Current Research on Endometriosis: An Interview with Prof. Michel Canis

“We need a completely different concept about this disease”

Trigger Warning

This article contains material of a highly sensitive nature including sexual assault, that may be triggering for some individuals.

Michel Canis is a professor for obstetrics and gynecology CHU Hospital in Clermont-Ferrand, France. He is their head of the department of surgical gynecology, and the director of a research unit on computer vision and endoscopy at the Pascal Institute Clermont-Ferrand. Professor Canis is involved in endometriosis research since the 1980’s and develops theories on its genesis and diagnosis. He pleads for raising different approaches to a better understanding of endometriosis in order to help patients in the best possible way.

Charlotte Weber: Thanks very much for taking the time today. Maybe could you introduce yourself briefly?

Prof. Michel Canis: I’m Michel Canis and I’m involved in Endometriosis since 1984. I was a member of the scientific committee of the First World Congress on Endometriosis in 1986. Since then, I’ve been working on Endometriosis mainly as a surgeon and in research. We have a research team in California which is doing a lot of fundamental works and basic research on Endometriosis.

Charlotte Weber: How did you come to specialize in Endometriosis?

Prof. Michel Canis: I was a resident in the department and one of the residents who was working with me suddenly decided to move to bowel surgery. The head of department called me and said “Michel, he was working on Endometriosis and prepared a review about it, but as he is moving to digestive surgery, he won’t do it. Would you accept to do it?”. At that time, I was a young resident, but I said “okay, I will try to do it”. I did a big review, but it was difficult to get references at that time, it was 1983/84. I wrote a review from about 300 references, which was a lot at that time. This was the beginning of the story, from this work we decided to organize the first World Meeting on Endometriosis. This was the start of the adventure.

Charlotte Weber: You were a surgeon and then you did research?

Prof. Michel Canis: I’m not really a busy researcher, but I can engage in discussions with them to ensure their work aligns with our clinical practice. Because if you do research without any connection to clinical practice, it doesn’t make any sense.

Charlotte Weber: What fascinates you about the topic and what is your main motivation regarding your research?

Prof. Michel Canis: It’s challenging trying to instill an understanding of why the disease is there, how it worsens or improves, and to understand the underlying pathophysiology. My feeling is that we are all stuck with the simple hypothesis that endometriosis is mysterious, enigmatic, and complex. We are unlikely to find any explanation using this hypothesis. We all know that many patients do have retrograde menstruation, which is a common occurrence among women. However, the other mechanisms proposed can be found in any woman, so that all these mechanisms do not explain why the disease begins. If we go with retrograde menstruation for example [Editor’s Note: a hypothesis suggesting that Endometriosis is caused by retrograde flow of menstrual blood through the fallopian tubes in the pelvic cavity (Sourial et al., 2014)], people always think that the disease is supposed to begin at menarche [Editor’s Note: Begin of the menstruation during puberty] and then to get worse and worse. I don’t think so. I think the disease is not always beginning in adolescence, not always beginning at menarche, but it may begin at very different times in a patient’s life.

Back in 2017 I proposed that trauma could be a cause of the disease. We do know that certain forms, like scar endometriosis, are related to C-section trauma. I also proposed that a different trauma could explain different forms of the disease in a way that the severity of the disease would not be related to the duration of its evolution. Instead, it would be related to the extent of the trauma which induced the disease. The question of evolution, or worsening, of the disease is then related not to for how long it is there, but to whether the trauma is still ongoing.

You maybe saw last week that a Japanese team suggested that a bacteriological explanation could be found in some patients. If this infection is not diagnosed, the disease could be worsening just because we are not treating the cause. When we give hormonal treatments, we stop the process. However, if we don’t treat the infection which it’s associated to, we probably don’t stop the trauma, so the disease may recur when we stop medical treatment. Whereas if we were using antibiotics to stop the disease at this point, when stopping amenorrhea [Editor’s Note: absence of menstruation during the reproductive life of a women], the disease would not come back. We need a completely different concept about this disease.

I’m not against the basic concepts related to genetics, immunology and so on. I have no problem with that. However, we have been working with this mysterious hypothesis for 40 years, since 1986, and the progresses have been very minimal for patients. Laparoscopic surgery has improved, IVF has improved tremendously. Imaging has also done a lot of progress. However, as far as treatments are concerned, we are still stuck with amenorrhea on one side and surgery on the other side, and no part of the treatment is based on understanding the disease.

Charlotte Weber: Could it be different kinds of trauma? Infections during the C-section for example?

