Highlights from WCE 2014 - Part 2

Let’s continue our exploration through the World Congress on Endometriosis 2014 and we’re going to delve into some of the research about what makes women with endo different from those without and how this could give us clues as to what causes endo in the first place.

A team from Australia made an interesting discovery regarding stem cells and endometriosis. You have probably heard about stem cells before, but why would they be of interest in endometriosis? Stem cells are the precursors to the different types of cells in your body and are mostly of use during the very early part of your development when you were a foetus growing new organs. But they still have some use as an adult, for example, inside the uterus there are a population of stem cells that your body uses to regrow the endometrium after each menstruation, which are unsurprisingly referred to as endometrial stem cells. If these cells can grow endometrium and endometriosis is endometrium-like tissue, it becomes clear how these stem cells could play a role in endometriosis. Some researchers believe that genetic changes associated with endometriosis result in some endometrial stem cells becoming displaced during embryo development, which go on to produce endometriotic lesions as a girl approaches adolescence. Others believe these stem cells are shed into the pelvic cavity by retrograde menstruation (where the menstrual blood goes into the pelvic cavity) and implant around the pelvis and then develop into endometriotic lesions.

This investigation by the Australian team looked at the number of endometrial stem cells in the blood, menstrual blood and peritoneal fluid of women with and without endometriosis. What they found was that, although the amount of peritoneal fluid was similar between the two groups, the number of viable endometrial stem cells in the peritoneal fluid was massively higher in women with endo. So how did those cells get there? Retrograde menstruation is a likely explanation, but they found no difference in the amount of stem cells in the menstrual blood between women with and without endo.  It could be that the immune system of women with endo doesn’t clear the refluxed stem cells and they just accumulate or maybe there is some other way these cells are getting into the pelvic cavity, at this moment nobody knows for sure.

Speaking of peritoneal fluid, a group from the US and Brazil analysed the peritoneal fluid looking for inflammatory factors that are related to endometriosis associated pain. What they found was that dyspareunia (painful sex), non-cyclic pain and infertility were not related to the inflammatory factors they were studying. What they did find though was that certain inflammatory factors were associated with dysmenorrhea (excessively painful periods). This has some potentially very interesting implications, particularly as dysmenorrhea is the most common symptom of endometriosis. This suggests that dysmenorrhea is caused by areas of chronic inflammation around the sites of endometriosis regardless of stage or location. If it were possible to find out how these inflammatory factors are being produced and find a way to reduce the level of these factors, in the future this could be a new way of treating the pain associated with endo. 

More highlights on the way soon...

Turning on its Head

Endometriosis is usually described as some variation of ‘patches of endometrium-like tissue growing elsewhere in the body’. This description though throws up several questions. For example, if endometriosis is related to the normal endometrium, what can this tell us about the disease and what is the connection between the two tissue types?

Initially the similarity of endometriosis to the normal endometrium led academics to believe endometriotic lesions were seeded in their locations by the backward flow of endometrial cells during menstruation. This made sense at the time because backward flowing menstruation (retrograde menstruation) is a thing that happens and the fact that endometrial cells were entering the pelvic cavity and endometriosis appeared to be endometrial in character seemed too much of a coincidence.

However, retrograde menstruation occurs almost universally in women of reproductive age, yet endometriosis affects around 10% of women, so clearly there was still something missing from this argument. Maybe the normal endometrium of women destined to have endometriosis is somehow different from other women. These days technology is such that we can analyse thousands of properties of cells at the molecular level, allowing an unprecedented degree of detailed characterisation of all the tissue types in the human body. Several studies have focussed on characterising the endometrium of women with and without endometriosis and found that; yes the endometrium in women with endometriosis is indeed different. The endometrium from women with endometriosis appears to have a higher ability to survive, proliferate and invade, seemingly filling in the missing part of the retrograde menstruation theory.

But, like all great mystery stories, the case is never wrapped up in a neat little package so early on. In recent years more and more evidence is coming to the fore, challenging the theory of retrograde menstruation. In particular there is now quite a significant amount of evidence to show the displaced endometrium that defines endometriosis is, in fact, present before you were even born. There are also rare documented cases of endometriosis in men, women who cannot menstruate and non-menstruating primates; so clearly there is the need for some radical re-thinking.

Maybe we’ve had the whole thing upside-down; maybe it is not the endometrium that dictates the fate of endometriosis, but endometriosis that dictates the fate of the endometrium. A collaborative research effort has provided some evidence to this very end (you can read the full article here). The authors of this study experimentally induced endometriosis in baboons by injecting endometrial cells into the pelvic cavity and letting them form endometriotic implants. They then compared the expression of genes within the endometrium of the baboons with experimentally induced endometriosis and disease free baboons over the course of 16 months. What they found was that the presence of endometriosis (even in its very early stages) led to marked changes (a total of 4,331 genes were altered) in the normal endometrium.

