Understanding endometriosis

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0:34All engine running. Absolute genius. Get this. Welcome. Welcome. This is the show where we bring you science. What that potentially means is discovery is advances research technology unbelievable. Without further ado, this is The Naked Scientist. Hello, welcome to The Naked Scientist podcast, the show that brings you the biggest breakthroughs and also talks to the major movers and shakers in the worlds of science, technology and medicine. I'm Chris Smith and today going under our microscope is the subject of endometriosis. What is it and what can we do about it?

1:16March marks Endometriosis Awareness Month. This is a condition where cells similar to the lining of the womb are found elsewhere around the body where they can trigger inflammation, bleeding and tissue damage. whilst in most cases these cells end up being found in the lining of the pelvis and related organs they can also crop up anywhere else in the body including even the lungs globally it affects around 190 million women of reproductive age and the symptoms include chronic pain heavier and more prolonged periods infertility gastrointestinal problems and impacts on sex well-being and mental health.

1:53Tarek Miskri is a gynaecologist at the Imperial Endometriosis Centre in London. Endometriosis, in a nutshell, is cells that look like endometrium, which is the lining of the womb, that are outside of the womb itself, often in the pelvis but sometimes in distant sites. And in these sites, it causes an inflammatory reaction that can cause pain, it can affect fertility and it can present with a range of different symptoms. If we look at the population of women around the planet, what fraction have this going on? Endometriosis is incredibly common depending on how hard you look for it at laparoscopy, which is a very common operation that we do to look inside the pelvis for a range of things.

2:39We can find endometriosis in up to one in ten women. If you look in groups of women who are struggling to conceive or have pain, then the frequency is much, much higher. It's estimated that about one and a half million women in the UK have endometriosis. It's World Endometriosis Month. So does this mean that this is genuinely a world problem? Or are there some populations that are much more prone to this? Others are relatively spared. Are there any other giveaways? Like if you have family members, are you more likely to get this yourself? What do we know about that sort of aspect of it? We definitely see that there's a genetic element to it.

3:17We see it run in families, for sure, but it's poorly understood to what degree genetics play a role and what degree there may be environmental factors that are contributing to this. other factors that may be important are the change in pattern of childbirth in the UK and other countries such as the US and Europe if you compare that to what we call the developing world where people have large families that's much more a model that we had in Europe 200 years ago and actually in a woman's entire reproductive life she may only have a relatively small number of periods because from an early age when menstruation starts she may then be pregnant or breastfeeding for the majority of her reproductive years whereas of course now it's much more common to have a smaller number of children and to delay childbirth until a later point of a woman's life.

4:10And how will a woman who's got this going on tend to present? What sorts of symptoms will she complain of? The most common presentation of endometriosis is pain. Pain typically during the periods but not necessarily limited to then and the second most common presentation will be with a delay in conceiving. Although it's important to understand that many women with endometriosis will have no problem getting pregnant. And why does it cause those symptoms? Endometriosis causes problems with fertility, probably through two mechanisms. Adhesions, which is scarring in the pelvis as a result of the inflammatory reaction that sticks things down.

4:50So the fallopian tubes, which are essential for transporting the egg and the sperm and the embryo, gets stuck down and can't function normally and that causes a physical problem with conception. The second mechanism is probably through the environment in the pelvis affecting egg quality, egg transport and embryo transport through inflammation. Tarek Misgree with an introduction to endometriosis and how does it affect people. He's based at the Imperial Endometriosis Centre in London. Now endometriosis isn't just a physical condition though, it does take a big psychological toll and it can affect education and willingness to go to school even and therefore impact life outcomes.

5:34This can be especially problematic when a woman doesn't realise what's behind her symptoms or when others aren't sympathetic towards the problem. Some say they feel unheard, others are told they're weak or that their discomfort is all in their heads. This was the case for our next guest Monica Thomas who was just 13 when the problem first started with period pains and extreme tiredness. Her pain worsened during menstruation and she often ended up skipping school. It started off with period pains and I was really tired and I didn't want to go to school especially when I was on my period I would bunk off from school and we lived in the countryside side so I would just go and lay on a field that's the only way I could really get comfortable was to just lay flat.

