The Size of the Problem

There has been some buzz lately about a new study into endometriosis - it’s been in news reports on a number of blogs and websites (such as this one and this one), you may have already heard about it. From the headlines in the news article you’ve probably gathered this new study is about the relationship between body size and endometriosis, specifically leaner women were found to be more at risk.

So, this study has found that thinner women are more likely to have endo; does this mean, in order to decrease your endo risk, you should all start reaching for the cakes and pies, forgo the use of even the most rudimental cutlery and just shovel food in your mouths with your hands like a mad combine harvester ploughing through a buffet?

Well no, definitely don’t do that. Most of the news outlets have done a pretty decent job of explaining the findings, but this month I’ll be looking over the original study and finding out exactly what was done, what was discovered and what we can learn from it.

Before we start though I know this study is controversial to some, so I will say I'm not going to comment on the worthiness of this study. I'm only going to give you an explanation of the findings and my interpretation thereof, then let you make up your own mind.

To start with it’s always a good idea to see if any other research like this has been done in the past and it turns out it has, and I’ve written about it before, way back in the dark murky past of 2010. So the finding that women with a low BMI are more likely to have endo isn’t a particularly new discovery. 

What’s different about this latest study? For a start it’s bigger, much bigger. The same US research group conducted a similar study in 2010 with 1,817 women with endo, this latest study includes 5,504 women with endo and the more people you have in your study, the more accurate your results. So where did they get all these women from? Well in the US since 1989, 116,430 female nurses from 14 different states have been filling in questionnaires about their health every 2 years. All this information together forms the Nurses’ Health Study II – a vast mine of information available to researchers looking into relationships between lifestyle and environment factors and the risk of all manner of illnesses.

This current study looked at all the questionnaires from 1989 to 2011, picked out the information from women who were diagnosed with endo and compared it to women who weren’t. The major factor being examined here was BMI, which is a ratio of height to weight. My BMI is around 20, which is classified as normal, but I’m a gangly leviathan, so someone who was a foot shorter than me but the same weight, would have a BMI of 28 and be classified as overweight (in my last post on this subject I air my grievances about BMI as a measure of body size).

BMI on its own isn’t a very reliable measure of body size, basically because a body builder and a fat guy could have the same BMI as it doesn’t take into account body shape. Fortunately BMI wasn’t the only factor these researchers were looking at; in order to get a better picture of body size they also took measurements of waist/hip ratio and waist circumference.

Anyway, enough of the methods, onto the results. The central finding of this study was that women with a higher BMI were less likely to be diagnosed with endometriosis – in fact morbidly obese women (i.e. with a BMI over 40) were 39% less likely to have a diagnosis of endometriosis than women with a BMI between 18.5 and 22.4.

What the researchers found was that there was an inverse correlation between endometriosis and BMI. What this means is that as BMI went up, endometriosis risk went down. Below is a graph from the paper which shows that relationship (the solid black line is the important one, don’t worry about the dashed lines).

Source:

http://humrep.oxfordjournals.org/content/early/2013/05/09/humrep.det120/F1.large.jpg 
(click to enlarge)

Interestingly this study found that this association was stronger in women who were also infertile, but there is an important point to take into consideration first. The average age of women at the time this information was collected was around the mid-thirties, so it is very likely they’ve been living with endo for a long time. BMI tends to increase with age and, more importantly, many women who have suffered endo long term take medications that cause weight gain. Therefore, wouldn’t it be better to look at the BMI of these women when they were younger? Yes, and that is exactly what the researchers did - they looked at the BMI of these women aged 18. Below is the graph of the result.

Source: http://humrep.oxfordjournals.org/content/early/2013/05/09/humrep.det120/F2.large.jpg
(click to enlarge)

As you can see it looks pretty much the same and, despite the fact that the result was slightly attenuated, morbidly obese women were still 25% less likely to be diagnosed with endo.

Now, one thing we must be careful of here is not to assume this means women with a higher BMI can’t get endometriosis, it just suggests they are less likely to have it when they are younger. For example, if we look at the results of this study, women with a BMI of around 21 had the ‘average’ rate of endo, which is 1 in 10. However women with a BMI of over 40 had a 39% reduction in their endo rate, which is equivalent to about 0.6 in 10. So, in women with a normal BMI, around 10 in 100 would be expected to have endo, however in women who are morbidly obese, 6 in 100 of them would be expected to have endo.

