Endometriosis: A Researcher’s Perspective

January 19, 2016

As an endometriosis researcher, I'm fascinated by the aetiology (the study of origins or causes) of the disease – in particular, the formation of lesions. In essence, my work aims to answer the question:

 

How do endometriosis lesions originate and develop, and

can we identify risk factors that predispose to lesion

formation?

 

Now endometriosis is a complex condition, and I do not claim to be an expert in all aspects of the disease. It seems though that many in the online endometriosis community do have questions about why scientific research in this field is conducted in the way it is. So, when I was asked to write this blog, it seemed like a great opportunity to try to bridge the gap between scientists and sufferers by sharing a researcher’s perspective. 

 

The fundamental challenge

 

A typical day for an endometriosis researcher might look like this: you rock up to the lab at 7am and get your things together for the tissue collection that's been organised in collaboration with the surgeon and his/her patient for that day. At 8am you're at the hospital to meet the woman with suspected endometriosis pre-surgery and confirm her willingness to participate in your study, and you complete the requisite paperwork. Like her and the surgeon, at this stage you're in the dark as to the severity of her disease or whether or not she even has endometriosis. At 8:30 you take your collection pack to theatre, hand it over to theatre personnel, and let the surgeon know that everything's in place. At 9am, you head back to the lab and work on one of your other experimental or writing tasks, before heading back to the hospital in the afternoon. Assuming one or more endometriosis lesions were removed from your research participant and there is sufficient material after the medical requirements (e.g., analysis by a pathologist) are satisfied, you pick up the precious samples and once more head back to the lab to process and store them for later analysis. 

 

Sounds easy enough, right? 

 

So why don't we have better answers to the question above?

 

Well, a fundamental problem with conducting research on endometriosis (and other chronic conditions) in this way is that you're limited to a single snapshot of disease development in time. No one knows how long the particular lesion of which you now have a sample had been growing or how it got there in the first place. It's akin to having a still shot from halfway through a movie, and being asked to reconstruct the plot up to that point. As someone who is interested in understanding how and why endometriotic lesions form, I think you can see why this approach can be somewhat limiting.

 

This is one reason why researchers turn to models of disease; to try and unpack the processes occurring earlier in disease progression that (in this case) lead to the point at which a piece of tissue that shouldn't be where it is has to be surgically removed. Although one attempts to use the best available literature and understanding as a basis, certain assumptions about disease aetiology must of course be made in developing a model. These are inherent limitations that must be acknowledged when analysing and disseminating the results of any study performed using the model, but they don’t necessarily invalidate them. In vivo (animal) models of disease are usually thought of as the ‘gold standard’ in research because, compared to in vitro (laboratory) models, in vivo models better recapitulate the huge variety and complexity of cellular and biochemical interactions that occur in patients.

 

Theories of endometriosis

 

Endometriosis is often referred to as a 'disease of theories.' Much of the scientific research on endometriosis to date (including our own) has been based on Sampson’s theory. As most readers will know, this theory postulates that shed endometrial fragments move backward through the fallopian tubes (i.e., retrograde flow) and emerge in to the abdominal cavity, where they attach to the various structures and by mechanisms that are not clear, become endometriotic lesions. This theory is heavily criticised by some in the endometriosis field, and other strong contenders to explain the origin of endometriosis, such as embryonic and stem cell theories, exist. I do not want to delve too deeply in to the controversies surrounding these theories in this blog, but I would make two points with regard to Sampson’s theory. 

 

One argument against Sampson’s theory is that retrograde menstruation is reported in a majority of women, yet only a relatively small percentage actually develop endometriosis. (As an aside, the reason why retrograde menstruation occurs at all is a fascinating but relatively understudied question – a possible explanation is that it may function to return valuable iron to the body that would otherwise be lost.1) Clearly, retrograde menstruation is not in and of itself an adequate explanation. It may be that endometriosis, like other complex conditions such as preeclampsia, requires one or more ‘hits’ or ‘insults’ in order to manifest itself. That is, retrograde menstruation alone is not sufficient to develop endometriosis – a second ‘hit’ (which may differ among women) such as compromised immune clearance mechanisms or greater-than-normal survival of endometrial fragments is needed. Retrograde menstruation sets the stage, but other players create the action. This could account for the discrepancy between the numbers of women in whom retrograde menstruation is reported, and the percentage who develop endometriosis. In other words, it’s how the bodies of the 10% of women who develop endometriosis deal with refluxed endometrial debris that holds the key to understanding lesion development.

 

Another argument used against Sampson’s theory seems to be that endometriotic lesions are not identical to endometrial tissue, and indeed, this is absolutely true. For example, whereas endometrial tissue contains abundant glands and ‘stromal’ cells that both support the function of the uterine lining, endometriotic lesions typically contain few glands that are much greater in volume (dilated) compared their endometrial counterparts with limited access to the tissue surface, while the stromal component of the tissue also differs markedly in its cellular composition. This is taken as evidence that the lesion cannot possibly have derived from an endometrial (uterine) source, but this may be a misinterpretation. Bearing in mind the fundamental problem of studying lesions I mentioned above, who can say that during the weeks/months/years since an endometrial fragment became attached (usually) within the peritoneal cavity, the differences between the tissues have not emerged as the body responds to this ‘invader’? I doubt that any endometriosis researcher actually believes that endometriotic lesions are the same as endometrial tissue from the uterus – the oft used phrase “endometriosis occurs when endometrial deposits grow outside the uterus” (or variations thereof) should be taken simply as shorthand for Sampson’s theory, necessitated by the tight character/word limits stipulated by publishers.

