Free Article Series: Fertility and Endometriosis

There are lots of articles being published on endometriosis all the time, (for example there were over a thousand articles either directly or indirectly related to endometriosis published last year) the main reason this blog exists is because the vast majority of these studies never get read by people actually affected by the disease. Mostly this is because these studies are published in scientific journals and/or hidden behind online paywalls only accessible to people in academic institutions, and even then the studies are written in very dry, scientific terms. 

Sometimes research in endometriosis makes it to the news, but often this is conveyed by journalists who, as well meaning as they can be, often misinterpret or exaggerate scientific information. I aim to write about the latest endometriosis research in a way anyone can read and understand, but there is so much being published all the time it difficult to cover it all here. Fortunately some research is made available for free for anyone to read, so I’m starting a series providing free articles on a certain theme each time. This time I’m going to be listing some of the most relevant, free articles concerning one of the major facets of endometriosis; fertility, how it affects women, how surgery affects pregnancy rate, how fertility therapy can help women with endometriosis and several other areas. Just click on the title of each article to be taken to the full text.

As mentioned though some of the articles are written in a rather dry prose and include a lot of detail about scientific methods and analysis that may not be relevant to the lay reader, so I would say the most important parts of some articles are the introductions/background and the discussion/conclusions, so feel free to skip to those parts to get the most interesting information. I’ve included the summary for each article so you can see which ones are of most interest to you.

Title: The impact of endometriosis on the outcome of Assisted Reproductive Technology.

Authors: González-Comadran M, Schwarze JE, Zegers-Hochschild F, Souza MD, Carreras R, Checa MÁ.

Published In: Reproductive Biology and Endocrinology. 2017 Jan 24;15(1):8. doi: 10.1186/s12958-016-0217-2.

Summary: Reproductive outcomes among women undergoing IVF and diagnosed with endometriosis-associated infertility do not differ significantly from women without the disease. Although women with endometriosis generate fewer oocytes, fertilization rate is not impaired and the likelihood of achieving a live birth is also not affected.

Title: Strong Association Between Endometriosis and Symptomatic Leiomyomas.

Authors: Nezhat C, Li A, Abed S, Balassiano E, Soliemannjad R, Nezhat A, Nezhat CH, Nezhat F.

Published In: Journal of the Society of Laproendoscopic Surgeons. 2016 Jul-Sep;20(3). pii: e2016.00053. doi: 10.4293/JSLS.2016.00053

Summary: In our patient population, 87.1% of patients with a chief concern of symptomatic fibroids also had a diagnosis of histology-proven endometriosis, which affirms the need for concomitant diagnosis and intraoperative treatment of both conditions. Overlooking the coexistence of endometriosis in women with symptomatic leiomyoma may lead to suboptimal treatment of fertility and persistent pelvic pain. It is important for physicians to be aware of the possibility of this association and to thoroughly evaluate the abdomen and pelvis for endometriosis at the time of myomectomy or hysterectomy in an effort to avoid the need for reoperation.

Title: Clinical analyses of endometriosis after conservative surgery.

Authors: Ke X, Qian H, Kang L, Wang J, Xie Y, Cheng Z.

Published In: International Journal of Clinical and Experimental Medicine. 2015 Nov 15;8(11):21703-6. eCollection 2015

Summary: Surgery can improve the symptom remission rate and fertility of patients. Postoperative drug therapy does not improve the chance of pregnancy

Title: The Surgical Treatment of Severe Endometriosis Positively Affects the Chance of Natural or Assisted Pregnancy Postoperatively.

Authors: Nesbitt-Hawes EM, Campbell N, Maley PE, Won H, Hooshmand D, Henry A, Ledger W, Abbott JA.

Published In: Biomed Research International. 2015;2015:438790. doi: 10.1155/2015/438790. Epub 2015 Jul 12.

Summary: These data provide information to women with suspected severe disease preoperatively concerning their likely postoperative fertility outcomes. Ours is a population with severe endometriosis, rather than an infertile population with endometriosis, so caution needs to be applied when applying these data to women with fertility issues alone.

