What are the
challenges facing women with endometriosis today? Ok, that’s a bit of an open
ended question and the answers to it would probably fill a library. To put it
another way, what are the main obstacles that need to be overcome for women
living with, or yet to be diagnosed with endometriosis? To my mind there are
three main areas that need to be addressed: 1) Better awareness and education
about endometriosis 2) Better medical treatments and better training in
surgical techniques for more surgeons 3) Better non-invasive diagnostic tests
for endometriosis.
For this
blog post I’m going to concentrate on the last point, because there has been a
real push recently into developing better non-invasive (and minimally invasive)
diagnostics. The current method for diagnosing endometriosis is the laparoscopy
and honestly, you’re not going to get a better diagnostic method than that
anytime soon in terms of accuracy and precision. Laparoscopy has several major
advantages; such as being able to assess the type/stage/location/extent of the
disease in one go and it gives the surgeon the opportunity to perform any minor
surgical interventions while they’re in there. Of course it does have its
drawbacks. For example, because laparoscopy is a surgical procedure that means
it takes time, and therefore money, to get it done. It’s pretty inconvenient
for the patient as well to have to wait for surgery (which, depending on where
you live, can take months) then be put under anaesthetic and operated on every
time your disease needs to be assessed with the downside that every surgery
carries risks even though they are very small. What about the women in poorer
countries who don’t have access to skilled surgeons with high tech equipment? Endometriosis
is likely to be greatly under-diagnosed in developing countries, purely because
there isn’t a simple non-invasive test that could, at the very least, confirm
or deny the presence of the disease.
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| Free image courtesy of FreeDigitalPhotos.net |
A
non-invasive test may also have some impact on, the quite frankly shocking,
diagnostic delay for endometriosis. The average woman with endometriosis may
have to wait anywhere from 6 to 8 years just
to be diagnosed. Mostly this delay is down to lack of education about the
condition in general practitioners and dismissal of the woman’s symptoms.
However, if a quick and simple test was available for endometriosis, more
doctors would be willing to administer it because it’s less hassle than getting
a referral for surgery. With a good non-invasive test you could, theoretically,
cut the diagnostic delay for endometriosis down from years to weeks! If the
non-invasive test came back positive, then a laparoscopy could be arranged to
assess the extent of the disease and decisions made about treatment options.
A good,
simple non-invasive test for endo could also, potentially, unlock a whole
wealth of information about the disease. For example, do you know what the rate
of endometriosis is in other countries around the world? Don’t feel bad if you
don’t know because nobody does; accurate measures of the prevalence of
endometriosis are only known for a handful of countries. If we knew the
prevalence of endometriosis in lots of countries (and the different populations
therein) we might see that some have a far greater/lower rate of endo than
others; closer investigation of the women in these populations could then be a
goldmine of new information about endometriosis, so it’s in everyone’s interest
to get good non-invasive tests developed.
Let us
fantasise for a moment and think how good it would be, if you suspected you had
endometriosis, to be able to walk into a doctor’s surgery, have some bloods
taken and then get the results of whether or not you have endometriosis back
within a few days? Yes, that would be great, but although this scenario is a
very real possibility in the future, it may take some time getting there. Why?
Because in order to create such a blood test we need to find something in the
blood that can distinguish between women with and without endometriosis with a
high degree of sensitivity (which is
the measure of how successful a test is at identifying positive cases). Markers
(usually specific proteins) in the blood, or any other bodily fluid for that matter, which can identify a
certain condition by being elevated or reduced are called biomarkers and there has been a flurry of research over the last
decade or so to find biomarkers for endometriosis.
