Future research directions in endometriosis

Professor Thomas D'Hooghe, MD, PhD and Associate Professor Agneta Bergqvist, MD, PhD

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Lone Hummelshøj: “My name is Lone Hummelshøj and I am the editor of Endometriosis Zone. I am here with Professor Thomas D’Hooghe from Leuven in Belgium and Associate Professor Agneta Bergqvist from the Karolinska Institute in Stockholm in Sweden. Dr. Bergqvist is also the Chairman of the ESHRE SIG, newly appointed this week, and Professor D’Hooghe is the Deputy Chair.

We are here to discuss research directions in endometriosis. Where are we today? What is actually lacking in the research that we’re seeing? What should the future directions be? Dr. D’Hooghe?”

Professor Thomas D'Hooghe, MD, PhD: “I think on the clinical level we need large, well-controlled studies including women with, and without infertility and pain, and women with, or without endometriosis as the cause of infertility and pain. We need to control for pelvic factors. We need endometriosis or normal pelvis, or something else, being the cysts or adhesions, and also we need to control for symptoms: being no symptoms, or pain or infertility, or a combination of both.

If we look at the endometriosis literature in clinical studies, we see that in many studies there are no control groups and if there are any, they are very limited. They usually are very biased. In many studies basically the conclusions are not justified by the data. I think that in clinical research this is the main limitation so far. We need better multicenter randomised trials.”

Lone Hummelshøj: “Do you agree with this Dr. Bergqvist?”

Associate Professor Agneta Bergqvist, MD, PhD: “For clinical studies, I agree completely. I think we also need to extend the genetic studies now that the techniques are coming, and to make clinical studies available. That is really important in humans.”

Lone Hummelshøj: “You co-chaired a session this morning at the ESHRE congress here in Madrid. What were the findings and the conclusions that came out of that meeting that could help direct future research?”

Professor Thomas D'Hooghe, MD, PhD: “I think some of the important data were on the molecular level of endometriosis, looking at factors produced by the endometrium and how they make a difference in women with or without endometriosis. Factors used in endometriotic lesions and also how they may be linked to the origin of the disease whether that’s endometrial, the peritoneum, or another source. I definitely think the area of proteonomics and genomics will help. We’ve seen a little bit of that this morning. The problem is these data are so complex, and the end analysis is quite advanced, that you need a high level of informatica analysis to make those data meaningful. We are just beginning trying to get some meaning out of it.”

Associate Professor Agneta Bergqvist, MD, PhD: “I agree completely. The proteonomics and genomics is the field we have to go into in humans.”

Professor Thomas D'Hooghe, MD, PhD: “The other issue that is very important, coming back to your first question, is the lack of focus of research is not only related to the lack of good clinical studies, but maybe more importantly to the lack of use of an existing, good primate model: being the baboon. Baboons, who have spontaneous endometriosis and also baboons in which you can induce endometriosis by using menstrual endometrium, injected into the pelvis and then having endometriotic lesions about one month later. In that model you can either look at ways to prevent the onset or development of endometriosis, by doing a core intervention giving new medication, or existing medication at the time of injection of menstrual endometrium. You can also wait till the disease is established and start from then, giving medication at that time.

Furthermore, you can also, once the baboons that have endometriosis are getting treated, look at the effect on fertility; because in the model you can very highly control for a menstrual cycle, for ovulation, for fertile males, for documentation of sexual intercourse, all factors, which we all know in humans are much more difficult to control because there is a huge variability. You can control that variability in baboons. 

The more I think, for fundamental studies, with this injection of menstrual endometrium inside the pelvis, you can create a kind of bio-culture, in vivo culture, looking at the reaction between three main factors; being menstrual endometrium, peritoneal fluids and peritoneum and try to look at the very origin of the disease at that level. That to me is the highest priority endometriosis research.” 

Associate Professor Agneta Bergqvist, MD, PhD: “I think that’s a good model. It’s a good model for studying implantation of endometrium, but are you sure that you’re studying the disease endometriosis? There are several data now indicating that women with endometriosis also have a high risk of other diseases. It’s not only malignancies but also other auto-immune diseases, hypo-thyroidism, and so on.

What’s the reliance on the baboon model to study the disease of endometriosis? Is the implantation of the endometrium just an indication of the disease? That’s one of my questions related to the baboon model. 

The other question is: there are data accumulating now indicating that the endometrium in women who develop endometriosis is disregulated in some way. What about the disregulation of the endometrium of the baboons that you use for inducing endometriosis?”

Professor Thomas D'Hooghe, MD, PhD: “I think these are very important points. I think the first issue, the disease endometriosis with its non-pelvic manifestations, being autoimmune diseases and cancer. Now, in baboons you have two ways to look at it. The induction model, which I think is especially interesting for looking at pathogenesis, early events in implantation, and the biology of that. And also how molecules that work on the endometrium, be it ectopic or utopic, can prevent or cure or suppress the disease. I think from that level it is very interesting.

