Thursday, 12 July 2018

And Now for Something Completely Deferent

I’ve wrote before on the subject of unusual presentations of endometriosis, mostly because they’re like a fascinating puzzle to unpick within the vast puzzle that is endometriosis, like a jigsaw made of rubik’s cubes. But it’s not only the inherent fascination with such oddities that interests me, but the fact that the unusual ways in which endometriosis occurs could tell us a great deal about how endometriosis arises in the vast majority of other cases. Perhaps the most unusual presentation is male endometriosis. I’m not talking about endometriosis is trans-men (mostly because there is little to no research in this area, which is a definite shame and something I would like to see rectified sooner rather than later), but endometriosis in cis-gendered males who, by all logic, should not be able to develop a condition that is typically associated with the uterus. It is something that should be impossible, but it happened anyway. I have covered this topic before, but there was another case report published in January of this year so I think its worth looking at this one and going over what this could mean for endometriosis in the wider context.

The case report (link to the full text article here) describes a 40 year old man who came to his doctor with intermittent abdominal pain moving down his right side, described as “a constant dull ache with intermittent sharp pains” and “feelings of being bloated with progressive abdominal discomfort”, is it sounding familiar to anyone yet? Aside from asthma and being a bit obese the patient was medically unremarkable, no long-term serious illnesses or unusual medical conditions to hint at what might be the cause of his pain, he didn’t even present with any other symptoms that would give the doctors a clue as to what the cause of the pain might be (like painful urination, painful/bloody bowel movements or diarrhoea that may indicate an infection or gastrointestinal issue). So the doctors decided to perform a series of scan and found a mass, measuring roughly 9cm x 5.6cm (about the size of a avocado) between the bladder and the rectum apparently arising from the vas deferens (the tube that takes sperm from the testicles to the prostate and the inspiration for the incredibly tortured pun the title of this post). If you look at figure (a) at this link you’ll be able to see it as the roundish, pear shaped object roughly halfway between the small white bit near the bottom and the long white spine.

The doctors concluded the mass was a fluid filled cyst of some kind so decided to perform a laparoscopy that then became a laparotomy to fully explore the pelvic area and remove the mass, which was then sent away to the lab for testing. When the results came back they had a “highly unexpected” diagnosis of endometriosis. The cyst was filled with a cloudy brown fluid while the lining was composed of endometrial epithelium and stroma (the cells you would normally find in the endometrium or an endometriotic cyst). In fact, the description of the cyst they found has some definite similarities to ovarian endometriotic cysts. The question posed then is, where on earth did it come from? Perhaps the few other case reports of endometriosis in males could help answer this.

The authors of this case report have gone through the literature and found all the other cases of endometriosis in males, which you can find in the link to the full text, but I’ll briefly summarise below

Patient Age
Location of Endometriosis
Risk Factors
Prostatic urethral crest
Not reported
Estrogen therapy for prostate cancer
Not reported
Attached to bladder
Stabbing pelvic pain
Surgery for hernia, liver chirrhosis
Swelling of the testis
Hormone therapy for prostate cancer
Surgical removal of testes
Scrotal pain
None reported
Between vas deferens and testes
Mass felt on epididymis
Hormone therapy for prostate cancer
Surgical removal of testes
Attached to bladder
Lower abdomen pain
Surgery for hernia, liver chirrhosis
Lower abdominal wall
Not reported
Hormone therapy for prostate cancer
Not reported
Not reported
Hormone therapy for prostate cancer
Not reported
Blood in urine
Hormone therapy for prostate cancer
Abdominal pain
Cancer of the testes
Surgical removal of left testicle
Ureterovesical junction
Swelling of the kidney
Hormone therapy for prostate cancer
Not reported
Ductus deferens
Discovered during hernia repair
Surgery for hernia
Ureteral orifice
Blood in urine
Hormone therapy for prostate cancer
Found within a tumour of the testes
Cyst next to tumour
Surgical removal of right testicle
Not reported
Not reported
Hormone therapy for prostate cancer
Not reported
Vas deferens
Abdominal pain

This is very much a simplified version of all the data in the published paper, it contains a brief overview of all the important information that was given. Do you notice any common themes running through these case reports? In the risk factors column there is an awfully high incidence of hormone therapy for prostate cancer, usually using estrogen-like drugs. In addition to this, other cases had increased estrogen due to liver cirrhosis, or obesity. Estrogen cant be working on its own though; liver cirrhosis and certainly obesity are common enough, yet what you see in the table above are all the cases of this unusual presentation of endometriosis known in the world (at the time I’m writing this anyway).

A few theories on the origin of endometriosis could provide an explanation for what we are seeing here. One of the more popular ones suggests that, during the development of a human embryo, pieces of tissue get left behind that can go on to be stimulated by estrogen to become endometriosis. As the embryo is developing it has two sets of tubes that will go on to form the reproductive organs, one called the Mullerian duct, the other, the Wolffian ducts, and the gonads. Given a certain set of biological signals from the embryo one set of ducts will regress and the other will develop into reproductive organs and the gonads will develop into either testes or ovaries. In basic terms if the embryo has a Y chromosome (and the SRY gene) the Mullerian ducts will regress and the Wolffian ducts will develop into all the various tubes leading from the testes and through the prostate. If the embryo doesn’t have the SRY gene, the Wolffian ducts regress and the fallopian tubes, uterus, cervix and vagina develop.

However, if the Mullerian ducts don’t regress completely they could, in theory, leave behind patches of tissue capable of developing into endometrial-like tissue when stimulated by estrogen, which I’ve talked about before. If this were the case we would expect endometriosis to develop around the bladder and ducts leading from the testes to the prostate, indeed this is what we see if we look at the table above. While this is indeed an attractive theory, there has been very little scientific testing done to show that these patches of Mullerian remnant tissue exist or that they can transform into endometriosis when stimulated with estrogen.

One of the most important factors to take note of here is menstruation, or rather the lack of thereof. None of the males in these case reports have a uterus, or have periods, so this has wider implications for the theories of endometriosis origin in women. Certainly, it casts serious doubt over the prevailing theory of endometriosis origin, retrograde menstruation, which states that pieces of endometrium are refluxed back into the pelvic cavity, where they implant and grow into endometriotic lesions. Sometimes understanding how something doesn’t work can be as important as understanding how it does work.

Monday, 18 June 2018

Prove It

Well, it’s been far too long since I’ve posted anything here, but after a bit of an absence I’m back again and ready to get spreading the word of endometriosis research. Firstly a quick note on where I’ve been. I finally finished my PhD (more on that in the future), which required a year or so of pretty hard concentration in the final race to the finish, this meant I didn’t have as much time write all the other things I like, such as this blog! But I didn’t forget about it and have been constantly reading all the latest endo research and occasionally updating the @EndoUpdate Twitter account ready for my return here.

For this blog post I’d like to talk about something that is not directly related to endometriosis, but is still very important, which I think everyone needs to know a bit about, and that is the criticism of evidence. We use our judgement of evidence in our everyday lives all the time, it’s what helps us survive, and stops us getting all our money stolen by an email claiming to be from a Nigerian prince looking to offer us millions in exchange for all our bank details. For some things the definitive proof of whether something is true or not can be fairly straightforward, or it can be hard to ascertain, but by employing well tested methods of evidence analysis, we can arrive at a more accurate conclusion.

Let’s suppose you meet someone who claims to be able to turn iron into gold, and when you challenge them to do it, they can’t, then that’s pretty good evidence they weren’t telling the truth. But what if they did do it, what if the person waved their hands and instead of a lump of grey metal there was now a shimmering piece of gold? Would you automatically assume they possessed genuine transmutative abilities? Probably not, because the way to the truth and the way in which we analyse evidence is a complex deductive process that can require a great deal of testing to arrive at an acceptable level of certainty that what we have found is correct.

Let’s go back to the previous example, how would you test that the man who appeared to turn iron into gold was actually doing so? More than likely you would suspect he was performing a magic trick, so you might suggest replacing the initial piece of iron with your own piece, or one supplied by an independent person. You might suggest moving the activity to a controlled environment, where multiple people can observe at different positions, you might think of ways to test the supposed ‘gold’ afterwards to check that the outcome was genuine, or filming the trick with a slow motion camera. Either way you would come up with a list of ways to test the idea that this person can turn iron into gold and each way would give you a piece of evidence that would lead to an overall conclusion. The trick is judging what quality of evidence each of those tests would provide. In the biological and medical sciences the assessment of evidence quality is extremely important, because in many cases there are people’s lives resting on the outcome of certain experiments or trials. One of the staples of evidence quality judgement in this field is the hierarchy of evidence, which often takes the form of a pyramid like the one below (although there are minor variations on this, the basic premise remains the same), with the highest quality of evidence at the top and the weakest at the bottom.

This is a simplified example of what constitutes good and bad evidence and is being somewhat superseded by other evidence classification systems such as the GRADE system, which I won’t go into here, but I recommend following the link and reading a bit about.

