Background
At present, the only way to conclusively diagnose endometriosis is laparoscopic inspection, preferably with histological confirmation. This contributes to the delay in the diagnosis of ...endometriosis which is 6–11 years. So far non-invasive diagnostic approaches such as ultrasound (US), MRI or blood tests do not have sufficient diagnostic power. Our aim was to develop and validate a non-invasive diagnostic test with a high sensitivity (80% or more) for symptomatic endometriosis patients, without US evidence of endometriosis, since this is the group most in need of a non-invasive test.
Methods
A total of 28 inflammatory and non-inflammatory plasma biomarkers were measured in 353 EDTA plasma samples collected at surgery from 121 controls without endometriosis at laparoscopy and from 232 women with endometriosis (minimal–mild n = 148; moderate–severe n = 84), including 175 women without preoperative US evidence of endometriosis. Surgery was done during menstrual (n = 83), follicular (n = 135) and luteal (n = 135) phases of the menstrual cycle. For analysis, the data were randomly divided into an independent training (n = 235) and a test (n = 118) data set. Statistical analysis was done using univariate and multivariate (logistic regression and least squares support vector machines (LS-SVM) approaches in training- and test data set separately to validate our findings.
Results
In the training set, two models of four biomarkers (Model 1: annexin V, VEGF, CA-125 and glycodelin; Model 2: annexin V, VEGF, CA-125 and sICAM-1) analysed in plasma, obtained during the menstrual phase, could predict US-negative endometriosis with a high sensitivity (81–90%) and an acceptable specificity (68–81%). The same two models predicted US-negative endometriosis in the independent validation test set with a high sensitivity (82%) and an acceptable specificity (63–75%).
Conclusions
In plasma samples obtained during menstruation, multivariate analysis of four biomarkers (annexin V, VEGF, CA-125 and sICAM-1/or glycodelin) enabled the diagnosis of endometriosis undetectable by US with a sensitivity of 81–90% and a specificity of 63–81% in independent training- and test data set. The next step is to apply these models for preoperative prediction of endometriosis in an independent set of patients with infertility and/or pain without US evidence of endometriosis, scheduled for laparoscopy.
BACKGROUND Lack of a non-invasive diagnostic test contributes to the long delay between onset of symptoms and diagnosis of endometriosis. The aim of this study was to evaluate the combined ...performance of six potential plasma biomarkers in the diagnosis of endometriosis. METHODS This case–control study was conducted in 294 infertile women, consisting of 93 women with a normal pelvis and 201 women with endometriosis. We measured plasma concentrations of interleukin (IL)-6, IL-8, tumour necrosis factor-alpha, high-sensitivity C-reactive protein (hsCRP), and cancer antigens CA-125 and CA-19-9. Analyses were done using the Kruskal–Wallis test, Mann–Whitney test, receiver operator characteristic, stepwise logistic regression and least squares support vector machines (LSSVM). RESULTS Plasma levels of IL-6, IL-8 and CA-125 were increased in all women with endometriosis and in those with minimal–mild endometriosis, compared with controls. In women with moderate–severe endometriosis, plasma levels of IL-6, IL-8 and CA-125, but also of hsCRP, were significantly higher than in controls. Using stepwise logistic regression, moderate–severe endometriosis was diagnosed with a sensitivity of 100% (specificity 84%) and minimal–mild endometriosis was detected with a sensitivity of 87% (specificity 71%) during the secretory phase. Using LSSVM analysis, minimal–mild endometriosis was diagnosed with a sensitivity of 94% (specificity 61%) during the secretory phase and with a sensitivity of 92% (specificity 63%) during the menstrual phase. CONCLUSIONS Advanced statistical analysis of a panel of six selected plasma biomarkers on samples obtained during the secretory phase or during menstruation allows the diagnosis of both minimal–mild and moderate–severe endometriosis with high sensitivity and clinically acceptable specificity.