Prof. Michel Canis: You also may imagine that if you have trauma to the ovaries, it’s very simple because trauma to the ovaries leads to ovulation or ovarian cysts, which then rupture the ovarian cortex [Editor’s Note: the outer portion of the ovaries]. These ruptures in the cortex could facilitate implantation of retrograde menstruation on the ovarian surface. We do know that this is a mechanism involved in ovarian cancer. We do know that this is possible. For the C-section, this is unfortunately also very simple to imagine. A lot of women do have trauma to the posterior side of the vagina. One cause could be delivery. I think as there is endometriosis after both C-section and vaginal delivery. Patients very often have pain, which begins just after delivery. These patients then say “after my second delivery my pain began”. We do have obvious reasons for that. However, such trauma could also be related to the violence in our society, I think. In France, one student out of 20 is raped during their studies.

We do know that a lot of women are subject to violence from their partner at home. Probably a lot of unpresented, discussed, and publicized trauma could be related to this kind of violence. We do have a lot of possible explanations, unfortunately. I think the world is getting more and more violent. This probably could explain why this disease could be more common. If you look at it this way, you have different explanations, and these may explain different phenotypes. I think it makes sense. This hypothesis could be crazy and could be wrong, but at least it raised new questions. This was the reason of the poster that we presented in Edinburgh. Because if the disease is supposed to begin at menarche and then get worse and worse, there should be a correlation between age of the patient and the severity of the lesions at the time of the initial diagnosis. It does make sense.

We did come back to an old cohort study that we conducted from 2003 to 2012, we collected prospectively all patients diagnosed for the first time with endometriosis. We excluded patients referred to us, but patients living in a specific geographical area. A very homogeneous population.

There was no correlation between age and the severity of the disease. No correlation between active implants or cysts and age of the patients. Very interestingly, the patients who were diagnosed after 40, most of them have been pregnant and delivered before. Suggesting that at least they were not infertile, even though they could have had endometriosis at that time. This study clearly demonstrates that the disease does not begin at menarche in all patients, so there is not only one explanation, but several ones. In this concept, endometriosis could be a syndrome related to the trauma, and the phenotype that we find is related to the trauma which induced the disease.

The management should probably be adapted. If you find minimal endometriosis in 40-year-old patients, probably no treatment is necessary because the disease is more likely to decrease or be stable. In contrast, if you have the same appearance in an adolescent, the disease may get worse because it’s much more inflammatory. The management should be adapted to the phenotype, and it doesn’t make any sense to propose 20 years of medical treatment to patients who have a stable disease. In this way we can possibly propose to individualize management, which is the concept of new medicines anyway.

Charlotte Weber: Do you think there might be different causes of endometriosis, for example endometriosis through genetics and endometriosis through trauma?

Prof. Michel Canis: Again, I have no problem with genetics as a reason. You may imagine that trauma is more likely to induce endometriosis in patients with genetic predispositions or those who have bad immunological defenses or are exposed to toxins. But the trauma should be there and the trauma is induces the disease more easily if there is a genetic predisposition and so on. This is not against any of the ongoing possible hypotheses. It’s just a different way to look at it.

We are sending out a call for hypotheses. I will try to get in touch with a number of experts in the world. We wrote a first draft together with a Chinese expert (Sin Wei Guo). We are going to try to propose to all these experts to publish it with us, and then, to propose their hypothesis on a dedicated website. Why are they doing this research? What is their theory behind it? If all these experts are coming with their idea, if we discuss these ideas together, we may have new and disruptive ideas for the future. If not, I think that coming back from Edinburgh, I had the feeling that we have made no progress since 1986 and I am afraid that feeling could be the same when coming back from endometriosis meetings organized in 20 years.

Science is getting more and more sophisticated. Genome wide studies are including more and more patients, but their clinical consequences are limited. If you look at the results , 40 loci [Editor’s Note: specific points, or sequences, in a gene of the human DNA] have been identified. That’s wonderful, however, it’s only including 3 percent of the patients. What is the clinical consequence of ? When we began genome studies in 2000, we were very hopeful. We thought at that time that within five or 10 years we would have a marker, we would have a new treatments. At the end of the day, 20 years later, we have no clinical improvements. If we don’t change the way of looking at diseases, we won’t get improvements. There will be a lot of reaearch papers with no clinical outcomes.

Charlotte Weber: What are future research ideas on how you can prove or analyze your idea? Do you have other projects in the future?

Prof. Michel Canis: First, I think we should look more than before into infections associated to endometriosis. I always thought that the diagnosis of infections associated to endometriosis was very difficult. We concluded that in 1986, because when you do a laparoscopic diagnosis, endometriosis is often red, and when you look at infection, it is also red. The distinction between one red and the other is very difficult. Obviously from the paper published last week, we should look at germs, which are currently not studied in gynecological practice. The microbiome of the endometrium [Editor’s Note: the community of microorganisms, like bacteria or fungi, surrounding the endometrium] include germs which are not usually looked for by gynecologist, so we should probably improve in this direction. I also think that we should go to sociological studies of scar traumata because I do think that violence and sexual violence is probably a major factor of this kind of delusions.