Let’s talk a little bit about each stage of the hierarchy of evidence and what they mean. At the bottom of the pyramid you have case reports, opinion papers and letters. The last two form expert opinion that, although may be well informed, is still only the view of an individual or small group who may be biased towards ideas they favour themselves or represent one specific view point out of many, equally or more valid ones. Case reports are individual reports of something occurring, we see these fairly frequently in endometriosis, for example here and here are examples published within the last few months. These are still important as they document unusual presentations or novel ways to treat a disease, but they are still only the experience of a small number of people.

Next is animal trials and in vitro studies. This is basic lab based research involving animals or models of disease using cells or tissue grown under lab conditions. This is very useful basic research as it informs the direction for all the above steps in the pyramid, but it has its limitations. For example, animal research has the obvious drawback of not being done in humans, but there are some experiments that need to be performed in the context of the complexity of a living organism, but are simply too dangerous to test on humans. Often animal and in vitro (cell and tissue) experiments may only test a specific component of a disease under certain conditions and not the disease as a whole, so while it gives us an indication as to how pieces of the overall puzzle fit together, or help us to answer a specific question, it doesn’t necessarily tell us how it will translate to the human body. This type of research is very often misinterpreted in media outlets, for example I wrote before about how evidence of this kind can be misrepresented or overblown in media reports, leading to false impressions being given to the reader for the sake of sensationalism. This type of problem is called ‘extrapolation’, in that a piece of work focussing on something narrow, like the behaviour of cells in a lab experiment, is widened to the belief that this same effect will be observed in human body. It would be like seeing a horse running really fast, and observing the horse has legs, and you see you also have legs, and believing that therefore you must be able to run as fast as a horse because you both have legs.

Next up is cross-sectional studies, where information is collected from a group, or groups, of people at a certain point in their life to examine the relationship between a disease and whatever else the researchers are interested in. So let’s say for example we want to know what the diet of women with and without endometriosis is like in Eastern Canada. We could have 1000 questionnaires and send 500 to women with endo (these would be the cases) and 500 women without endometriosis (these would be the controls) in Newfoundland asking them about their diet and compare the responses. Sounds simple enough right? Well yes, on the surface, but there are lots of ways in which a study (and hence the evidence it provides) can be made better or worse. For example, in this hypothetical questionnaire, is it being sent out to cases and controls of roughly the same age? Do the cases have the same type of endo? Do they have the same symptoms? Are they from similar cultures that would have similar diets or very different cultures that would eat different foods? Do they have other conditions that may be affected by diet, or that diet might affect? How are you measuring food intake? Are you sure you have selected enough cases and controls to make the conclusions valid? What do you do if lots of people in one group don’t respond? These are just a few of the considerations that should be made when designing the study and taken into account when assessing the quality of the evidence that the results provide. If any of those considerations aren’t accounted for then this introduces error into your results, the more error there is, the weaker the evidence it provides.

The next rung on the pyramid is case-control studies. We discussed a bit about what cases and controls are in the cross-sectional study, but case-control studies are a bit different. For this type of study we would still be compared with endometriosis to women without like the cross-sectional study, but the information collected on them would be ‘retrospective’ i.e. asking them questions, or looking back through medical records, for information on things that happened in the past. The things we’re looking at could be any number of different categories, from exposure to environmental pollutants, to previous medications, to lifestyle and living conditions over time and so on. Let’s imagine a fictional study where we wanted to know if living in the countryside or the city during childhood years was associated with endometriosis in adult life. We could use a case-control study to ask women about where they lived and how rural/urban that place was. From this information we could compare the case and control groups to make a judgement on whether women with endo were more or less likely to live in an urban environment when they we children. The results of this would be presented as ‘odds’, and would be reported as something like ‘women with endometriosis are X times more likely to live in a city during childhood’. Now, can you see how this could be deliberately or unintentionally misinterpreted by a website, blog or news outlet? A finding such as this could easily become a sensationalist article with a title like ‘city living causes endometriosis!’, but that isn’t what the research was saying at all, it was just saying that women diagnosed with endometriosis as adults were more likely to live in a city as a child. It may be that there is some causal link between city living and endometriosis, but you would need a whole other study to confirm that idea. An important phrase here is ‘correlation does not equal causation’. This means that just because two factors change with one another, does not mean one is caused by the other.
A great example of this is at this link, which shows that, in the US up until 2007, the age of Miss America followed the exact same trend as the number of people killed by steam. Not very likely that those two are actually related. Another issue with case-control studies is that they rely on recalled information, in our example people had to recall the details of the environment they grew up in as children, which relies on the accuracy of human memory, which has inherent flaws. Another problem is that the association with urban living could be due to something else entirely (like the differences in diet between urban and rural communities), a factor that would be overlooked because it wasn’t included in the study design. Case-control studies are therefore good jumping off points for future research but don’t necessarily give the whole picture and the accuracy of their conclusions depends a great deal on how well they were designed. 

Moving up again, we get to the cohort study. Previously we have seen that a cross-sectional study looks at the present, case-control studies look at the past, but prospective cohort studies look at the future. Let’s say we want to investigate how the diet of women with endometriosis affects their day to day pain levels. With a cohort study you would recruit groups of women with endometriosis who have different dietary habits, like vegans, vegetarians, omnivores etc. then give them questionnaires to fill out (or get them to attend regular meetings with you) to gather information about their diet and day to day pain. This would continue for however long you planned the study for, it could be any amount of time really, a year, 3 years or even 20 years (studies conducted over a long period of time are called ‘longitudinal’). However long it was, once you reached the end of the study you would then be able to compare all the data from the different groups and see whether one type of diet was better or worse than the other for day to day endometriosis related pain. One thing you have to be careful of here are ‘cofounding variables’. Because people’s lives are complex and varied, diet is unlikely to be the only thing influencing pain, confounding variables in this study could be all manner of other factors like: exercise level, type of endometriosis, medication, stress, other medical conditions besides endo, healthcare access, financial stability, support network, etc etc. Fortunately, although these confounding variables can lower the significance of a discovery and weaken the strength of evidence it provides, if they are taken into consideration while planning the study and recorded as the study progresses, they can accounted for with fancy mathematical statistics. A solution to the confounding variable problem is ‘matching’ patients, this basically means making sure the women in your chosen groups have similar characteristics, for example making sure they are all of similar ages, BMI, activity levels and on the same medications. This does drastically reduced the confounding problem, but narrows the scope your result to a very particular population.
So let’s imagine you did this study and it turned out that, over 5 years, in Caucasian women with endometriosis aged 20-30, with moderate levels of exercise, not taking any hormonal medication or pain killers, those with a vegetarian diet experienced less pain than vegans or omnivores. It’s a very specific answer to a very specific question, and it would be very wrong for someone else to take that finding and report it as ‘women with endometriosis reduce pain with veggie diet’ because what our imaginary study found was not applicable to all women with endo, just the cohort we selected.

Getting into very strong evidence territory now we arrive at the Randomised Control Trial (RCT).   In the world of medicine, testing whether or not a new treatment, be it a drug or therapy of any kind, is the most crucial part to healing. Therefore having the tools and skill necessary to get good evidence on a new treatment is a shining example of how proper evidence testing can make a huge difference to people’s lives. Imagine that you have invented a drug, you’ve gone through all the lab testing and now you’ve got approval to test it in humans as a new treatment for endometriosis. How do you ensure the test is fair, and provides the best evidence that the drug does or doesn’t work? Fortunately you don’t have to worry about that because hundreds of years of painful scientific work, often costing the lives of many people, have refined the process to a randomised controlled trial. So let’s break down each step to see why it is useful.

Firstly you have a group of volunteers who should be matched like we discussed before i.e. relatively similar in terms of age, disease type, BMI etc, who are willing to test the new drug. The people will be allocated into different groups, but to do this they should be ‘randomised’. That is, the way in which people are put into groups is random, so you could identify people by numbers then use a random number generator to put them in one group or another. This is done to prevent people with certain characteristics (either known or unknown) all being put into one group, essentially it is done to make sure each group has a good mix of people.

The next step is assign a treatment type to each group. In the case of the new drug you have developed, this would be Group 1 and Group 2 for example. Group 1 will be the treatment group who will receive the real drug, while Group 2 will be the ‘control’ group who will receive a placebo or no drug at all. A control group is essential to make sure the outcome you are measuring (in this case let’s say it is pain relief), is due to the intervention you are testing (i.e. your drug). The reason for this is that some people may get better or worse without any treatment, or their symptoms might change as a matter of course. In essence without a control group how would you know that the drug you’re testing was responsible for pain relief and not just people getting better by themselves?
                Placebos play an important part in drug testing, these are things with no medical value whatsoever (like sugar pills) given to patients in the control group, but they look and are administered in the exact same way as the real drug. This is to take into account ‘the placebo effect’, a bizarre but very real effect noted in medical trials, where some people will notice improvements even if they are just taking sugar pills i.e. their body reacts in the same way it would as if it was taking the real drug. This effect doesn’t happen for everyone of course, it only occurs in a very small number of people, but it is enough to alter the results of clinical trial. The placebo effect is a particular problem when testing pain relieving drugs or anxiety and depression modulating drugs, where the psychology of a patient can alter the presentation of their symptoms. There is also the flipside of the placebo effect which is the ‘nocebo’ effect. This is where someone’s symptoms will get worse if they believe what they are taking will harm them, even if it has no active ingredients at all.  A neat little animation about placebos can be found here. You may very well ask, why bother with a placebo at all? Just give the control group an older version of the treatment. Well you’d be pretty sharp in this observation because the use of placebos has raised some ethical concerns, especially when dealing with drug trials for potentially life-saving therapies. Modern clinical trials usually will compare old and new treatments and may just include a placebo group to get a baseline of patient reactions to taking what they believe is a drug treatment.

