels of antigamete antibodies in serum and peritoneal fluid of women with endometriosis and/or infertility. DESIGN: Antibody activity against human sperm and porcine oocytes was analyzed in selected subgroups of women. SETTING: Clinic of reproduction. PATIENT(S): Women with endometriosis and/or infertility. INTERVENTION(S): No treatment was implemented before peritoneal fluid and blood sample collection. MAIN OUTCOME MEASURE(S): Quantitative ELISA. RESULT(S): Four groups of women (n = 98) were analyzed for the presence of antizona and antisperm antibodies: infertile with endometriosis (n = 30), idiopathic infertility (n = 28), fertile with endometriosis (n = 20), and healthy fertile controls (n = 20). Antibodies were analyzed simultaneously in serum and peritoneal fluid. No statistically significant differences in antibody levels were detected in serum samples among the analyzed groups. The median values for antizona and antisperm antibodies in peritoneal fluid were significantly higher in women with idiopathic infertility than in the control group. In women with unexplained infertility, a high degree of correlation (Spearman) was found between the presence of antizona antibodies in peritoneal fluid and serum (r = 0.579). A positive predictive value of 80% was calculated for the presence of antizona antibodies (>5 ng/oocyte) in the peritoneal fluid of patients with infertility. CONCLUSION(S): Antizona antibodies locally produced in the peritoneal fluid have diagnostic value for infertility status; however, they cannot be treated as a marker or prognostic factor for minimal endometriosis and/or its treatment.     

Vascular endothelial growth factor and interleukin-6 in peritoneal fluid of women with endometriosis

OBJECTIVE(S): To determine [1] vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) levels in peritoneal fluid from women with endometriosis and compare them with those from oral contraceptive (OC) users and normal cycling women and [2] any correlation between VEGF and IL-6 concentrations. DESIGN: Controlled clinical study. SETTING: University medical center. PATIENT(S): Patients undergoing laparoscopy for infertility or other benign gynecologic conditions. INTERVENTION(S): Peritoneal fluid samples were collected. MAIN OUTCOME MEASURE(S): Levels of VEGF and IL-6 in peritoneal fluid were determined. RESULT(S): Compared with normal controls or women with less severe endometriosis (implant scores of 5 or less), women with more advanced endometriosis (implant scores of 6 or more) have elevated VEGF and IL-6 levels in peritoneal fluid. Compared with normal controls, markedly suppressed IL-6 but similar VEGF levels were found in peritoneal fluid from OC users. Neither VEGF nor IL-6 varied cyclically in normal women or those with endometriosis. There was no correlation between levels of VEGF and IL-6 in peritoneal fluid. There was no correlation between implant scores and VEGF or IL-6 levels. CONCLUSION: The inflammation associated with endometriosis, through increased levels of peritoneal fluid VEGF, may promote angiogenesis for the progressive growth of endometriosis. Effective treatment of endometriosis by combination estrogen-progestin pills may involve the suppression of such inflammatory responses.     

Cytokine profiles in serum and peritoneal fluid from infertile women with and without endometriosis

OBJECTIVE: To study the serum and peritoneal fluid cytokine profiles in infertile women with minimal/mild active endometriosis. METHODS: Fifty-seven consecutive infertile women undergoing laparoscopy for unexplained infertility had peritoneal fluid and serum samples obtained at the time of laparoscopy. The levels of interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-1 beta (IL-1 beta), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-alpha), monocyte chemotatic protein-1 (MCP-1), RANTES, platelet derived growth factor (PDGF), soluble Fas (sFas), and soluble Fas Ligand (sFasL) in peritoneal fluid and serum were measured to compare the concentration in both biological fluids, in women who have minimal/mild red endometriosis using women with no endometriosis as controls. RESULTS: Peritoneal fluid levels of MCP-1, IL-8 and IL-6 were significantly higher in the endometriosis group (P < 0.012, P = 0.003, and P = 0.015, respectively). There was no significant difference in the peritoneal fluid levels of IL-1 beta, TNF-alpha, RANTES, VEGF, PDGF, sFas and sFasL in the two groups. Although serum levels of IL-8 were higher in women with endometriosis, the difference was not significant (P = 0.07). Serum levels of PDGF, IL-6, RANTES, IL-1 beta, TNF-alpha, and sFas, were not significantly different in the two groups. CONCLUSION: The elevated levels of MCP-1, IL-6, and IL-8 in peritoneal fluid but not serum may indicate the importance of local macrophage activating factors in the pathogenesis of endometriosis.     