Title: Oocyte quality is decreased in women with minimal or mild endometriosis.

Authors: Xu B, Guo N, Zhang XM, Shi W, Tong XH, Iqbal F, Liu YS.

Published In: Scientific Reports. 2015 May 29;5:10779. doi: 10.1038/srep10779

Summary: Endometriosis, a pathological condition in which the endometrium grows outside the uterus, is one of the most common causes of female infertility; it is diagnosed in 25-40% of infertile women. The mechanism by which endometriosis affects the fertility of females remains largely unknown. We examined the ultrastructure of oocytes from patients with minimal or mild endometriosis and control females undergoing in vitro fertilization (IVF) treatment. Our results suggest that decreased oocyte quality because of impaired mitochondrial structure and functions probably an important factor affecting the fertility of endometriosis patients.

Title: Treatment of endometriosis in women desiring fertility.

Authors: Mavrelos D, Saridogan E.

Published In: Journal of Obstetrics and Gynaecology of India. 2015 Feb;65(1):11-6. doi: 10.1007/s13224-014-0652-y.

Summary: Endometriosis is a common condition affecting a significant proportion of women in their reproductive age. Apart from the impact of endometriosis on the quality of life of these patients, it also can have an impact on the potential of these women to have a family. The options for treating women with endometriosis desiring a family include surgery or assisted reproduction techniques. The choice of treatment will depend on the stage of disease and the characteristics of the couple seeking help. We review here the latest evidence on the management of endometriosis in women desiring fertility and describe our current practice.

Title: Low birth weight is strongly associated with the risk of deep infiltrating endometriosis: results of a 743 case-control study.

Authors: Borghese B, Sibiude J, Santulli P, Lafay Pillet MC, Marcellin L, Brosens I, Chapron C.

Published In: PLoS One. 2015 Feb 13;10(2):e0117387. doi: 10.1371/journal.pone.0117387.

Summary: The influence of intrauterine environment on the risk of endometriosis is still controversial. Whether birth weight modifies the risk of endometriosis in adulthood remains an open question. For this purpose, we designed a case-control study involving 743 women operated on for benign gynecological indications from January 2004 to December 2011. Among patients with LBW, the risk is almost two-times higher to develop DIE. This association could reflect common signalling pathways between endometriosis and fetal growth regulation. There is also the possibility of a role played by placental insufficiency on the development of the neonate's pelvis and the occurrence of neonatal uterine bleeding that could have consequences on the risk of severe endometriosis.

Title: Endometriosis and infertility: how and when to treat?

Authors: Fadhlaoui A, Bouquet de la Jolinière J, Feki A.

Published In: Frontiers of Surgery. 2014 Jul 2;1:24. doi: 10.3389/fsurg.2014.00024.

Summary: Endometriosis is defined as the presence of endometrial-like tissue (glands or stroma) outside the uterus, which induces a chronic inflammatory reaction. Although endometriosis impairs fertility, it does not usually completely prevent conception. The question of evidence based-medicine guidelines in endometriosis-associated infertility is weak in many situations. Therefore, we will highlight in this issue where the challenges are.

Title: Fertility: Assessment and Treatment for People with Fertility Problems (book)

(endometriosis covered in chapter 10)

