June Roundup

Its summer time! If you live in the UK that means you’re enjoying a hosepipe ban at the same time your caravan is floating down what used to be the high street.

Does using the hosepipe to lash yourself to a lamp-post violate the terms of the ban?

Anyway, enough of my stereotypical British weather bashing; we’ve got endometriosis news to go through.

If you read last month’s post you may recall I reported on a case of male endometriosis; “It’s another report of endometriosis occurring in a man” I said, “I say ‘another’ as if it happens all the time, but this is only the fifth or so record of endo in a man, ever” I said, flippantly rebuked myself. Haha, yeh endometriosis in a man, it’s not like it happens every week is it? Well fate sure likes to make me feel like an idiot because, not more than a week after I joked about the infrequency of male endometriosis, there was another case report in the literature. 

A highly realistic portrait of my reaction

Unlike last month’s report though, where the man in question had mysteriously developed endometriosis after taking anti-estrogen therapy for infertility, this latest case is more what you would call a ‘typical’ case of male endometriosis and it just goes to show how strange the world is when the phrase ‘typical male endometriosis’ exists. This reason I call this case typical is because the man in this latest case was an elderly gentleman undergoing long-term estrogen therapy for prostate cancer. Out of the 6 cases of male endometriosis I know of, 4 have been in men undergoing estrogen therapy for prostate cancer. This could be further evidence of endometriosis arising from metaplasia, where some cells in the human body have the ability to transform in endometrial cells given the correct stimulus (which in this case, would be estrogen). Of course it could also be that endometriosis arose in this man due to embryonic rests, where tiny fragments of the primitive female reproductive system are found in men and can become active given the correct stimulus (estrogen, again). Either way, understanding the origin of endometriosis in males, may uncover some of the key mysteries of how endometriosis develops in women, so I’ll be keeping an eye on this.

Seeing as we’re on the subject of strange cases of endometriosis, I nearly fell off my chair when I found an article making reference to endometriosis in horses.  I’ve only ever seen reported cases of naturally occuring endometriosis in primates, so to suddenly see reports in horses threw me somewhat; especially as there were cases of this so-called horse endometriosis going back decades! Has this strange phenomena been under my nose all these years, an important piece of the endometriosis puzzle left ignored?

No, no it has’t. It turns out that when the term endometriosis is applied to horses, it doesn’t mean endometriosis. Allow me to clarify; horse ‘endometriosis’ refers to a progressive degeneration of the endometrium inside the uterus, leading to problems conceiving and retaining foetuses. That’s bad for the horses, but that’s not what endometriosis is. Endometriosis is correctly defined as the presence of endometrial glands and stroma in locations outside the uterus. So, veterinarians have dropped a massive ball on this one and need to come up with a different name for the endometrial degeneration seen in horses, sorry guys, ‘endometriosis’ is taken.

Moving on now to something we’d all like to see, and that’s better diagnostic methods for endometriosis. It seems that research into new diagnostics for endometriosis is really taking off at the moment as I’m seeing more and more papers on the subject being published, which can only be a good thing.

The first of the studies published this month is from Oxford, UK, which looked at whether it was possible to predict the outcome of a woman’s laparoscopy by asking her to fill in a questionnaire regarding her symptoms and other characteristics (such as overall health and previous diagnoses of other conditions). This was a fairly large study including 1,396 women that hadn’t yet been diagnosed with endometriosis from nineteen hospitals across 13 countries. What the researchers found was that by asking the right questions it was possible to identify women most likely to be diagnosed with stage III and IV endometriosis with a good degree of accuracy. This is important for several reasons; firstly it will allow women with a high risk of stage III and IV endometriosis to be identified earlier, thus decreasing diagnosis times. Secondly, if the surgeon knows what to expect before doing a laparoscopy it will make it easier for them to plan ahead with regard to what they are likely to encounter and how to treat it.

Next up is a study from Poland looking at markers to help diagnosis of endometriosis in girls aged between 13 and 19. Specifically these researchers were looking for markers in the blood or peritoneal fluid that may identify young girls as having endometriosis. This study took 50 girls who underwent laparoscopies for chronic pelvic pain and then, depending on the results of their surgery, divided them into two groups. Group 1 consisted of 33 girls who were diagnosed with endometriosis and Group 2 was the remaining 17 girls who had no evidence of endometriosis. The researchers then analysed the blood and peritoneal fluid of the girls from each of these groups for levels of proteins called interleukin-4 (IL-4) and interleukin-2 (IL-2). These proteins are involved in regulating the immune system and are also know to be involved in the process of inflammation. They found that, in the girls with endometriosis, levels of IL-4 were significantly higher in both the blood and peritoneal fluid and levels of IL-2 were lower. This is excellent news as it could be a way of developing a blood test for endometriosis in young girls with chronic pelvic pain, which would decrease diagnosis times and hopefully mean they get treatment sooner. That said, laparoscopy would still be a necessity to confirm the diagnosis because, although an accurate blood test would tell you if endo was present, it wouldn’t be able to tell you where the disease was, how severe it was or if any adhesions are present. It’s still a massive step in the right direction though.