So what of the other body size factors being investigated? The results of this study showed that a larger waist circumference was also associated with a lower risk of endo, but only for infertile women and there was no association with height and endo. Waist-to-hip ratio was a harder result to call as a lot of women didn’t have that information recorded. Although the researchers found that women with the smallest waist-to-hip ratio had a 3 fold increased risk of endo, this was only based on data from eight women, so it’s probably best not to pay much attention to that result until it can be verified.

Now we know the results, the next big question is, why might this be the case? At first appearance it doesn’t make sense, fat cells can produce estrogen, so the more fat cells you have the higher levels of estrogen you have. Being as endometriosis is an estrogen dependant disorder, shouldn’t women with more fat (and therefore a higher BMI) be more susceptible to the disease? Similarly, being underweight as a child is associated with later menarche and less menses, yet women with endo are known to have, on average, and earlier menarche so that doesn’t seem to add up either.

There are several ideas as to why we are seeing these results. It is known that obese women are more likely to have Polycystic Ovarian Syndrome (PCOS) and some researchers think that PCOS may be ‘protective’ against endo due to a reduced number of menstrual cycles and higher levels of androgen hormones which could suppress endo lesions. Although without knowing which women had PCOS in this study we can’t tell if this is the case. The androgen link may be important though. Studies have suggested that androgen hormones are elevated in obese young girls and women regardless of them having PCOS. Therefore, a higher level of androgens in obese girls and women may suppress endo and explain why we see a lower risk of endo in the high BMI group.

The authors of this study also suggest there may be a diagnostic bias for obese and morbidly obese women. Surgeons may be less likely to want to perform a laparoscopy on these women as it is just more difficult, therefore they would be less likely to be confirmed with endo. However, the authors point out that if this were the case there wouldn’t be such a strong association between endo and BMI in infertile women compared to women with pain symptoms alone.

There are several other factors that can modify BMI, such as medications, lifestyle factors and co-morbid conditions and these all need to be considered when examining a relationship between endo and BMI, which as far as I can see, this present study did not take into account. Another consideration about this study is the population of women from which it was drawn. All the women from whom the information was taken were nurses employed in that profession for at most 20 years. As endometriosis presenting with severe symptoms would hinder a woman’s ability to maintain long-term employment (especially a physically demanded job, like nursing), then it is likely that women with severe endo symptoms were not proportionally represented in this study, which may skew the results to favour women with less severe forms of the disease, who in turn would be more physically active and hence, have a lower BMI.

Of course it could be that whatever makes a woman susceptible to endo also makes her more likely to have a lower BMI at a younger age. A growing body of evidence suggests that endometriosis is condition you are born with and is hereditary - so it may, or may not, be that whatever genetic/epigenetic factors result in a woman developing endo, also affect her metabolism or fat deposition resulting in her having a lower BMI before she started taking hormonal medication. Unfortunately there are still a lot of questions that need to be answered before we can make any definite conclusions here, but when we eventually answer those questions, we will have a better understanding of this paradoxical disease.

This is my interpretation of the current study, as ever though I encourage everyone to do their own research and draw their own conclusions, so below is a link to the study I have been talking about this month, which you can read and download, in full, for free.

http://humrep.oxfordjournals.org/content/early/2013/05/09/humrep.det120.full.pdf+html

Research Roundup

Fresh from the success of endometriosis awareness month endometriosis research has continued apace. Unfortunately I’ve been quite busy lately so I haven’t had much time to write a detailed overview on any research this month. But, what I will do is briefly cover some of the highlights of endometriosis research that has been published over April.

To start us off is an article from South Korea looking into the effect of laparoscopic surgery for endo and its effect on the ability to conceive naturally. This study took 43 infertile women with endometriosis and followed up their conception rates 12 months after they underwent laparoscopic surgery to remove their disease. The overall result was 18 out of 43 women (41.9%) had conceived naturally after 12 months. As fertility issues are a major concern for women with endometriosis it is good to know surgical intervention can improve the likelihood of conceiving. (You can read the full article, for free, here)

Next is an encouraging piece of research looking at serious investigation into new treatments for the pain associated with endometriosis. This latest study from Brazil was a Phase II clinical trial (basically a detailed check to see if a drug works before it is put on the market) of melatonin for the treatment of endometriosis associated pain symptoms. You may have heard of melatonin before, it is produced by your body at different levels during the day and is responsible for telling your body when to wake up and go to sleep, but it also acts as an anti-inflammatory and analgesic. Results of this trial showed 10mg melatonin daily for 8 weeks reduced daily pain scores by 39.8% and dysmenorrhoea (excessively painful periods) by 38% also reducing the need for taking other pain killers by 80%. As an added bonus melatonin was also found to improve sleep quality with no severe side effects.

