Friday, 28 March 2014

Endometriosis: Improving the wellbeing of couples

Whilst this blog is mostly concerned with clinical and lab-based research into endometriosis, there is other research being carried out that it equally informative and deserving of our attention.

In point of fact a new piece of research has been published from my old alma mater about the impact of endometriosis on relationships, with viewpoints from both the male and female perspectives.

So if, like me, you are in a relationship with someone with endo, or are a woman with endometriosis in a relationship (or even if you're not), this will be a very interesting read.

To read the full report click on this link

Endometriosis Awareness Month – Part 3

Endometriosis awareness month marches forward, quite literally. As you may have seen there have been awareness events taking place in many countries. Women with endometriosis and their supporters have been marching through major cities all over the world to help raise awareness for endometriosis and they have done an exemplary job.

Unfortunately I couldn’t make it to the UK event, but seeing the great turnout in all the cities and all the people who talked about it on Twitter/Facebook/blogs/forums etc, really showed just how much endometriosis awareness has changed for the better in the last decade. It certainly makes me hopeful for the future wellbeing of women with endo.

Speaking of the future, let’s have a look through some of the current research that will hopefully contribute to better prospects for women with endo everywhere.

We start then with a study from Denmark, which assessed the long-term reproductive status of women with and without endometriosis. To do this investigators examined medical records from tens of thousands of women across four national registries from 1977 to 2009.

 What they found was that, over the time course examined, women with endometriosis had around 7% fewer childbirths and 8% fewer naturally conceived children than women without endo. Not a massive surprise there; it’s well known that women with endo can find it difficult to get pregnant. Interestingly though the researchers found that as time went on (from 1980 to 1998), more women with endo had children, suggesting that it takes a long time for women with endo to conceive naturally (of course we must also remember that assisted reproduction wasn’t introduced until 1980). What is quite interesting is that they found that women with endometriosis were more likely to get pregnant with ART than women without by a small percentage.

This study also found that, for women with endo, the risk of ectopic pregnancy was twice that of women without. In addition, there were 21% more miscarriages in the group of women with endo. The reasons as to why this was the case remain unclear, it may be that the presence of active endometriosis in the pelvic area negatively affects pregnancy outcome somehow. Although, as the authors point out, there are other studies that have shown no increased risk of ectopic pregnancies in women with endo, so the jury is still out. In addition this study found that women with endo undergoing ART were at an increased risk of miscarriage, however another recent study found no increase in miscarriage risk. So whilst these studies are informative, they only represent the experiences of a certain population of women. 

One of problems with this study was that some of the women said to be diagnosed with endo, were only suspected to have it, not because they had laparoscopic diagnosis, meaning they may have had endo, or not, or another condition. Another issue is that this study wasn’t able to follow women throughout their entire reproductive life, so they didn’t have a complete picture of all the women’s reproductive history.

Nevertheless, what this study does tell us is that women with endo may require special prenatal care. If results such as these are the same in other countries it certainly suggests that additional provisions need to be made for women with endo (such as better monitoring of foetal and maternal health) and the medical community needs to be aware of this.

Moving on then, from the problems women with endo have to suffer with, to the ways in which the medical community is trying to solve those problems. Laparoscopic surgery is considered the best way of surgically removing endometriosis, but you need a good surgeon at the helm. Another problem is that not all endometriosis can be found and removed easily. One of the most troublesome forms of endo is deeply infiltrated endometriosis (DIE). This type of endo is very commonly associated with the most painful symptoms, such as chronic pelvic pain, painful sex, painful urination and painful bowel movements (depending on where the DIE is and how deep it has infiltrated).

Removing DIE is quite a challenge then, even for a skilled surgeon, which is why some surgeons are now trying robot assisted laparoscopy. Using ‘the robot’ does offer several advantages, such as better precision, better visualisation and more freedom to manoeuvre the instruments. Of course the downsides are that a surgeon will have to learn to use the robot and it is very, very expensive. Another point raised it that using the robot lacks a ‘tactile response’, that is, surgeons cannot feel the resistance or tension of some organs/tissues that might give them an idea of how to proceed with the surgery.