A further step in an RCT is ‘double blinding’. You remember that the placebo and nocebo effect are problems because they occur when people have an expectation of the outcome, well the same goes for those who are recording the results. If you are a doctor monitoring patients taking a drug being trialled, and you know whether they are taking the real drug or placebo, you are more likely to notice positive effects in the treatment group than the placebo group, because the doctor too is biased by their expectation of a particular outcome. Double-blinding removes this by making sure that neither the patient, nor the doctors administering the treatment, know which the real drug is and which the placebo/old drug is. Usually this is achieved by giving the medications and/or patient groups code numbers instead of names. So patient 1 might be randomised into group 1 and given drug code named ‘DRG01’ by a doctor. Neither the patient nor the doctor knows whether group 1 is the treatment or control group and whether drug ‘DRG01’ is the real drug or fake drug, therefore their expectations cannot influence the results. Once the trial is complete and the results have been collected, the researchers will be given access to what the codes mean and they can decrypt which patient had what drug and do their analysis.

Once enough randomised controlled trails and other scientific investigations have been done on a particular subject, these can be put together into a Meta-analysis or Systematic Review. This is where experts in a particular area gather all the available evidence about a particular subject (like ‘does drug A perform better than drug B at relieving pain?’), review it and write it up as an analysis of the strengths and weaknesses of all the evidence they have found. This is considered to be the highest and most reliable form of evidence, because the weak evidence is sorted from the strong and by comparing the results of many strong studies we can finally arrive at a definitive answer to the original question.

As important as what understanding is evidence, is understanding what is not evidence.  There is an exhaustive list of things that are not evidence, but here are some of the most common ones: YouTube videos, personal anecdotes (something like “oh a friend of friend tried this and it really helped”), gut feelings, websites that don’t reference their sources (or that use weak evidence and over interpretation), random one offs and blind luck (we’ve all heard anecdotes like “my grandad smoked 20 cigarettes a day and lived until he was 90!” while ignoring the thousands upon thousands of people who die early due to smoking related illness) and most news reports about medicine. These are not sources of evidence in any way, shape or form and that is which is proposed without evidence, can be dismissed without evidence. Unfortunately our brain can trick us, or be tricked, into thinking in certain ways that mean we shun evidence in favour of unreliable information. A great book on the subject is ‘Thinking Fast and Slow’ by Daniel Kahneman, which to not do it justice, explains how our brains like to save mental energy where they can. When presented with an argument our brains will default to the easiest conclusion based on our previously held beliefs rather than go for the mentally taxing complex and logical process of information evaluation. Like I said, I haven’t done the book justice, but if you’re interested in why your brain thinks the way it does, it’s worth a read.

A factor that plays into how we respond to evidence is something that is very human and difficult to get rid of, and that is bias. We are all biased in some way, we think our sports team is the best, our kids are the best, our country is the best and even sometimes that our thoughts and ideas are the best and we will often defend those biases against even the most compelling evidence. Scientists are just as prone to bias as anyone else and, although we have systems of evidence assessment I have talked about today, it still creeps in. One of the best examples is ‘conformation bias’, which is looking for evidence that supports our beliefs while ignoring evidence that disproves it. It also encompasses being more critical of evidence that disproves what we believe while ignoring the flaws in evidence that supports them (a good example of this is ‘cherry picking’, where someone will go through hundreds of pieces of evidence until they find one or two that support what they believe). I have seen this many times in my professional life, and I’ll admit I’ve found myself doing it sometimes as well, so it’s a difficult trait to rid yourself of.  

Bias is also prominently evident in scientific publishing, where there is a huge bias towards only positive results being accepted for publication. It is based on the (false) assumption that negative results are inherently not worth as much as positive findings. However knowing that something doesn’t work (like a drug for endometriosis) is just as important as knowing it does work. When we are dealing with people’s health, we must try to put these biases aside for the good of those being treated, if this is not the case and a person, or organisation, are ignoring evidence in favour of their own biases, then they do not have the patients wellbeing at heart, and are instead concerned with someone else (like reputation, fame, or most commonly, money).

Ok so let’s suppose you are a research scientist, you’ve got your snazzy lab coat and have been working hard on a drug that you think would be a great treatment for severe period pain women with endometriosis suffer with. The imaginary drug you have developed is the very creatively named ‘Drug X’. This drug is based on a compound that is naturally found in bananas, but you have modified the chemistry of the compound to make it easier to absorb by the body, so it’s a different compound from the naturally occurring one. Over the years and years you’ve done all your scientific experiments and have managed to perform a well-designed clinical trial which has shown that Drug X is actually effective at reducing severe period pain in women with endometriosis after they have had surgery, you even manage to get the results published in a prestigious journal. Can you take a guess, based on what we’ve learned so far, about what could happen to your results? There is a chain of interpretation of your research, which is very close to the interpretation of research I have seen actually seen happen in real life, that can lead to your findings being misinterpreted and used to spread false information. Below is an example of what could happen after the initial research paper was published.

Although this particular example is based on entirely fictional research, you may see similarities between this and real world reporting of scientific research. I’ve used this as an example of something you may come across in day to day life and with what we have learned throughout this post, hopefully you’ll cast a more suspicious and critical eye over any such claims in the future. In addition, it is often very difficult for someone outside of academic/research institutions to get hold of an original article due to restricted access and most articles being behind expensive paywalls. Similarly, academic writing is often quite specialised and difficult to understand unless you happen to be an expert in that field, so the majority of people rely on interpretation of this research elsewhere and put their trust in other to interpret the research correctly. What I’ve been discussing today hopefully gives you a better idea of how to interpret the interpretations and exercise caution when reading news about endometriosis.

People often think of scientists as being very rigid and closed minded, and in some cases that may be true, but a good scientist is one who is willing to accept any conclusion based on the proper evidence, and the more remarkable the claim, the more remarkable the evidence required to prove it. Similarly a real scientist is willing to change their mind based on new evidence, even if it means rejecting a deeply cherished belief. Of course there are some things we simply don’t know yet, and our natural instinct is to try and fill those gaps in our knowledge with some sort of explanation, but sometimes it ok to say “I don’t know” and wait until the answer is proven. Those gaps in our knowledge though are ripe fruit for those who push fraudulent information and quack remedies. Scientists certainly don’t have all the answers, but the ones we do have are the best ones (for now).

If you read that someone is claiming they have a cure for endometriosis, hopefully what I’ve written here will give you the basis to understand the evidence they present to support that claim (if any) and how strong or weak that evidence is. There are also other further reading resources to really sharpen your evidence assessing skills, such as these few to get started:

Ben Goldacre’s Books – Bad Science and Bad Pharma and accompanying blog

The Systems to Rate the Strength of Scientific Evidence – by the Agency for Healthcare Research and Quality

A favourite quote of mine, which has been attributed to many people over the years is “keep your mind open – but not so much that your brain falls out

Thursday, 16 February 2017

Free Article Series: Fertility and Endometriosis

There are lots of articles being published on endometriosis all the time, (for example there were over a thousand articles either directly or indirectly related to endometriosis published last year) the main reason this blog exists is because the vast majority of these studies never get read by people actually affected by the disease. Mostly this is because these studies are published in scientific journals and/or hidden behind online paywalls only accessible to people in academic institutions, and even then the studies are written in very dry, scientific terms. 

Sometimes research in endometriosis makes it to the news, but often this is conveyed by journalists who, as well meaning as they can be, often misinterpret or exaggerate scientific information. I aim to write about the latest endometriosis research in a way anyone can read and understand, but there is so much being published all the time it difficult to cover it all here. Fortunately some research is made available for free for anyone to read, so I’m starting a series providing free articles on a certain theme each time. This time I’m going to be listing some of the most relevant, free articles concerning one of the major facets of endometriosis; fertility, how it affects women, how surgery affects pregnancy rate, how fertility therapy can help women with endometriosis and several other areas. Just click on the title of each article to be taken to the full text.

As mentioned though some of the articles are written in a rather dry prose and include a lot of detail about scientific methods and analysis that may not be relevant to the lay reader, so I would say the most important parts of some articles are the introductions/background and the discussion/conclusions, so feel free to skip to those parts to get the most interesting information. I’ve included the summary for each article so you can see which ones are of most interest to you.

Authors: González-Comadran M, Schwarze JE, Zegers-Hochschild F, Souza MD, Carreras R, Checa MÁ.
Published In: Reproductive Biology and Endocrinology. 2017 Jan 24;15(1):8. doi: 10.1186/s12958-016-0217-2.
Summary: Reproductive outcomes among women undergoing IVF and diagnosed with endometriosis-associated infertility do not differ significantly from women without the disease. Although women with endometriosis generate fewer oocytes, fertilization rate is not impaired and the likelihood of achieving a live birth is also not affected.