Next is a continuation of investigations into the relationship between environmental pollutants and endometriosis. All the conducted research thus far has failed to provide any conclusive proof of linking one type of pollutant to endometriosis. This latest study hopes to add some weight to the argument by exploring the relationship between Bisphenol A and 14 Phthalate metabolites in women undergoing laparoscopy or MRI. This study found that, in the women undergoing MRI, 6 phthalates were associated with a higher likelihood of being diagnosed with endometriosis. However, in women undergoing laparoscopy and histological confirmation (which is the superior diagnostic method) only two phthalates were found to be associated with an increased risk of being diagnosed with endometriosis. This study highlights the need for researchers to pay special attention to the way studies are conducted when looking at environmental exposures and endometriosis. From my own point of view I think it may be worth looking at younger girls when designing experiments. Every current study has been focussed on adult women with endometriosis, but if endometriosis is a condition you are born with (which the current evidence certainly suggests) then in-utero and early life exposures to pollutants will be more important.

I have written before about the relationship between ovarian endometriosis and ovarian cancer. Having ovarian endometriosis for a long period of time can increase your risk of ovarian cancer, but only by a very small percent. Nevertheless some women with endo may wonder what effects surgical or medical therapy may have on their ovarian cancer risk. A recent study from Sweden has done exactly that by examining medical records of women diagnosed with epithelial ovarian cancer at least one year after being diagnosed with endometriosis and calculating if surgical or medical therapies had any effect. What this study found was that women with endometriosis who had a single ovary removed, or had radical excision of all visible endometriosis, had a significant reduction in their ovarian cancer risk. This study provides further evidence that complete removal of all endometriosis should be a number one priority for all doctors dealing with the disease.

Quicker surgical intervention for endometriosis can only come from quicker diagnosis of endometriosis. This could be achieved with non-invasive tests for endometriosis before laparoscopy - identifying patients with a high likelihood of the disease in an objective way. I’ve reported previously about the current progress of non-invasive tests, but these are just stand alone tests; what if different non-invasive tests were combined? A study from Egypt has shown that combining a blood test for interleukin-6 (a substance produced in your body in response to infection or trauma) with a test for nerve fibres in the endometrium, can push the diagnostic sensitivity for minimal-mild endometriosis to 100% Clearly more research needs to be done in this area to validate these results, but in the future multiple tests from a single blood sample may be able to identify women with endometriosis.

It may seem fairly obvious to anyone who has any spent any length of time with, or near anyone with, endometriosis that the disease can severely impact the sufferers ability to work. However, just knowing its true isn’t enough, in order to convince policy makers, we need empirical evidence that endometriosis has an impact on a woman’s ability to work. What that means is we need scientific studies comparing women with and without endometriosis to show, in numbers and statistics, the true devastating effect of the disease. Fortunately there have been studies in the past conducted for this very reason and now there is another from Denmark. This study gave questionnaires to 610 women diagnosed with endometriosis and 751 reference women relating to health and work ability. Perhaps unsurprisingly this study found that endometriosis was associated with more sick days and low work ability, which in turn was associated with tiredness, daily pain and high pain levels. All obvious things you would think, but we need studies such as these to highlight the impact of endometriosis and get society and governments to take the disease more seriously.

That’s all I’ve got for this month, don’t forget to follow me on Twitter @EndoUpdateBlog for shorter, but more frequent, updates!

Endometriosis Awareness Month 2013 – Part V

So another Endometriosis Awareness Month draws to a close and we should all be very proud of the achievements we made, whether it’s telling a friend about endometriosis or delivering the keynote address at an international symposium, everything we do matters. Of course, raising endometriosis awareness is an ever continuing endeavour, but with ever growing numbers of women having their voices heard it’ll not be long before the harmony of the righteous drowns the words of the ignorant.

So for the last blog post of this month I’ll be doing a quick overview of all the research I haven’t had a chance to cover in more detail.

To start us off is a paper examining other medical conditions young women with endometriosis suffer from. This study took 138 adolescent women who were diagnosed with endometriosis before the age of 21 and recorded the prevalence of any co-morbid pain conditions (interstitial cystitis, irritable bowel syndrome, chronic headaches, chronic low back pain, vulvodynia, fibromyalgia, temporomandibular joint disease, and chronic fatigue syndrome), mood conditions (depression and anxiety), and asthma. This study found that 56% of the girls suffered from co-morbid pain syndromes (with IBS being the most common), 48% had mood disorders (with depression being, unsurprisingly, the most common), additionally 26% also suffered from asthma. Interestingly 27.5% of the girls had a first degree relative with endometriosis. What this study highlights is the importance of recognising the signs and symptoms of endometriosis in young women, both by family and medical practitioners, because endometriosis, like many other chronic conditions, often has a greater chance of being treated successfully if diagnosed early.