To look at the disease, it is a little bit more complicated in baboons with induced endometriosis but then you have to rely on the large baboon colonies that exist, for instance, in the United States. Now papers are coming out showing endometriosis and adenomyosis naturally. Also there are reports that in colonies in the United States endometriosis in baboons is a life-threatening disease, in the sense that it causes bowel obstruction if you don’t treat it. In that way we see that the variability of endometriosis in women is mirrored in the way it is present in baboons.

It depends where you look. For instance in Kenya at the Institute of Primate Research where I did most of my research, you basically look at baboons who have been pregnant in the wild and that have been captured; whereas, in the United States, there are colonies where baboons have been bred throughout several generations. So we have much more of a life history and can look at more disease factors, and not only at implantation and events occurring afterwards.

In terms of testing new molecules, one has to realise that in the model between mice and men, primates are perfect to really test a number of new compounds before their application in women: specifically looking at safety and efficacy, which are very important issues. But I agree there are certainly limitations with the baboon model.”

Associate Professor Agneta Bergqvist, MD, PhD: “Have you done any genetic studies to compare baboons with spontaneous endometriosis and induced endometriosis? Genetic studies in the endometrium or…?”

Professor Thomas D'Hooghe, MD, PhD: “That’s a very good question. We haven’t done that yet. We are now going to the level of looking at menstrual endometrium and looking at DNA and protein expression of different compounds that are important. The problem is that in the colony where I am working, the proportion of baboons with spontaneous endometriosis is limited. Even in the colony at San Antonio, where they have 2,000 baboons, the number of animals with spontaneous endometriosis is limited if you look at it. I think the population of baboons with spontaneous endometriosis is simply too small to have meaningful data on a large scale. It would be quite an enormous effort to keep many baboons in captivity. I don’t think that’s fully justified.

But the point is taken and I think that’s a limitation. Genetics I think is something that is a little bit harder to study in baboons although I have to add that studies by Zondervan and Kennedy in rhesus monkey colonies, also in the United States, have previously shown a familiar risk. So there are studies out there, not in baboons but in other primates, where one has been able to look at the linkage studies and come to some interesting conclusions. It is possible but not easy.”

Associate Professor Agneta Bergqvist, MD, PhD: “So there is no absolutely optimal model for endometriosis?”

Professor Thomas D'Hooghe, MD, PhD: “No, one has to go for the best models available. That’s absolutely true.”

Lone Hummelshøj: “So bearing this in mind: that we don’t have an optimal solution what would your thoughts be on the future? Future directions of research, which I believe your paper, that is just about to be published, is called?”

Professor Thomas D'Hooghe, MD, PhD: “That’s right. I think better clinical trials, more use of primate models and the baboon model specifically. Also in terms of patient awareness, I think the mentality of many doctors has to change. One has to think about diagnosis of endometriosis earlier, when people complain of pain or infertility or a combination of both. One has to take into account chronic disease issues, quality of life issues, all things that are lacking now, and most of all I think physicians have to be honest to their patients.

We know that for instance, pain-related relief in endometriosis is only suppressed by medication. If you stop the medication it comes back. After endometriosis surgery for moderate to severe endometriosis, the cumulative recurrence rate is meaningful since it is in the order of 50% within 2 years, as we have recently presented. So it is real. It’s not necessarily a sign of bad surgery it’s just occurring for reasons that we do not completely know. Maybe it’s impossible to do a complete resection for microscopic areas we cannot see during surgery. Maybe it’s a new disease, occurring again. Maybe these are just high-risk patients that have the disease coming from places we don’t expect. There is a lot of confusion there.

One has to look at it, unfortunately, as a disease that at this moment cannot be fully treated, especially as related to pain. That’s why coping with the disease, like with any chronic disease, is becoming more and more important, while at the same time you are trying to develop new molecules.

I think the most important new area here is in the area of new potential medical treatment. Where one doesn’t have to suppress the cycle but where one targets specific inflammatory components. One of the promising things that we’ve been able to show and present at the American Society of Reproductive Medicine meeting in 2001, is that if you give TNF binding proteins to block TNF alpha activity, at the same time as you inject menstrual endometrium, then you can prevent to a large extent the onset of endometriosis, I mean the development of endometriosis in baboons. Moreover, you can fully prevent the development of endometriosis-related adhesions.

Of course that’s only a preliminary study. But if confirmed in women, the interesting thing is if it works, it suppresses the lesion, it suppresses the symptoms, but it doesn’t suppress the menstrual cycle. 

Eventually if these products are safe during conception then one could even dream, I say dream at this moment, about conceiving during medical treatment for endometriosis without wondering about hormonal products or surgery anymore. 

What I am saying now is very preliminary but that’s the way I like to think about the disease, especially for future treatment.”

Lone Hummelshøj: “Bearing in mind one of the things you mentioned was that recurrence rates are high, both with medical treatment and with surgical treatment, yet for some women the disease goes away. And some women don’t seem to have the other symptoms that Dr. Bergqvist mentioned, allergies, the immune problems, or even malignancies. Stephen Kennedy has posed the big question: are we dealing with more than one disease? Would the two of you like to comment on that?” 

