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.