Authors: Various

Summary: This guideline offers best practice advice on assisting people of reproductive age who have problems conceiving. It is estimated that infertility affects about one in seven heterosexual couples in the UK. Since the original NICE guideline on fertility was published in 2004 there has been a small increase in the prevalence of fertility problems and a greater proportion of people now seeking help for such problems. The main causes of infertility in the UK are (percentage figures indicate approximate prevalence): ovulatory disorders (25%); tubal damage (20%); factors in the male causing infertility (30%); uterine or peritoneal disorders (10%). In about 25% of cases infertility is unexplained, with no identified male or female cause. In about 40% of cases disorders are found in both the man and the woman. Uterine or endometrial factors, gamete or embryo defects, and pelvic conditions such as endometriosis may also play a role. Given the range of causes of fertility problems, the provision of appropriate investigations is critical. These investigations include semen analysis; assessment of ovulation, tubal damage and uterine abnormalities; and screening for infections such as Chlamydia trachomatis and susceptibility to rubella. Once a diagnosis has been established, treatment falls into three main types: medical treatment to restore fertility (for example the use of drugs for ovulation induction); surgical treatment to restore fertility (for example laparoscopy for ablation of endometriosis); assisted reproduction technology (ART) – any treatment that deals with means of conception other than vaginal coitus; frequently involving the handling of gametes or embryos.

Title: Laparoscopic surgery for subfertility related to endometriosis: a meta-analysis.

Authors: Jin X, Ruiz Beguerie J.

Published in: Taiwan Journal of Obstetrics and Gynecology. 2014 Sep;53(3):303-8. doi: 10.1016/j.tjog.2013.02.004.

Summary: The use of laparoscopic surgery in the treatment of subfertility related to minimal endometriosis may increase the chances of future pregnancy and live birth

Title: The impact of endometriosis on IVF/ICSI outcomes.

Authors: Dong X, Liao X, Wang R, Zhang H.

Published in: International Journal of Clinical and Experimental Pathology. 2013 Aug 15;6(9):1911-8.

Summary: Except reduced implantation rate in stage III-IV endometriosis group, no differences were found in other pregnancy parameters. This study suggests that IVF/ICSI yielded similar pregnancy outcomes in patients with different stages ofendometriosis and patients with tubal infertility. Therefore, IVF/ICSI can be considered as an effective approach for managingendometriosis-associated infertility.

Title: Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility.

Authors: Macer ML, Taylor HS.

Published in: Obstet Gynecol Clin North Am. 2012 Dec;39(4):535-49. doi:10.1016/j.ogc.2012.10.002.

Summary: Endometriosis has been associated with infertility; however, the mechanisms by which it affects fertility are still not fully understood. This article reviews the proposed mechanisms of endometriosis pathogenesis, its effects on fertility, and treatments of endometriosis-associated infertility. Theories on the cause of the disease include retrograde menstruation, coelomic metaplasia, altered immunity, stem cells, and genetics. Endometriosis affects gametes and embryos, the fallopian tubes and embryo transport, and the eutopic endometrium; these abnormalities likely all impact fertility. Current treatment options of endometriosis-associated infertility include surgery, superovulation with intrauterine insemination, and in vitro fertilization. We also discuss potential future treatments for endometriosis-related infertility.

Title: Minimal and mild endometriosis negatively impact on pregnancy outcome.

Authors: Carvalho LF, Below A, Abrão MS, Agarwal A.

Published in: Revista de Associacao Medica Brasileira (1992). 2012 Sep-Oct;58(5):607-14.

Summary: Endometriosis, a highly prevalent gynecological disease, can lead to infertility in moderate to severe cases. Whether minimal stages are associated with infertility is still unclear. The purpose of this systematic review is to present studies regarding the association between pregnancy rates and the presence of early stages of endometriosis.

Title: Vitamin D and fertility: a systematic review.

Authors: Lerchbaum E, Obermayer-Pietsch B.

Published In: European Journal of Endocrinology. 2012 May;166(5):765-78. doi: 10.1530/EJE-11-0984.

Summary: Vitamin D has been well-known for its function in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. There is some evidence that in addition to sex steroid hormones, the classic regulators of human reproduction, vitamin D also modulates reproductive processes in women and men

Title: Endometriosis and infertility.

Authors: Bulletti C, Coccia ME, Battistoni S, Borini A.

Published in: Journal of Assisted Reproduction and Genetics. 2010 Aug;27(8):441-7. doi: 10.1007/s10815-010-9436-1.

