Misery loves company..

..and endometriosis is that proverbial misery. Very rarely have I encountered someone with endo who only has endo. However, knowing what conditions are actually associated with endo and which ones just occur by chance is important to build up a complete picture of what it actually means to suffer from endometriosis and that, for some women, it is not just about the lesions.

Below is a table summarising some of the studies looking at which conditions are, or aren’t, associated with endo. It is by no means an exhaustive list of the studies into comorbidities and endo because that would’ve taken a very long time. But I have tried to include all the major studies and the ones I think people will find most interesting. There’s also some studies that just don’t exist, which I would’ve like to include. For example, I couldn’t find any good studies on the association between endometriosis and polycystic ovarian syndrome (PCOS), which was a shame.

Sorry about the long boring table with a bunch of dry stats and figures, buts that the reality of science unfortunately.

Study population	Finding	Link
3680 members of the endometriosis association surgically diagnosed with endometriosis	Condition % women in this study % women in general population Systemic lupus erythematosus 0.8% 0.04% Multiple sclerosis 0.5% 0.07% Rheumatoid arthritis 1.8% 1.2% Sjogren’s syndrome 0.6% 0.02% Diabetes melitus 1.5% 1.3% Hypothydroidism 9.6% 1.4% Hyperthyroidism 1.7% 1.9% Fibromyalgia 5.9% 3.4% Chronic fatigue syndrome 4.6% 0.02% Asthma 12% 6% Overall allergies and asthma were reported in 61% of women with endo, compared to 18% of the general US population	http://www.ncbi.nlm.nih.gov/pubmed/12351553
4331 members of the endometriosis association surgically diagnosed with endometriosis	Condition % women in this study % women in general population Melanoma 0.67% 0.17% Breast cancer 0.37% 0.68% Ovarian cancer* 0.23% 0.07% Non-hodgkins lymphoma 0.05% 0.06% Recurrent upper respiratory tract infection 35.2% 7.1% Candiditiasis 3.8% 3.7% Recurrent vaginal infections 29.3% 10% Addison’s disease 0.23% 0.009% Cushing’s syndrome 0.09% <0 .001="" p="">	http://www.ncbi.nlm.nih.gov/pubmed/19945097
37,434 women diagnosed with endometriosis on the National Swedish Inpatient Register cross-referenced with the National Swedish Cancer Register between 1969 and 2000	Cancer type Number of cases observed in endo patients Number of cases expected (based on general population) Gastric 54 60 Pancreatic 81 67 Lung 181 192 Breast 1288 1244 Cervical 51 80 Endometrial 92 78 Ovarian * 122 85 Bladder 64 67 Melanoma 186 160 Non-Hodgkin’s lymphoma 113 91 Leukaemia 54 56 All cancers 3349 3234 *Increased risk in ovarian cancer mostly attributed to women aged 50+ with a long standing history of ovarian endometriosis	http://www.ncbi.nlm.nih.gov/pubmed/16431901
138 women aged 24 or under diagnosed with endometriosis	Asthma present in 22.5% of women	http://www.ncbi.nlm.nih.gov/pubmed/23507008
467 women diagnosed with endometriosis, 412 women without endometriosis	4.9% of the women with endo reported having asthma, 5.3% of the women without endo reported having asthma, no difference between severity of asthma was observed between the groups	http://www.ncbi.nlm.nih.gov/pubmed/16155083
113 women diagnosed with endometriosis, 170 people of both genders from the general population	More women with endometriosis tested positive on a prick test for allergies (45.6%), than those of the general population (24.7%)	http://www.ncbi.nlm.nih.gov/pubmed/18490013
501 women diagnosed with endometriosis, 188 women without endometriosis	9% of the women with endo reported having asthma, compared to 4.3% of women without 56.7% of the women with endo reported having allergies compared to 23.4% of women without No differences were observed between different stages of endometriosis 48.3% of women with endo reported a family history of allergies compared to 9.6% of women without	http://www.ncbi.nlm.nih.gov/pubmed/22369407
43 women with endometriosis, 43 women without endometriosis	Eczema, hay fever and food sensitivities were significantly more common in women with endometriosis	http://www.ncbi.nlm.nih.gov/pubmed/3453197
