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Friday, 31 August 2012

Looking Ahead


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.  

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.
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.

1 comment:

  1. Your blog gives me hope! It's really interesting to read as well, so glad I found it. Thank you :)

    ReplyDelete