Therefore studies are needed to assess how well robot assisted surgeries fair in removing DIE. That is the subject of a recent paper from centres across the world.  This study looked at robot assisted operative results from 164 operations on women with DIE in different places to see how well the surgeons and patients faired.

Overall the average time for surgery was 180 minutes and the average hospital stay was 4 days, which, given the low rate of complications, seems like a long stay to me, but that may be due to different approaches to post-operative care in different centres/countries. 113 patients were followed up after an average of 10 months and 86.7% were found to be pain free, which is a god result by anyone’s standards.  

Other studies have shown that while robot assisted surgery takes slightly longer and is comparable in outcomes to conventional surgery with respect to stage I and II endometriosis, it may be beneficial for advanced stage endometriosis and has a lower risk of needing laparotomy.  

At the moment then the current evidence suggests that robot assisted and normal laparoscopy perform equally well in some respects, but that robot assisted surgery may be beneficial for women with advanced stage disease. However, more studies directly comparing the two surgical approaches are needed.

I will leave you then with an unusual case of endometriosis. A 52 year old man was sent for a CT scan after complaining about pelvic pain. What the doctors found was an inch long ‘cyst’ that, upon closer examination was found to be a tube like structure, with a muscular layer on the outside and an endometrial layer on the inside. Essentially this was a small uterus, but as it is displaced endometrium it still classifies as endometriosis (or endomyometriosis, to be technically correct). Unlike other male endometriosis cases, this patient hadn’t been undergoing any hormonal therapy and the man in question had no genetic or hormonal abnormalities that could account for this finding. In addition the patient had previously undergone surgery for a hernia near the area in which the ‘uterus’ had been found, so one would think this area of the body would have been examined thoroughly previously, indicating this problem may have arisen quite recently.

Friday, 7 March 2014

Endometriosis Awareness Month - Part 2

Endometriosis is a disease of many facets, pain being the most obvious and prevalent one. However there are other aspects of the disease that have a significant impact on the sufferer that receive less attention. One such aspect is infections.

Despite studies showing that women with endometriosis are more commonly affected by respiratory tract infections and recurrent vaginal infections, there is relatively little investigation into the reason behind this observation.  Some point to alterations in the immune system of women with endo that may reduce the body’s defence against to infection. Other studies found the menstrual blood of women with endo has higher levels of factors which promote the growth of certain bacteria.

Whatever the cause may be, it is still an area if ongoing interest and there have been two studies published very recently investigating different types of infection in women with endo.

The first study, from Japan, was designed to see if there is any association between endometriosis and endometritis. Endometritis is often confused for endometriosis, if only for the similarity of the words, but they are in fact very different conditions. Endometritis is an inflammation of endometrium, which can be due to infection by a number of different bacteria and, although generally may not present with any symptoms, it can cause lower abdominal pain, vaginal discharge and fever. 

This study took 34 women with endometriosis and 37 without endometriosis, who were undergoing hysterectomy, and analysed their endometrium for signs of endometritis. Most of the characteristics of the women (such as age/BMI/menstrual cycle length) didn’t significantly vary. However, adenomysosis was found in 47% of the women with endo, but only 8% of the women without endo. In addition, fibroids were found in 68% of the women with endo and 95% of the women without (but we must remember these were women scheduled for hysterectomy, so it would be expected to see high percentages of uterine conditions).

After analysing the endometrium the investigators found there was a significant association between having endometriosis and chronic endometritis. 53% of the women with endo were also diagnosed with endometritis, but only 27% of the women without endo had endometritis.

Breaking endometriosis cases down by stage also yielded some interesting results, below is what the investigators found

Endometriosis Stage
Percentage of women with endometritis
Stage I
Stage II
Stage III
Stage IV

The increase in endometritis as stage increases (up to stage III) is an interesting find, but the number of women used for this part of the analysis was very small, which might make the results seem more significant than they would be if you repeated this study with a larger number of patients. It would have been interesting to see if endometritis was associated with any specific symptoms of endometriosis (such as dysmenorrhea, chronic pelvic pain, subfertility etc) as stage of disease is not really related to severity of symptoms.