37,661 women diagnosed with endometriosis identified from the Danish Hospital Discharge register from 1977-2007	No increase in the risk of multiple sclerosis, systemic lupus erythematosus or Sjorgren syndrome were observed for women with endometriosis	http://www.ncbi.nlm.nih.gov/pubmed/21471158
37,661 women diagnosed with endometriosis identified from the Danish Hospital Discharge register from 1977-2007	Women with endometriosis were found to be at a higher risk of inflammatory bowel disease, Crohn’s disease and ulcerative colitis.	http://www.ncbi.nlm.nih.gov/pubmed/22184069
7,259 women with endometriosis, 535,818 women without	A higher rate of nickel allergy was observed in women with endometriosis, no increase in risk of allergic rhinitis, atopic dermatitis and contact dermatitis was observed.	http://www.ncbi.nlm.nih.gov/pubmed/25976177
120 women diagnosed with endometriosis and 1,500 healthy women having blood tests and intestinal biopsy for celiac disease	Celiac disease was found in 2.5% of the women with endometriosis compared to 0.66% of the endo-free women	http://www.ncbi.nlm.nih.gov/pubmed/19400413
223 women diagnosed with endometriosis 246 women without endometriosis having blood tests for celiac disease	Celiac disease was found in 2.2% of women with endometriosis compared to 0.8% of the endo-free women	http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988867/
34 patients with endometriosis, 37 without endometriosis undergoing hysterectomy	Chronic endometritis (inflammation of the endometrium) was observed in 53% of women with endometriosis and 27% of the women without endo	http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928198/
1,618 women with a preoperative clinical and ultrasound diagnosis of endometriosis	Adenomyosis was found in 21.8% of these women. Adenomyosis was significantly associated with deeply infiltrating endometriosis	http://www.ncbi.nlm.nih.gov/pubmed/25201608
331 women undergoing surgery for benign gynaecological conditions	Endometriosis was found in 28% of women with fibroids and 43.5% of women with adenomyosis	http://www.ncbi.nlm.nih.gov/pubmed/24765891
182 women with endometriosis, 240 women with uterine fibroids, 183 women undergoing laparoscopic sterilisation	Of the women aged 35-39, 5.7% of the control group had fibroids, 14.1% of the endometriosis group had fibroids Of the women aged 40-44, 11.6% of the control group had fibroids, 25% of the endometriosis group had fibroids Of the women aged 45+, 22.2% of the control group had fibroids, 46.5% of the endometriosis group had fibroids	http://www.ncbi.nlm.nih.gov/pubmed/21772738
220 premenopausal women aged 40-50 years old undergoing hysterectomy	Endometriosis was found in 40.4% of women with adenomyosis, 22.7% of women with fibroids and 34.1% of women with both adenomyosis and fibroids	http://www.ncbi.nlm.nih.gov/pubmed/23140029
143 women undergoing MRI who had a previous history of endometriosis	Depending on the criteria used for diagnosing adenomyosis, the co-occurrence of adenomyosis in endometriosis patients varied from 58-91%	http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355446/
257 women with confirmed endometriosis, 253 women with no history of endo symptoms	Fibromyalgia was found in 0.78% of women with endo and 0.79% of women without endo	http://www.ncbi.nlm.nih.gov/pubmed/24410333
Records of 20,220 patients with endometriosis, 263,767 endo-free controls taken from the National Health Insurance Research Database of Taiwan from 2000-2007	Women with endometriosis were found to be at a higher risk of migraine than the endo-free women	http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307779/
6,076 women with endometriosis, 30,380 endo-free controls taken from the National Health Insurance Research Database of Taiwan from 2000-2005	Irritable bowel syndrome was diagnosed in 4.2% of the women with endo and 2.2% of the women without	http://www.ncbi.nlm.nih.gov/pubmed/25916604
101 women surgically diagnosed with endometriosis	Irritable bowel syndrome was diagnosed in 14% of these patients	http://www.ncbi.nlm.nih.gov/pubmed/19832874
Nine studies including 1,016 patients with chronic pelvic pain	Endometriosis and interstitial cystitis were found together in 48% of patients	http://www.ncbi.nlm.nih.gov/pubmed/23419614