This potentially turns accepted wisdom on its head, in that women with endometriosis are not born with a defective endometrium that gives rise to endometriosis via retrograde menstruation. Rather, if we are to take all the above evidence into account, it appears endometriosis is a condition you are born with that, when the endometriotic implants ‘mature’ lead to changes in the function of the normal endometrium, thus perhaps also accounting for the fertility issues women with endo suffer from.

However, one big questions still remains – how does endometriosis communicate with the normal endometrium to illicit these changes?  If we disregard the notion that endometrial cells can display quantum entanglement then there must be a signalling pathway between the two cell types. The first idea that comes to mind is something to do with the production of inflammatory factors by endometriotic lesions. Lesions produce a number of inflammatory factors that are also regulators of gene expression which, hypothetically, could travel to the normal endometrium and alter its gene expression, but that’s just an educated guess.

Even with new evidence making us rethink the development of endometriosis, invariably we find ourselves with more questions than answers - for example:

If the endometriotic implants are removed, do the changes to the normal endometrium revert back, or are the changes induced by endometriosis permanent?

If displaced endometrium is found before birth, how does it get there? Müllerianosis? Mesenchymal stem cells? Both? Something else?

What are the genetic/epigenetic/environmental factors that influence the displacement of endometrial cells?

Why does endometriosis only occur in certain primates species?

Does retrograde menstruation have any role to play in endometriosis and if not, why not? Could some cases of endometriosis be due to retrograde menstruation and others not, meaning there are multiple pathways to endometriosis development?

There is still a long way to go before we completely comprehend endometriosis, but with each passing year the walls blocking our understanding are chipped away until eventually, the truth will be revealed.

Update

Just wanted to say sorry for not posting anything for a while, between my day job and writing my thesis I haven’t had much time to do much else. Anyway, enough of my excuse making, I thought I’d give a quick update on what has been going on in the field of endometriosis research in the past couple of weeks. Here is a quick selection of some of the more interesting articles published.

Since my last post on the 8th of September there have been 96 papers published on endometriosis with a wide variety of subjects (according to PubMed).

There have been several publications on the link between ovarian cancer and endometriosis. There have even been a few papers on the involvement of epigenetic mechanisms in endometriosis (my specialist field).

There was also a paper which found 30% of the patients with endometriosis they examined also had irritable bowel syndrome or constipation.

Aromatase inhibitors were found to be effective at reducing the proliferation of endometriotic implants in a mouse model.

Phthalates, which are artificial compounds thought to act as an oestrogen and very hard to pronounce, were found to be no higher in the urine of Japanese women with endometriosis when compared to controls. However, this study falls into a trap that is a personal pet peeve of mine, which is analysing the levels of these compounds in women who already have the disease. A better study design would be to analyse the frequency of endometriosis either in the children of women exposed to artificial oestrogenic compounds or in women exposed at a very young age.

Contrary to the above, levels of another type of synthetic oestrogen, Bisphenol A and B, were found to be higher in the blood serum of women with endometriosis.

IVF treatment does not increase the risk of endometriosis recurrence.

Endometriosis was diagnosed in two sisters with Glanzmann's thrombasthenia (GT), a very rare blood clotting disorder which leads to prolonged bleeding. This is considered significant as women with GT are more likely to have prolonged periods of menstrual bleeding, a factor which is thought to increase the susceptibility to endometriosis. This perhaps garnishes some support for the retrograde menstruation origin theory of endometriosis.

Apparently marmosets (a type of small New World monkey) can develop endometriosis.

If you have are of the type A blood group, you are 2.9 fold more at risk of endometriosis. The relationship between blood groups and endometriosis remains to be explained.

It appears that the normal endometrium of women with endometriosis has increased proliferative activity, meaning that it grows quicker than normal. What could be causing this increased proliferation remains to be found.

Pregnant women with endometriosis are apparently more at risk of suffering spontaneous hemoperitoneum (bleeding into the peritoneal cavity). However, I should point out that hemoperitoneum is rare.

Interesting case report of a 42 year old woman who, even after a hysterectomy and right oopherectomy, still presented with monthly bleeding. The cause was found to be an endometriotic cyst on the left ovary.

That is the news for now, hopefully I’ll get to post more soon.

Round in Circles

That’s what it feels like sometimes when dealing with endometriosis, like you’re in a boat with an oar on only one side, just paddling away but ultimately going no-where. Then hurray! Someone throws you another oar, but it’s bigger than the other one so you end up moving forward slightly but still round in circles. What you really need is an outboard motor of some kind, or maybe some sails....sorry I seem to have lost where I was going with that metaphor. Anyway, the oars in this case represent the two big conflicting ideas about where endometriosis comes from, namely retrograde menstruation and coelomic metaplasia. I’ve spoken about these conflicting notions before along with the theory of mullerianosis back in May and how there is evidence for both cases.