BACKGROUND Endometriosis occurs in 10% of women and is currently diagnosed by invasive laparoscopic testing. We tested the hypothesis that endometrial gene expression in late secretory phase ...endometrium differs between patients with and without endometriosis. METHODS Ten patients with laparoscopically proven endometriosis (minimal/mild n = 5 and moderate/severe n = 5) and six controls, underwent endometrial biopsy in the late secretory phase (Day 23 onwards). Microarray interrogation of eutopic endometrial gene expression was performed. RESULTS Microarray data were obtained for all control samples and eight samples from the endometriosis patients (n = 4 minimal/mild, n = 4 moderate/severe disease). Eight genes were identified as up-regulated and one gene was down-regulated in all endometriotic samples (more than 1.75-fold, P < 0.01). Real-time PCR analysis of protocadherin-17 (PCDH17), protein tyrosine phosphatase, receptor type, R (PTPRR) and interleukin-6 signal transducer (IL6ST) expression validated the microarray findings. CONCLUSIONS Expression of very few transcripts differs, in late secretory eutopic endometrium, between controls and patients with endometriosis. The median fold changes of these genes are small. No transcripts were identified that could discriminate between minimal/mild and moderate/severe endometriosis. Therefore, interrogation of the late secretory endometrial transcriptome is not likely to form the basis of a minimally invasive diagnostic test for endometriosis.
Endometriosis, a chronic gynecologic disease frequently resulting in chronic pelvic pain, severe dysmenorrhoea, and subfertility, is defined as the presence of endometrial tissue at extrauterine ...locations, most commonly on the peritoneum and ovaries. Conclusive diagnosis requires laparoscopic surgery followed by histological confirmation. The treatment options -at present- are limited to hormonal therapies and/or surgical ablation of the lesions, and are characterized by high recurrence rates, significant side-effects and limited duration of administration. The pathogenesis of endometriosis is still unclear and numerous immunological and inflammatory factors have been suggested to be involved in the development of the disease, including interleukin (IL)-1, IL-2, IL-6, IL-8, IL-12, tumour necrosis factor -alpha (TNF-alpha), regulated on activation, normal T-Cell expressed and secreted (RANTES) and its receptor cognate chemokine receptor 1 (CCR1), peroxisome proliferator activated receptors (PPARs), matrix metalloproteinases (MMPs) and cyclooxygenase (COX). Another crucial mechanism in endometriosis is the vascularisation of the endometriotic lesions, with a key role for vascular endothelial growth factor (VEGF). Recently, protease activated receptors (PARs), mitogen-activated protein kinases (MAPKs) and tyrosine kinases have also been associated with the pathophysiology of endometriosis. The aim of this article is to discuss molecules that have recently been found to have connections with the pathogenesis of endometriosis, as potential targets to develop new methods for noninvasive diagnosis and for novel medical management of this disease. This review also critically addresses how these molecules can be tested in basic, preclinical and clinical research, the status of this research and the importance of potential side effects.
A 1993 study reporting the link between exposure to dioxin and the risk of developing endometriosis in rhesus monkeys prompted many investigators to look suspiciously at dioxin. Since 1993, many in ...vitro, animal and epidemiological studies have been published, but the link between dioxin exposure and endometriosis is still unclear. The aim of our review is to present a summary of the biological effects of dioxin and its aryl hydrocarbon receptor, and to reassess the evidence presented in published, in vitro, preclinical and epidemiological studies regarding the association between dioxins and endometriosis. Although in vitro and animal studies provide results in support for a role of dioxins in the pathogenesis of endometriosis, caution should be exercised since these findings are mostly context dependent and since negative findings from these studies are rarely published. On the basis of our review of original epidemiological studies, no significant evidence can be found to support a link between dioxins and endometriosis in women. This observation can be explained by positive publication bias and by significant methodological problems associated with these studies, or by the absence of such a link. In conclusion, it seems that there is insufficient evidence at this moment in support of the hypothesis that dioxin exposure may lead to increased risk of developing endometriosis in women.
Endometriosis is more frequently diagnosed in patients with infertility than in a normal population. The goal of this paper is to give an overview of the clinical and fundamental evidence for a ...possible link between endometriosis and (recurrent) miscarriage or implantation failure after treatment with assisted reproductive technology. According to the literature, there is insufficient evidence for an association between endometriosis and (recurrent) miscarriage, but there is, however, epidemiological evidence to support the link between endometriosis and recurrent implantation failure after assisted reproduction. This can possibly be explained by alterations in humoral and cell-mediated immunity in women with endometriosis. Humoral immunological changes include increased formation of antibodies against endometrial antigens, anti-laminin-1 auto-antibodies and other auto-immune antibodies (e.g. antiphospholipid). Cell-mediated immunological changes include alterations in peritoneal and follicular fluid immune cells and cytokines. The possible negative effect of these immunological changes on folliculogenesis, ovulation, oocyte quality, early embryonic development and implantation in women with endometriosis suggests that infertility in endometriosis patients may be related to alterations within the follicle or oocyte, resulting in embryos with decreased ability to implant.