Associate Professor Agneta Bergqvist, MD, PhD: “In several other chronic diseases, the disease comes and goes. That is common in chronic diseases, I mean the symptoms come and go even if you’re carrying the disease all the time. The linkage to other symptoms varies, like in other chronic diseases. 

In this way I don’t think endometriosis differs from other chronic diseases, especially as it is different in different women. There are some indications that there are polygenetic factors involved that might be expressed differently in different women. 

I think we also have to consider that this is a chronic disease, that is not only a pelvic disease. Extra-genital endometriosis is not completely uncommon and that has to be considered more. We have to educate our colleagues in other specialities that endometriosis may occur in other organs. I think it is our duty to educate them to identify and treat endometriosis in other locations.”

Professor Thomas D'Hooghe, MD, PhD: “I agree on the part of the chronic disease. I don’t see a pathophysiological basis to artificially split the disease in two or three different disease types as has been done in the past, and is still being done by several people. I like to look at it as a continuity of minimal disease to very severe disease. The reason why I think that is that it is very rarely that one sees only ovarian, or only deep, or only peritoneal disease. In many cases it’s a combination of several things. 

If the patient has recurrent disease, it’s very often that sometimes it’s peritoneal recurrence, sometimes it’s ovarian, sometimes it’s deep. I think those categories are too simple. We look at the chronic disease with different levels of activity in a person’s lifetime, with suppression during medication, temporary eradication during surgery: but it is essentially the same disease.

The big question is why does endometriosis become more aggressive in some women than in others, and there a genetic explanation may actually come up with a risk profile that is related to this autoimmunity, cancer and maybe other things? I like to think about that and maybe a factor, that is co-determining retrograde menstruation, painful menses, autoimmunity problems, cancer problems, and all of that. It will be very complex. It is already complex. I think we have to be careful to simplify into, this is the disease and this is physiology. I don’t think this is reflecting real problems that the patients have when really endometriosis is presenting.

Also, I think we lack data on the natural history of endometriosis. The data that we have in women in the largest studies that have followed women for two years, and we have no more further data than two years, there were only seven patients; but endometriosis was progressive in most of these patients. 

I think it is fair to conclude that endometriosis will be progressive in at least 50% of patients with a diagnosis. That is evident if you look at the data. It’s a considerable proportion of women that will have progression. The issue is, what is the rate of progression? Progression can be slower, can be faster and this is also confirmed by studies in baboons where we also show that in the model of spontaneous endometriosis, that it is a progressive disease. Unfortunately we are confronted with this idea of progression in at least 50%. In some women indeed regression, in some women stability and I think that factor really adds to the complexity that you cannot just simplify and say this is the disease and this is physiology.”

Lone Hummelshøj: “In conclusion, where are we? Are we just starting? Are we half way there, are we almost there? What are your thoughts?”

Professor Thomas D'Hooghe, MD, PhD: “At the moment the key word is inflammation. If you look at inflammation you have to look at inflammation in the pelvis, in relation to retrograde menstruation, in relation to implantation, in relation to recurrence of endometriosis, in relation to success of treatment. Many of the new compounds are also directed towards trying to block specific steps of inflammation but at the same time trying to block local oestrogen production in endometriotic lesions. I think that’s the way we have to go in terms of treatment. I think that is for the patients the most important thing.”

Associate Professor Agneta Bergqvist, MD, PhD: “The introduction of the concept of inflammation in endometriosis some years ago was the beginning. The possibilities of using genomics and proteonomics to define the patient and to define the disease, I think that is the future. In that perspective I think we are at the beginning: to define the disease, and if you define the disease we can find out the treatment.”

Lone Hummelshøj: “Thought-provoking stuff, thank you very much!”

Comment:
What are genomics and proteonomics? Please explain TNF proteins and binding activity.

I think the researchers should use the list of women who have or have had the disease, rather than relying only on baboons or seven women with advanced endo. There is a WEALTH of info that can be taken from these women. Design a questionnaire that is simple, women check off what they have experienced. Have several different forms. One for those who take drugs, one for those who have had surgery, one for those who do natural remedies, one for those who have tried it all. Thanks.

Jess Young

Response:
Proteomics: the science that deals with the analysis of proteins (presence, activity, function, dysfunction) in body tissues and fluids with respect to specific diseases

Genomics: the science that deals with the analysis of DNA (gene activity and expression)  in body tissues and fluids with respect to specific diseases.

TNF is a molecule that is important in inflammation. TNF binding protein blocks the activity of TNF and selectively inhibits inflammation.

Of course research in women is extremely important, but there are things that cannot be researched in women for practical and ethical reasons.  You cannot do a laparoscopy twice a year to study the spontaneous evolution of endometriosis. It is very difficult to study the biology of retrograde menstruation in women. It is very difficult to do studies in women on how to prevent the development of endometriosis. However, baboons are very close to humans: they have the same reproductive system and function, endometriosis occurs spontaneously and can be induced, and is therefore the best model, in my opinion, to do preclinical research, and to learn more about what can work and why, for later application in women. In this research, baboons are essentially treated like women.

Professor Thomas D'Hooghe