Summary: Endometriosis is a debilitating condition characterized by high recurrence rates. The aetiology and pathogenesis remain unclear. Typically, endometriosis causes pain and infertility, although 20-25% of patients are asymptomatic. The principal aims of therapy include relief of symptoms, resolution of existing endometriotic implants, and prevention of new foci of ectopic endometrial tissue. Current therapeutic approaches are far from being curative; they focus on managing the clinical symptoms of the disease rather than fighting the disease. Specific combinations of medical, surgical, and psychological treatments can ameliorate the quality of life of women with endometriosis. The benefits of these treatments have not been entirely demonstrated, particularly in terms of expectations that women hold for their own lives. Although theoretically advantageous, there is no evidence that a combination medical-surgical treatment significantly enhances fertility, and it may unnecessarily delay further fertility therapy. Randomized controlled trials are required to demonstrate the efficacy of different treatments.

Access to articles is provided by US National Library of Medicine and National Institutes of Health as well as individual publishers

Highlights from WCE 2014 - Part 3

Carrying on with our WCE 2014 highlights, let’s have a look at some of the research into fertility issues and endometriosis. Reduced fertility is one of the major problems faced by women with endometriosis, yet there are still many mysteries surrounding how endometriosis affects fertility.

In order to shed at least some light on the issue an Italian research team investigated how ovarian endometriosis (endometrioma) can affect the viability of ovarian follicles in women undergoing IVF. What they found was that follicles closer to endometrioma showed higher levels of iron. Iron, of course, is important for your body but in endometriomas iron accumulates in high amounts, probably due to blood filling the inside of the cyst. These high levels of iron can be toxic to anything close by, in this case, ovarian follicles. This leads to impaired development of the follicle and perhaps partly explains why so many women with endometrioma/s find it hard to conceive.

If you have an endometrioma, chances are you’ll want surgery to remove it, but you’ll also want to know what the risk of recurrence is and what factors influence that risk. A team from Brazil looked at the records from 202 women undergoing laparoscopic excision of endometrioma between and 2003-2012 and analysed those records to see what influenced endometrioma recurrence. They found that the overall rate of endometrioma recurrence was 16.4% and that factors such as age, race, symptoms, exercise, number of children and type of surgical procedure had no effect on recurrence rates. However, they found that having a cyst larger than 6cm (which is pretty large) and stopping medical therapy after surgery significantly increased the chance of endometrioma recurrence (although the abstract didn’t specify which medical therapy was used). Because of the side effects associated with some of the medical treatments for endometriosis, it is unsurprising some women need to stop treatment. However, if stopping treatment means an increased risk of disease recurrence, then more work needs to be put into ensuring other, more tolerable medical options are made available.

Speaking of IVF, some women who suffer with fertility issues may consider IVF as a means of conception. It is therefore important for women with endo to know if their condition may affect their IVF outcome. A group from France compared 291 women with endo to 1316 women without to see what the effects, if any, endo made to the delivery rates after undergoing IVF. What the researchers found was that, in the women who had good ovarian stimulation response and high quality embryos, the total cumulative successful delivery rate for fresh and frozen embryos was 52.3% for women with endo and 45.8% for women without. Although women with endo had lower rates of good ovarian stimulation, the overall outcome was no different between women with and without endo. This suggests that having endo (regardless of stage) may not impact the success of IVF.

Although it appears that endo doesn’t affect the success of IVF, it would still be good to have some way of improving IVF outcomes. A group from New Zealand has been conducting a randomised, controlled trial to see if a drug called Lipiodol has any benefit on IVF outcomes, as their initial tests showed this treatment improved the fertility of women with endo much more than women who couldn’t conceive but didn’t have endo. Lipiodol can normally be used for hysterosalpingography (a procedure used to determine the shape of the uterus and fallopian tubes) and is injected into the uterine cavity so comes into contact with the endometrium. The authors of this study think that Lipiodol ‘bathes’ the endometrium, making it more receptive to a fertilized egg. Their results are still very preliminary so should be met with cautious optimism, but are still encouraging. The women who received IVF alone achieved a live delivery in 22.7% of cases, but the women who had Lipiodol treatment plus IVF achieved a live delivery 43.8%. These results are encouraging, but we’ll have to wait until the clinical trials have been completed and the results properly analyzed before drawing any firm conclusions.