To examine messenger (m) RNA expression of aromatase, cytokines, and adhesion factors in women with and without endometriosis.
Patients with endometriosis were compared with control patients.
...University Hospital Gasthuisberg, Leuven, Belgium.
A total of 35 patients who had laparoscopic surgery during the luteal phase (n = 20) or the menstrual phase (n = 15) were selected for this study based on cycle phase and presence/absence of endometriosis.
Tissues of endometrium and macroscopically normal peritoneum were collected during hysteroscopy and laparoscopic surgery, respectively, from 24 women with revised American Society for Reproductive Medicine stage (rASRM) stages I-II (n = 12) and III-IV (n = 12) endometriosis and 11 control patients with normal pelvic. Tissue samples were selected from a tissue bank, based on the phase of the cycle (menstrual or luteal) and the presence/absence of endometriosis.
The mRNA levels of aromatase, vimentin, vascular cell adhesion molecule 1 (VCAM-1), alpha(V) and beta(3) integrins, interleukin (IL)-1 beta, regulated on activation normal T-cell expressed and secreted (RANTES), and monocyte chemotactic protein 1 (MCP-1) were evaluated using real-time reverse transcriptase polymerase chain reaction.
During menstrual phase, increased endometrial mRNA levels of alpha(V) integrin, combined alpha(V)beta(3) integrins, and increased peritoneal IL-1 beta mRNA levels--but decreased peritoneal MCP-1 mRNA levels--were observed in women with endometriosis compared with control subjects. During luteal phase, endometrial mRNA levels of IL-1 beta and RANTES were increased in women with endometriosis compared with control subjects. Endometrial aromatase mRNA expression was higher in women with endometriosis than in control subjects in combined phases. Women with endometriosis had increased peritoneal mRNA expression of RANTES and VCAM-1 during menstrual compared with luteal phase.
Aberrant mRNA expression of aromatase, cytokines, and adhesion factors in endometrium and peritoneum suggests that both tissues are involved in the pathogenesis of endometriosis.
To examine differential messenger RNA (mRNA) expression of relevant cytokines, metalloproteases, growth and adhesion factors in endometrium and peritoneum from women with endometriosis when compared ...with women without the disease during menstrual and luteal phases of the cycle.
Patients with endometriosis were compared with control patients.
University hospital.
A total of 35 patients (20 patients during the luteal phase and 15 patients during the menstrual phase) were selected for this study on the basis of cycle phase and presence or absence of endometriosis.
In this study, endometriosis was laparoscopically and histologically confirmed in 24 women with endometriosis of revised American Society for Reproductive Medicine (ASRM) stage I-II (n = 12) and revised ASRM stage III-IV (n = 12), and the presence of a normal pelvis was documented by laparoscopy in 11 control patients. The macroscopically normal peritoneum tissues were collected from lateral wall left or right, near the colon ascendens or descendens.
The expression levels were determined as ratios between the target molecules and beta-actin as housekeeping gene.
In women with endometriosis, peritoneal mRNA levels of matrix metalloproteinase (MMP)-3, transforming growth factor-beta, interleukin (IL)-6, and intercellular adhesion molecule-1 and endometrial mRNA levels of MMP-3, tumor necrosis factor (TNF)-alpha, and IL-8 were significantly higher during the menstrual phase when compared with luteal phase. During the menstrual phase of the cycle, both endometrial expression of TNF-alpha, IL-8, and MMP-3 mRNA levels and peritoneal expression of transforming growth factor-beta, IL-6, and intercellular adhesion molecule-1 mRNA levels were significantly higher in women with endometriosis when compared with controls. Immunohistochemical staining confirmed the presence of TNF-alpha in peritoneum and endometrium in both women with endometriosis and controls.
Increased endometrial and peritoneal cytokine mRNA expression during menstruation may contribute to a pelvic inflammatory microenvironment favoring the development of endometriosis.
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