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. 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.
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. 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. 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). 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. 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. 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.