I also think that we should go to sociological studies, because I do think that violence and sexual violence will probably appear as a major factor. These studies are very difficult, very intimate questions for the patients, but I think that we will have studies in the field. In the department, previous violence during adolescence is unfortunately common in patients who complained of chronic pain or severe dysmenorrhea. We are trying to start working on that while being very careful because we are touching intimate subjects for the families. You can break a family doing that because you can induce a big conflict between the husband, the grandfather, or whoever. I do remember that it occurred in the family of a woman I met several years ago. Her daughter, who was 10 years old, was abused by her grandfather. It may be very dangerous, but we must try. I think we must go this way.

We also need studies following up these young patients to see whether the disease is getting worse, if the number of implants is increasing, if they are increasing in size. We do know that a big study was performed by Thomas d’Hooghe a long time ago in a baboon colony in Kenya. He did repeated laparoscopies, who were menstruating. He saw that in some animal, new lesions were appearing but some lesions were also disappearing. I remember very well talking about this with a micro surgeon from Belgium a long time ago, a big expert for endometriosis, and he said “Michel, it’s wonderful. This is incredible. Some lesions are appearing and others are disappearing. They are like mushrooms”. More recently when thinking of my hypothesis of trauma and because I also studied the peritoneum, knowing that It’s very easy to remove the surfactant and the superficial peritoneal cells to create a traumatized area which will allow an easy implantation of the cells. I proposed a different interpretation of these results. Lesions appearing and disappearing meant not that the disease was very active. In contrast, some were induced by trauma to the peritoneum induced by the laparoscopy and others were healing spontaneously because the disease was not progressive. This is a different interpretation of the same study and the same results.

With this idea in mind, I once came to speak with Professor Fazlebas, who is doing also baboon studies, but in the US. I said to him “okay, I think that the research you published shows that the disease is getting worse in baboons and that this is related to the consequences of repeated laparoscopies. At the end of my presentation, he said “Michel, I agree with you. Our results are just demonstrating that laparoscopy is traumatic enough to facilitate new implants”. If you have a different view, you may have different interpretation. Some of them might wrong, but the problem is not whether you are right or wrong. The problem is to try to raise different approaches, different ideas to understand what we are facing.

Charlotte Weber: If you were right, this would have a consequence for diagnosis, you wouldn’t do laparoscopy if there was another way.

Prof. Michel Canis: The question is about the diagnosis. It’s very difficult to know which trauma we need to look at. As a matter of fact, today I have no idea of which trauma is enough to induce the disease in patients. I don’t know. If there are severe lesions or deep endometriosis with nodules, you can diagnose using imaging. But we should be careful, because radiologists nowadays tend to over-diagnose the disease, which is probably worse than under-diagnosing. However, when you are looking for minimal disease, I think we still need a laparoscopic evaluation. When including patients in this kind of studies, I would still suggest that surgical evaluation is interesting. If we would not do that, we will only look at patients with severe disease, large nodules, large cysts. However, we also know that pain may be related to or associated with minimal diseases. In many situations we still need a surgical confirmation if we want to have a complete picture. The data from our old cohort also showed that 75 percent of patients don’t have stage four disease. Stage one, two and three disease, where more than 70 percent.

The worst cases are often discussed today because everyone wants to speak about bowel surgery, bowel resection, or ureteral implantation. Yes, that is possible. However, if you look on population-based studies, this is not the majority. The majority does not have a very severe form of the disease. That’s the reason why we could potentially focus on the most severe cases when looking only at non-surgical diagnosis. If we would have a marker, a biological one, there could be a way to have a diagnosis in a different way. However, again, we should be careful on what we are going to diagnose because overdiagnosis could be worse. For example, if you diagnose a 17-year old woman because the marker is positive, she thinks that she has a chronic disease which will get worse and worse. That she will have pain for years, that she will not be pregnant, that sex will always be painful. I don’t think this is a very good program for young women.

Charlotte Weber: Thank you very much for taking your time to answer our questions and sharing your interesting ideas and views on endometriosis with us, Prof. Michel Canis! Have a nice day and goodbye!

References

Sourial S, Tempest N, Hapangama DK. Theories on the pathogenesis of endometriosis. Int J Reprod Med. 2014;2014:179515. doi: 10.1155/2014/179515. Epub 2014 Feb 12. PMID: 25763392; PMCID: PMC4334056.

Charlotte Weber
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