Sticking with novel diagnostics and a study from Atlanta examining the differences in the endometrium between women with and without endometriosis. There have been several studies over the years that have shown that the normal endometrium in women with endometriosis is different in certain ways to the endometrium in women without endometriosis. Most notably the recent finding that women with endometriosis are much more likely to have nerve fibres in their endometrium. This latest study is a logical extension of this as they were looking at the levels of proteins that cause nerves to grow (called neurotrophins) in the endometrium. What they found was that there was a far higher level of proteins called BDNF and NT-4/5 in the endometrium of women with endometriosis. What this means is that there are now ways to identify women with endometriosis purely from an endometrial biopsy. Although this still wouldn’t be able to replace a laparoscopy, it all goes towards reducing diagnosis times and may even be able to predict a woman’s fertility status, giving her the best options for treatment.

Speaking of fertility, you may recall last month I talked about the outcome of IVF in women with endometriosis and how women with endometriosis were more at risk of preterm birth (though the child’s overall health wasn’t affected). Well this month a study may go some way to explain why this might be the case. This latest investigation suggests that it is inflammation that plays a role in preterm birth in women with endo. It has been known for a long time that endometriosis is a disease of chronic inflammation and it’s not surprising when you look a little deeper at how the disease works. We’ve probably all seem pictures of what an endometriotic implant looks like, usually a red or bluey-black spot that grows and bleeds. Your body reacts to this in much the same way it would to any other injury, i.e. it initiates an inflammatory reaction. If you cut your hand this inflammatory reaction speeds up the healing process and helps prevent infection; but inside your body this inflammatory reaction to the endometriosis is persistent and is thought by some to contribute to the pain generated by endometriotic implants. Your body controls the inflammatory reaction by secreting proteins which tell the immune system when and where to initiate it and we find a very high level of these inflammatory proteins in the peritoneal fluid and blood of women with endometriosis. All these inflammatory proteins floating around in your body may have an effect on your ability to conceive and subsequently may also put you at an increased risk of preterm birth. It will probably come as little surprise then that another study, published very recently, found that pregnancy rates were significantly improved after endometriotic implants had been surgically removed.  

A quick rundown of a couple more stories before we end for this month. Starting with a review from authors in Oxford, UK looking at the evidence concerning the age at which a girl starts her periods (menarche) and how this relates to her subsequent risk of developing endometriosis. The authors examined 45 papers published between 1980 and 2011 and found that, once they had narrowed the studies down to those with the best methodology, that a woman with endometriosis is 55% more likely to have started her periods earlier than a woman without endo.  Of course that’s not a massive majority because it means if you picked two women at random, one with endo and one without, only around half the time the woman with endo would have started her periods earlier. It’s still significant though and it raises the question of whether an early menarche is cause or effect, i.e. do you have endometriosis because you started your periods early, or did you start your periods early because you have endo? These questions still remain unanswered.

Finally is a piece of research about vitamin supplementation for the treatment of endo pain symptoms. In the past I’ve read plenty of supposed ‘research’ about vitamin supplements as a panacea for everything from cancer to AIDS and invariably they turn out to be a complete load of bullcrap by some quack doctor trying to exploitatively sell their worthless snake oil to desperate and  vulnerable people.

Your typical cure-all vitamin supplement doctor

However, I am glad to say this latest research is nothing like that and is infact a serious scientific investigation into the effect of taking supplements of vitamins E and C on the painful symptoms of endometriosis. In order to test this the researchers took 59 women with endo and randomly assigned them to one of two groups; one group got the vitamin supplements (1200 IU of vitamin E and 1000mg of vitamin C) and the other group got a placebo (a fake pill that has no active ingredient).  What they found was that the women who received the vitamins had a 43% improvement in everyday pain; dysmenorrhoea (excessive period pain) was decreased 37% and dyspareunia (painful sex) was decreased 24%. Inflammatory markers, like the one I was taking about above, were also decreased in the group who took the vitamins. The one criticism I have of this study though is that it wasn’t double blind, and by that I don’t mean everyone having tape put over their eyes. Double-blinding means that neither the patient getting the treatment nor the doctor administering it knows whether they are having the real treatment or the fake placebo. The reason this is done is because in some people, if they don’t know they’re taking the fake pill, their body will react to the fake pill in the same way it would to the genuine treatment (this is called the placebo effect and we still don’t understand why it happens). But if a patient knows they are getting the fake pill this placebo effect disappears so we can’t accurately compare patient’s reaction to the genuine and fake pills.