6:19My friends at school they all had periods but they didn't really have kind of the difficulties that I did they were able to manage like going to school and manage PE and things like that I didn't really have the energy and I was just in too much pain to to do it so I did go to the GPs but they put me on the contraceptive implant and I was kind of sent on my way. so that's a hormone implant which although it's a contraceptive also helps to manage some of the symptoms of endometriosis did that improve the symptoms when you went down that path to start with initially it did yeah but then it didn't so then i had it removed the implant actually made me bleed for a year consistently as that year went on my pains and my cramps were getting a lot worse and then I then started to kind of suffer with bowel symptoms as well and that kind of, it just progressed quite quickly.

7:13But you've got a slightly unusual form of endometriosis because it hasn't confined its activity just to your abdomen. It's gone to other places in your case, I understand. It's gone to my chest on the outside of my lungs, so in my chest cavity, so my diaphragm pleura. It makes me have a lot of chest pain, A lot of wheezing, breathlessness, struggle with flights of stairs Even down to laughing, crying, hiccuping, sneezing It causes me such bad pain, even when I'm not on my period So this is every day of my life I have really bad, severe chest pains I have points of the month where it's a lot worse than others But I live with this every day And even just a flight of stairs is really, really challenging for me and there are days where I cannot get out of bed because I'm in too much pain.

8:07It runs its risks, so we have risks of bleeding into the chest cavity and risk of lung collapses, but at the moment none of that has been found on any of my scans, but the lesions are there. So this has had a huge impact on your life, hasn't it? Yeah, massively. It's changed my whole entire existence and the impact that has to not only your physical health, but also your mental well-being and your kind of self-belief and how you feel about yourself. It changes everything. Monica Thomas there. Well, now we're going to examine what actually causes endometriosis. Leah Wenger is a co-founder of Soclana Bio.

8:52They're a research company that are developing better ways to study and diagnose the disease, approaches which they hope long term are going to lead to new drugs to treat it. The diagnosis of endometriosis will mean that that person effectively have bits of the uterus the lining of it the endometrium outside of their uterus so that can be anywhere from around the ovaries to within the intestines and have very varying ranges of infiltration severity. There is a huge range of how and when people manifest from very early on to very late and I think that's probably indicative that there are likely to be many different causes that instigate the disease but that there's probably a shared mechanism of how it propagates and how it persists and how these lesions just don't go away.

9:39One proposal is that when a girl or woman has a period that you get this process of retrograde menstruation that instead of things just coming outside the body some blood goes up inside taking endometrial lining with it and it then gets all over the place and that might be one way in which it accesses other areas. Correct and that's probably one of the most well accepted theories of the disease and it's quite unique to primates in a way because actually the way our anatomy is structured where our fallopian tubes within the uterus connect with our ovaries there's a gap and that's where we think that these cells and the menstrual fluid can effectively fall into that gap and migrate.

10:21That can explain many, many cases in terms of where these lesions are, what happens. But actually, really interestingly, some studies have shown that if you look at a woman during surgery, for instance, if a woman has a period during surgery, many women will actually show signs of this retrograde menstruation, but don't have endometriosis. In fact, up to 90 % of women can be thought to have this retrograde menstruation, but only 10 % are thought to have endometriosis. So although it's a very well accepted theory, there's still a lot that isn't explained, both scenarios in which that might not happen, and actually why in some people that happens and they don't have endometriosis.

10:59The question then becomes, well, if this happens to everybody, why do the few then get the problem that they get? Do we know? Do we have theories for that? There's certain theories, but I would say that there isn't one that's very, very well accepted. The really interesting thing is you're talking about 10 % of the population, right? Or 10 % of women as an estimate, which means that there's not going to be one very specific genetic factor that explains why some people are more predisposed. In fact, the genetics aren't that strongly at the moment showing one mechanism. We believe that it's probably a lot of combinations of mistimed things that can happen, whether you have a big inflammatory event, a big infection, or certain events that might predispose you.