子宫内膜异位症患者腹腔液肿瘤坏死因子α和白细胞介素6的？…

子解子宫内膜内异症患者腹腔液肿瘤坏死因子α和白细胞介素６（ＩＬ－６）水平的变化及对人精子活动力和鼠胚胎发育的影响。方法将行诊断性腹腔镜检查的不孕患者２５例,根据术后诊断分为内异症组（１４例）和对照组（１１例,盆腔正常）,利用双抗体夹心法检测其腹腔液和腹腔巨噬细胞培养上清液中ＴＮＦ－α和ＩＬ－６和水平。并将两组的腹腔液分别与人精子和鼠２细胞期胚进行体外培养,观察萁 上人精子活动力鼠２细胞期胚胎发育的     

基质金属蛋白酶9及其组织抑制剂1在子宫内膜异位症组织中的表达

目的探讨基质金属蛋白酶9(MMP-9)及其组织抑制剂1(TTMP-1)在子宫内膜异位症(内异症)患者异位内膜及在位内膜中的表达,及其在内异症发病中的作用。方法选取38例根据美国生育学会修订的内异症分期法,诊断为内异症患者的卵巢内膜异位囊肿标本38份、腹膜红色病变标本16份及同期在位内膜35份组织作为研究组,以及非内异症患者的子宫内膜标本20份作为对照组。采用RT-PCR半定量技术,检测上述不同组织中MMP-9mRNA及TIMP-1mRNA的表达率及表达强度。结果两组所有标本均有TIMP-1mRNA表达,部分标本有MMP-9mRNA表达。研究组中,卵巢异位囊肿及腹膜红色病变组织MMP-9mRNA表达率分别为45%及56%,表达强度分别为0·46±0·22及0·33±0·12;同期在位内膜MMP-9mRNA表达率为57%,表达强度为0·49±0·28。卵巢异位囊肿、腹膜红色病变及同期在位内膜组织TIMP-1mRNA表达强度分别为1·67±0·79、1·45±0·68及2·31±1·21,前两者与后者比较,差异有统计学意义(P<0·05)。研究组在位内膜及对照组MMP-9的表达率分别为57%及45%;表达强度分别为0·49±0·28及0·29±0·12,两组比较,差异有统计学意义(P<0·05)。研究组在位内膜及对照组TIMP-1mRNA的表达强度分别为2·31±1·21及2·40±0·89。结论内异症患者在位内膜MMP-9mRNA的表达增强,促进了内膜的异位种植。异位内膜TIMP-1mRNA的表达减弱,可促使内异症病变的发展。     

Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis: a rationale for endometriotic invasiveness

OBJECTIVE: To investigate mRNA expression of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-3 (TIMP-3) in ectopic endometriosis tissue and uterine endometrium from women with and without endometriosis throughout the menstrual cycle. DESIGN: Molecular studies in human tissue. SETTING: Department of Gynecology and Obstetrics, Reproductive Immunology Laboratory, Stanford University Medical Center. PATIENT(S): Fifty-three premenopausal woman (23 women with endometriosis and 30 women without endometriosis undergoing laparoscopic surgery). Endometrium and ectopic endometriosis tissue were obtained at the time of surgery. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): mRNA expression from eutopic and ectopic endometrium was analyzed by quantitative, competitive PCR. RESULT(S): Both uterine endometrium and ectopic endometriotic tissue from women with endometriosis expressed significantly (P<.05) lower levels of TIMP-3 than endometrium from normal women. Also, ectopic endometrium expressed higher levels of MMP-9 and a higher ratio of MMP-9/TIMP-3 than eutopic endometrium from normal and endometriosis patients. CONCLUSION(S): These results suggest that ectopic and eutopic endometrium from endometriosis patients may be more invasive and prone to peritoneal implantation because of greater MMP and less TIMP-3 mRNA expression than endometrium from women without endometriosis. Thus, increased proteolytic activity may be one of the reasons for the invasive properties of the endometrium, resulting in the development of endometriosis.     