It is confusing and no-one truly understands the placebo effect, but it has a real effect on drug trials so it must be taken into account. Nevertheless it is nice to see some proper science going into vitamin research, however I hope this doesn’t become a green light for charlatans to charge £50 for a bottle of vitamin tablets. If you want to try vitamin supplements for yourself I recommend your local pharmacy (I get a month’s worth of vitamin pills from mine for 99p which is roughly $1.50). If it works for you, that’d be fantastic, if not then you never know, next month they might find a cure (hey it has to happen sometime).

You’re never too old, or too young

Quick, if I were to ask you to name any times in a woman’s life when she shouldn’t suffer from endometriosis, what would you say? Most likely, anyone with a basic knowledge of the disease will say premenarcheal (before her periods start) and postmenopausal (after menopause) because endometriosis is a disease dependant on hormones, right? So before and after the time a woman can menstruate there should be no chance of endometriosis developing, it’s just logical to think that way.

Well if life teaches us anything, it’s that some things are not logical, and endometriosis is one of those things. In terms of logicality, endometriosis is kind of like sticking your head in a washing machine filled with Salvador Dali and M.C Esher paintings.

Pictured: endometriosis

Because of this there are cases (albeit very rare cases) of endometriosis occurring in young girls and older women. Of note there have been reports of symptomatic endometriosis in girls as young as 8 and in women as old as 80. So how can we explain these odd, seemingly illogical occurrences, can we even explain them?

The answer is a resounding “well, sort of”. Endometriosis in postmenopausal women is perhaps the easier of the two entities to explain. Postmenopausal women may be taking hormone replacement therapy (HRT) which would provide any endometriotic implants with a steady supply of estrogen to keep them going. Some reports have even stated that postmenopausal women taking HRT have an increased, but poorly defined, risk of previous endometriosis recurring.

But (and there is always a ‘but’ to complicate matters), there have also been reports of postmenopausal women with no past history of the disease, suddenly developing endometriosis. There are a number of explanations for this though. Firstly, the woman may have had endometriosis lingering in her body all along, and any number of contributory factors may have suddenly caused it to grow. Secondly, if the woman has had any major surgery in her pelvic area (e.g. hysterectomy, oopherectomy etc) tiny bits of the endometrium may have been spread around her pelvic cavity during surgery, which may then implant to form endometriosis later on (this mechanism is thought to be one of the ways surgical scar endometriosis occurs).

An unanswered question remains though, if a woman is past menopause and not taking HRT how does the endometriosis get the estrogen it needs to survive? After menopause a woman’s ovaries begin to shut down and a drastic reduction in estrogen production occurs over a period of about 4 years. However, androgens are still produced, albeit at a diminishing rate, by the adrenal glands and ovaries after menopause. Androgens are another group of hormones that could loosely be described as being responsible for the development of masculine characteristics. Women also produce androgens, but at a lower level than men and androgens in women can be converted into estrogen. However, you need certain enzymes to convert androgens to estrogens, the most famous of which is aromatase.

Aromatase is an enzyme whose job it is to take hormones like testosterone and convert them into estrogen. Aromatase is expressed in a number of cell types including the ovaries, fat cells, endometrium and guess where else? That’s right, in some but not all, endometriotic cells too. This means that any endometriotic implant that expresses the aromatase enzyme can essentially make its own estrogen. Even with the low levels of androgens produced in postmenopausal women, endometriosis with active aromatase could produce its own estrogen and hence survive in a woman who has gone through the menopause.

Well, you may think, that all sounds very plausible but is there any evidence to substantiate this little theory of yours? Good question and yes there is. You see, there is a group of drugs called aromatase inhibitors that are sometimes given to women with endometriosis and there are no prizes for guessing that these drugs inhibit the aromatase enzyme. In some cases of women with postmenopausal endometriosis there is evidence to suggest treatment with aromatase inhibitors can significantly reduce their symptoms. Of course, the problem with aromatase inhibitors is that they decrease estrogen levels even further, which if you are past the menopause it probably going to lead to complications and adverse side effects.

But what of premenarcheal endometriosis? There is, some good evidence, which I have mentioned previously, concerning the discovery of displaced endometrium, a hallmark of endometriosis, being found in unborn human foetuses. Conveniently, the research group who made these previous discoveries have recently published another paper of their largest study yet confirming the cells that preclude endometriosis can be found in girls before they are even born. So, it would appear we have a possible answer for why such young girls can develop endometriosis; the bigger question though is how, and therein lies the rub.

At present the ‘how’ is the unanswerable question. Is there any reasonable explanation for how girls who haven’t even reached puberty can develop endometriosis? There are of course arguments that environmental pollutants can bring about the development of endometriosis, but the evidence for this is rather weak and highly debated so we can’t (or rather shouldn’t) draw any conclusions from that particular line of evidence, yet.

There are so many factors which are thought to influence the development of endometriosis such as; genetics, epigenetics, diet, lifestyle, environment, immune function, family history, that we may never have a singular cause for endometriosis. Some women may inherit it, some women may acquire it. Perhaps we need not think of endometriosis as one giant jigsaw to be pieced together; perhaps we need to see each case as its own, individual puzzle.