Endometriosis Foundation of America 2014
Outsmarting Endo - Liselotte Mettler, MD, PhD
Decades of Progress in the Clinical Care of Endometriosis
Good morning everybody. My name is Lone and I am going to be moderating today. Today is your meeting basically. We are here to talk about endometriosis and hopefully answer burning questions from yourselves so use this as an opportunity to ask the experts the questions you have about the disease.
We are going to kick off with yesterday's honoree, Professor Lilo Mettler from Kiel in Germany. She is one of the pioneers in endometriosis. Sometimes I think when you are struggling with your pain or your infertility it can be very difficult to understand that loads and loads of people around the world are actually committed to improving the lives of women with endometriosis. Lilo is one of them and she is going to talk about what has been happening over the last couple of decades in terms of progress in managing the disease. Without further ado, Lilo, over to you.
To explain a little bit about what Lone does around the world, she really helps with all the patients' associations. We first met I think it was before 1990. I wondered how patients come into medical meetings but they have come to our meetings all around the world. Meetings like yours are many times, I do not know, Lone can better say it, held and we are happy to sit with the patients and share our opinions and learn from you.
For example, I work in northern Germany on the Baltic Sea, a very small section compared to New York with our little bay the Kiel Förde. But we are connected in Europe by a net, which is called the European Endometriosis Liga. It is a patient site where they can get information on the internet and ask questions of the doctors. We have a kind of expert panel and we get all these questions. I always wonder why their doctors do not answer these questions. Somehow patients do not have the right relationship with their doctors and this is sad. Every doctor really tries to but maybe not hard enough or maybe does not make the time.
When I think about my very active years I was very focused on surgery for endometriosis. It took me 20 years to really understand that I cannot solve every problem with surgery. Many of our younger doctors are like that, they think they can solve the problem with surgery and that is it. We know today that a very small portion of the disease can get malignant as Tommy just said in yesterday's meeting. It is an enigmatic disease that we can live with - it does not lead to death. That is so important to understand. We need society to wake up and help carry the burden. There should never be a moment when a patient says, "Okay, that's it". And there should never be a doctor that says, "Okay my dear, Mrs. Smith, I have tried everything with you. There's nothing more I can do, goodbye". That is not a nice doctor he should always find something in a little corner. We know in our own life and in many other situations that everyone is different. We cannot create a scheme. For a disease where we do not have a 100 percent cure, as it is with endometriosis, we cannot work with a scheme, not everything is the same for every patient.
I want to give you a bit of an overview on endometriosis. The endometrium, which is the tissue inside the uterus - and I wish that Tamer on one occasion you could show your animation to this audience as well. Dr. Seckin has made an animation of how endometriosis gets into our body. It is very difficult for us doctors to understand - how can this tissue that is inside the uterus that produces menstruation - how can that form cysts outside? How can some lesions get into the lung? How do lesions get to distant places? Mostly we are concerned with endometriosis in the minor pelvis, in the genital tract and here you can see that this genital tract is deformed, the tubes are deformed, the ovaries have cysts, the bottom part - is there any flesh to show? This part here, which we call the Pouch of Douglas, is filled with lesions and this produces pain. It produces infertility by adhesions. Sometimes when the cysts get big and press on the bladder it can produce irritations of the bladder and of the rectum.
How can this female disease demand political awareness? That is the word we used yesterday, political, but just public awareness? This comes from many activities around the world. This month is Endometriosis Awareness month and there is going to be a run in Washington. There are many societies, I mentioned the European Endometriosis Liga where we have an expert panel. For instance, 30 years ago I found our German Endometriosis Society, which meets biannually. There are many national and international endometriosis patients' associations we will come to in the afternoon.
The European Endometriosis Liga asks patients to find a doctor, ask the experts and the experts will of course in many cases re-refer the patients with their doctors but with the right questions.
