Endometriosis Awareness Month - Part II

Each year endometriosis awareness month seems to get bigger and bigger. I would highly recommend checking out the hashtag #endometriosis if you’re on Twitter to keep up with all the news and events from around the world.

For this week’s blog post I’m going to be putting some ideas out there about the origin of endometriosis. Not the way in which the disease originates in the body (there could be a whole book written on that subject), but where and when endometriosis actually came from in the history of humanity.

Some people tend to think of endometriosis as ‘modern’ condition, however there are several great resources examining the history of endometriosis, for example Dr Nezhat’s paper and Dr Redwine’s book, which suggest that endometriosis has been known about for thousands of years under different names and guises. But this week I’m going even further back, to the beginning.

With that in mind let’s start at the beginning, which is always a good place to start. In order to find the origin of endometriosis I started by searching for which animals are known to develop endo spontaneously (there are numerous animals that can be induced to have ‘experimental endometriosis’ but I’m only interested in animals in which endo has been found to occur naturally). Having a thorough search through the literature I discovered endo has been documented in the following animals (see the end of the blogpost for the references).

Human (obviously)          Rhesus Macaque

Gorilla                              Cynomolgus monkey

Olive Baboon                   Taiwan Macaque

Yellow Baboon                 Pigtail Macaque

Hamandryas Baboon        Debrazza’s monkey

Guinea Baboon                African Green monkey

Dog Face Baboon            Gray-cheeked mangabey

Mandrill                           White-tufted-ear marmoset

One interesting thing you may notice straight away is that all the species noted above are primates. Endometriosis has never been documented as occurring in any non-primate species (there is a condition affecting livestock called endometriosis, but I won’t be counting that as it refers to degeneration of the endometrium, not the same thing as the real endometriosis). This tells us there is something these animals have in common, not shared by other animals that allows them to develop endometriosis. Given that the majority of these cases of endometriosis  in primates have been discovered by accident or when performing autopsies on the animals, it is highly likely that there are other primate species in which endo is yet to be discovered (chimpanzee’s, our closest relatives, are conspicuously absent from the list, for example).

What can we do then with the above information? To answer that lets look at how all those species listed above relate to one another. We know from 150 years of evolutionary biology that all living creatures on earth are related to one another in a fantastically complex tree of life of which we are only a tiny branch.

http://www.utexas.edu/features/graphics/2008/tree/tree3.jpg

(for a more detailed look at our place in the tree of life, see here http://www.zo.utexas.edu/faculty/antisense/tree.pdf)

Zooming in on the part of that tree that contains the primates we can see our relation to those animals closest to us.

Click to enlarge

Believe it or not, this is a simplified version of the primate family tree, there are numerous species that I’ve left out because they’re extinct and I’ve omitted several species and grouped together others to keep it as simple as I can whilst retaining the important information. Now if we connect all the species in which endo has been found, we can see something very interesting.

Click to enlarge

The red lines connect all the species in which endometriosis has been documented thus far, so now we see the natural history of endometriosis. The arrow near the bottom shows the point at which, from the evidence we have, it is plausible to suggest endometriosis originated. Whatever long extinct animal lived at this point, it passed on the predisposition to endometriosis to its relatives. What that predisposition was exactly remains to be clarified. It must be a genetic predisposition, but knowing exactly what gene or genes are responsible we cannot say. Mostly because there is little agreement as to what genes are associated with endo in humans, let alone across the boundary of species. Whatever it was it changed something, perhaps the way in which the reproductive system developed, perhaps the way in which the reproductive organs function, at the moment we can’t say.

If we suppose that endometriosis did originate at this point, we can now theorise as to when endometriosis arose by finding when the species it originated in lived. Looking at where all the red lines converge we can see it is at the point in time when the group of primates containing the marmosets (called the New World Primates) split from the group of primates containing humans, chimps, macaques etc (called the Old World Primates). The common relative of these groups is thought to have lived in north Africa near Egypt ^1,2, as this is where the highest proportion of such fossils are found. Analysis of the age of these fossils put them at around 33-35 million years old ². However, using genetic analysis to date species separation based on how closely related they are puts the date at around 43 million years ago ³. From this evidence we can tentatively theorise that endometriosis could be tens of millions of years old; older than human history records, older than humanity itself.

We tend to think of endometriosis in terms of human history and why shouldn’t we? Endometriosis affects us in the here and now, but if we consider our past it may give us hints to the answers we’ve been looking for. For example, if we know what animals can develop endo and which ones cannot, then perhaps we should find out why that is. What is it about these animals that make them different? By answering this question we could finally understand what predisposes an individual to endo and maybe even how to stop it.

11.  Fleagle J. Primate adaptation and evolution 2nd Edition (Academic Press, San Diego, 1999)

22.  Kappelman J, Simons E, Swisher C. New age determinations for the Eocene-Oligocene boundary sediments in the Fayum depression, northern Egypt. J Geol, 100, 647-668 (1992)

33.  Steiper ME, Young NM. Primate molecular divergence dates. Mol Phylogenet Evol, 41(2), 384-394 (2006).

References for cases of primate endometriosis

Gorilla: Doré M, Lagacé A. Spontaneous External Endometriosis in a Gorilla (Gorilla gorilla). Can Vet J, 26(11), 347-349 (1985)

Olive baboon and Yellow baboon: D'Hooghe TM, Bambra CS, De Jonge I, Lauweryns JM, Raeymaekers BM, Koninckx PR. The effect of pregnancy on endometriosis in baboons (Papio anubis, Papio cynocephalus). Archives of gynecology and obstetrics, 261(1), 15-19 (1997).

