Treatments of Endometriosis Around the World

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Dr. Mark Perloe: "We're here at the first Congress on Controversies in Obstetrics and Gynecology in Prague. I'm here with Professor William Ledger from Sheffield, U.K., and I'm wondering if you would tell us about your project here at the meeting."

Professor William Ledger: "What we're running here is a interactive session, trying to determine variations in practice or treatment of endometriosis around the world. One of things which is quite obvious to those of us that work in the area is variation in practice. In a meeting of colleagues from the U.S., for example, the way they manage patients with endometriosis seems quite different from the way we think we should be doing it in the U.K. So we've got a panel of experts from the U.S. and the U.K. who are going to work through a model using an actual patient history. We'll stop at various points in her history and determine how we would manage the case on the two sides of the Atlantic. We then are able to interact with the audience who come from many countries around the world, and they'll be able to vote on how they would have managed the case at these different points in her history. I think, overall, it will be fascinating to see whether there are big differences in practice around the world and trying to reach some sort of a consensus as how to manage these problems."

Dr. Mark Perloe: "I think there are so many factors that might affect the decision making. In the U.S. we find that the disease may, because of the symptoms, present to a family practice, to a urologist or a gastrointestinal specialist, or maybe to a physician who is working in a HMO where there's insurance coverage for one way where the patient primarily has to pay. Are those issues and wide variations seen in the U.K., as well, in similar fashion as the U.S.?"

Professor William Ledger: "I think there's some nice data that's showing that the delay in diagnosis of endometriosis is one of the major problems. It's as you say - they don't present to physicians in different disciplines who don't understand gynecology. They often are not aware of the importance of pelvic exam and the findings that they should be looking for and who, therefore, delay the diagnosis with inappropriate treatment. The mean time to diagnosis endometriosis is something like seven or eight years which I think is way too long."

Dr. Mark Perloe: "Yes, that still appears to be a factor, though an inordinate delay in women who present with systems to a gynecologist."

Professor William Ledger: "I hope that's changing, and I hope that meetings like this are going to move that process further along. One of the big debates now is whether we should be laparoscoping when there's pelvic pain or whether we should offer them treatment with a GnRH analogue as a first line diagnosis, as well as treatment. Because if they respond to an analogue, it may be that we've made the diagnosis of endometriosis without having to perform a surgical procedure."

Dr. Mark Perloe: "Are you doing that presently in your practice?"

Professor William Ledger: "In my practice - no, it seems rather too radical for the rather conservative part of England I now work in. But again, speaking to colleagues in the U.S., this is what they're piloting at the moment. It needs to be researched. Depending on all of this is there's so little research evidence out there that most of us practice according to our gut feeling and our medical training rather than in an evidence based way. And this is really where the focus has to be made in endometriosis, we need more proper randomized studies to tell us the answers to these questions."

Dr. Mark Perloe: "It's hard when you're looking at pregnancy as an end point. It's an easy objective measure but when you're talking about symptom control, it's a lot harder because the symptoms don't always correlate with the extent of visible or apparent disease. So obtaining objective evidence may be hard when it talks about controlling the patient's sense of wellness during the latter half of the cycle."

Professor William Ledger: "But do you not agree that these problems can be solved, and the way to solve them is to adopt a true multidisciplinary approach in the management of endometriosis? I think for too long gynecologists have maintained possession of this disease in terms of its management. I think many people have been reluctant to involve nutritionists, pain experts, and psychologists in the light of a really meaningful way in the management of the patient. If we were to do that, they have good methods of measuring pain score, feeling of wellness as you say, scales of depression, anxiety and the like which we do in a somewhat amateurish way. We do the best we can but this is not our training."

Dr. Mark Perloe: "There are tools such as EuroQoL and SF36 that may be very valuable if it were encouraged to include these in the in-studies to measure effectiveness. You mentioned the controversy surrounding initial use of the GnRH analogue in the patient as far as part of your diagnostic evaluation. I think in our country, predominantly birth control pills or non-steroidals, may be the initial approach. What time frame do you think a trial would be appropriate before saying that a patient had failed the trial, perhaps, before moving on and other findings on physical exam such as cul-de-sac nodularity, that might take you to surgery right in the beginning?"

