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.

She’s definitely born with it

Way back when I first started this blog in April 2009 you may remember I reported on the finding that endometriosis had been discovered in unborn foetuses. This evidence pretty much provides conclusive proof that endometriosis is a disease you are born with. Well a very recent study from the same research group in Italy has confirmed their previous findings. After performing autopsies on 13 human foetuses, deceased from placental pathology or miscarriage, they found one 25 week old foetus showed clear evidence of endometriosis. It is now becoming clear that endometriosis is a disease you are born with, the only trouble is we still don’t know why.

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.