There is
already a sort-of established blood test that is offered to some women for
suspected endometriosis, the CA-125 antigen test. You can read more about the
test here
and something you’ll probably quickly notice is that it’s not really a test for
endometriosis, but rather a test to monitor the progression of certain cancer
types that has been co-opted for endometriosis, because in some women with endo, their CA-125 levels are high. But if you read through the above link you’ll
also notice that there are many other conditions that raise CA-125 levels, so
it’s not very reliable. But is it accurate? A recent study found that the
sensitivity of the CA-125 test was around 68% at a given value. In terms of
medical tests, that’s not accurate, especially when you consider this means the
test will be wrong one in three times. Other studies have shown the sensitivity
of the CA-125 test to be as low as 20% for diagnosing endometriosis in general.
So it’s time to put the CA-125 test behind us and look forward to what up and
coming tests are on the horizon that may prove more effective.
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| Free image courtesy of FreeDigitalPhotos.net |
A blood test
for endometriosis is a good place to start, so below is a table of some of the
research that has been done to look for endometriosis biomarkers in the blood.
|
Name of Biomarker
|
Sensitivity
|
Type of Endometriosis
|
Reference
|
|
Interleukin-8
|
78.2%
|
Ovarian endometriosis
|
|
|
Interleukin-33
|
-
|
Deeply infiltrating endometriosis
|
|
|
Activin A and Follistatin
|
-
|
Ovarian endometriosis
|
|
|
anti-TPM3a-autoAb
anti-TPM3c-autoAb
anti-TPM3d-autoAb
anti-SLP2a-autoAb
anti-SLP2c-autoAb
anti-TMOD3b-autoAb
anti-TMOD3c-autoAb
anti-TMOD3d-autoAb
|
61%
44%
78%
50%
61%
61%
78%
78%
|
Early stages of endometriosis
|
|
|
PEDF
|
-
|
Endometriosis in general
|
|
|
3 Unidentified Proteins
|
89.3%
|
Endometriosis in general
|
|
|
anti-ST5
|
80%
|
Stage II endometriosis
|
|
|
Interleukin-6
|
71%
|
Endometriosis in general
|
|
|
Vitamin E
Glutathionine
|
-
|
Endometriosis associated with infertility
|
|
|
IMP1 autoantibody
|
85.7%
|
Endometriosis in general
|
|
|
18 Unidentified Proteins
|
90.9%
|
Endometriosis in general
|
|
|
anti-PDIK1L-autoAb
|
59.4%
|
Endometriosis in general
|
|
|
Anti mullerian hormone
|
-
|
Stage III-IV endometriosis
|
|
|
VEGF-A
|
-
|
Stage III-IV endometriosis
|
|
|
Follistatin
|
92%
|
Ovarian endometriosis
|
|
|
Cell free DNA
|
70%
|
Minimal to Mild endometriosis
|
|
|
CCR1 mRNA + MCP-1 + CA-125
|
92.2%
|
Endometriosis in general
|
|
|
Two unidentified proteins
|
86.7%
|
Endometriosis in general
|
|
|
Interleukin-8
|
71.4%
|
Ovarian endometriosis
|
|
|
Five unidentified proteins
|
91.7%
|
Endometriosis in general
|
|
|
GREM1
|
-
|
Endometriosis in general
|
|
|
CXCL10
|
-
|
Endometriosis in general
|
|
|
PON1 activity and lipid hyperoxidase
|
-
|
Endometriosis by stage
|
|
|
Antiendometrial antibody
|
87%
|
Endometriosis in general
|
|
|
Interleukin-6
|
71%
|
Endometriosis in general
|
|
|
Vitamin D
|
-
|
Endometriosis in general
|
(Biomarkers where the sensitivity isn’t given were stated to
be significantly different in the endometriosis group/s)
As you can
see there are some quite promising results being obtained and these are only
the studies going back as far as 2007. The
above table is only a small representation of the blood test research that has
been done and an even smaller representation of the total research
investigating novel diagnostics for endometriosis. For example, what could be
easier than a blood test? Well how about a urine test? I don’t think you could
get a simpler test than that and below is some of the research that has gone
into looking at developing a urine test for endometriosis.
