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.  

The Kids Aren’t Alright – Part II

One of the many misconceptions around endometriosis is that it is a disease solely afflicting adult women in their mid-thirties. This belief was prevalent for many, many years and still lingers today. However, whilst it may be true that most women with endo are usually diagnosed in their twenties or thirties, the truth is the symptoms of endo appear far earlier and, through dismissal of symptoms leading to diagnostic delay, the true age at which endometriosis presents is overlooked.

Fortunately today there seems to be a drive to increase study and awareness about endometriosis in young women. Today I am going to discuss one such study from the US, a free, full text version of the article you can find here.

This study included 25 cases of girls under 21 years old undergoing laparoscopy for pelvic pain who had no previous diagnosis of endometriosis either from laparoscopy or radiological methods (ultrasound, MRI etc). Information was collected from all patients before and after surgery to see what the characteristics of endometriosis in these patients could tell us about adolescent endo (albeit in a small cohort, but you’ve got to start somewhere).

The average age of the patients in this group was 17.2 years old. Interestingly 14 out of the 25 (56%) reported a family history of endometriosis. This is far higher than what you would expect if it was a group of girls selected at random from the general population. What this means is that risk of developing endometriosis at a young age is significantly increased by a family history of endo, a fact that doctors and women with endo who have daughters need to be very aware of. The results of this study do seem to suggest that parents with endo are more than capable of advocating their case though, as 44% of referrals came from the patient’s mother.

In terms of the symptoms the girls experienced, the most common gynaecological symptoms were the ones most typically associated with endo, such as dysmenorrhoea (excessively painful periods) in 64% and abnormal/irregular bleeding in 60%. This is an issue of particular importance as these symptoms can lead to days missed from school every month, potentially damaging a young girls prospects in adulthood. Only 4 out of the 25 patients reported dyspareunia (painful sex), but being as only 8 out of the 25 reported being sexually active, dyspareunia is a poor measure of endo risk in this population. 

Of the gastrointestinal symptoms nausea was the most common, being present in nearly half (44%) of all patients. Between a quarter and fifth of all patients experienced some other gastro symptoms, such as constipation or diarrhoea. Fatigue, an often unrecognised symptom of endo, was also present in around a quarter of all patients and seems to get more common with age.

A very high degree of variation was reported in the time it took from the initial visit to a physician to diagnosis. The range in this cohort varied from 1 month to 9 years, with the delay between onset of symptoms and diagnosis being 2 years on average. This just goes to show how important it is for doctors to be well educated in recognising the signs of endometriosis in adolescent girls and adult women.

The authors of this study mentioned another survey of over 4000 women diagnosed with endo. Two thirds of these women said their symptoms appeared during adolescence and that their symptoms were far less likely to be taken seriously when they were young that when they were adults.

After the 25 patients had received surgery it was discovered that 17 had stage I disease, 5 had stage II, 3 had stage II and none had stage IV. These are similar findings to a study published just a few weeks earlier which included 55 girls aged under 19 who were found to have endo. It is also unsurprising to find that no cases of stage IV endo as previous studies also report a very low rate of ovarian endometriotic cysts in adolescents. However, severe stage endometriosis in young women is not unheard of, particularly after the age of 17, and therefore should not be dismissed. An observation made by the authors was that the appearance of endometriosis in adolescents can be different to that of adult women. For example, they noted that the predominant lesion types were subtle atypical lesions like clear, white and red, whereas in adult women surgeons would be more likely to see the darker, blueish-black lesions. This is an important factor that needs to be taken into consideration by surgeons as the subtler forms of endo can be easily missed.

After a 1 year follow up 80% of the patients had improved or resolved pain, however this was a relatively short follow up period and, as different patients received different post-operative treatment, it’s hard to say how this affected the resolution of symptoms.

Nevertheless, this article raises several important issues surrounding endometriosis in young women. In particular how it can present in a different manner, both symptomatically and physically, to endo in adult women and how better characterisation of adolescent endometriosis can lead to quicker diagnosis, better treatment outcomes and an overall lessening of the burden of endometriosis on women and society.

A Seminal Piece of Work

Remember when you are at school and there would always be rumours and stories going around the playground, like eating popping candy and drinking cola would make your stomach explode. Well it seems like the media’s attempts at reporting scientific news has become the new school playground.

