Blood biomarkers for the non‐invasive diagnosis of endometriosis

Abstract

Background

About 10% of reproductive‐aged women suffer from endometriosis, a costly chronic disease causing pelvic pain and subfertility. Laparoscopy is the gold standard diagnostic test for endometriosis, but is expensive and carries surgical risks. Currently, there are no non‐invasive or minimally invasive tests available in clinical practice to accurately diagnose endometriosis. Although other reviews have assessed the ability of blood tests to diagnose endometriosis, this is the first review to use Cochrane methods, providing an update on the rapidly expanding literature in this field.

Objectives

To evaluate blood biomarkers as replacement tests for diagnostic surgery and as triage tests to inform decisions on surgery for endometriosis. Specific objectives include:

1. To provide summary estimates of the diagnostic accuracy of blood biomarkers for the diagnosis of peritoneal, ovarian and deep infiltrating pelvic endometriosis, compared to surgical diagnosis as a reference standard.

2. To assess the diagnostic utility of biomarkers that could differentiate ovarian endometrioma from other ovarian masses.

Search methods

We did not restrict the searches to particular study designs, language or publication dates. We searched CENTRAL to July 2015, MEDLINE and EMBASE to May 2015, as well as these databases to 20 April 2015: CINAHL, PsycINFO, Web of Science, LILACS, OAIster, TRIP, ClinicalTrials.gov, DARE and PubMed.

Selection criteria

We considered published, peer‐reviewed, randomised controlled or cross‐sectional studies of any size, including 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). We included studies comparing the diagnostic test accuracy of one or more blood biomarkers with the findings of surgical visualisation of endometriotic lesions.

Data collection and analysis

Two authors independently collected and performed a quality assessment of data from each study. For each diagnostic test, we classified the data as positive or negative for the surgical detection of endometriosis, and we calculated sensitivity and specificity estimates. We used the bivariate model to obtain pooled estimates of sensitivity and specificity whenever sufficient datasets were available. The predetermined criteria for a clinically useful blood test to replace diagnostic surgery were a sensitivity of 0.94 and a specificity of 0.79 to detect endometriosis. We set the criteria for triage tests at a sensitivity of ≥ 0.95 and a specificity of ≥ 0.50, which 'rules out' the diagnosis with high accuracy if there is a negative test result (SnOUT test), or a sensitivity of ≥ 0.50 and a specificity of ≥ 0.95, which 'rules in' the diagnosis with high accuracy if there is a positive result (SpIN test).

Main results

We included 141 studies that involved 15,141 participants and evaluated 122 blood biomarkers. All the studies were of poor methodological quality. Studies evaluated the blood biomarkers either in a specific phase of the menstrual cycle or irrespective of the cycle phase, and they tested for them in serum, plasma or whole blood. Included women were a selected population with a high frequency of endometriosis (10% to 85%), in which surgery was indicated for endometriosis, infertility work‐up or ovarian mass. Seventy studies evaluated the diagnostic performance of 47 blood biomarkers for endometriosis (44 single‐marker tests and 30 combined tests of two to six blood biomarkers). These were angiogenesis/growth factors, apoptosis markers, cell adhesion molecules, high‐throughput markers, hormonal markers, immune system/inflammatory markers, oxidative stress markers, microRNAs, tumour markers and other proteins. Most of these biomarkers were assessed in small individual studies, often using different cut‐off thresholds, and we could only perform meta‐analyses on the data sets for anti‐endometrial antibodies, interleukin‐6 (IL‐6), cancer antigen‐19.9 (CA‐19.9) and CA‐125. Diagnostic estimates varied significantly between studies for each of these biomarkers, and CA‐125 was the only marker with sufficient data to reliably assess sources of heterogeneity.

The mean sensitivities and specificities of anti‐endometrial antibodies (4 studies, 759 women) were 0.81 (95% confidence interval (CI) 0.76 to 0.87) and 0.75 (95% CI 0.46 to 1.00). For IL‐6, with a cut‐off value of > 1.90 to 2.00 pg/ml (3 studies, 309 women), sensitivity was 0.63 (95% CI 0.52 to 0.75) and specificity was 0.69 (95% CI 0.57 to 0.82). For CA‐19.9, with a cut‐off value of > 37.0 IU/ml (3 studies, 330 women), sensitivity was 0.36 (95% CI 0.26 to 0.45) and specificity was 0.87 (95% CI 0.75 to 0.99).