In one corner we have the stalwart theory of retrograde menstruation, which is generally accepted as how endometriosis comes into being, and there is evidence to support this. The fact that endometriosis bares such resemblance to normal endometrium, that endometriosis is found most frequently on the pelvic organs and experimental evidence which reported that forced surgical induction of retrograde menstruation in monkeys led to the development of endometriosis in 50% of cases.

In the other corner is coelomic metaplasia, which suggests that there are cells that already exist all throughout the body that can transform into functional endometrium given the correct stimulus. This theory best explains how endometriosis can arise in organs such as the brain and lungs and even the rare cases of endometriosis in males.

A body blow has just been dealt to retrograde menstruation in the form of a study that has just been published in the Journal of Paediatric and Adolescent Gynaecology. This study reported a case of endometriosis in a 20 year old girl who complained of serious pelvic pains. That’s nothing exceptional in itself, until you know that the girl also had Mayer-Rokitansky-Küster-Hauser syndrome, mercifully also known as MRKH. MRKH is characterised by the incomplete development of the female reproductive organs, in this case the girl did not have a uterus. Therefore, retrograde menstruation would have been impossible and cannot account for the development of her endometriosis, but coelomic metaplasia could. This round goes to coelomic metaplasia.

You’ll be glad to hear that this story has a happy ending though. The girl in question underwent electrocautery to destroy her endometriosis and was placed on oral contraceptives to reduce her symptoms, which significantly reduced her pain.

So the retrograde menstruation/coelomic metaplasia debate looks like it will have no resolve just yet. Nevermind, just keep on paddling.

Maybe she's born with it

If you suffer from endometriosis you may have pondered on how you came to have the disease. Did you inherit it from a family member? Did the disease arise from something you were exposed to whilst you were still in the womb? Or did exposure to something factors during childhood or adulthood bring on the disease? It’s not just sufferers that are puzzled by this question, scientists also wonder how and why some women get endometriosis and have had a fair go at trying to answer it.

You may have heard about some of the theories going around. Retrograde menstruation is the go-to theory for explaining how endometriosis comes to be. This basically states that during a period although most of the blood exits via the vagina, some of the blood travels upward into the fallopian tubes and out into area surrounding your various reproductive organs. This blood contains endometrial tissue (that normally lines the womb) which is thought to implant on the organs it settles on and grow to become endometriosis. There’s a neat little animation explaining how retrograde menstruation works on the Endometriosis Research Foundation website and can be found here.

The problem with this theory is that it has been found that 90% of women experience retrograde menstruation, so how come only 10% of women get endometriosis? The retrograde menstruation theory also assumes that menstruation is nessacary for endometriosis to develop. Well an interesting study has just been published in the journal of Experimental and Clinical Cancer Research which has presented some new evidence suggesting women are born with endometriosis.

This study took on the task of dissecting 36 human female foetuses, which had either been aborted or died of natural causes, and looked for evidence of displaced endometrial tissue, the hallmark of endometriosis. What they found was that out of the 36 foetuses, 4 showed evidence of endometriosis. This was remarkable for two reasons, one for the fact that endometriosis had apparently been found in developing foetuses, suggesting that women are in fact born with endometriosis, and two because 4 out of 36 individuals with endometriosis is roughly what you would expect to find in an adult female population.

As interesting as this is, the question remains, how does this displaced endometrial tissue get there? Retrograde menstruation clearly cannot be the answer. The authors of this research suggested that there is an error during the foetal development of the reproductive organs. You see when the foetus is in its very early stages of development it is neither male nor female, it has two sets of ducts, the Wolffian duct (which goes on to become the male reproductive organs) and the Müllerian duct (which goes on to become the female reproductive organs). There is a nice diagram of the various ducts and how they develop here.

The body sends signals to these ducts telling them to become the correct part. So if you were a female the Wolffian duct would disappear and your body would send signals to different parts of the Müllerian duct saying “ok this bit becomes an ovary, this bit becomes a uterus, this bit is the endometrium, this bit becomes a vagina etc etc”. The trouble comes when these signals get muddled (possibly environmental toxicants are messing up the signal, or the messages your DNA is sending are wrong) you get the wrong bits growing in the wrong place. This is basically what these researchers are suggesting, that during the body’s early development, the signals are getting mixed for whatever reason and bits of endometrium end up developing where they shouldn’t (this is called ‘Müllerianosis’), then when puberty hits these bits of displaced endometrium that have been lying dormant since birth become active, and the result is endometriosis.

Overall it’s an interesting new theory on the origin of endometriosis to consider however, there will need to be much more investigation along this line before it is widely accepted, but provides the background work for future research. Additionally if this theory becomes accepted then the next question to ask will be “So what’s messing up the signals?” You can read the article in its entirety by following the links on this page.