May Roundup

It’s an increasingly busy time for endometriosis research at the moment. In the last 31 days there have been 111 articles published on endometriosis, which means an average of just over 3 articles every day. That’s also pretty impressive when you consider that, in the same period of time ten years ago, there were only 33 articles published! So the march of progress rolls ever onward and it’s nice to know endometriosis isn’t being left behind; however this means it’s becoming harder for me to keep up with the research!  I shouldn’t complain really, so instead I’ll get on with a roundup of this month’s top endo research highlights.

I’ll start off with what, at first glance, would appear to be a report from the Twilight Zone. It’s another report of endometriosis occurring in a man. 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’ve reported on endometriosis in males before and it is a very unusual thing to find for several, probably quite obvious reasons. However, previously reported cases have been in elderly men undergoing estrogen therapy for prostate cancer. The thought behind this was that the estrogen somehow caused certain cells in the male body to transform into endometrial cells. This new report throws a bit of a spanner into the works. If you click on the above link you should be able to read the full article, but basically a man was admitted to hospital with an inguinal hernia (a hernia located just above the testicles, in line with the bladder). Upon surgical inspection a cyst was discovered that was found to have endometriosis within in it. The really puzzling part here is that the man was undergoing anti-estrogen therapy for infertility, so how could the endometriosis possibly have developed? It makes no sense. 

Seriously, this picture makes more sense

 The authors of the paper point out that there are three main theories about how endometriosis develops; transplantation (aka retrograde menstruation), metaplasia and embryonic rest. Transplantation can be discounted straight away; metaplasia could make some sense as it relies on the transformation of tissue under the influence of inflammation or hormones, but the man was taking anti-estrogen medication so that doesn’t quite hold. That leaves embryonic rest theory. This basically states that, during development, microscopic pieces of the tubes which go on to form the reproductive organs end up getting misplaced around the body. These tiny pieces can then go on to develop into what we see as endometriosis. If this was to happen in a man, we would expect to see endometriosis developing along the ejaculatory and diferent ducts, which is exactly what the authors found, so it looks like we have a winner for embryonic rest theory.

Next up is study on the effects of different causes of infertility on the outcome of IVF/ICSI. Many women with endometriosis also present with subfertility or infertility, therefore a higher number of women with endo are likely to employ assisted reproduction technologies (ART) if they cannot conceive naturally. This may lead some women to wonder if all the problems endo causes will have any impact on the health of their baby. This study aims to answer those questions by taking patient records from 255 Finnish women (29 of whom were diagnosed with endometriosis) that had undergone successful assisted reproduction of some variety and comparing them to women who conceived naturally.

What they found was that women with endometriosis who underwent ART were at the highest risk of pre-term birth and thus, were more likely to have babies of low birth weight. However, though this may sound scary, the authors also found that these babies required an amount of neonatal care similar to that of all the other subgroups of women, indicating that though the babies were small, they were also healthy. Interestingly, although this was a relatively small study, it found that women with endo who conceived with ART were less likely to have a previous miscarriage, a chronically ill baby or foetal demise than healthy women who conceived naturally. So if you do have endometriosis and are considering IVF or another type of ART, hopefully this study will put your mind at rest a bit. If you would like to read the full article, you can by following this link.