Authors: Nezhat C, Li A, Abed S, Balassiano E, Soliemannjad R, Nezhat A, Nezhat CH, Nezhat F.
Published In: Journal of the Society of Laproendoscopic Surgeons. 2016 Jul-Sep;20(3). pii: e2016.00053. doi: 10.4293/JSLS.2016.00053
Summary: In our patient population, 87.1% of patients with a chief concern of symptomatic fibroids also had a diagnosis of histology-proven endometriosis, which affirms the need for concomitant diagnosis and intraoperative treatment of both conditions. Overlooking the coexistence of endometriosis in women with symptomatic leiomyoma may lead to suboptimal treatment of fertility and persistent pelvic pain. It is important for physicians to be aware of the possibility of this association and to thoroughly evaluate the abdomen and pelvis for endometriosis at the time of myomectomy or hysterectomy in an effort to avoid the need for reoperation.

Authors: Ke X, Qian H, Kang L, Wang J, Xie Y, Cheng Z.
Published In: International Journal of Clinical and Experimental Medicine. 2015 Nov 15;8(11):21703-6. eCollection 2015
Summary: Surgery can improve the symptom remission rate and fertility of patients. Postoperative drug therapy does not improve the chance of pregnancy

Authors: Nesbitt-Hawes EM, Campbell N, Maley PE, Won H, Hooshmand D, Henry A, Ledger W, Abbott JA.
Published In: Biomed Research International. 2015;2015:438790. doi: 10.1155/2015/438790. Epub 2015 Jul 12.
Summary: These data provide information to women with suspected severe disease preoperatively concerning their likely postoperative fertility outcomes. Ours is a population with severe endometriosis, rather than an infertile population with endometriosis, so caution needs to be applied when applying these data to women with fertility issues alone.

Authors: Xu B, Guo N, Zhang XM, Shi W, Tong XH, Iqbal F, Liu YS.
Published In: Scientific Reports. 2015 May 29;5:10779. doi: 10.1038/srep10779
Summary: Endometriosis, a pathological condition in which the endometrium grows outside the uterus, is one of the most common causes of female infertility; it is diagnosed in 25-40% of infertile women. The mechanism by which endometriosis affects the fertility of females remains largely unknown. We examined the ultrastructure of oocytes from patients with minimal or mild endometriosis and control females undergoing in vitro fertilization (IVF) treatment. Our results suggest that decreased oocyte quality because of impaired mitochondrial structure and functions probably an important factor affecting the fertility of endometriosis patients.

Authors: Mavrelos D, Saridogan E.
Published In: Journal of Obstetrics and Gynaecology of India. 2015 Feb;65(1):11-6. doi: 10.1007/s13224-014-0652-y.
Summary: Endometriosis is a common condition affecting a significant proportion of women in their reproductive age. Apart from the impact of endometriosis on the quality of life of these patients, it also can have an impact on the potential of these women to have a family. The options for treating women with endometriosis desiring a family include surgery or assisted reproduction techniques. The choice of treatment will depend on the stage of disease and the characteristics of the couple seeking help. We review here the latest evidence on the management of endometriosis in women desiring fertility and describe our current practice.

Authors: Borghese B, Sibiude J, Santulli P, Lafay Pillet MC, Marcellin L, Brosens I, Chapron C.
Published In: PLoS One. 2015 Feb 13;10(2):e0117387. doi: 10.1371/journal.pone.0117387.
Summary: The influence of intrauterine environment on the risk of endometriosis is still controversial. Whether birth weight modifies the risk of endometriosis in adulthood remains an open question. For this purpose, we designed a case-control study involving 743 women operated on for benign gynecological indications from January 2004 to December 2011. Among patients with LBW, the risk is almost two-times higher to develop DIE. This association could reflect common signalling pathways between endometriosis and fetal growth regulation. There is also the possibility of a role played by placental insufficiency on the development of the neonate's pelvis and the occurrence of neonatal uterine bleeding that could have consequences on the risk of severe endometriosis.

Authors: Fadhlaoui A, Bouquet de la Jolinière J, Feki A.
Published In: Frontiers of Surgery. 2014 Jul 2;1:24. doi: 10.3389/fsurg.2014.00024.
Summary: Endometriosis is defined as the presence of endometrial-like tissue (glands or stroma) outside the uterus, which induces a chronic inflammatory reaction. Although endometriosis impairs fertility, it does not usually completely prevent conception. The question of evidence based-medicine guidelines in endometriosis-associated infertility is weak in many situations. Therefore, we will highlight in this issue where the challenges are.

(endometriosis covered in chapter 10)
Authors: Various
Summary: This guideline offers best practice advice on assisting people of reproductive age who have problems conceiving. It is estimated that infertility affects about one in seven heterosexual couples in the UK. Since the original NICE guideline on fertility was published in 2004 there has been a small increase in the prevalence of fertility problems and a greater proportion of people now seeking help for such problems. The main causes of infertility in the UK are (percentage figures indicate approximate prevalence): ovulatory disorders (25%); tubal damage (20%); factors in the male causing infertility (30%); uterine or peritoneal disorders (10%). In about 25% of cases infertility is unexplained, with no identified male or female cause. In about 40% of cases disorders are found in both the man and the woman. Uterine or endometrial factors, gamete or embryo defects, and pelvic conditions such as endometriosis may also play a role. Given the range of causes of fertility problems, the provision of appropriate investigations is critical. These investigations include semen analysis; assessment of ovulation, tubal damage and uterine abnormalities; and screening for infections such as Chlamydia trachomatis and susceptibility to rubella. Once a diagnosis has been established, treatment falls into three main types: medical treatment to restore fertility (for example the use of drugs for ovulation induction); surgical treatment to restore fertility (for example laparoscopy for ablation of endometriosis); assisted reproduction technology (ART) – any treatment that deals with means of conception other than vaginal coitus; frequently involving the handling of gametes or embryos.

Authors: Jin X, Ruiz Beguerie J.
Published in: Taiwan Journal of Obstetrics and Gynecology. 2014 Sep;53(3):303-8. doi: 10.1016/j.tjog.2013.02.004.
Summary: The use of laparoscopic surgery in the treatment of subfertility related to minimal endometriosis may increase the chances of future pregnancy and live birth

Authors: Dong X, Liao X, Wang R, Zhang H.
Published in: International Journal of Clinical and Experimental Pathology. 2013 Aug 15;6(9):1911-8.
Summary: Except reduced implantation rate in stage III-IV endometriosis group, no differences were found in other pregnancy parameters. This study suggests that IVF/ICSI yielded similar pregnancy outcomes in patients with different stages ofendometriosis and patients with tubal infertility. Therefore, IVF/ICSI can be considered as an effective approach for managingendometriosis-associated infertility.

Authors: Macer ML, Taylor HS.
Published in: Obstet Gynecol Clin North Am. 2012 Dec;39(4):535-49. doi:10.1016/j.ogc.2012.10.002.
Summary: Endometriosis has been associated with infertility; however, the mechanisms by which it affects fertility are still not fully understood. This article reviews the proposed mechanisms of endometriosis pathogenesis, its effects on fertility, and treatments of endometriosis-associated infertility. Theories on the cause of the disease include retrograde menstruation, coelomic metaplasia, altered immunity, stem cells, and genetics. Endometriosis affects gametes and embryos, the fallopian tubes and embryo transport, and the eutopic endometrium; these abnormalities likely all impact fertility. Current treatment options of endometriosis-associated infertility include surgery, superovulation with intrauterine insemination, and in vitro fertilization. We also discuss potential future treatments for endometriosis-related infertility.

Authors: Carvalho LF, Below A, Abrão MS, Agarwal A.
Published in: Revista de Associacao Medica Brasileira (1992). 2012 Sep-Oct;58(5):607-14.
Summary: Endometriosis, a highly prevalent gynecological disease, can lead to infertility in moderate to severe cases. Whether minimal stages are associated with infertility is still unclear. The purpose of this systematic review is to present studies regarding the association between pregnancy rates and the presence of early stages of endometriosis.

Authors: Lerchbaum E, Obermayer-Pietsch B.
Published In: European Journal of Endocrinology. 2012 May;166(5):765-78. doi: 10.1530/EJE-11-0984.
Summary: Vitamin D has been well-known for its function in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. There is some evidence that in addition to sex steroid hormones, the classic regulators of human reproduction, vitamin D also modulates reproductive processes in women and men

Authors: Bulletti C, Coccia ME, Battistoni S, Borini A.
Published in: Journal of Assisted Reproduction and Genetics. 2010 Aug;27(8):441-7. doi: 10.1007/s10815-010-9436-1.
Summary: Endometriosis is a debilitating condition characterized by high recurrence rates. The aetiology and pathogenesis remain unclear. Typically, endometriosis causes pain and infertility, although 20-25% of patients are asymptomatic. The principal aims of therapy include relief of symptoms, resolution of existing endometriotic implants, and prevention of new foci of ectopic endometrial tissue. Current therapeutic approaches are far from being curative; they focus on managing the clinical symptoms of the disease rather than fighting the disease. Specific combinations of medical, surgical, and psychological treatments can ameliorate the quality of life of women with endometriosis. The benefits of these treatments have not been entirely demonstrated, particularly in terms of expectations that women hold for their own lives. Although theoretically advantageous, there is no evidence that a combination medical-surgical treatment significantly enhances fertility, and it may unnecessarily delay further fertility therapy. Randomized controlled trials are required to demonstrate the efficacy of different treatments.