 I’ve reported previously about the economic cost of endometriosis; it’s a sad fact, but a fact none the less, that if you want politicians and world leaders to take notice of something, tell them how much money it’s costing them. Recently there has been much greater interest in quantifying the economic burden of endometriosis and every study that does so vastly increases the chance of people standing up and taking notice. A new study from Austria does just that by calculating the healthcare costs of endometriosis in the country. This study concluded that, in total, endometriosis costs Austria €328 million (£278 million or $422 million) per year*, which as the authors point out, is comparable to the cost of Parkinson’s disease. The authors also make a good point with their concluding remarks in the abstract “The question arises as to whether more timely diagnosis, followed by better-targeted treatment, might have the potential to reduce these costs”. No doubt it would, whilst at the same time benefiting the patients.

*This may be a rather conservative estimate. If we take the total population of females of reproductive age in Austria (women aged 15-55) we get a total of 2,339,000 (according to The World Bank HNP Stats 2010). If we then assume an endometriosis prevalence of 10%, which would expected for a developed country like Austria, we get an estimate of 233,900 endometriosis cases. If we then multiply this by the average cost per endo patient (€7,712 according to this latest study), we get a grand total of €1,803,836,800 which is an awful lot more than previously estimated.

The fact that endometriosis has to be confirmed via an invasive laparoscopy is always going to get researchers interested in looking at different ways to assess the disease without operating on a patient. Several different imaging techniques exist today that allow us to peer inside the body without having to open it up. One of the best imaging techniques is MRI (Magnetic Resonance Imaging), therefore researchers will naturally want to investigate the use of MRI for assessing endometriosis before laparoscopic surgery. A recent study from Germany took this line of thinking further and examined what locations of endometriosis MRI is best at detecting. This study took 152 women with suspected endometriosis and gave them an MRI scan before they went for laparoscopic investigation. After the laparoscopies had been performed they then compared these results to the ones from the MRI to see how accurate the MRI was.

What they found was MRI seems to be very good at identifying endometriosis of the bladder, reasonably good at identifying endometriosis in the Pouch of Douglas, colon and ovaries, but not that good at identifying endometriosis of the peritoneum, which is a shame because peritoneal endo is the most common form of the disease. Still, refinement of the technique in the future may allow for better imaging of endometriosis prior to laparoscopic surgery, giving surgeons a ‘heads up’ as to where to expect to find endometriosis and hence, be more efficient with excising the disease.

Next is an interesting piece of research from France; this study took data from the French E3N cohort, which is a massive collection of information from 98,995 women aged 40-65 who were given questionnaires  in 1990, then follow up questionnaires every 2-3 years detailing aspects of their lives, past and present. What this study did was to look for those women who were surgically diagnosed with endometriosis (2,684 in total) and compare their early life activities and exposure with other women.  

The results of this study suggested that women with endometriosis had an earlier menarche and shorter menstrual cycles before the age of 17. In terms of environment, women with endo were more likely to have lived on a farm for 3+ months (although there was no link to a specific farm animal), had more exposure to indoor passive smoking, experienced food deprivation during WWII and walked for more than 5 hours a week between the ages of 8-15.

It’s difficult to know what to make of this information though; the results about menarche and menstrual cycle confirm what has been reported before, but the significance of the link to environmental exposures listed is a little harder to explain. The only link I can think of between farm living and endometriosis would be exposure to pesticides, as there has been some evidence linking organochlorine pesticides to endo, but most women with endo don’t grow up on a farm so it’s hard to draw a definitive conclusion. The association with passive smoking and exercise is even more of a head scratcher. Both smoking and regular exercise are thought to lower or attenuate estrogen production, being as endo is an estrogen dependant disease, one would think lower estrogen meant less disease risk, so these results are a bit puzzling.

Of course there are some sources of error that can creep into studies such as this, the main one being recollection. The questionnaires gathered data about environmental exposures from the ages of 8-17, but the participants were already aged 40-65 when the questionnaires were given. I’m 30 and I don’t think I could confidentially quantify how many hours of exercise I had, per day, when I was 8. So although this study certainly gave some interesting results, we definitely need further investigation into some of the associated environmental exposures and endometriosis.