I say this for several reasons, but particularly because of reports I’ve seen online recently concerning a study into the effect of seminal fluid on endometriosis. Seminal fluid is the major component of semen and, if these reports are to be believed then “It is now understood that exposure of the endometrium, which is the inner lining of the uterus, to seminal fluid may contribute to the progression of the endometriosis in women.” That is a direct quote from one web site attempting to give an account of some new research that was published recently and, in typical fashion, they have misquoted the original research, probably didn’t read the original article and relied solely on vox pops and sensationalism.

Let’s go back to the original research then, which was published here and a press release from the university it was conducted at was written here. For some reason the journal in which the research was published is probably the only journal my university doesn’t have a subscription to, so I can’t read the full article. Therefore the comments I’ll make here are based on the abstract for the article.

To start then these researchers are interested in transforming growth factor beta (TGFβ), a chemical messenger in your body that is involved in cell growth and death. I use the word TGFβ as a singular, but it actually refers to a whole family of messengers comprising over 30 members with a variety of different functions. To be more specific then, these researchers found that a deficiency of TGFβ-1 in mice impaired their development of experimentally induced endometriosis, implicating TGFβ-1 as important for the establishment and growth of endo.  Human seminal fluid has a high concentration of TGFβ, therefore the researchers postulated that exposure so seminal fluid may influence the growth of endometriosis.

To test this they took samples of human endometrium, exposed some of the samples to seminal fluid and some to a normal growth solution. They then surgically implanted the endometrial samples in mice and after two weeks noted that the endometrial tissue that had been exposed to seminal fluid had just over a fourfold increase in volume. On the face of it then it would seem that exposure to seminal fluid does increase the growth of endometriotic lesions. However there are several assumptions made in this study that could impact the relevance of the results.

•  It assumes the normal endometrium is the same as endometriosis. Granted the endometrium and endometriosis do look similar, however in recent years it has been discovered that there are hundreds of differences between them. Therefore the way an experimentally induced endometriotic lesion reacts to a stimulus could be very different from the way a human lesion reacts. 

•  I couldn’t find out whether or not the researchers used the endometrium from a woman with or without endometriosis, but this is also a key point. The normal endometrium from women with and without endo differs in a number of aspects. Of particular relevance is the fact that the endometrium of women with endo has a higher level of TGFβ-1 than women without endo. This could mean that endometrial cells from women with endo are more sensitive to TGFβ (but that depends on whether they have the receptors to recognise TGFβ as well). 

•  Animal models are a continuing source of contention. Unfortunately though they are the only way in which complex diseases can be studied in a living system, so until something better comes along we’re stuck with them. The first issue is that the mice used were immunodeficient i.e. their immune systems were dampened down so they wouldn’t reject the implanted endometrium). This could mean that the way in which the endometriotic implant grew in the animal was different to how it would grow in a human. Secondly, mice don’t have the same menstrual cycle as humans, in fact they don’t have a menstrual cycle at all, they have an estrous cycle. Estrogen and progesterone can alter the production of TGFβ-1 by the endometrium so the cyclic variation and the effect of hormone therapies needs to be taken into consideration. 

• Another thing I couldn’t find out is what the dose of seminal fluid they pre-treated the endometrium was before implanting it in the mouse. This is important because we need to know whether it was physiologically relevant i.e. does the dose they used correspond to what would be found in the human body, in particular, how much seminal fluid actually reaches the pelvic cavity after intercourse and could come into contact with endometriosis.

•  The peritoneum (the layer of tissue that surrounds the reproductive organs) secretes TGFβ-1 itself in women with endometriosis leading to an increase in TGFβ-1 in peritoneal fluid from women with endo. Therefore the amount of TGFβ-1 that seminal fluid contributes may be insignificant compared to the amount already produced around the endometriotic lesions by the peritoneum. 

Overall then it is hard to say whether human endometriosis is ever exposed to seminal fluid or if it can influence the growth of endometriosis in humans, certainly I don’t see any evidence to make me believe exposure to seminal fluid causes endometriosis. For some women with endometriosis sex can lead to pain both during and after, but I would think this is down to pressure and torsion put on the pelvic area that is already sensitised due to of endometriosis, rather than exposure to components of semen.  

Whilst there are limitations to this research, it does give us some interesting points to think about. In particular the effect of TGFβ on the normal endometrium, how this differs between women with and without endometriosis and how this could affect fertility. For example, TGFβs are suspected to be involved in the early development of the embryo and their production changes throughout the menstrual cycle. Finding out if these changes are altered in women with and without endo and if this effects the growth and receptivity of the endometrium is definitely worth investigating.