 

As scientists, we analyse the conundrum that is endometriosis in terms of hypotheses, and weigh up the balance of evidence in favour of or not supporting them. The reality is that no one knows with certainty how endometriosis lesions occur. Theories are rarely rejected outright, because one can never rule out the possibility that new evidence that supports the hypothesis will come to light further down the track.

 

Researchers and Patients – bridging the gap

 

I think that one of the complicating factors when conveying information from the lab to the patient stems from different ways in which these two groups think about endometriosis. Unlike other chronic diseases such as diabetes, where there is a clear and classic perturbation to normal physiology (i.e., elevated and uncontrolled blood glucose levels) that can be modelled in the laboratory without disagreement, endometriosis could be defined differently depending on your perspective. For example, a woman with endometriosis may consider her symptomatology – pain, dysmenhorrea, dyspareunia, etc. However, there is no clear correlation between the presence of lesions and these symptoms, and it is difficult for the researcher to model the disease on the basis of the latter. Therefore, a researcher by necessity typically thinks of endometriosis in anatomical terms – the presence of endometrium-like tissue outside the uterus. Given that the disease is clinically defined by the presence of lesions, this is arguably a reasonable stance. Unfortunately, this comes with the major caveat of our poor understanding of the underlying disease process, as alluded to above.

 

When we published a paper recently I noticed several comments along the lines of “this story seems to be incomplete” and I thought it would be worth explaining why this may seem to be the case. A thorough piece of research usually looks at a scientific question from a number of different angles - the data on which all has to be explained and discussed – with the result that seemingly not much new information has been gained in the end. The effect is even greater for a new line of investigation, which may require additional validation and explanation. Unfortunately science moves slowly, and a paper has to be circumscribed for practical reasons.

 

A better kind of informed

 

Related to bridging the gap between researchers and patients, I would like to touch on the dissemination of research findings to women with endometriosis and their families. The rise of the internet and the proliferation of social media forums and non-mainstream internet media sites has led to a greater accessibility of information for non-researchers. Undoubtedly, this is hugely beneficial for many sufferers of the disease. However, it is no substitute for rigorously peer-reviewed literature. Published scientific papers have typically been reviewed by at least two independent experts in the field. Contrast this with blogs, which are really just opinion pieces (even ones with citations). So, I would advise being at least as critical of blogs and opinion pieces on the web (including this one!) as you are of research papers. (Of course, patients’ personal experiences with endo are entirely valid and not subject to scrutiny in this way.) 

 

Scientific papers are usually published in one of two formats – original manuscripts, and reviews. Both can be valuable sources of information for patients. I would particularly recommend review articles, because although these will be slightly less up to date compared to the source material, they will contain much less technical jargon and usually neatly compress the findings and implications of many papers into a shorter space. Although some scientific journals require subscriptions, these days many papers are published as “open access,” meaning that they are freely available to anyone. You don’t have to be a scientist or attend a university to download them. If a paper is not available via open access, why not email the corresponding author and ask them for the full text? Much of the time they will be happy to send you a pdf copy if they’re not constrained by publication copyright issues. Although reading scientific papers may seem daunting to a non-researcher, I would encourage women with endometriosis to try. It might be a bit of a slog at first, but I think most people’s scientific literacy would improve over time, with the result of being better informed about their disease.

 

In closing…

 

The scientists who work on endometriosis face a catch 22 situation: we can’t model the disease properly without understanding the aetiology, and we can’t understand the aetiology without trying to model the disease. Should we throw in the towel and stick to in vitro studies on cells and tissues, or is a new piece of information on endometriosis from an in vivo model with caveats better than nothing? In an environment of declining financial resources and enormous competition from other fields, the challenge of maintaining endometriosis as a funding priority is considerable. The work of advocacy groups such as Endometriosis Australia in providing visibility to this otherwise hidden condition is invaluable, and patients, treatment providers and researchers should also cooperate to maintain the profile of the disease. Overly harsh criticism of endo research and the scientists who produce it serves no-one’s ends. Instead, stronger engagement between endometriosis stakeholders will be mutually beneficial, and the end result is likely to be better treatment outcomes for endometriosis sufferers – a worthy goal for all of us to work towards.

 

1   Kunz, G. & Leyendecker, G. Uterine peristaltic activity during the menstrual cycle: characterization, regulation, function and dysfunction. Reproductive BioMedicine Online 4, Supplement 3, 5-9, doi:http://dx.doi.org/10.1016/S1472-6483(12)60108-4 (2002).

 

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