D'Hooghe TM, Bambra CS, Raeymaekers BM, Koninckx PR. Serial laparoscopies over 30 months show that endometriosis in captive baboons (Papio anubis, Papio cynocephalus) is a progressive disease. Fertility and sterility, 65(3), 645-649 (1996)

Hamadryas baboon: Shalev M, Ciurea D, Deligdisch L. Endometriosis and stromal tumor in a baboon (Papio hamadryas). Laboratory animal science, 42(2), 204-208 (1992).

Guinea baboon: Dallwig RK, Langan JN, Hatch DA, Terio KA, Demitros C. Bilateral hydronephrosis secondary to endometriosis managed by endoscopic ureteral stent placement in a captive Guinea baboon (Papio papio). J Zoo Wildl Med, 42(4), 747-750 (2011).

Dog face baboon: Folse DS, Stout LC. Endometriosis in a baboon (Papio doguera). Laboratory animal science, 28(2), 217-219 (1978)

Rhesus macaque: Zondervan KT, Weeks DE, Colman R et al. Familial aggregation of endometriosis in a large pedigree of rhesus macaques. Human reproduction (Oxford, England), 19(2), 448-455 (2004)

Crab eating macaque: Fanton JW, Hubbard GB. Spontaneous endometriosis in a cynomolgus monkey (Macaca fascicularis). Laboratory animal science, 33(6), 597-599 (1983)

Formosan macaque: Chin S. Endometriosis and pyometra in a Taiwan rhesus (Macaca cyclopis). J Chin Soc Vet Sci, 20, 58-64 (1994)

Pigtail macaque: DiGiacomo RF, Hooks JJ, Sulima MP, Gibbs CJ, Jr., Gajdusek DC. Pelvic endometriosis and simian foamy virus infection in a pigtailed macaque. Journal of the American Veterinary Medical Association, 171(9), 859-861 (1977)

De Brazza’s monkey: Binhazim AA, Tarara RP, Suleman MA. Spontaneous external endometriosis in a De Brazza's monkey. J Comp Pathol, 101(4), 471-474 (1989)

African green monkey: Cary C, Peter G, Schiffer S. A case report and review of endometriosis in nonhuman primates. Laboratory animal science, 32, 426 (1982)

Magabey: Schmidt R, Hartfiel D. Endometriosis in a Gray-Cheeked Mangaby [Cercocebus albigena]. J Zoo An Med, 9(2), 42-45 (1978).

Mandrill: Pirarat N, Kesdangsakolwut S, Chotiapisitkul S, Assarasakorn S. Spontaneous diabetes mellitus in captive Mandrillus sphinx monkeys: a case report. J Med Primatol, 37(3), 162-165 (2008).

Nakamura S, Ochiai K, Ochi A, Ito M, Kamiya T, Yamamoto H. Spontaneous Endometriosis in a Mandrill (Mandrillus sphinx). J Comp Pathol).

Marmoset: Spontaneous pathology of the common marmoset (Callithrix jacchus) and tamarins (Saguinus oedipus, Saguinus mystax). J Med Primatol, 38(5), 347-359 (2009).

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.  

Update

Just wanted to say sorry for not posting anything for a while, between my day job and writing my thesis I haven’t had much time to do much else. Anyway, enough of my excuse making, I thought I’d give a quick update on what has been going on in the field of endometriosis research in the past couple of weeks. Here is a quick selection of some of the more interesting articles published.

Since my last post on the 8th of September there have been 96 papers published on endometriosis with a wide variety of subjects (according to PubMed).

There have been several publications on the link between ovarian cancer and endometriosis. There have even been a few papers on the involvement of epigenetic mechanisms in endometriosis (my specialist field).

There was also a paper which found 30% of the patients with endometriosis they examined also had irritable bowel syndrome or constipation.

Aromatase inhibitors were found to be effective at reducing the proliferation of endometriotic implants in a mouse model.

Phthalates, which are artificial compounds thought to act as an oestrogen and very hard to pronounce, were found to be no higher in the urine of Japanese women with endometriosis when compared to controls. However, this study falls into a trap that is a personal pet peeve of mine, which is analysing the levels of these compounds in women who already have the disease. A better study design would be to analyse the frequency of endometriosis either in the children of women exposed to artificial oestrogenic compounds or in women exposed at a very young age.

Contrary to the above, levels of another type of synthetic oestrogen, Bisphenol A and B, were found to be higher in the blood serum of women with endometriosis.

IVF treatment does not increase the risk of endometriosis recurrence.

Endometriosis was diagnosed in two sisters with Glanzmann's thrombasthenia (GT), a very rare blood clotting disorder which leads to prolonged bleeding. This is considered significant as women with GT are more likely to have prolonged periods of menstrual bleeding, a factor which is thought to increase the susceptibility to endometriosis. This perhaps garnishes some support for the retrograde menstruation origin theory of endometriosis.

Apparently marmosets (a type of small New World monkey) can develop endometriosis.

If you have are of the type A blood group, you are 2.9 fold more at risk of endometriosis. The relationship between blood groups and endometriosis remains to be explained.

It appears that the normal endometrium of women with endometriosis has increased proliferative activity, meaning that it grows quicker than normal. What could be causing this increased proliferation remains to be found.

Pregnant women with endometriosis are apparently more at risk of suffering spontaneous hemoperitoneum (bleeding into the peritoneal cavity). However, I should point out that hemoperitoneum is rare.

Interesting case report of a 42 year old woman who, even after a hysterectomy and right oopherectomy, still presented with monthly bleeding. The cause was found to be an endometriotic cyst on the left ovary.

That is the news for now, hopefully I’ll get to post more soon.