11:44The problem then happens is when you start getting endometriosis, it's a self-fulfilling feedforward system. So effectively, you have these lesions and you have more inflammation and it gets worse and worse. So there might be very different causes to getting them. But then once you have them, they establish very quickly through these feedforward mechanisms. And the point you're making about it perhaps being multi-mechanistic, Monica, whom we just heard from has actually got a problem in her lungs she's got the deposits also around her lungs she was saying so she actually has periods into her chest cavity which gives her excruciating chest pain as well so there must be more to it than just blood going the wrong way the the tissue must be getting into the bloodstream as well and in some people taking root elsewhere there's some evidence that cells can go through lymphatic systems so through vessels that are a bit like your blood vessels but length in the rest of your body there's some evidence that it could be stem cells from at birth and in some people you know that that effectively have these symptoms from puberty that could be an explanation where these these lesions have always been there and effectively just triggered at puberty so there's quite a few different ones and yeah that's part of the reason why it's such a hard disease to study.

13:00You mentioned primates earlier do they get this or are we unique in suffering from it as far as we can tell? Some non-human primates also get spontaneous endometriosis and actually there have been some interesting studies that say that if you just behaviourally look at some primates that might display pain during menstruation you can actually pick out some of the primates that have endometriosis so we are not fully unique. We're pretty unique in that not many species get it but non-human primates do. That must frustrate our efforts and ability to study it then if we haven't got an animal we can look at and watch the process like we can with certain diseases infections in a mouse let's say it must make it harder absolutely i mean i think that's a big hurdle that the field is facing as a whole primates are obviously not the kind of animal that you can easily and you should easily do lots of different studies on and so that's definitely why a big big motivation for starting cyclana and actually working on in vitro human models so models in a lab in a dish that can get as close as we can to humans because we recognise that currently the mouse models and other animals we use aren't up to scratch in terms of discovery process for the disease.

14:11So your approach is trying to capture menstruation in a Petri dish effectively so you've got something you can watch. Yes so capture the whole dynamics of that phase from the moment where the lining is built up all the way to the menstruation phase and capture how that can go wrong in disease, not just with cells, but also with their environment and the matrix in which cells tend to evolve. So we're collecting quite a bit of data. We're building these 3D models of the disease to really get to targets that if we have a therapeutic model and we know in a dish, this is what endometriosis looks like, when we have a drug that works, we're going to be quite confident that it's got a chance of working in patients.

14:50How do you actually make that work then? Do you literally culture cells that are similar to the ones that would line a uterus in a dish and feed them hormones to make them do what the uterine lining would normally do? Pretty much. We actually directly use cells from the uterus. And I think that's one thing that's really important with a disease that we understand so little about is trying to get as close as we can to that mechanism. And there's two ways to do that, either through biopsies that can happen quite routinely in the clinic, and we get some biopsy tissue and also through menstrual fluid because obviously with menstrual fluid you've got the opportunity of capturing cells that in at least in the retrograde menstruation theory are thought to directly seed those lesions so so we're collecting both both types and working with those and as you said prodding them with different hormones different cytokines and seeing how they respond to that.

15:37Lea Wenger she's at Suclana Bio and we'll hear from Lea's colleague Kevin Shalhoub a little bit later on about how their culture system is beginning to reveal some new avenues for treating endometriosis in the future.

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16:43Music in the programme is sponsored by Epidemic Sound. Perfect music for audio and video productions. This is the Naked Scientist podcast with me, Chris Smith. And this week we are examining endometriosis and what science is doing to try to tackle the problem. Before we look at the future, though, what does treating endometriosis look like right now? There's no cure for the condition yet. So what can we offer? Sharon Davidesco is a complex gynaecology and endometriosis fellow at King's College Hospital. So the way I describe it is as if the lining of the womb is a specialised army and these soldiers are trained to dig trenches and build a fortress every month during the period.

17:28What happens in endometriosis is some of these soldiers are exiled to other countries, the problem being that they're still responding to headquarters, the brain, And every month during their period, their signal comes to dig trenches and set off flares. And this is causing collateral damage in other organs like the bladder and the bowel. And as we've been hearing earlier on in the programme, that produces the onward consequences. What sort of management options are open to a woman suffering these problems, though? There are several options and choosing them is very individualised and will depend on the goals of the patient, whether it's managing pain or fertility.

18:14But they usually fall into one of four categories. The first category being the hormonal medications. So if you will, the signal that is coming to these exiled soldiers is oestrogen, a hormone. and the strength of this hormone leads to the volume of the symptoms. So the hormone medications turn up and down the volume of these symptoms. The medications in this category include the contraceptive pill or the progesterones. They don't make these exiled soldiers leave, but they do stop the signals from reaching them. There are also some non-hormonal options like anti-inflammatories or nerve blockers.