Access to articles is provided by US National Library of Medicine and National Institutes of Health as well as individual publishers

Friday, 3 February 2017

Endometriosis - Going Back to Basics

This is a blogpost I’ve been meaning to do for a while now. In this blog I mostly write about specific research with a pretty narrow focus, but what about the general information about endometriosis that people might want to know? There are of course many good resources out there in the vast expanse that is the internet, but at the same time there is misinformation and bad advice out there as well. With that in mind I’m going to try and put together a list of, what I think, is useful information for anyone starting their journey into endo, or those who simply want to know more about it. As the title says it is very much the basics so I’ve provided some links throughout this post to longer articles that cover certain topics in more detail. If I’ve missed out anything glaringly obvious, or there is something you’d like to know and want me to add to this list, add a comment to the bottom of this post, or tweet me @endoupdateblog

To begin with then, let’s start with the most obvious and basic question

What is Endometriosis?

Endometriosis, those six unwieldy syllables, means different things to different people. To the suffer it is a malign, invisible tormentor. To the doctors/surgeons it is a minefield of trial and error.  To the researcher it is an enigmatic mystery to be solved. But I doubt you came here to read about the philosophical descriptions of endometriosis (and if you did, sorry, maybe I’ll cover that in a different blog post). I’m guessing you want to know what endometriosis physically is. Before I do that however, some prerequisite knowledge is needed about the female reproductive system.

If you’re reading this you either possess, or at the very least know about, the uterus (womb).
Image Courtesy of By OpenStax College [CC BY 3.0 (], via Wikimedia Commons

Inside the uterus is a thick muscular layer called the myometrium, this is responsible for contractions during labour and those wonderful menstrual cramps I know women are so fond of [sarcasm]. The inner lining layer of the uterus is called endometrium, which is the ‘functional’ part. The endometrium is the part of the uterus that grows and sheds with each menstrual cycle and is responsible for the bleeding that I know women are so fond of [more sarcasm]. I’ve written before about how the endometrium and the menstrual cycle work so I won’t cover that here. The point to take away is that the endometrium is inside the uterus and during the menstrual cycle it grows and then breaks down and sheds off during menstruation.

Endometriosis is defined as patches of endometrium-like tissue (called endometriotic lesions) outside the uterus. Now I use the term ‘endometrium-like’ purposefully here. You see the patches of tissue that comprise endometriosis resemble the endometrium when looked at under a microscope. However several studies, which have analysed endometriosis and the endometrium at the molecular level, have shown there are numerous differences between the two tissue types. In any case endometriosis is often referred to as ectopic endometrium (literally meaning ‘out of place endometrium), or endometriotic tissue, whereas the normal endometrium is often referred to as the eutopic endometrium. Endometriosis is still responsive to hormones in a similar manner to the normal endometrium, so the theory goes that, throughout the menstrual cycle, endometriosis grows and bleeds, but unlike the normal endometrium, the blood has nowhere to go because its inside the pelvic cavity. Whether or not endometriosis does actually ‘bleed’ is somewhat contentious, but the presence of endometriotic lesions does certainly lead to inflammation, pain, subfertility and a myriad of other horrible symptoms depending on the extent and location of endometriosis.

Almost as important as what endometriosis is, is what endometriosis is not. Endometriosis is not an infection of any kind, it’s not communicable, it’s not a cancer and is not fatal, however just because something is not fatal, doesn’t mean it can’t take your life away.

Also you cannot define endometriosis purely by its symptoms, endometriosis is not just painful periods. Sure, some women with endometriosis have painful periods, some don’t, some women have pain so severe it is literally disabling, but endometriosis is a complex condition that requires holistic and often personalised approach. For example, one woman with endo may have severe pelvic pain, depression, anxiety and bowel pain, whereas another woman may have no pain or psychological symptoms, but is infertile, these two cases would require very specific and different approaches.  

Which brings me to my next point: the types of endometriosis.

Endometriosis is subject to a grading system depending on the extent and type of the disease, which you can read about in more detail here. Endometriosis is usually categorised into four stages (minimal, mild, moderate and severe), which depend on the type, extent and location of the disease.  Although the stages sound fairly descriptive of the disease, that is not necessarily the case. The stage of disease doesn’t always correlate with the symptoms experienced, so a woman with severe disease can have no symptoms and a women with minimal disease can have debilitating symptoms and vice versa.

In the broadest terms there are three types of endometriosis. Superficial endometriosis are lesions that can be found anywhere around the pelvic area. However, they are most frequently found on the surface of organs/ligaments/structures of the pelvis and can be as small as to be almost invisible to the naked eye, or about as large as a pea and any size in between. This type of endo comes in a variety of different colours: red lesions are considered to be ‘active’ in that they produce inflammatory factors and can have a dense network of blood vessels supplying them, blue/black lesions are similar to red but are seen as an older form of the disease, white lesions are thought to represent even older and inactive endometriosis, but often have a lot of scar tissue associated with them which can pull or restrict the surrounding tissue leading to pain. There is some evidence to suggest that superficial endometriosis undergoes a transition from red > blue > white, but how and at what speed this transition occurs isn’t known.

The next type is endometriotic cysts. These are most commonly found on the ovaries and are cysts filled with old blood that takes on a brown colour, giving them the undeservedly pleasant name ‘chocolate cysts’. These cysts can grow to be quite large, ranging from a few centimetres on average, to massive cysts in very rare cases. Because they affect the ovaries, endometriotic cysts tend to be associated with decreases in fertility, fortunately there are treatment options available to restore fertility to women with endometriosis associated subfertility, but I’ll be discussing that later on.

The third type is deeply infiltrating endometriosis (DIE). As the name suggests these are lesions that are actually dug into the tissue of the pelvis. Because DIE can penetrate into tissues it can be quite challenging for surgeons to remove completely and has been known to cause some of the more severe symptoms associated with endometriosis.

Although endometriosis is mostly found in the pelvis, there are other, rarer forms of the disease that can be found elsewhere, this is termed ‘extra-pelvic’ or ‘extra-genital’ endometriosis. I’ve tried to list all the places endometriosis can be found in the human body (that we know of) and it would seem it can be found almost anywhere. However, it is definitely worth remembering that endometriosis outside the pelvis is extremely rare, some cases of endometriosis in places you wouldn’t expect to find it have only been reported once.

What are the symptoms of endometriosis?

To put it one way; everything, nothing and all things in between. In less simplistic terms endometriosis can present with no symptoms at all. Some women are only diagnosed when they are having an operation for another condition, or when there is an investigation for something linked to endo, like fertility issues. However, for those who do get symptoms, the most common one is pain, pain pain pain and more pain, plus other things as well because apparently all that pain isn’t enough. The most common pain symptom of endometriosis is dysmenorrhoea (pronounced DIS-MEN-OH-RE-AH), which is defined as excessively painful periods that cause interference to the daily life of the sufferer and is experienced by half to two-thirds of women with endometriosis at some point in their life.

Now even I know that ‘normal’ periods (if there is such a thing) aren’t like the tampon commercials make them out to be; it’s not all blue liquid and laughing while playing beach volleyball. However, if your periods are causing you to regularly miss school/work or social occasions because they are so painful, this is not ok and could very well be a sign of an underlying medical condition, like endometriosis. I can’t emphasise this point enough because there is a massive delay in diagnosis experienced by women with endometriosis. On average this delay is 7-9 years, depending on where you live and what healthcare you have access to, so there can be shorter or longer diagnosis times. Either way such a long diagnostic delay is utterly unacceptable. Can you imagine going to a doctor, in excruciating pain, and being told “sure, I’ll tell you what’s wrong with you, in seven years”? Chances are you wouldn’t be happy about that. Unfortunately that is the reality many women with endo have to face.

A factor that doesn’t help the diagnostic delay is that the most accurate way to diagnose endometriosis is with a surgical operation called laparoscopy, where cameras are inserted into the pelvic cavity and the surgeon has a good examination of the pelvic organs. If the surgeon finds something suspicious they can take a biopsy and send it away to be analysed to confirm the presence of endometriosis. Finding endometriosis, of course, is dependent on the skill and experience of the surgeon.

There are non-invasive imaging techniques that can aid in the diagnosis of endometriosis. Ultrasound, for example, can be useful in finding ovarian endometriotic cysts, whilst MRI can identify cysts, distortion of the pelvic organs caused by endometriosis and can look inside organs without the need for surgery. However, these techniques have nowhere near the accuracy of actually looking into the pelvis with a camera. Unfortunately there is no accurate blood test for endometriosis, however many research groups are working hard on this, not as a replacement for laparoscopy, but as a means of identifying women at high risk of endometriosis and reducing diagnostic delay.