You may notice that some of the studies are contradictory or in disagreement. The reason for this is usually differences in the design of each study. Some studies might separate patients by stage of endo, whereas other lump them all together in one group. Generally the more participants in each study the more representative it will be of the population being studied. Another factor is how the data from each patient is collected; is it collected by reviewing medical records, or is it from surveys patients have filled out where they had to recall information? The latter is always more accurate than the former. Yet another point is, if the study is comparing women with and without endo, how are the different groups chosen? For example, do the women in the endometriosis group have a surgical diagnosis? Or just an imaging method diagnosis , like ultrasound? What about the group they are being compared to, are they ‘endo-free’ or ‘healthy’ controls? An endo-free control group could include women with other health conditions, whereas a ‘healthy’ control groups should have no other chronic illnesses.

Another point along these lines is how the women with and without endometriosis are ‘matched’. Matching is basically comparing like with like and it is an important aspect to consider when conducting studies like the ones above. After all, would it be accurate to compare a 20 year old, non-smoker with a BMI of 18, with a 65 year old, smoker with a BMI of 34? Definitely not. All of these factors can influence the results of a study.

So what can we learn from these studies? Firstly it’s important to interpret the information in the correct way. For instance, when looking at the studies on how common endo is in women with fibroids and adeno, it’s important to know how common each of those conditions is in the general population, which is why it’s handy that some studies give the incidence of other conditions in the general population. Fibroids are extremely common (around 50-70% of women will have fibroids by the time they are 50 years old) so finding fibroids in women with endo is no big surprise (although some studies suggest fibroids might be more common in endo women). However, adenomyosis is thought to affect around 8-20% of women. So studies finding adenomyosis in nearly half of women with endo (or more) clearly suggest and association between the two conditions (and being that adenomyosis is displaced endometrial-like tissue inside the wall of the uterus, rather than outside the uterus itself, the two conditions could have a shared origin).

All of the studies agree that there is no overall increased risk of cancer for women with endometriosis, however there does seem to be some small increases in risk for ovarian cancer. This increase can be attributed to women with long standing ovarian endometriosis, but on the plus side, another study has shown that women with endometriosis and ovarian cancer have a much higher survival rate than women with ovarian cancer but without endo.  This is most likely due to increased monitoring of women with endo (more ultrasounds/laparoscopies etc).

This raises another interesting point to think about. Could the increase in diagnosis of certain health conditions in women with endo actually be due to under diagnosis in the general population? Women with endo are likely more aware of their own health status, because having a chronic illness means you are constantly paying attention to your health. Also because women with endo have more doctors’ visits, more scans and more investigatory procedures while navigating the minefield that is endo diagnosis and treatment, they are more likely to have other health conditions diagnosed as well.

There also seems to be an increase in the co-occurrence of allergies, asthma and immune disorders in women with endo. There are a multitude of studies showing alteration of different components of the immune system in women with endometriosis. In particular endometriotic lesions secrete chemical messages that activate a type of immune cell called a macrophage. The macrophages produces certain chemical messages that activate other types of immune cells, called Th2 cells, that then go on to activate the immune cells responsible for allergic inflammation. What all that means is that the presence of endometriosis could prime the immune system to be more sensitive to allergic stimuli, perhaps explaining the higher occurrence of allergies and asthma in women with endo.

What this also means is that endometriosis isn’t always just about endometriosis. Often there are other health conditions found in association with endo, meaning that simply focussing on one isn’t enough and that a broad, multidisciplinary view is needed when treating women with endo.

A Total Bitch

Just to be clear I’m talking about a dog, a female dog, the one that is the subject of this article and the occurrence of probably the rarest and most unusual form of endometriosis I’ve ever seen.