Moving on now to a couple of studies from our Teutonic cousins; the first of which looks at the age distribution of women with endometriosis. This study took information from 42,079 women who were diagnosed with endometriosis in Germany between 2005 and 2006 and divided them into three age groups; premenopausal (0-45 years), perimenopausal (45-55 years) and postmenopausal (55-95 years). What they found was that the majority of women with endo were in the premenopausal group (33,814 or 80.36%). That doesn’t come as much of a surprise as it’s the largest age group and the one we most commonly find women with endo in. What was quite surprising was the finding that 7,191 (17.09%) women with endo were in the perimenopausal group and 1,074 (2.55%) were in the postmenopausal group; which means nearly 1 in 20 women diagnosed with endo were over 45. This shows that endometriosis does not discriminate by age and that it is important for medical professionals to know that just because your periods have stopped, it doesn’t necessarily mean your endo has.

The second study from Germany examined the cost of endometriosis in terms of in-patient treatment in 2006. Coincidentally this follows on nicely from the previously study which was looking at number of women diagnosed and this one looks at the cost of treating those women. These authors found that a total of 20,835 women were admitted to hospital for endo treatment in 2006 at an average cost of 3,056.21€ each. In total this brings the cost of treating all those endo patients to 40,708,716.26€. That’s just in-patients treatment as well, it doesn’t take into consideration the addition cost of lost work productivity, out-patient costs, or other economic factors that endo impacts on. It wasn’t long ago that I posted about a study that examined the total cost of endo, and if 40 million Euros sounds like a large amount of money, the true cost is likely to be 10 fold.

The final study for this month seems a little controversial to me. Not because there is anything particularly offensive or contentious said, but the conclusions that are drawn are tenuous to my eye. You can read the summary here and make up your own mind, but I’ll tell you what I think. To summarise, the authors of this study conclude that endometriosis is rare in rural, isolated communities such as those in Northern Uganda, because the women there have a high number of children, have more teen pregnancies and a longer duration of breast feeding. An interesting conclusion but I can see several flaws in it. Firstly, I’m not sure I agree wholeheartedly with the opening statement “Women in Western nations are exposed to an "unnatural" high number of menstrual cycles”. Maybe it’s just the way it’s worded, but I don’t like that sentence. I can see where they are coming from; women in Western countries start their periods earlier and have fewer children than those in developing countries. But how is this ‘unnatural’? What is a 'natural' amount of menstrual cycles? Is there such a thing?

Also it doesn’t seem to take into account that women in developed countries have a far greater use of the contraceptive pill, which means fewer, lighter periods. For example, in the UK in 2008, 84% of women of reproductive age were taking the contraceptive pill; compare this to only 15% of women of the same age group in Nigeria (Source: Worldbank, I couldn’t find the stats for Uganda). So surely this indicates that saying women in the Western world have an ‘unnaturally’ high number of menstrual cycles, isn’t necessarily correct.

Another thing that’s bugging me is that, out of the 528 gynaecological consultancies performed over a year at the Ugandan Aber district hospital, only 1 woman was diagnosed with endometriosis thus, the authors conclude, it is rare in this part of the world. However, even in wealthy western countries, there is a very high rate of misdiagnosis and endometriosis specialists who can accurately and thoroughly diagnose the disease are in short supply; so how can you expect the same level of diagnostic accuracy in small rural hospital in a developing nation with no specialist training? It is very likely endometriosis is far more common than reported here, but inadequate facilities and ‘masking’ of the disease by high pregnancy rates leads to under-reporting of endometriosis in this part of the world.

Pictured: The developing and developed world; sadly the one on the right is only marginally better at diagnosing endo than the one on the left

 One last thing is that it’s assumed that number of menstrual cycles (and hence menstruation itself) is important for the development of endometriosis. Whilst there is still some debate about this, consider the fact I have reported (in this post and previously) on cases of male endometriosis, endometriosis in unborn foetuses, endometriosis in women who can’t menstruate and even endometriosis in animals that can’t menstruate. So I’ll leave you to think about how relevant menstruation may be in the development of endometriosis.

The problem is, I’m quite familiar with the work of the authors who wrote this paper and it’s usually enlightening and insightful. This is why I am somewhat dismayed to see this study where conclusions seem to have been drawn hastily and without much thought to alternative explanations.