|
Name of Biomarker
|
Sensitivity
|
Type of Endometriosis
|
Reference
|
|
Vitamin D Binding protein
|
58%
|
Endometriosis in general
|
|
|
Unknown protein
Unknown protein
Unknown protein
|
75%
82%
75%
|
Endometriosis in general and by stage
|
|
|
Cytokeratin-19
|
-
|
Endometriosis in general
|
Research
into urine tests for endometriosis is in its infancy at the moment, so a
working urine test for endometriosis is likely to be a long way off, if it ever
arrives at all. A blood or urine test would be considered ‘non-invasive’
diagnostic tests for endometriosis because it doesn’t involve any medical
devices going into any part of you. Laparoscopy, as a surgical procedure is
considered ‘minimally invasive’ because it involves smaller incisions that
laparotomy. However, there is a middle ground between
non-invasive tests and laparoscopy. These are tests that don’t involve surgery,
but do involve taking samples from inside you (the standard smear test for
cervical cancer is a good example of such a test). Below is another table of some of the
research being done to develop
‘less-minimally-invasive-than-surgery-but-not-quite-non-invasive’ tests for endometriosis
(I might have to think of a better wording for that).
|
Biomarker
|
Type of Test
|
Type of Endometriosis
|
Reference
|
|
Adiponectin
|
Sampling of peritoneal fluid
|
Endometriosis in general
|
|
|
Endometrial leukocytes
|
Sampling of the endometrium
|
Endometriosis in general
|
|
|
Neurotrophins
|
Sampling of the endometrium
|
Endometriosis in general
|
|
|
Nerve growth factor
|
Sampling of peritoneal fluid
|
Endometriosis in general
|
|
|
Endometrial nerve fibre density
|
Sampling of the endometrium
|
Endometriosis in general
|
|
|
Interleukin-15
|
Sampling of peritoneal fluid
|
Endometriosis in general
|
|
|
Tumour Necrosis Factor-alpha
|
Sampling of peritoneal fluid
|
Endometriosis in general
|
|
|
Leptin
|
Sampling of peritoneal fluid
|
Infertile women with endometriosis
|
|
|
Iron
|
Sampling of peritoneal fluid
|
Endometriosis by stage
|
|
|
CD44
|
Sampling of peritoneal fluid
|
Endometriosis in general
|
|
|
Ferritin
|
Sampling of peritoneal fluid
|
Endometriosis by stage
|
|
|
CA19-9 and CA15-3
|
Sampling of peritoneal fluid
|
Endometriosis in general
|
|
|
IL-6 and Tumour Necrosis Factor- alpha
|
Sampling of blood and peritoneal fluid
|
Endometriosis in general
|
|
|
Nitric Oxide
|
Sampling of peritoneal fluid
|
Endometriosis in general
|
These less
invasive tests show promise, but they mostly involve either an endometrial
biopsy or peritoneal
fluid analysis which look distinctly less comfortable than a simple, run of
the mill blood test. In addition they involve getting a whole new type of test
off the ground, which unfortunately can take years. But what if you could take
and existing non-invasive diagnostic test, that is already used in some centres
to look for endo (such as ultrasound or MRI) and modify it so it’s better at
detecting endometriosis. Luckily I’m not the first person to come up with that
idea so some research has already been done in this direction. Guess what? There’s
another table below outlining research into modifying existing imaging
techniques for endometriosis.