Altered expression of interleukin-18 in the peritoneal fluid of women with endometriosis

OBJECTIVE: Peritoneal fluid (PF) inflammatory factors may participate in the pathogenesis of endometriosis. The aim of this study was to investigate PF interleukin (IL)-18 levels in women with and without endometriosis. DESIGN: Controlled clinical study. SETTING: Women undergoing laparoscopy at a university hospital. PATIENT(S): Fifty women with previously untreated endometriosis, 8 women on GnRH agonists for endometriosis, and 18 control women with normal pelvic anatomy who were undergoing tubal ligation. INTERVENTION(S): Peritoneal fluid IL-18 levels as measured by ELISA. MAIN OUTCOME MEASURE(S): Peritoneal fluid IL-18 levels. RESULT(S): Peritoneal fluid IL-18 levels were significantly higher in women with previously untreated endometriosis (mean +/- SEM, 91.1 +/- 6.5 pg/mL) than in control women (59.4 +/- 2.0 pg/mL). Interestingly, women with superficial (100.0 +/- 10.2 pg/mL) and deep peritoneal implants (94.0 +/- 10.8 pg/mL) had significantly higher PF IL-18 levels than did women with endometriomas (57.8 +/- 1.8 pg/mL). Similarly, women with stage I-II endometriosis (97.3 +/- 8.0 pg/mL), but not women with stage III-IV endometriosis (74.9 +/- 9.9 pg/mL), had significantly higher PF IL-18 levels than did control women. Peritoneal fluid IL-18 levels were significantly higher in the luteal phase than in the follicular phase but did not discriminate between women with pelvic pain or infertility. CONCLUSION(S): Peritoneal fluid IL-18 is elevated in women with peritoneal, minimal- to mild-stage endometriosis.     

MMP-9及TIMP-1在子宫内膜异位症患者腹水及血清中的表达

目的:从蛋白水平检测内异症患者血清和腹水中MMP9及TIMP1浓度,探讨MMP9、TIMP1及腹水微环境在内异症发病中的作用。方法:收集47例RAFSI～IV期内异症患者的腹水,30例非内异症患者的腹水;从血清库中获取27例内异症患者血清,并收集26例正常妇女的血清作为对照。用ELISA法检测血清及腹水MMP9及TIMP1水平。结果:内异症患者腹水TIMP1与非内异症对照组无明显差异,但MMP9的水平明显高于对照组;内异症患者血清中MMP9的浓度与正常对照组差异有显著性,血清TIMP1的水平与对照组无明显差异,血清中MMP9/TIMP1的比值明显高于对照组;内异症患者血清MMP9浓度明显比腹水高,而TIMP1浓度明显比腹水低,因而血清中MMP9/TIMP1的比值是腹水的700倍左右。结论:MMP9及TIMP1参与内异症的发病,MMP9/TIMP1比值的测定具有临床意义;腹水微环境和内异症发生发展相互影响;血清的蛋白水解潜能远远大于腹水,其意义和解释需要进一步研究。     

Early endometriosis invades the extracellular matrix.

OBJECTIVES: To investigate whether the aminoterminal propeptides of type III procollagen are increased in patients with early endometriosis and to demonstrate that the subtle lesion of endometriosis is an active stage of the disease. DESIGN: Aminoterminal propeptide of type III procollagen was determined in serum and peritoneal fluid (PF) of 100 consecutive patients undergoing laparoscopy. SETTING: Academisch Ziekenhuis Maastricht, The Netherlands, a tertiary care center. RESULTS: Aminoterminal propeptide PF levels were significantly higher in women with early lesions of endometriosis compared with levels in two groups of controls, i.e., fertile, cycling, women without the disease (P = 0.019) and women on oral contraceptives without the disease (P = 0.036). No difference was found in aminoterminal propeptide PF levels when comparing patients with early lesions of endometriosis and patients with unexplained infertility, the third control group. Aminoterminal propeptide PF levels of patients with endometriosis without early lesions were not different from PF levels in controls. CONCLUSION: The early lesion is an active stage of endometriosis, invading the extracellular matrix. In women with unexplained infertility active, microscopic endometriosis may be present.