18:59These are really just earplugs. They help tolerate the noise of the signal, but they don't actually stop the conflict. So you've still got the problem, but it dampens it down. It basically deafens those soldiers to the signals from headquarters. So they're still loitering where they shouldn't be. They just don't cause as much damage. Exactly that, Chris. Another option within that group, if we want to have a local security guard, if you will, is putting in a hormonal coil or a myrena. It's a brilliant piece of engineering. It's a local solution. Instead of sending hormones through the entire bloodstream, which can have side effects for some patients, this is very much stationed at the gates of the womb.

19:43It keeps the environment quiet exactly where it matters the most. And it thins the lining so much that much of the ammunition of the painful period just simply isn't there anymore. Why does that approach actually work? Because these Mirena systems, which are secreting hormones just into the lining of the uterus, it goes around the body, doesn't it? That will stop more soldiers coming out of the lining of the uterus and going where they shouldn't. But what about the ones that are already elsewhere where they shouldn't be? Is there enough of a hormone dampening effect that that just makes them go quiet?

20:20That is the theory behind the treatment in this case is in addition to preventing there being, as we say, any more soldiers invading additional countries, we're also utilising the volume effect of turning down the oestrogen mass which is leading to these symptoms happening. So it's double of the effect and that's why it is so useful in cases of endometriosis. Most of the options you've discussed so far are ways of controlling the symptoms and stopping the inflammation that's causing a lot of the problem. If a woman wants to get pregnant, is that when you're almost certain to need surgery if things are severe enough?

21:04Some women may require surgery in order to attain their fertility goals. However, in some cases, it would be recommended to pursue fertility independently and I would highly recommend to get fertility specific input before making any decision to have surgery for endometriosis. But we do know that endometriosis can reduce fertility by almost creating an assault course with roadblocks from sticky tissue inside the body and also because of the inflammation from the presence of the endometriosis causing a hostile environment and activating the immune system on overdrive. And for these patients, surgery can be very useful.

21:47And it is the only way to actually physically remove the disease. So if medications are about turning down the volume or giving earplugs, then surgery is about evicting the unwanted house guests. It isn't always the first step, but it is the most definitive one. Whether we use the traditional laparoscopy, the straight stick keyhole surgery, or the newer and more advanced robotic technology, the goal is always going to be the same, which is to cut out the disease by the roots rather than just burning the surface. What do you actually do to effect the evictions then? You're almost like sending the bailiffs in, aren't you?

22:27You're the bailiff. You're going in saying we're going to get rid of this tissue that shouldn't be there. How do you actually do it? We're talking about some very, very small areas which are very, very close to important other things in the pelvis. So we use our instruments, very small instruments, almost not bigger than a grain of rice, to delicately peel off areas of the disease from the tissues and the houses, if you will, that they're not meant to be squatting in. And by this way, we're really pulling it out from the roots so that it won't grow back afterwards. what do your success rates look like so if a woman has a bad problem with endometriosis and it can be linked to inability to fall pregnant so that's her goal she wants to get pregnant if you go in and do these sorts of surgeries how often does that result in the outcome that woman wants i'm not sure that the data for pregnancies exists however for pain relief we do know that there is a 50 to 60 percent improvement in symptoms quoted from national audits on surgical outcomes for endometriosis and this can vary widely for symptom by symptom and patient by patient but overall the surgeries are contributing to better outcomes especially if we then combine that with additional hormonal medications afterwards to treat any micro seeds of disease that might have been missed during the surgery.

24:03And what about recurrence? Once this has been done, how high is the woman's likelihood of having a repeat problem? Does it come back? The numbers that I most recently have seen quoted in the literature talk about a 10 % risk of recurrence within a year of symptoms after an endometriosis surgery. In the same place? Or does it then say, well, I've been evicted from that residence, I'll move elsewhere? It's a mix, Chris. Sometimes we find it exactly where it was and sometimes we do find new areas of disease. It is certainly a tough nut to crack, isn't it? Sharon Davidesco there, she's at King's College Hospital.