Who are experts? They are just doctors who are really interested in getting into the depths of this disease. In one specialty, like gynecology, there are many diseases that we find so some of us get together and go into the depths of endometriosis and have developed special knowledge. Endometriosis Awareness 2014 takes us to many people. I do not really understand - in Washington we are expecting one million - that is just the slogan? Last night at the ball I learned that a vodka bottle of $25 to $50 could make $10,900. It is just the way of how we bring it up. It was so nice to see that. For me it is astonishing. One came up with a big sum but then it went down, down, down, "Oh, I give $100, I give $100, I give $100" and then quickly $10,900 was pulled together.
My dear ladies and few gentlemen present, endometriosis can have a devastating effect on the quality of life due to the painful symptoms. It is the biggest cause of infertility in females and it carries a huge personal and social cost.
Some other activities...we are now in Scandinavia, I have heard that in Denmark there is something planned in Copenhagen, a big demonstration for endometriosis. In Germany I am active with something we have planned for Berlin on the 13th of March and there are many things happening around the world. From the doctors' side of the Endometriosis Society there is a big circle of friends. It is interesting that the disease also brings us together as friends. All the speakers today know each other from many meetings and many conferences. Here is Professor Seckin and Lone Hummelshøj together with lots of other friends that are busy investigating endometriosis and have said that over our period of life - I am now at it for 40 years - we have not really reached the final solution. But for many, many things we have not reached the solution in a lifetime. It takes many decades to come to that.
The background of endometriosis is known to us, I do not have to go into detail. We doctors need a classification to see how the patients are doing in follow up and to see if there has been some success. All these classifications lack - they are lacking, lacking, lacking. Some depend on just the morphological expression. Others depend on pain. Others depend on the infiltration and it is really difficult to get a whole picture.
A simple one that we use is the endoscopic endometriosis classification but that is only possible if we do endoscopic surgery, a laparoscopy that we can really see where the locations are. Below five mm, stage one. Are they above five mm, stage two, are they together with whole adhesions in the genital tract, stage three or are there distant ones, in the lungs, the bowel and other locations. There is the American Fertility classification which is much more extensive but also a morphological one.
Now, if at the first laparoscopy, we find small lesions on the bladder, if we have to say this is stage one, that is not very extensive, but some patients have a lot of pain with these small lesions and we have to pay attention. Then there is stage two where we have more adhesions and stage three when we have big endometriomas, big ovarian cysts for example. When we have stage four there is a lot of bowel participation. This is more complex in both the diagnosis and surgery. You have to see how big the invasiveness is towards the bladder and bowel and have to plan the surgery correctly.
The Enzian classification - named after the flower in the Austrian Alps - we got together a group of doctors and asked how is it invading the different size? How can we use it for our patients when we see them again and have a little comparison? If we plan another surgery we have to plan if the bowel is part of it with a general surgeon or with an expert surgeon. This all has to be planned beforehand. If we think there is a bladder infiltration we have to cut that out. If the ureter is within the endometriotic field we really have to know how to prepare the ureter.
If a patient comes in where I suspect some infiltration in the bowel, what do I do? The patient comes with the classic symptoms and we suspect an infiltration in the bowel. We should really do an ultrasound from the vagina and from the bowel, from the rectum the end part of the bowel and see if there is infiltration of the bowel. In case there is an infiltration of the rectal wall the surgery has to be planned very differently than if there is not. If there is infiltration of the rectal wall there has to be a laparoscopy planned, maybe a laparotomy simultaneously with a colorectal surgeon over the gynecologist who is an expert. To plan it we can only look and cannot excise - this is not right.
If there is no rectal infiltration the doctor should at that time do that differentiation. If he does not do it he should send the patient to someone who will do it. It is also our request that the doctors have to learn. If there is no reaction to the rectal wall then a laparoscopy can be performed by a good gynecologist who does not do rectal surgery. Rectal surgery is a specific difficulty and you have to know it and you have to have done it. This is how I would classify a patient before I do the surgery. If we have to plan it with a general surgeon we have to specially plan it and inform about it before because it has to be the combined work of the two of us.
If it is adjacent to the rectal wall then we can make an excision and the gynecologist can do it alone. This is a plan of how we work in each stage of more advanced endometriosis.