|
Imaging method
|
Type of Endometriosis
|
Sensitivity
|
Reference
|
|
3-T MRI
|
Deeply infiltrating endo
|
93%
|
|
|
3D MRI
|
Deeply infiltrating endo
|
-
|
|
|
Ultrasmall supermagnetic iron oxide enhanced MRI
|
Experimentally induced endo
|
-
|
|
|
Gadofosveset-tridosium enhanced MRI
|
Experimentally induced endo
|
-
|
|
|
Tenderness guided transvaginal ultrasonography
|
Recto-sigmoidal endo
|
73%
|
|
|
Contrast enhanced MR-colonography
|
Colorectal endo
|
76% for experienced radiologist
62% for less experienced radiologist
|
|
|
Endoscopic rectal unltrasound with elastosonography
|
Rectosigmoidal endo
|
-
|
|
|
Thin section oblique axial T2-weighted MRI
|
Uterosacaral ligament endo
|
73-93% depending on location
|
|
|
Introital 3D ultrasonography
|
Rectovaginal endo
|
78.6%
|
|
|
Endoscopic ultrasound-guided fine needle aspiration
|
Rectosigmoidal endo
|
-
|
Most of the
above tests have their good and bad points. Some of the positives are that these
tests would be relatively quick and painless and also would be able to give
some indication of where and how extensive the disease is. Perhaps the biggest
advantage of these imaging tests is that they are mostly available right now,
it’s just better awareness that is needed to get more women diagnosed using
these methods. Another advantage is that most of these imaging techniques would
also be able to detect other types of pathology (such as uterine abnormalities,
fibroids, adenomyosis, ovarian cysts etc) at the same time, saving guesswork as
to the source of the suffering. Of course, the downsides are that some of these
tests require very expensive equipment, so again the women in poorer countries
won’t see the benefits. Also, as one of the studies highlights, the accuracy of
the test is dependent on the experience of the person doing the interpreting of
the results. So in order to get the best results you’re going to need the best
people, who are usually in short supply.
In order to
achieve the highest degree of accuracy, a future diagnostic test for
endometriosis would probably be a combination of some of the different
biomarkers listed above and maybe also different techniques.
One of the
questions that’s probably running through your mind having read all of the
above is “if so much research is being done, why don’t we have a good
non-invasive test for endometriosis yet?” that’s a very good question and I
don’t honestly know myself. I do know that it takes a very long time to get a
new test up and running, especially if it means using a set of different
biomarkers. Firstly the new test has to be extensively validated i.e. does it
actually work, then the test has to be refined, then procedures and guidelines
put in place for its use, then it has to be promoted so medical processionals
know it exists. All of this can take many, many years, so how long will it be
before we see a new diagnostic test for endometriosis that actually works?
Unfortunately I don’t know, but with so much research being put into this area
I’m hopeful that it will be sooner rather than later.
Of course
none of the above biomarker tests would be an adequate replacement for a
laparoscopy, but rather an early warning system for women who experience many
of the unpleasant symptoms associated with endometriosis but don’t yet have a
diagnosis. I’m not really one for trying to predict events yet to transpire,
but if pressed on the matter I’d say diagnosis and treatment of endometriosis
in the (hopefully not too distant) future will be something like this:
A girl
experiences the classical symptoms of endometriosis, such as painful, heavy
periods, pain during sex, persistent pelvic pain etc, so she goes to see her
general practitioner. Depending on how far in the future we’re looking, her
doctor may be able to immediately perform a urine sample test using a dipstick
created to change colour in the presence of a certain urinary biomarker for
endometriosis. But if such a test doesn’t exist, her doctor would then most
likely send her for a blood test, which may come back showing biomarker levels
indicating endometriosis is the source of her suffering. The doctor would then send her to the hospital
to have a specialised MRI scan (or other scanning technique) which will show
where and how extensive her endometriosis is. Again, depending on how far into
the future we’re looking, computer software with advanced pattern recognition technology
may be able to pinpoint areas of endometriosis, thus negating the problem of
the disease being missed by less experienced human operators. The girl would
then be referred to a gynaecologist who, using the scan results as a guide, is
able to plan and schedule surgery for the girl to have her endometriosis
removed, possibly with robot-assisted surgery.
 |
| I suppose it depends on what sort of future we're living in as to which type of robot you'll get |
I may be
being a little optimistic here, but this is how I envisage the future of
endometriosis diagnosis and treatment. The above scenario should take no more
than a few months from start to finish (although it depends on how good your
healthcare system is) but it would still be a vast improvement on the 6-8 year
average women with endometriosis have to wait just to be diagnosed. The future
can’t get here soon enough.