24:44Well, let's take a look to the future now. Kevin Chaloux is at Ciclana Bio. To recap what we were hearing about earlier, they're using a tissue engineering technique to effectively grow endometriosis in a culture dish so they can learn more about the condition itself and use that knowledge to inform the development of next generation treatments. It's really, really important to think about endometriosis like just about any other chronic inflammatory disease as something that happens at a tissue level. That That means not just the cells that are in that tissue, but also this kind of dark matter of the tissue, the extracellular matrix.

25:21And, you know, I'll talk about ECM a little bit. It's really the way to think about this is that it's just the kind of scaffolding is the structure that holds your tissue together. Pull on your skin or pull on your bones. It's matrix that's pulling back. That extracellular matrix is really, really important structurally. It's a scaffolding, but it also turns out to be a sort of template for the cells that signals to the cells about what to do in the tissue. And what we're learning is that when you start to look at this disease and other diseases like it at a more tissue level, thinking about the matrix and the environment of these cells, you suddenly start realizing that the way that cells behave within that are very, very different than when you look at them in isolation, which is typically what most drug companies and pharma have been doing and even researchers in general.

26:05So we're just trying to take a little bit more of a three-dimensional zoomed out view of what's going on within that tissue and understanding how cells behave within a diseased tissue in that sense, in a healthy tissue. And then from those behaviors, understand better how we can actually make diseased tissue behave more like a healthy tissue. In essence, then we've got cells sitting in this matrix, the scaffolding that holds them all in the right place. And that is sending signals to cells, guiding their behavior. So when we're looking at uterine lining cells and saying they're abnormal. They might not be abnormal at all.

26:41It might be that there's some aberrant signals coming off of the matrix that's making them misbehave. Is that what you're getting at? That's absolutely what I'm getting at. Yes, it could be that there's something a bit wrong with the cells, but we absolutely think there's something wrong with the matrix, such that if you were to fix the cells and do nothing about the matrix, then the cells would go back to being diseased again. And we've seen this in several instances. You can fix the cells, you can target the cells. But if you do nothing about that environment, that diseased environment, that environment contains the memory of that disease.

27:12And it's going to put the cells back into that bad place that they were in before. And that's exactly the kind of philosophy that we're taking in this company is that we want to fix that. We want to turn the whole environment into something healthy so that health is propagated as opposed to disease. How do you know, though, that the matrix is the initiator? How do you know that it's that that starts the ball rolling and it's not that there's an endometriosis problem and that makes the matrix become reactively unhealthy and then it becomes that self-fulfilling prophecy just smoldering we don't know that the matrix is what causes it uh it could be that there's an initial inflammatory uh event that causes it it could be any number of causes we're actually much more interested in what's propagating of the disease the point is is that you know if you just have a huge inflammatory stimulus, a huge inflammatory insult in a tissue, you can actually put the matrix into a place where it's essentially an inflammatory matrix.

28:06And this is, like I said earlier, that matrix can hold the memory of that inflammation. And so even if it's not the initiator, we believe that the fact that you have this sort of inflammatory matrix that kind of just keeps feeding forward, that keeps propagating, it keeps driving the disease. So even if it wasn't the cause, we must intervene in that matrix that's holding the memory of that disease. Can you make an inflammatory lesion in that way? If you know what the matrix looks like when it makes it happen, can you therefore confer that behavior on what was previously healthy matrix and thus prove this seems to be propagating the disease?

28:43That's exactly what we're doing. We are learning exactly what an inflammatory matrix looks like. And when we make that sort of inflammatory matrix and we put even healthy cells on it and give them the sorts of inflammatory stimuli they might experience on a normal basis in the endometrium, they actually get more inflamed than they would if they're on a healthy matrix. That inflammatory matrix makes them respond much more extremely to stimuli than they would in a healthy matrix. That's the essential point here. And what has changed about the matrix to make it do that? Is it that there are different proteins there?

29:18Are there different cells that join the matrix? Do you know what puts it into that inflammatory or pro-inflammatory state? We're in the process of learning a lot about what puts it into that inflammatory state. There's some extreme cases of that inflammatory state, things like fibrosis, which many people possibly have heard of. You know, fibrosis can be heart disease, things like that. You can get cirrhosis of the liver as fibrosis. This is an extreme case of that, where you have collagen, which is one of the main components of the matrix. And I think many people have heard of that. It's the main component of a lot of your tissue matrix.