We know that endometriosis can occur in some strange places, like in the brain or in the heart, or in some animals you wouldn’t expect, like monkeys, or in some people you wouldn’t expect, like men or very young children, but this is a stand-out case.

There are several reasons this case stands out so much to me. Firstly is that, looking at all the other odd occurrences of endo, whilst they are indeed odd, they are not entirely unforeseen. For example, endo occurs in humans, so to find it other parts of the human body apart from near the reproductive organs and to find it in young girls or men is weird, but not totally irrational. By the same logic, because we are so closely related to primates genetically, it is not unexpected that some species of ape or monkey will have endometriosis too. What is unexpected though is endo in an animal very dissimilar to humans and one that, by all accounts, has never been shown to have endo and shouldn’t be able to have it.

To summarise this case, an 11 year old female German Shepherd was brought to a vet in Brazil, but died unexpectedly during an examination. Upon dissection the vets found a large growth behind the uterus and ovaries which they later identified as an endometrioma, a large cystic growth filled with solid tissue and blood. Endometriomas are cysts where the outer layer is made up of tissue resembling the normal endometrium and is filled with blood that can become broken down to a brown fluid – giving rise to the name ‘chocolate cyst’. Endometriomas commonly arise in the ovary in women, but can occur in other places like behind the uterus and on the ligaments that hold the uterus in place.

Why would we not expect to see endometriosis in dogs? Mainly because the reproductive system of a dog is very different to that of a human. Dogs do not have a menstrual cycle like humans, they have an estrous cycle and while the hormonal changes across the estrous cycle can be seen as similar to the menstrual cycle, the physical changes are quite different and the time scales between the stages of different cycles vary significantly. One of the most important examples is that if the dog doesn’t become pregnant, the endometrium will be reabsorbed by the uterus, whereas in human the endometrium is shed during menses. This raises the question of how the endometrioma appeared.

For a long time now it has been suggested that endometriosis arises from endometrial cells shed during menses passing backwards through the fallopian tubes and out into the pelvic cavity, where they implant and grow into endometriotic lesions. This is a process termed ‘retrograde menstruation’ and is favoured by many (but not me) as the best explanation of the origin of endometriosis. How then could we have an endometrioma in an animal that doesn’t menstruate? A theory put forward many years ago, called coelomic metaplasia, suggested that certain forms of endometriosis arise from hormonal changes, which induce transformation of the thin layer of tissue that surrounds the reproductive organs (the coelomic mesothelium). This seems a logical explanation for endometriosis of the ovary as the ovaries produce high levels of estrogen. It also provides a decent explanation for the extremely rare instances of endometriosis in men, all of whom had been undergoing hormone therapy for prostate cancer.  The authors of this article also point out that tumour and other types of cysts derived from the coelomic mesothelium are fairly common in female dogs, meaning this could be another, overlooked type. Could this explain an endometrioma in a dog? Possibly, although the vets noted no hormonal imbalances in the dog and no pathology of the ovaries that would result in altered hormone production. One other discovery that may give a hint as to how this endometrioma arose was the presence of bundles of smooth muscle found in the cyst. Normally smooth muscle wouldn’t be found in an endometrioma, so its presence suggests not a simple endometrioma, but a uterus like mass. How this might come about is speculative, it could be a birth defect that was only diagnosed when it became serious.

A big question then is – how come this is the first case of an endometrioma being reported in dogs? Dogs are brought to the vet all the time, there are probably millions of dogs visits to vets every year, why is this the first case? The short answer to that is, I don’t really know. It may be that endometriomas are simply not recognised as endometriomas in dogs. In this case study the authors state “based solely on the macroscopic mass, especially the red color and the presence of cavities filled with coagulated blood, an initial diagnosis of hemangiosarcoma was made in this dog”. So it could be endometriomas are being mistaken for cancer in dogs, but I don’t know if microscopic analysis is routinely performed on dog tumours so it’s hard to tell if this is the case.

The incidence of endometriosis in non-human species is an area that has received very little attention save for a few species of monkey used in lab experiments. It may be that endometriosis is extremely rare in non-human species, or it is underdiagnosed either due to lack of awareness or microscopic analysis of animal tumours isn’t a routine procedure. Either way it would appear endometriosis is not a uniquely human concern.  