From the studies I’ve read and the women I’ve spoken to, the most significant contributor to this diagnostic delay is invalidation of the sufferer’s symptoms. Some women with endometriosis, particularly young girls with symptoms of the disease, are told by medical professionals that painful periods are ‘normal’. Women are often prescribed painkillers or contraceptive pills to manage their symptoms. Whilst these treatments can offer some relief, they can be ineffective in some women. These women can often face further struggle to get their symptoms taken seriously and can end up being labelled as hysterical (hysteria literally translates as ‘suffering of the womb’) and can have their symptoms ascribed to psychological rather than physical conditions.

It is true that women with endometriosis are at an increased risk of being diagnosed with mood disorders, depression and anxiety. However, studies have also shown that after successful surgery to remove endometriosis, depressive symptoms regress and overall emotional wellbeing increases. This is extremely important to note as it shows that the physical symptoms of endometriosis can be causative of the psychological symptoms, not the other way around. Of course it is possible that psychological disturbances could lead to alteration in pain perception, meaning that a vicious cycle can be established where pain leads to depression, which leads to increased pain sensitivity, which leads to more depression and so on and so on, but at the head of it all is the disease itself. 

Another of the common pain symptoms associated with endometriosis is chronic pelvic pain, which affects around a third of women with endo. This differs from dysmenorrhoea in that it doesn’t necessarily refer to pelvic pain during menstruation and can be caused by numerous other diseases or conditions. Chronic pelvic pain can be continuous or intermittent and can be associated with a variety of factors, for example exercise, specific foods or certain activities, or it may just come on randomly.

Painful sex (also known as dyspareunia – pronounced DIS-PAR-YOO-NEE-AH) is one of the symptoms of endometriosis that doesn’t get much attention despite the fact it affects a third to two-thirds of women with endometriosis.  Part of the reason dyspareunia gets little acknowledgement is that it is a very personal and private matter, which can understandably be difficult to talk about openly. Studies have indicated that women who have endometriosis (particularly DIE) behind the vagina, in an area known as the rectovaginal septum, are more likely to suffer from dyspareunia. One of the most challenging aspects of this symptom is the effect it can have on relationships. I myself know how important it is to have an open dialogue with partners to ensure they understand the physical limitations endometriosis can place on the sufferer, but I’ll be discussing more on that later.

There are whole host of others symptoms that can be associated with endometriosis that vary from person to person in terms of frequency and severity. Some of these include: leg pain, bloating, painful urination, painful bowel movements, heavy menstrual bleeding, spotting in between periods and fatigue.   

Endometriosis is also the proverbial misery that loves company. Rarely does a woman have endometriosis and nothing else.  I wrote a whole blog post on the subject, which you can read here, that gives details on some of the most informative studies looking at which other conditions are, and are not, found more frequently in women with endo.

As you can probably tell from reading this far, there are an awful lot of potential presentations and symptoms of endometriosis, some women may present with nearly all of them, some women may present with none. Each person’s journey with endometriosis will have elements that are shared with many other sufferers, but at the same time will have elements that are very specific to their own personal experience of the disease. This unfortunately, also makes endometriosis all the more difficult to diagnose and treat effectively.

Who gets endometriosis?

That’s a good question. Unfortunately there is very little good quality information available that could give us an answer. We do know that endometriosis affects around 1 in 10 women of reproductive age, but it would seem that endometriosis can affect anyone, of any age (I’ve read case reports of endometriosis in infants and women in their seventies, although I should point out these cases are very, very rare) and of any race/socioeconomic background.

Studies have shown that women with a family history of endometriosis are more likely to have the disease. This implies there is a strong genetic component to endometriosis and that the risk can be passed from parent to child. This doesn’t mean that a woman with endometriosis is guaranteed to pass the disease to her daughter; rather the chance of her daughter having endometriosis is increased. Endometriosis can also appear in women with no family history, the causes for this ‘spontaneous’ form of the disease are still hotly debated, in fact no-one truly knows why endometriosis occurs at all, but there are plenty of ideas, some of which I’ll be discussing later.

We do see that women aged 21-35 are more likely to be diagnosed than women of other age brackets. This has led to the misconception that endometriosis is a ‘career woman’s disease’, which afflicts those women who delay childbearing to further their career. This notion is not only insulting to women, it is also factually incorrect.

In my view there are two main reasons that endometriosis appears to be more common in in women in their mid-twenties to early thirties. Firstly, the symptoms of endometriosis tend to appear in adolescence, if you factor in the aforementioned diagnostic delay of 7-9 years then it becomes apparent diagnosed occurs in your mid-twenties.  Secondly, the notion that delaying childbirth is somehow responsible for causing endometriosis is simply wrong. There is some evidence to suggest that, during pregnancy, the symptoms of endometriosis can subside. However, symptoms can rapidly return after giving birth. Having children is in no way a cure for endometriosis. It is also incredibly insensitive to suggest to a woman, who has a condition characterised by high rates of fertility problems, that delaying childbearing is the cause for said condition, or that having children is the solution to it. That is like telling a person in a wheelchair that not walking is the cause for their paralysis and it can be cured by going for a jog.

From what I have learnt over the years it would seem that the reason endometriosis is so commonly diagnosed in women of a particular age range, is not because of the choices or lifestyle of the women in question, but because of lack of awareness and education about endometriosis. This is endemic, not only amongst the public, but also in the medical community. There are a great deal of myths and misinformation about endometriosis (several of which I have wrote about previously) and women with endo often have to become experts on the subject themselves in order to justify their illness to others.

I have encountered this ignorance personally, mostly in the form of bizarre theories about what causes endometriosis and how it should be treated (my favourite one to date was the doctor, yes a doctor, that said endometriosis can be caused by wearing your trousers too tight!). The most important weapon any woman with endometriosis can have is knowledge. Resources and information are plentiful, but the best piece of advice I could give is always ask for evidence. If someone suggests a treatment, ask what studies support their assertion. Where does the evidence come from? Are there studies that show how effective it is? Asking just a few simple questions like this can quickly reveal which claims have no basis in evidence.

Fortunately there are many great organisations out there that are fighting for better awareness and education for endometriosis and they are doing a great job of it. I myself have noticed a distinct improvement in endometriosis awareness in the last 10 years, so the future looks bright.

What are the treatments?

There are many treatments for endometriosis, but no cure. That itself is a contentious statement and lies in the tricky semantics of the word ‘cure’. Some would argue that surgery which removes all endometriosis and gets rid of its symptoms is a cure, but with endometriosis there is always a chance the disease could recur, maybe not for years or decades, but there is still a chance and if a person’s disease relapses, then they were never truly cured. We could get bogged down in this argument about meaning all day, so let’s not do that. Instead let’s discuss what the treatments for endometriosis are and their effectiveness.

Endometriosis is not a ‘one disease, one treatment’ affair, there are many treatment options open for women with endometriosis and it is often quite a minefield of trial and error to find the right one. Something that definitely needs to be considered is that endometriosis is rarely a disease of just one symptom. Endometriosis requires a holistic approach to therapy that considers all aspects and impact the disease has on a person’s life.

Most women when they are first diagnosed, or when they are suspected to have endometriosis, are prescribed painkillers. These vary in effectiveness with some women finding minor relief and some women finding no relief at all. In others the pain can be so severe as to require very strong painkillers like codeine or morphine. Painkillers though do nothing to treat the disease itself, merely to reduce the symptoms, if pain symptoms are severe then further treatment needs to be sought.

There are several types of hormonal medication that women with endometriosis may be offered, the most common ones are:

·         Birth control pills (BCPs) contain a form of estrogen and a progestin (which acts like progesterone). These are also known as ‘combined’ pills as they combine two hormone types in one pill. The rationale for using this treatment is that endometriosis needs estrogen to remain active, the pill reduces the amount of estrogen in the body to a constant low level. You may wonder why, if endometriosis needs estrogen, does the pill have estrogen in it? Estrogen is added to prevent some side effects like breakthrough bleeding and actually works to make the pill a more effective as a contraceptive. It is thought that endometriosis requires a certain threshold of estrogen to remain active. The combination pill contains such a low dose of estrogen that it is below this threshold and therefore safe for treating endometriosis.

There are many different brands and formulations of birth control pills so it’s always worth asking your doctor what the exact composition of your medication is (although this should also be provided on the instruction insert that comes with your medications). The way in which the formulation of the pill varies determines whether it is monophasic or multiphasic. Monophasic pills contain the same levels of each hormone in each pill, multiphasic drugs on the other hand, deliver different levels of hormones over the course of a month. The multiphasic drugs were developed in order to reduce some of the unwanted side effects of monophasic drugs.

