Review question
Can physicians use biomarkers (distinctive molecules, genes or other characteristics that appear in certain conditions) to reduce the need to surgically diagnose endometriosis?
Background
The endometrium refers to the tissue that lines the womb and is shed during menstruation. Women with endometriosis have endometrial tissue growing outside the womb, within the pelvic cavity. This tissue responds to reproductive hormones causing painful periods, chronic lower abdominal pain and difficulty conceiving. Currently the only reliable way of diagnosing endometriosis is to perform keyhole surgery and visualise the endometriotic deposits inside the abdomen. Because surgery is risky and expensive, various tests within the endometrium that can be obtained during an in-office womb sampling procedure have been assessed for their ability to detect endometriosis non-invasively or with minimal invasion. An accurate test could lead to the diagnosis of endometriosis without the need for surgery, or it could reduce the need for diagnostic surgery so only women who were most likely to have endometriosis would require it. Review teams have also evaluated other non-invasive ways of diagnosing endometriosis using blood, urine and imaging tests as well as a combination of several testing methods in separate Cochrane reviews within this series.
Study characteristics
The evidence in this review is current to April 2015. We included 54 studies involving 2729 participants. All studies evaluated reproductive-aged women who were undertaking diagnostic surgery to investigate symptoms of endometriosis or for other indications. Twenty-six studies evaluated the role of 22 different biomarkers in diagnosing endometriosis, and 31 studies identified 77 additional biomarkers that had no value in differentiating between women with and without the disease.
Key results and quality of evidence
Only two of the assessed biomarkers, a neural fibre marker PGP 9.5 and hormonal marker CYP19, were assessed in sufficient number of studies to obtain meaningful results. PGP 9.5 identified endometriosis with enough accuracy to replace surgical diagnosis. Several additional biomarkers (endometrial proteome, 17βHSD2, IL-1R2, caldesmon and other neural markers) show promise in detecting endometriosis, but there are too few studies to be sure of their diagnostic value.
The studies differed in how they were conducted, which groups of women were studied and how the surgery was undertaken. The reports were of low methodological quality, which is why readers cannot consider these results to be reliable unless confirmed in large, high quality studies. Overall, there is not enough evidence to recommend any endometrial test for use in clinical practice for the diagnosis of endometriosis.
Future research
Further high quality research is necessary to accurately evaluate the diagnostic potential of the endometrial biomarkers for the diagnosis of endometriosis.
We could not statistically evaluate most of the biomarkers assessed in this review in a meaningful way. In view of the low quality of most of the included studies, the findings of this review should be interpreted with caution. Although PGP 9.5 met the criteria for a replacement test, it demonstrated considerable inter study heterogeneity in diagnostic estimates, the source of which could not be determined. Several endometrial biomarkers, such as endometrial proteome, 17βHSD2, IL-1R2, caldesmon and other neural markers (VIP, CGRP, SP, NPY and combination of VIP, PGP 9.5 and SP) showed promising evidence of diagnostic accuracy, but there was insufficient or poor quality evidence for any clinical recommendations. Laparoscopy remains the gold standard for the diagnosis of endometriosis, and using any non-invasive tests should only be undertaken in a research setting. We have also identified a number of biomarkers that demonstrated no diagnostic value for endometriosis. We recommend that researchers direct future studies towards biomarkers with high diagnostic potential in good quality diagnostic studies.
About 10% of reproductive-aged women suffer from endometriosis, which is a costly, chronic disease that causes pelvic pain and subfertility. Laparoscopy is the gold standard diagnostic test for endometriosis, but it is expensive and carries surgical risks. Currently, there are no non-invasive tests available in clinical practice that accurately diagnose endometriosis. This is the first diagnostic test accuracy review of endometrial biomarkers for endometriosis that utilises Cochrane methodologies, providing an update on the rapidly expanding literature in this field.
To determine the diagnostic accuracy of the endometrial biomarkers for pelvic endometriosis, using a surgical diagnosis as the reference standard. We evaluated the tests as replacement tests for diagnostic surgery and as triage tests to inform decisions to undertake surgery for endometriosis.
We did not restrict the searches to particular study designs, language or publication dates. To identify trials, we searched the following databases: CENTRAL (2015, July), MEDLINE (inception to May 2015), EMBASE (inception to May 2015), CINAHL (inception to April 2015), PsycINFO (inception to April 2015), Web of Science (inception to April 2015), LILACS (inception to April 2015), OAIster (inception to April 2015), TRIP (inception to April 2015) and ClinicalTrials.gov (inception to April 2015). We searched DARE and PubMed databases up to April 2015 to identify reviews and guidelines as sources of references to potentially relevant studies. We also performed searches for papers recently published and not yet indexed in the major databases. The search strategies incorporated words in the title, abstract, text words across the record and the medical subject headings (MeSH).
We considered published peer-reviewed, randomised controlled or cross-sectional studies of any size that included prospectively collected samples from any population of reproductive-aged women suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE).
Two authors independently extracted data from each study and performed a quality assessment. For each endometrial diagnostic test, we classified the data as positive or negative for the surgical detection of endometriosis and calculated the estimates of sensitivity and specificity. We considered two or more tests evaluated in the same cohort as separate data sets. We used the bivariate model to obtain pooled estimates of sensitivity and specificity whenever sufficient data were available. The predetermined criteria for a clinically useful test to replace diagnostic surgery was one with a sensitivity of 94% and a specificity of 79%. The criteria for triage tests were set at sensitivity at or above 95% and specificity at or above 50%, which in case of negative results rules out the diagnosis (SnOUT test) or sensitivity at or above 50% with specificity at or above 95%, which in case of positive result rules in the diagnosis (SpIN test).
We included 54 studies involving 2729 participants, most of which were of poor methodological quality. The studies evaluated endometrial biomarkers either in specific phases of the menstrual cycle or outside of it, and the studies tested the biomarkers either in menstrual fluid, in whole endometrial tissue or in separate endometrial components. Twenty-seven studies evaluated the diagnostic performance of 22 endometrial biomarkers for endometriosis. These were angiogenesis and growth factors (PROK-1), cell-adhesion molecules (integrins α3β1, α4β1, β1 and α6), DNA-repair molecules (hTERT), endometrial and mitochondrial proteome, hormonal markers (CYP19, 17βHSD2, ER-α, ER-β), inflammatory markers (IL-1R2), myogenic markers (caldesmon, CALD-1), neural markers (PGP 9.5, VIP, CGRP, SP, NPY, NF) and tumour markers (CA-125). Most of these biomarkers were assessed in single studies, whilst only data for PGP 9.5 and CYP19 were available for meta-analysis. These two biomarkers demonstrated significant diversity for the diagnostic estimates between the studies; however, the data were too limited to reliably determine the sources of heterogeneity. The mean sensitivities and specificities of PGP 9.5 (7 studies, 361 women) were 0.96 (95% confidence interval (CI) 0.91 to 1.00) and 0.86 (95% CI 0.70 to 1.00), after excluding one outlier study, and for CYP19 (8 studies, 444 women), they were were 0.77 (95% CI 0.70 to 0.85) and 0.74 (95% CI 0.65 to 84), respectively. We could not statistically evaluate other biomarkers in a meaningful way. An additional 31 studies evaluated 77 biomarkers that showed no evidence of differences in expression levels between the groups of women with and without endometriosis.