What kind of therapeutic strategies do we have? We can say, "Okay, wait and see" and wait and see is not always the worst but of course you cannot wait and see for years. You can wait and see for a few months and see if that pain is during every menstruation or how it is. Is it maybe connected with bowel symptoms? Then we have to decide whether we want to do a surgical diagnosis because the diagnosis is not _______ by laparoscopic excision and histological diagnosis; or do we do a conservative, mostly medical treatment, which is okay for a certain period of time if the symptoms go away. That cannot be done over several years but it can be done for one or two years in a young girl and the symptoms go away. We do not have to be aggressive and go straight away to surgery.
Now we come to the surgical treatment. According to the American Society of Reproductive Medicine "endometriosis should be viewed as a chronic disease that needs a lifelong managing plan". I think that that is very nicely expressed. We learn that it is not done with one surgery. We cannot tell the girl, "I need to do a laparoscopy on you and finish", that is not the way it has to go.
"Pain relief is achieved in most patients who undergo laparoscopic ablation/resection of endometriosis and adhesiolysis. But, the risk of recurrence is estimated to be as high as 40 percent". That is very high at ten years follow up with 20 to 30 percent. That has been discovered by so many people so we must tell the patients at the beginning that we are not going to have a 100 percent solution. But what is 100 percent in life? We just have to go step-by-step.
We did an endometrioma study and I just want to give you one evaluation - patients with ovarian cysts. We retrospectively studied 2,558 patients operated on in our center with ovarian tumors. Five hundred and fifty were histologically verified as endometriomas. That was over a period of maybe four or five years. It is quite a large group of patients that had endometriomas. What did we find in these 550 patients? Risk factors for recurrence are given. According to our findings if the patients are very young, if they have not had a child and if there are very large cysts - in these patients it is better to tell them that we know there is recurrence in higher percentage. But it does not mean that we do not need to do the surgery because we have to have the histological diagnosis. But just do not build up that this operation is going to solve the problem.
We looked into various factors of what we could learn from this retrospective evaluation. We could learn that absence of pre-operative pain correlated with better post-operative results. This is nearly self-understood. But it is also just effects that we know that pain patients have worse results. You have to screen better than before. We found that the absence of post-operative dysmenorrhea correlated with prognostically better post-operative results of patients after the surgery had no painful periods then they did not have many recurrences. This was statistically significant as you can see from this slide.
Fortunately for you we have to do that because we have to see what the best treatments are. We cannot just say we "think it is better to do it", we really should have evidence for it. That is done in cancer patients and it is done in other patients. It is good that it is done because it also shows us the limits and it shows us what is at least a little bit better. What is a little bit better should help.
I will just skip over these results. Larger cysts were found to be more - and then a whole new treatment was added. There was a better result. The highest pregnancy rates occurred after combined surgical and hormonal treatment. That is also an interesting finding if we have patients with infertility and added after the surgery, even if we excised everything that we could see. We added a three month hormonal depressive treatment and had a better success rate. According to the malignancies, as mentioned by Dr. Seckin, we also found we had a 0.4 percent of patients - cell phone interruption - we had two patients in that 550 who had a connection to a malignancy in the long run, which I think is important that we found because some people say ‘no, this never occurs and we treat patients with IVF if they have endometriomas. It does not matter". I mean, there is a certain correct attitude to not excise one endometrioma after another and treat with IVF but not to wait like five or ten years because of course you have to think about that tendency. This was just an evaluation of these 550 patients.
Recently we made a larger evaluation comparing three strategies. Probably most of you have had some of these therapies. We compared in a group of 150 patients each the medical treatment alone, which was Visanne, this is a progesterone modulator; surgical treatment and combined treatment. Then we looked at the patients two, three and four months later in a second look laparoscopy and found out how their endometriosis was. We found that the optimal treatment was the combined treatment. Also, looking at pregnancy rates we had again the combined treatment. In a recent evaluation, which we published in the AAGL journal, you can see that of the patients that had all stages of one, two and three endometriosis afterwards there was a large group that had no endometriosis. Unfortunately some of them left with some endometriotic lesions with some symptoms. The pregnancy rate was the highest in the combined treatment.