·         Progestin only pills (POPs), or mini-pills, only contain a progestin; these tend to be used if a patient finds the side effects of the combination pill intolerable. At present there is no evidence to suggest whether POPs or BCPs are better for the treatment of endometriosis, but because of how differently each woman may react to each drugs, it is difficult to say which is best. Medical guidelines suggest BCPs and POPs are used as a first line treatment for endometriosis and can be safely taken for long periods of time, provided the side effects are tolerable. Progestins can also be given as an injection (the most well-known being depo-provera), and via an intrauterine device (commonly known as the coil), which provides more local delivery of the drug, in theory reducing the side effects. Injections and the coil have the advantage of providing long term therapy without having to take pills every day, but the disadvantage that, if side effects become problematic, the drug cannot be stopped as easily as pills can. It is always a good idea to discuss with your doctor which form of treatment is right for you, particularly as medications designed to prevent conception aren’t ideal of you want to conceive anytime soon.

·         Gonadotrophin releasing hormone analogues (GnRHa) are, as the name suggests, drugs that mimic the effect of GnRH in the body. These drugs work by dramatically reducing the production of estrogen by the ovaries, essentially putting the body into a false menopause and are generally used as a second line treatment for endometriosis. Although GnRHa’s have been shown to have some beneficial effects in reducing the symptoms of endometriosis (however evidence shows their benefit is comparable to that of other treatments like the coil and BCPs) and improving conception if given for 3 months prior to trying to conceive, they often come with a hefty amount of side effects and cannot be taken for longer than 6 months without increasing the risk of causing permanent health problems. The menopause-like state they induce can result in side effects like mood swings, weight changes, hot flashes, vaginal dryness and loss of bone density to name but a few, which means this is where careful consideration needs to be made in terms of downsides weighed up against benefits.  A popular option offered to women to reduce the side effects of this treatment is ‘add back’ therapy. This is essentially hormone replacement therapy (HRT), where a small dose of estrogen is given to alleviate the side effects of estrogen withdrawal. You may wonder why or how estrogen can be given to women when estrogen is implicated in the growth of endo. It is believed there is a threshold level of estrogen needed to stimulate the endo, any dose of estrogen given below that level shouldn’t cause the growth of endometriosis. Nevertheless any women on HRT who experiences a relapse of endometriosis symptoms needs to consult her doctor as soon as possible.

·         Aromatase inhibitors haven’t been used to treat endometriosis for a very long time so there isn’t as much evidence about their effectiveness as other drugs. Sometimes endometriosis doesn’t respond to other forms of treatment mentioned above. This can be due to the endometriotic lesion having an enzyme called ‘aromatase’ active in it. Endometriosis relies on estrogen to stay active, therefore most treatments either limit or reduce the amount of estrogen the ovaries produce. However if endometriosis has the aromatase enzyme, it can synthesise its own estrogen, essentially becoming independent of the hormones produced by the ovaries and becoming a disease that does not respond to first and second line treatments (this is known as refractory endometriosis). For this kind of endometriosis aromatase inhibitors may be offered. This treatment is especially useful for older women with endometriosis, who are nearing (or past) the menopause, or who may be ineligible for surgery. These drugs do drastically reduce estrogen production in the body though, so can have similar side effects to GnRH analogues, therefore monitoring side effects, particularly in older patients, needs to be undertaken carefully.

Something important to take into consideration though is that, if the symptoms of endometriosis don’t respond well to initial treatment, other conditions must be accounted for too. Endometriosis and adenomyosis are found very frequently together as are adhesions in women with endometriosis, therefore it is important that doctors conduct a thorough investigation to determine exactly what conditions they are dealing with and how best to treat them.

·         Alternative or complimentary therapies are often sought by women suffering the symptoms of endometriosis to try in conjunction with other treatments. Again I would reiterate that doing your research is the most important thing to do, especially where alternative therapies are concerned, mainly because they are not regulated or subject to the same standards of quality control and testing as conventional medicine. One approach that many women benefit from is dietary changes. This doesn’t work for everyone, but if there is the possibility of some relief from the symptoms of endo, it’s always worth giving a try. There are lots of different resources out there that can advise with endo diets and specific recipes and programs to follow, which at the core suggest: eliminating red meat, gluten, diary, processed foods and refined sugars, whilst increasing intake of green vegetables, fruit and omega-3 fatty acid containing foods, so have a look around and see what you can find. One extra bit of advice though, remember there is no such thing as a miracle cure and always be wary of those with an agenda to push or a product to sell, anyone who truly has your best interests at heart will offer advice freely.

·          One of the main concerns of many women with endometriosis is the effect the disease can have on fertility. The true effect of endometriosis on fertility is not one of clear distinction. The proportion of infertile women with endometriosis is reported to be anywhere between 9-50%. Although, before going any further, we need to define infertility and subfertility. Infertility is defined as not being able to conceive at all, however many women with endometriosis are in fact subfertile, meaning that they are able to conceive, but it is much more difficult. It is reported that monthly chances of conception drop from around 25% to 2-10% in women with endo, making becoming pregnant problematic. There are also problems that can occur during pregnancy to consider, some evidence suggests complications like preterm birth, preeclampsia and placenta previa are more common in women with endo, but as long as these risks are recognised by doctors and midwives then any risk to the mother and child should be minimised. One of the most obvious causes of reduced fertility is endometriosis affecting the ovaries (although endo can also have effects on hormonal balance and the structure of the fallopian tubes which affects fertility as well). The presence of endometriosis does not only affect the ovaries; even if an egg is fertilised it must implant in the endometrium to develop. The endometrium has a very narrow timeframe when implantation of the developing embryo can occur, called the ‘window of implantation’.  There have been many studies that have concluded there are several differences in the endometrium of women with and without endometriosis. The big question is though, what clinical implications do those differences have?  Studies have shown that several genes are altered during the window of implantation in the endometrium of women with endometriosis and this may contribute to the reduced fertility some women with endo experience. There is a much more in depth article on the effect of endometriosis on pregnancy outcomes you can read, for free, here.

Women suffering from fertility issues may decide to undergo assisted reproduction technology (ART) to aid in achieving pregnancy. ART can refer to therapies such as fertility medication and in vitro fertilisation (IVF), which are the more common forms of ART. The studies that have been conducted on the use of ART in women with endometriosis have found that having endo doesn’t appear to alter the success of these treatments.

Medical therapy does, and always will, have its uses in managing endometriosis, and hopefully will only improve as the years go by and our understanding of the disease and the progression of technology marches ever onward. However, at present medical therapies don’t get rid of the disease itself, rather they aim to alleviate the symptoms. The best long term results from the symptoms of endo come from surgery to physically remove the disease. In order to diagnose and surgically treat endometriosis a laparoscopy is the most common type of surgery performed. This involves inserting several ‘arms’ (which are like metal tubes) into the pelvis that have various attachments like a camera and manipulators or surgical scissors or a laser etc. Depending on how complex the surgery is and what needs to be done depends on how many tools the surgeon will have to use. Usually with laparoscopy you will end up with several small (about 1-1.5cm long) incisions around the pelvic area.

The advantage of laparoscopy is that endometriosis can be diagnosed and treated during the same operation, if time permits, though some women will have to have a diagnostic laparoscopy separate from a therapeutic one.  The different surgical procedures can be classified in two ways depending on the extent of the surgery that needs to be done.

·         Conservative surgery is a term given to surgical procedures that generally spare the removal of whole organs, instead focussing on removal of the disease itself. This can be done using two methods; ablation of the lesions and excision of the lesions. Ablation involves using heat to burn away and destroy the lesions (often using a laser), whereas excision actually cuts out and removes the lesions (which can also be done using a laser). Both excision and ablation have their place in endometriosis surgery, ablation can be more useful if cutting out an area of endometriosis could prove dangerous. For example, when it comes to operating on the ovaries, cutting out a cyst (cystectomy) may lead to damage of the underlying tissues of the ovary, leading to reduced fertility. For example, due to the nature of endometriotic ovarian cysts, when surgically removing them 54-69% of ovarian tissue can be removed too compared to only 6% when dealing with other ovarian cyst types. Some studies have suggested that ablating ovarian endometriotic cysts may increase the rate future pregnancy, especially when using IVF.

 There are few studies that actually examine the difference between the effectiveness of ablation and excision for endometriosis. Those that have been done suggest that both techniques are roughly equally effective for the treatment of minimal endometriosis, but excision is the preferable option for deep lesions and ovarian endometriotic cysts, as it leads to better symptom improvement and less likelihood of the disease recurring, but as mentioned above careful consideration needs to be made when weighing up the outcomes desired by the patient.

·         Radical surgery involves the whole or partial removal of organs for the treatment of endometriosis. This can be as a result of deep endometriosis infiltrating the bowel (which can occur in 6-35% of deep endo cases) or the urinary tract (which can occur in 1-5% of deep endo cases). Other forms of radical surgery include hysterectomy, salpingectomy (removal of the fallopian tubes) and oophorectomy (removal of one or both ovaries). You may wonder why a hysterectomy would be beneficial for endometriosis, after all the lesions are the cause of the symptoms and they are most frequently found around the uterus, not on it. As mentioned before, adenomyosis and endometriosis are two conditions found very frequently together and unfortunately hysterectomy is the most effective treatment for adenomyosis. Hysterectomy though is not a viable treatment option for endometriosis alone and, although some insist on grasping to the idea that hysterectomy is somehow a cure for endometriosis, this is simply not the case.