Continuing with the theme of environmental exposures by moving on to heavy metal now and no I don’t mean men with long black hair and multiple facial piercing thrashing a guitar. I’m talking about a study conducted with Sri Lankan women with endometriosis, the aim of which was to assess the levels of Nickel, Lead and Cadmium metal in their blood (you can read the full article for free here). You might wonder what the point of looking at these specific metals would be, especially in relation to endometriosis. Well, it turns out that these metals have been documented as being able to activate estrogen receptors, effectively mimicking the action of estrogen within the body, earning them the name ‘metalloestrogens’. What this study found was that levels of Cadmium and Lead were not significantly altered in women with endo compared to disease free women. However the level of Nickel in the blood of the women with endo was significantly higher. To date there have been very, very few other such studies examining the levels of these metalloestrogens in women with endo so, at the moment, this field of investigation is in its infancy. Nevertheless, it looks like a promising area to follow for those interested in environmental exposures in relation to endometriosis.

The field of drug treatment for endometriosis moves pretty slowly. Drugs designed specifically for the treatment of endo are basically non-existent. Most of the drugs used for endo treatment today have been co-opted/altered from drugs for the treatment of other conditions. For example:

Leuprolide acetate – Initially used to treat prostate cancer

Medroxyprogesterone acetate – Used as a contraceptive

Birth control pills – Contraceptives

Danazol – Used for menstrual disorders (although Danazol was the first drug specifically to treat endometriosis, it is now over 40 years old and has an unfavourable side effect profile).

Recently there has been the development of Dienogest, which although used primarily as a contraceptive, was also designed with endometriosis treatment in mind. But that still means we’re getting a new endo specific treatment every 40 years or so, which is poor progress even by the most optimistic of standards.

In light of the lack of new drugs, other drugs are still being found that should help treat endo; two classes of which are Aromatase inhibitors and Cyclooxygenase (COX-2) inhibitors, which were designed for the treatment of breast cancer and autoimmune conditions respectively. The reason these are used for the treatment of endo is that they inhibit key enzymes endometriotic cells use to synthesise their own estrogen supply. Wouldn’t it be a good idea then, to use these types of drugs in combination to suppress endometriosis? It turns out maybe not. A recent study on mice examining the effect of an aromatase inhibitor (Anastrozole) and a COX-2 inhibitor (Celecoxib) found that, although these drugs worked well on their own to reduce the reduce of the growth of endometriosis, in combination they actually reversed their effects. Studies such as this highlight the need for better testing of drugs ‘borrowed’ from other treatments and the urgent need for drugs designed specifically for endometriosis.

Next up a study assessing the prevalence of endometriosis in women with adenomyosis and leiomyoma (uterine fibroids). This study took 220 women aged 40-50 who were undergoing hysterectomy for adenomyosis and/or fibroids; during their surgery these women had a thorough examination of the pelvic region conducted to look for any endometriosis. This study discovered endometriosis in 28.6% of all the women. Endometriosis was found in 40.4% of the women with adenomyosis only, endometriosis was found in 22.7% of the women with fibroids only and endometriosis was found in 34.1% of the women who had both adenomyosis and fibroids. These results show that these three conditions are frequently found together. It would’ve been interesting to see if these results were similar for different age groups but that’s something for future study.

It’s interesting that endometriosis and adenomyosis are found together so often because they are both characterised by endometrial-like cell displacement (although in adenomyosis the endometrial cells are found inside the muscle wall of the uterus). All together this provides a bit more evidence that endometriosis and adenomyosis are related, possibly established before birth and may even share a similar origin.

 Penultimately, here are a few case reports from the rogue’s gallery of endometriosis appearing in unusual places. First is a report of endometriosis of the perineum and secondly is a case report of endometriosis of the mons pubis.

Finally on our whistle stop tour through endometriosis research is a reminder that endometriosis is not a uniquely human concern. There are 16 species of primate (including ourselves) that can develop endo and it’s no stretch of the imagination to assume that the disease is as horrible for our monkey cousins as it is for us. So we’ll end on a lighter note with a study from Germany looking at medically treating marmosets with endometriosis. The authors of this study noted that marmosets with endometriosis showed significant deviations in social behaviour and cognitive tasks, which is unsurprising if they’re in pain all the time. The researchers gave the marmosets an unspecified medical treatment and noted that it improved their social and cognitive function. So at least it was a happy ending for the monkeys.

Thus concludes this run of blog posts for endo awareness 2013, hopefully you’ve learned something new, I know I have. It’s heartening to know that research into endometriosis is more popular than ever and looks set to gain ever more interest in the future.