In a recent evaluation this also showed that we can use all the weapons we have for endometriotic treatment.
I just have three slides on the topic of adenomyosis. Who knows what adenomyosis is? It is endometriosis within the muscle of the uterus. Adenomyosis is also a painful disease and if a patient wants to have children you cannot take out the uterus. That is not a solution. If she is beyond child bearing age this is an option. In patients with adenomyosis there is infiltration into the myometrium. We had a nice lecture yesterday from our colleague Antonio from Portugal who will speak to you later on the infiltration of adenomyosis. It can be this way or it can be the other way.
From a surgical point of view hysterectomy is currently considered the most and only effective treatment. We should do it as a sub-total hysterectomy in my opinion because that is the least traumatic in patients that have finished their child bearing age or that just cannot tolerate the pain anymore after several treatment trials. However, we can also try to do selective excisions of lesions and that is possible in patients with infertility if these lesions are available.
We could spend a long time on adenomyosis as a topic by itself but lots of knowledge has come up over the last 30 to 40 years. Focal excisions can be done. A good suppressive treatment can be done over a longer period of time and hysterectomy is not the first choice in very painful adenomyosis.
I now come to the medical treatment. Tell me, how many of you have received medical treatment, hormones for endometriosis - so, a few. The medical treatment is what I would say is the second arm of the doctor. Of course if there is an infertility patient the medical ovulation suppressive treatment does not help as that is taking away from getting pregnant, but maybe for a period of time. We have to see how that can be combined. There are four medical treatment patterns. One is just to take the pain away, which medically we call analgesia. The suppression of ovulatory function, there is no ovulation - egg jump in the middle of the cycle. Direct action of endometrial implants; if we put something into the uterus, an IUD with hormones. Or we can think, we had lectures yesterday, about the modulation of the immune system and vascular system, which is a very interesting research area. Many results have been obtained in the last 30 years. But, for the treatment of the patient, Lone you agree, very little really is available, not to say nothing to speak honestly.
So, we can use no treatment; non-hormonal drugs, analgesics; oral contraceptive pills, which is still used in some cases with good results; progesterone; progesterone modulators; Danazol; GnRH analogues with add back therapy - this is a suppressive therapy where we add some hormones to help tolerate the suppression and hot flashes, etc. and still be effective with a low level of hormones being added. And there are new drugs like progesterone modulators and Visanne.
The classic pain killers; aspirin inhibits COX 1 and 2. We are tying to find a therapeutic window with ovulation suppression with little hot flashes and with the possibility that the endometrium does not grow. There are many interacting factors which doctors have to know about to apply all this.
For the patients it is important that we never give up. No pain is permanent. That is something we can really accept for endometriosis. I have had so many patients that have had terrible histories writing to us this and that. If you meet with them you do find a solution. You do find a solution with physiotherapy and this and that therapy. Permanent pain is very, very rare. However, sometimes it leads to a decision to take the uterus and ovaries out. That I have also experienced with some patients that were well after that.
The end point of medical treatment is pain control, restoration of fertility and prevention of recurrence. How do we achieve this medically by stopping invasive growth of the tissue? Choosing a treatment of course depends on the patient also, it is not the same for a 20 or 40 year old. The age of the patient, the associated infertility if she wants to have children or has completed that, associated pain - very important, and if it is a recurrence of endometriosis. It is different to treat if the patient returns and returns with recurrences or if it is the first time. Other drugs to give are Gestrinone, Mifepristone, Cyproterone acetate, maybe some of you have seen these.
There are also specific conditions, parous women with dysmenorrhea as a main symptom; Levonorgestrel-releasing intra-uterine devices like Marina; hysterectomized women with residual disease. There are also patients with the uterus removed that may have problems. This is to be considered and also pregnant patients. Two years ago we had a famous meeting of endometriosis experts in Montpellier that Lone arranged. A publication came out from this group, a very interesting paper stating that in pregnancy there can also be pain. Some doctors will tell you that when you are pregnant your endometriosis is resolved. Just get pregnant! It is not true. There are so many cases that describe that there can be severe pain in pregnancies. So there is no one solution for everyone.