Studies assessed CA‐125 at different thresholds, demonstrating the following mean sensitivities and specificities: for cut‐off > 10.0 to 14.7 U/ml: 0.70 (95% CI 0.63 to 0.77) and 0.64 (95% CI 0.47 to 0.82); for cut‐off > 16.0 to 17.6 U/ml: 0.56 (95% CI 0.24, 0.88) and 0.91 (95% CI 0.75, 1.00); for cut‐off > 20.0 U/ml: 0.67 (95% CI 0.50 to 0.85) and 0.69 (95% CI 0.58 to 0.80); for cut‐off > 25.0 to 26.0 U/ml: 0.73 (95% CI 0.67 to 0.79) and 0.70 (95% CI 0.63 to 0.77); for cut‐off > 30.0 to 33.0 U/ml: 0.62 (95% CI 0.45 to 0.79) and 0.76 (95% CI 0.53 to 1.00); and for cut‐off > 35.0 to 36.0 U/ml: 0.40 (95% CI 0.32 to 0.49) and 0.91 (95% CI 0.88 to 0.94).

We could not statistically evaluate other biomarkers meaningfully, including biomarkers that were assessed for their ability to differentiate endometrioma from other benign ovarian cysts.

Eighty‐two studies evaluated 97 biomarkers that did not differentiate women with endometriosis from disease‐free controls. Of these, 22 biomarkers demonstrated conflicting results, with some studies showing differential expression and others no evidence of a difference between the endometriosis and control groups.

Authors' conclusions

Of the biomarkers that were subjected to meta‐analysis, none consistently met the criteria for a replacement or triage diagnostic test. A subset of blood biomarkers could prove useful either for detecting pelvic endometriosis or for differentiating ovarian endometrioma from other benign ovarian masses, but there was insufficient evidence to draw meaningful conclusions. Overall, none of the biomarkers displayed enough accuracy to be used clinically outside a research setting. We also identified blood biomarkers that demonstrated no diagnostic value in endometriosis and recommend focusing research resources on evaluating other more clinically useful biomarkers.

Plain language summary

Blood biomarkers for the non‐invasive diagnosis of endometriosis

Review Question

How accurate are blood tests in detecting endometriosis? Can any blood test be accurate enough to replace or reduce the need for surgery in the diagnosis of endometriosis?

Background

Women with endometriosis have endometrial tissue (the tissue that lines the womb and is shed during menstruation) 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 endometrial deposits inside the abdomen. Because surgery is risky and expensive, we evaluated whether the results of blood tests (blood biomarkers) can help to detect endometriosis non‐invasively. An accurate blood test could lead to the diagnosis of endometriosis without the need for surgery, or it could reduce the need for diagnostic surgery to a group of women who were most likely to have endometriosis. Separate Cochrane reviews from this series evaluate other non‐invasive ways of diagnosing endometriosis using urine, imaging, endometrial and combination tests.

Study characteristics

The evidence included in this review is current to July 2015. We included 141 studies involving 15,141 participants. All studies evaluated reproductive‐aged women who were undertaking diagnostic surgery because they were suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE). Cancer antigen‐125 (CA‐125) was the most common blood biomarker studied. Seventy studies evaluated 47 blood biomarkers that were expressed differently in women with and without endometriosis, and 82 studies identified 97 biomarkers that did not distinguish between the two groups. Twenty‐two biomarkers were in both categories.

Key results

Only four of the assessed biomarkers (anti‐endometrial Abs (anti‐endometrial autoantibodies), interleukin‐6 (IL‐6), CA‐19.9 and CA‐125) were evaluated by enough studies to provide a meaningful assessment of test accuracy. None of these tests was accurate enough to replace diagnostic surgery. Several studies identified biomarkers that might be of value in diagnosing endometriosis, but there are too few reports to be sure of their diagnostic benefit. Overall, there is not enough evidence to recommend testing for any blood biomarker in clinical practice to diagnose endometriosis.

Quality of the evidence

Generally, the reports were of low methodological quality, and most blood tests were only assessed by a single or a small number of studies. When the same biomarker was studied, there were significant differences in how studies were conducted, the group of women studied and the cut‐offs used to determine a positive result.

Future research

More high quality research trials are necessary to accurately assess the diagnostic potential of certain blood biomarkers, whose diagnostic value for endometriosis was suggested by a limited number of studies.