When discussing their findings, the investigators suggested that endometritis in women with endometriosis may not necessarily be due to infection. Endometritis was defined, in this instance, by the presence of plasma cells (a type of white blood cell) in the endometrium not the direct observation of bacteria. The endometrium of women with endometriosis has a number of alterations; so there may be some factor produced by the endometrium of women with endo that causes these plasma cells to appear. It could even be that the cause of endometritis in women with endo lies outside the uterus. The pelvic environment is linked to the uterus via the fallopian tubes, therefore it is possible that some inflammatory factor produced by endometriosis might travel into the uterus and cause the changes that were observed in this study. As is usually the case with a new discovery, it raises more questions than it answers, but this certainly opens the door to new areas of research.

Onto the next study then, from Israel, which investigated pelvic inflammatory disease (PID) in women with endometriosis. PID is one of the common misdiagnoses of women with endo as the symptoms (such as pelvic pain, painful sex, heavy, painful periods) are quite similar to those of endo, though PID may not have any obvious symptoms. PID is caused by a bacterial infection in the vagina or cervix, which then spreads up into the uterus or fallopian tubes, it can be diagnosed with a cervical swab and is usually successfully treated with a course of antibiotics.

The investigators reviewed medical records of women admitted to their hospital, between 2008 and 2011, for either PID or tubo-ovarian abscess (TOA, basically an abscess of the fallopian tube or ovary) and divided them into two groups. Group 1 was 21 women who also had stage III-IV endometriosis and group 2 was 127 women without endometriosis.

Unsurprisingly when the records were reviewed the investigators found that women in group 1 had much more fertility treatments or IVF than those in group 2. What was surprising was the way PID or TOA affected women with endo. In this study, women with endo experienced significantly more severe PID infections which required a longer hospital stay, a higher rate of failure to respond to antibiotics and, in some cases, surgical intervention.

The authors point out that PID and TOA seemed to be more likely to develop in women with endo after undergoing fertility treatments, in particular IVF. This may have something to do with the association of ovarian endometriotic cysts (endometrioma) with TOA. The authors suggest that the blood and fluid that builds up inside an endometrioma might serve as a kind of ‘growth serum’ for bacteria and if a cyst is ruptured (either naturally or is pierced during surgery or oocyte retrieval) it could potentially spread infection through the reproductive organs.

It would be interesting to repeat this study with more women of stage I-II endometriosis to see if the association holds, or whether severe PID infections are only more common in women with stage III-IV disease who have recently undergone fertility treatment. Obviously it would be beneficial to follow this up with studies into how to prevent severe PID in women with endometriosis or how to better treat it. The authors found that 76% of the women with endometriosis had already undergone at least one surgery which didn’t seem to decrease their risk of developing PID. Perhaps modifying surgical approaches to include cleaning of the pelvic area or treating women with ruptured endometrioma with antibiotics after surgery as a precaution may help? Again there is still much work to be done before we have some answers and better clinical care for women with endo can be achieved, but now the problem has been highlighted, we can work towards a solution.

As an aside, a fellow endo blogger and activist from Brazil who writes the Endometriose e Eu blog is currently in the running to win award for her writing. It would be awesome if anyone reading this could vote for her blog to help put endo in the spotlight in Brazil. Simply go to this page and in the top right you should see boxes to vote by email and Facebook, obrigado!

Saturday, 1 March 2014

Endometriosis Awareness Month 2014 - Part 1

It’s always a good thing when progress in endometriosis research gets into the public eye and the previous weeks have been just such a time. Many of you will have already seen the reports on sites such as here and here and, like me, are excited about where this new research will lead.