Some newer drugs aiming at hormonal targets are aromatase inhibitors, GnRH antagonists and progesterone agonists. I will not put all the names up. But one I'm sure that is recently in the States, Visanne - oh, it is not in the States? In Europe Dienogest, which is an older progesterone has been around for 20 years but is now re-discovered and is effective and selective. You give it as 2 mg per day and it is very effective. Why is it not in the States, Food & Drug is more aggressive?
(For drugs to be approved you have to do what is called placebo studies. They have been impossible to perform here because if you are in pain and you are not actually allowed to take anything for six months to prove that a drug is working against placebo - the studies just fell apart. It is not being monitored.)
Because in America it is more restrictive, with a good reason of course with a good reason, they really want to have wonderful tests before they allow something. But that is how it is in different parts of the world. This has been released in Europe for the last two years and is used widely.
I just want to end now with the topic of pain. For patients with pain we have to have specific criteria and we have to listen to them. Many have problems with sexuality with endometriosis. Deep dyspareunia - there are many papers from Dr. Sweeten about the relationship between pain symptoms and the anatomic location of deep, infiltrating endometriosis. Women with endometriosis have a ninefold increase in risk of experiencing this symptom compared with the general female population.
Small lesions that you see by looking in the vagina then have further locations inside the body. There is a biological, psychological and physical tension and we can follow this pattern and really find out why deep dyspareunia is a sincere problem for our patients. There have been evaluations like these variations in sexual satisfaction. In the patient's group with endometriosis, called group U, all the patients had a much lower satisfaction that was pain related compared to the other patients. There is, or has to be, recognition from the doctor that endometriosis can create pain and can interfere with the patient's life, work, personal situation, marriage, etc.
If we put up the two strategies of surgery and medical treatment we have to say that from the time of Aristotle we have made lots of advances but we still cannot really say that for this patient there is only surgery, for this one only medical treatment. We have to say that at the moment surgery gives us a diagnosis and we believe that excision is the real target but we have to think about the individual patient of course and a combination of the available medical treatments as well.
If you compare the progestins and the recurrence of deep infiltrating endometriosis given to other drugs you see that there is a similar relief found in the comparison of Danazol and progestins. If you compare the hormonal values you also see that mostly they come out to the same effect. So really, we do not know what is better for the patient. We can only say we have to give both drugs to find a solution. If you see here in this interesting evaluation from ______ he compared the desire, the arousal, the lubrication, the orgasm, the satisfaction and the pain. All of them showed compared in the surgical and medical treatment and in the long run they came to the same result in a period of 12 months.
For the reduction of pelvic pain, comparison of different drugs, we have not really found the solution as yet. But in this study from my colleague Strowitzki in Heidelberg comparing the very demanding treatment of Leuprolide acetate GnRH analogue with a simple progesterone that within 24 weeks the same effect is reached. Of course we do now use this preparation dienogest, Visanne, because it does not have as many side effects as GnRH agonists have.
Let me conclude; the interaction between endometriosis and endometriosis associated pain is complex. Deep dyspareunia is only a part of global sexual function, especially in endometriosis. The high incidence of sexual dysfunction in endometriosis patients is underestimated. Long-time social consequences for partner and relationship are largely unknown. Psychopathology may increase endometriosis associated pain and sexual dysfunction. Little evidence that surgery/medical treatments improve global sexual function is given.
What do we require for our patients? We require family understanding and true compassion for the individual woman and family comprehension of the biological part of the disease. As this meeting has shown we really need to make this awareness to each other, to the doctors, to the politicians and to society; a social and political understanding of our society of this vicious cycle of pain and life disruption. Try to understand them, give them hope and do not leave them alone - that is for us doctors. Relate openly in work and employment situations.
I would like to end with telling you life is like sailing. It is not always in a straight line. We are having an endometriosis conference at the end of April in Sao Paulo and we, as doctors and scientists, are going to try to relate to all these problems.
Thank you very much.