Endometriosis and Miscarriage

I’ve been hearing a lot in the news recently about endometriosis and miscarriage. I’ve seen reports on various news websites, which I won’t link to here because I noticed most of them are strewn with errors, the best summary is here on the endometriosis.org website.

I shan’t repeat what has already been written about the research too much, but I will try to add a few points that I think are worth addressing. Firstly, endometriosis and miscarriage (or any pregnancy complication for that matter) are serious problems and if one exacerbates the other that is cause for more attention to be paid to both. Given the fact that women with endometriosis can struggle to become pregnant, it is therefore extremely important for potential parents and medical professionals to know how best to care for pregnant women with endo if they are in a high risk group for any complications. 

To very quickly re-iterate the study’s findings; a group assessing the medical records of 5,375 women with confirmed endo and 8,280 women without endo between 1981 and 2010 from a database of records from all the state hospitals in Scotland found that the women with endo had a 76% increased risk of miscarriage. This is where I would like to make my first point. Hardly any of the reports on news sites make clear what that actually means, a 76% increase from what? It turns out miscarriages are more common than I thought and most occur during the very, very early stages of pregnancy. They may even occur before the woman even knows she’s pregnant. Of those women that do progress into pregnancy, depending on who you ask, the risk of miscarriage is around 1 in 6 to 1 in 5, which equates to 17-20%. So what does the 76% increase for women with endo actually mean?  It means the risk of miscarriage for women with endo rises to 30-35%. For anyone who wants to see the math (and I’m sure you do *sarcasm*) it goes like this 

There was also a noted increase in the risk of ectopic pregnancy in women with endo, a  2.7 times greater risk to be precise. The rate of ectopic pregnancies is much smaller than miscarriage, around 1 in 100. For women with endo then, this would increase the risk of ectopic pregnancy to around 3 in 100, a seemingly small, but nonetheless important, increase. 

This isn’t the first large study into adverse pregnancy outcomes in women with endometriosis which drew a similar conclusion. A study published in 2014 from Denmark analysed the records of 24,667 women with endo compared to 98.668 from endo-free women between 1977-2009. This study found the risk of miscarriage in women with endo rose to 24%, or around 1 in 4 women. This study also raised a good point regarding adverse pregnancy outcomes and the method of conception. Because of the subfertility experienced by women with endo, they are far more likely to undergo assisted reproductive therapy (ART) like in-vitro fertilisation (IVF). A study reviewing all current research on this topic was published in January this year and concluded that, for women with stage I-II endo undergoing ART the miscarriage rates were the same as the for endo-free women,  for women with stage III-IV though there was a lower rate of live births.

A deeper analysis is needed of the current data to really pull out some specific clinically relevant information. For example, as we have just seen, there may be a difference in pregnancy outcomes for women with different stages of endometriosis. Another issue to clarify would be does any specific hormonal therapy prior to conception have any effect on the outcomes. 

It would seem then that the evidence available certainly suggests that endometriosis is associated with an increase in adverse pregnancy outcomes. This information is most needed in the hands of obstetricians and midwives who can carefully monitor pregnant women with endo and react quickly to any warning signs that may endanger the life of the mother or child. 

A big question that remains then is why do women with endo have this increased risk? It is not simply enough to pay extra attention to pregnant women with endo, we need to know what causes the problems in the first place and how to correct them. Several studies, including my own research, have found that the endometrium in women with endo differs from that of endo-free women in several ways. Being as the endometrium is the point of contact for the developing embryo and its receptivity essentially dictates the embryo’s fate, more investigation is needed into endometrial alterations. Some studies have noted changes in the immune cells of the endometrium of women with endo, which may result in poor initial attachment of the embryo to the endometrium. This may then result in a decrease in viability of the developing foetus resulting in an increased risk of pregnancy loss. Further study is needed to discover how the endometrium of women with endo differs from endo-free women, how these differences affect the function of the endometrium and how this may be corrected.