I remember reading about the announcement of this research project and the establishment of the MIT Centre for Gynepathology Research way back when it first started in 2009. I was particularly impressed by the fact that research was being conducted at MIT, one of the most prestigious research centres in the world. The research group is being headed up by Professor Linda Griffith, who you may or may not know was part of the team that created the mouse with a human ear on its back that was all over the newspapers in the late 90’s. Prof Griffith has had quite the illustrious career, decorated with numerous awards (including the MacAuthur genius grant, which as the name suggests, is not handed out to just anyone), but it was the experiences of her teenage niece with endometriosis that brought home the dire need for better understanding of the disease and reproductive health in general. So, she and her collaborators established the MIT Centre for Gynepathology Research and have been busy ever since trying to pick apart this disease we call endo.  

Now the fruits of their labour are being harvested and it’s time to see what impact this will have and where this can take us in the future.

Given the prestige associated with this research group it is unsurprising that this article is a tour de force of endometriosis research, which should be held aloft as a shining example of how science is meant to be done. What do I mean by that? Well ideally any investigative research should tell a story, almost like a crime novel. There should be a beginning, where the problem is established and suspects identified. A middle, were the suspects are narrowed down and the evidence against them investigated. And an end, where the culprit is identified and the motives discussed. So then, let us read this article as if the researchers were detectives and we’re accompanying them as they try to solve a tricky case. The crime? Aiding and abetting endometriosis.


Please read this rest of this post in the voice of a grizzled, old detective, ideally in a darkened office with a cigar in one hand and glass of whiskey in the other, melancholic jazz music playing in the background.
We arrive then at the crime scene, a strangely familiar place I recall from pictures I feel I’ve seen a hundred times, I’m informed it’s the peritoneal environment, the area inside the pelvis where endometriosis is normally found. What could’ve caused endometriosis here?  Hmm that’s a tough question, perhaps better suited for another time, but it seems endometriosis had an accomplice; something was helping endometriosis cause suffering.  The signs point to inflammation, it’s known to cause pain and may even contribute to sub-fertility, there are so many factors that cause inflammation though this is going to be a tough case, but we’ve got to start somewhere.

I know what you’re thinking, why not just stop inflammation, there are drugs out there that can do that.  The detective points out there have been several studies and trials in animals looking at drugs that reduce inflammation. However, in animal studies although you can measure if certain drugs reduce the growth of endometriosis, you can’t measure factors like pain symptoms, infertility or disease recurrence, which are far more relevant to women with the disease.  

Speaking of which, time to see what the victims have to tell us in all this. 57 women with endometriosis were recruited for this investigation (who were divided into two groups based on whether they were taking treatment or not) and 20 women undergoing surgery who were found not to have endometriosis (called the controls).

Looking at the information collected on the women might give us some clues. For example, women with endometriosis (either treated or untreated) had significantly higher occurrences of dysmenorrhea, dyspareunia and pelvic pain than controls, even though the majority of the control women had leiomyoma (fibroids). Nothing much new there, we knew endometriosis was a real piece of work, wouldn’t hesitate to kick you when you were down.

Perhaps we need to look at the crime scene again, there’s seem to be some sort of puddle in here, ah yes, it’s the peritoneal fluid. Peritoneal fluid is basically just the liquid inside the pelvic cavity where all your reproductive organs are, but it can hold all sorts of clues. The detectives took the peritoneal fluid away for analysis, when they came back they told us although the amount of fluid didn’t vary much (less fluid was seen in women with endometriosis of the rectovaginal cul-de-sac and ovaries), the number of leukocytes was much, much higher in women with endometriosis regardless of whether they were receiving treatment or not. Leukocytes (pronounced loo-co-sites) aka white blood cells, they’re an important part of the immune system, usually the good guys, helping to fight off infection and remove harmful material from the body. Were they just witnesses or were they hiding something? The thing about white blood cells is they have a number of appearances, each with their own particular skills and talents in keeping the immune system running. The fact that there seems to be an excess of these cells in the peritoneal fluid of women with endometriosis makes it look like they were trying to help fight the endometriosis, maybe it’s all just a front.  