Careful consideration needs to be made when deciding the optimal surgical approach for different types of endometriosis and the conditions associated with it. For example, although the risk is still low, radical surgery does carry an increased risk in operative and post-operative complications, some of which can be severe, which is why it is always important to discuss the surgical procedure you are going to undergo with your surgeon.

What causes endometriosis?

And the award for the most contentious question in endometriosis goes to…this one! The absolute truth of the matter is that no-one knows for certain what causes endometriosis. There are a few theories though, which at best explain certain aspects of the disease, but as yet there isn’t a unified theory of endometriosis. I’ll give a brief overview of some of the most popular theories here, if however you would like to read an in depth article on the history of endometriosis you can do, here.

Perhaps the most widely known theory is that of retrograde menstruation. This theory was developed in the 1920’s by a U.S physician by the name of John Sampson. He postulated that, during regular menstruation, most of the blood and lining of the uterus (the endometrium) would exit the body in the usual manner, but some would travel up through the fallopian tubes and out into the peritoneal space (which is where the reproductive organs sit). Once there the endometrial fragments implant on and around the surface of the reproductive organs and form growths that are fed by the hormone produced by the body and result in what we call endometriosis.

At the time this theory made an awful lot of sense. Observing endometriosis down the microscope, there are obvious visual similarities between endometriosis and the normal endometrium. Additionally the process of endometrial fragments travelling up and out from the uterus (retrograde menstruation) is known to occur in 90% of women. Furthermore endometriotic lesions seemed to react to hormones in a similar manner to the normal endometrium (i.e. growing when exposed to estrogen). Not only this but over the years using animal models of endometriosis, fragments of the endometrium were injected into the peritoneal space of monkeys, mice and rats to mimic retrograde menstruation and, lo and behold, endometriotic lesions formed. So it’s easy to understand why this theory gained so much traction and popularity. However, as the march of progress continued and research methods became more advanced, some holes in this theory became apparent.

Perhaps the most obvious question to ask would be – if retrograde menstruation is the cause of endometriosis, and retrograde menstruation happens in 90% of women, why don’t 90% of women have endometriosis? It is known that women with endo show alterations in their immune system that could allow endometriosis to form. In particular, women with endo show alterations in the immune cells that would normally clear away the refluxed endometrial fragments, making it easier for the cells to implant around the reproductive organs.

Detailed analysis of endometriotic lesions however, has shown that there are distinct differences in the genetic, protein and gene regulation profiles and sensitivity to hormones between endometriosis and the normal endometrium indicating they are quite different tissue types. Certain types of endometriosis are difficult to explain with the retrograde menstruation theory, in particular endometriosis outside the pelvic area. Endometriosis has been found in almost every organ in the body (as I’ve written about previously), although it should be noted that some cases of extra-pelvic endo are extremely rare, sometimes only one case exists. Perhaps some of the most damning evidence against retrograde menstruation comes from case reports of endometriosis in unborn foetuses, women who cannot menstruate, animals that don’t menstruate  and in men (although there have only been a handful of male endometriosis cases reported worldwide).

The evidence of endometriosis like patches in unborn foetuses certainly suggests endometriosis, or at the least the propensity to develop it, is something you are born with. Familial and genetic studies support this as it has been found that there are genetic alterations more common in women with endo and women with a first degree relative with endometriosis, are much more likely to develop the disease too.

 So what could the answer be? Several other theories have been proposed about how endometriosis could arise. One suggested that, under the influence of hormones like estrogen, normal tissue in the pelvis could transform into endometrial-like tissue. This has led to researchers pointing the finger at environmental pollutants that mimic the effect of estrogen in the body. Although some research has been done into this area, the results are far from conclusive. Experiments done in the

Other theories have taken this further by suggesting that, during the very early development of the reproductive organs in the foetus, some of the tissue that would go on to become the uterus gets ‘misplaced’. When a girl reaches puberty and hormone levels rise, these patches of tissue mature into endometriotic lesions. This explanation would certainly account for the cases of endometriosis in men as all of them have been men undergoing hormone therapy for prostate cancer. You can find a much more detailed analysis of explanations regarding the origin of endometriosis here.

Of course, it could be there is no single cause for endometriosis and there are multiple mechanisms by which the disease can arise. What we do know about the origin of endometriosis can be summarised as

-          Most women with endometriosis report the symptoms appearing in adolescence, particularly near puberty, suggesting hormones play a role in the onset of disease symptoms
-          Endometriosis appears to be a condition you are born with, or you are born with an increased risk of developing the disease. There is nothing you do in life to ‘get’ or ‘catch’ endometriosis, that is down to fate alone.
-          Endometriosis displays a strong genetic component and seems to run in families, this can obviously be a concern for mothers with daughters. However, there is nothing one can do to prevent someone having endometriosis, women with endometriosis need an effective support network and that should start at home. So I’ve always said, the best thing a young girl with endometriosis can have is a mother who understands.
-          Although endometriosis can run in families, it can also occur spontaneously in women with no family history. These cases are more of a mystery and no one really knows how or why they occur. Of course there are plenty of other immune conditions, neurological conditions and cancers, which have a genetic component and can just arise seeming out of nowhere, so it could very well be that endometriosis is no different.
-          Endometriosis doesn’t appear to affect any race, or ethnic group disproportionally like other disease such as fibroids or diabetes. However no large studies have been conducted to investigate whether this is true or not.
-          Other medical conditions such as immune conditions seem to be more frequent in women in endo, suggesting whatever influences the development of endometriosis also influences the risk of other conditions as well

Information for Partners and Family Members

I’ve been the partner of a woman with endometriosis for 17 years at the time I’m writing this and also I’ve been the son of a woman with endometriosis all my life; it has been the inspiration for me to study endometriosis professionally and why I write this blog.

Over the years there are few lessons that I’ve learnt that I hope others will find useful in supporting someone with endometriosis. I should point out that I can only talk from the male partners perspective, because that is what I am, I hope this advice is applicable to everyone, but if there are specific issues or experiences you know of that apply to same sex couples, or if you are a trans person with endo, I’d love to hear about your experiences either in the comments or message me @endoupdateblog on twitter.

Perhaps the most important thing I’ve learnt is that many women with endo have to face continual invalidation of their symptoms from people in general and medical professionals sometimes. Endometriosis is not a visible disability, many women with endo look fine (don’t ever say to someone with endo “but you look fine”) which makes it difficult to know exactly what the condition can do unless you’ve had a great deal of personal experience with it. So simply believing someone with endo when they describe what’s wrong, or how they are feeling is very important. Another point is understanding the limitations that endometriosis can put on someone. Endo can result in pain during certain times and ‘flare ups’ that mean the person cannot do everyday activities and this is especially frustrating for them, so it is essential to not make them feel blamed or at fault; it is the disease’s fault, not there’s. I found that an individual’s endometriosis is like a separate entity that has its own moods and character, if you come to know that character you know how best to respond to it, so you don’t feel helpless and actually feel helpful.

Feelings of guilt at not being able to go out and socialise or do everyday things, are common in women with endo and other chronic conditions, therefore be mindful of how you respond to someone’s limitations so as not to cause or worsen feelings of guilt. That is not to say you need to be treading on eggshells or offering pity to people with endo, just that a bit of patience, understanding and consideration will go a long way.

Of course as with many chronic illnesses intimacy between partners can become an issue. This can be especially the case with endometriosis as the condition can lead to symptoms that make sex too painful and the treatments can decrease libido. A partner of someone who experiences these symptoms needs to understand that sex isn’t the be all and end all of a relationship, most of you probably know that already, but women with endo can sometimes feel pressured or like they have to satisfy their partner. If this is the case it’s up to you to reassure her that intimacy isn’t just about sex and remind her of all the other wonderful things about her that are the real reason you’re together. And sometimes it might be that you both do want sex, but don’t forget that sex isn’t just one thing, there are lots and lots of things to try that can be good for both you; different positions, taking it slow, lots of foreplay, use your imagination! Be patient.

One of the most difficult aspects of being a partner or family member of someone with endo is seeing someone you love in pain but being unable to do anything about it. I’ve experienced this feeling of helplessness a lot myself, but educating yourself about the disease and how it affects the person you care about will give you real insights into things you can do to help. No, you will not be able to cure them, but learning about treatments and how that person’s endo works will allow you to have an open dialogue with them about their condition and what the little things are you can do that make a big difference. Sometimes it can as simple as knowing when to make a hot water bottle to knowing not to plan an event or activity during certain times of the month, it all helps lower the burden of endometriosis.

I can’t emphasise enough the importance of education about endometriosis, being able to talk to someone openly and frankly about their condition improves a relationship between two people by creating ways for them to talk and interact which would otherwise be shut off because of the illness. An illness like endometriosis doesn’t have to be a barrier between people, it can be the exact opposite, you’ve got to put the time and effort, but the helping someone you care about is worth it.

Further information

There are loads of other good endometriosis information sites out there, notable ones include:

If I’ve missed any sites out that you think should be on this list, add them to the comments below, links to personal blogs are also welcome, however a strict policy I have on this blog is that no adverts or links to sites containing adverts for products or services that have not been tested with an adequate level of scientific rigor will be allowed.