The detectives investigating this case needed to identify some specific factors that are linked to symptom severity, they needed to name some names. A crime like endometriosis, it’s got chronic inflammation written all over it. Time to line some punks up against the wall and get them to talk. The prime suspects are factors produced by the body that could cause inflammation, such as cytokines, chemokines and growth factors.

So the peritoneal fluid was collected and the levels of 50 different inflammatory factors within it were analysed. If any of these factors were found to be elevated in women with endometriosis that’d be the first list of suspects. It might even tell us who was responsible for helping endometriosis cause so much suffering. So did they find any increase? Yeh they did. Of the fifty different factors, ten were found to be associated with endometriosis. Further analysis showed that five of these factors were elevated in women with stage III/IV disease, although no specific factors were found to be associated with stage I/II disease.

Things were looking promising, the case was going well, but assessing endometriosis by stage doesn’t make things easy when it comes to identifying factors that relate to symptoms, mainly because the stage of endometriosis you have isn’t really related to what symptoms you get, endometriosis is tricky like that. Fortunately the detectives knew a way around this; they split the samples from untreated women with endometriosis into two groups. One group whose pattern of inflammatory factors was very similar to controls and another group who had at least four factors which were significantly different from controls. What they found was a collection of thirteen factors, a ‘fingerprint’ of increased inflammation associated with severe presentations of endometriosis with reduced fertility - looks like they had a breakthrough that could blow this case wide open. Unfortunately they weren’t able to find any fingerprints associated with any specific type of endometriosis (peritoneal/ovarian/deeply infiltrating) or associated with any specific symptom. This could’ve been down to the number/age of women investigated or the fact that most of the controls (i.e. the women they were comparing to endometriosis patients) had fibroids.   

That was a problem for another day though, other investigations could be carried out in the future with more women, the important thing was the fingerprint had been found, now it was time to see who matched. Something about those leukocytes we came across earlier didn’t feel right, the detectives thought so too. After running the fingerprint against different kinds of leukocytes, they got a hit. The finger was pointed squarely at the big eaters, aka macrophages. Like the other leukocytes macrophages were normally the good guys, it was their job to destroy diseased or infected cells, by engulfing and digesting them and to signal other immune cells to come join the party.
Turns out this isn’t the first time macrophages have been the prime suspect. They are seen to be very important in endometriosis; they’re just a bit screwed up though. Looking over the notes from another case it turns out they hate endometriosis too, they react to the disease as if it were a wound, trying to do their job and ‘fix’ the injury but end up secreting factors that actually encourage the survival of endometriosis instead. Kinda like trying to put out a bonfire with petrol.

Is that the end of the case though? Should we just lock up the macrophages and throw away the key? Maybe there’s more going on here, macrophages are trying to be the good guys, but something is telling macrophages to produces these inflammatory factors that help endometriosis - the detectives think it’s time to look even deeper into this mystery. Within the cells of your body there are all sorts of different signals that tell a cell what to do and how to do it. Amongst these signals are ones that switch on genes and one such signalling mechanism, called the JNK signalling pathway, was found to be responsible for the inflammatory activity of macrophages. So the true culprit has been found, case closed? Not quite, endometriosis has many different accomplices and although one of the major ones has been identified there is still much work to do. Damn, and I was only two days away from retirement.

Now we’ve got to the end of this story, if we run the story in reverse, we can see how this could lead to new treatments for endo. For example, if a drug is developed to inhibit the JNK signalling pathway in macrophages in the peritoneum, this will stop the macrophages producing the inflammatory factors that are associated with endometriosis which may reduce symptoms or shrink the disease. Although I have pointed out the limitations of animal studies earlier they still have some use. For example, using mice, other researchers have already shown that inhibiting this JNK signalling pathway reduces the growth of endometriosis (interestingly this treatment did not seem to alter hormone action). Whether or not this will lead to better treatments in humans remains to be seen, however it is certainly a great leap in the right direction.