Professor William Ledger: "I think, you're looking at a spectrum of disease. At the one end of that spectrum is the woman in her middle thirties with severe dysmenorrhea, dyspareunia, cyclical symptoms, finding an irregularity on the uterus sacral ligaments on pelvic exam, who most certainly has endometriosis and almost does not need to be laparoscoped for diagnostic purposes. Now you might wish to offer a surgical solution to that problem but do actually have much doubt in our minds about the pathology. You then look at the other end of the spectrum as someone who is perhaps a lot younger, who has severe problem with pelvic pain but not in a particular non-cyclical way, without significant findings on pelvic exam, perhaps with superficial problems with dyspareunia rather than deep. That is much more the diagnostic change. Traditionally, one would offer laparoscopy in that case even in someone who's maybe only twenty-two or twenty-three years of age. That's not bad management in any way but the idea that I find quite attractive is exposing the GnRH analogue, say for three months only, and suppress the ovarian function. If the cause of the pain is related to an ovarian endocrine drive, that drive is interrupted, and the pain is treated properly - then we have an answer."

Dr. Mark Perloe: "So with that answer, would that then suggest continued suppression with add-back ad infinitum or do you then use that to indicate that the patient ought to be treated surgically?

Professor William Ledger: "This is the interest in the case we're presenting today because I think this physician is managing a chronic and incurable disease. Firstly, you have to negotiate with that individual how she wants her management to be run. She needs to have the biggest say in whether surgery is used, whether drugs are used, and what combination for how long. Secondly, try to do as conservative as possible, these women almost invariably want to maintain their options regarding fertility. If they present at the age of twenty-four, more than likely they're planning children later in their lives, and we need to look very hard to avoid any unnecessary damage to ovarian function from the fertility perspective. So you mix and match, if we have a diagnosis, as you say, birth control pills in some women will work well for a certain length of time. Often the pain will break through later so then we move on up the ladder of treatment medically or if she prefers it, the laparoscopic approach with diathermy to the lesions. Monitoring these days with ultrasound and MRI perhaps is much better than it used to be so we can look for disease progression physically but in terms of treating the symptoms, I think a conservative approach is the one that one would adopt."

Dr. Mark Perloe: "The patient with recurrent disease, that's a different story because you don't have to go in. While the initial surgery may have been performed by a less skilled individual, often there's not documentation or adequate documentation regarding the treatment steps that occurred surgically the first time around. So you're faced with deciding there again the same issue - do we do another surgery or do we consider a GnRH analogue? Is your thinking different there?"

Professor William Ledger: "I think so, the evidence is clear that surgery done in specialty centers by people who have a true interest in this disease and who operate on it frequently has better outcome. I think that is beyond doubt now. Someone who comes having had treatment elsewhere in a small district unit that does general obstetrics and gynecology, I think probably one would want to re-laparoscope. Our own practice now, and very interestingly also in talking to colleagues from the U.S. from consensus, they routinely video procedures and offer the videos to the patient. That's very different because if she can come with objective evidence with what was done in the previous procedure, we don't need to repeat it. But if that wasn't done, and again, this is the exception rather than the rule, I think nowadays to allow patients to see their own procedure, I think this is a fantastic offer to make to someone - to let them see their disease. If they don't have evidence, then I think it's appropriate to re-laparoscope first as a diagnostic procedure and then move on to analogue treatment unless there is major progression surgically."

Dr. Mark Perloe: "Unfortunately in the U.S., insurance companies are advising physicians against doing that. But as a physician who sees patients referred in for either infertility or persistent pain, I'm hindered in my ability to make the diagnosis or to make a determine whether surgery may be appropriate when I lack that visual evidence."

Professor William Ledger: "We're trying a mini-laparoscope at the moment, and there's quite little data out there again with this sort of device, a 3-mm fiberoptic device which can be used without a general anesthetic, cutting the costs and the time involved tremendously. I don't think there's much scope for it as a surgical tool for operative laparoscopy, but in this kind of circumstance where one's trying to reach a diagnosis to inspect the pelvis and look for disease progression, maybe there's a part for that, and it would keep costs down."

Dr. Mark Perloe: "Larry Demco has shown some very interesting work suggesting that the pain is often not where we see the lesion. Have you had a similar experience in terms of finding that you would treat the patient differently based on the findings with conscious pain mapping?"

Professor William Ledger: "I think it's quite scary actually, that we have been burning lesions of endometriosis for many years now in the belief that we're treating pain. And as you say, the evidence clearly is that the site of the pain is often not where the visible lesion is. How you get around that, I'm not sure because trying to undertake surgical treatment on a conscious patient, I think, is going beyond what most women will accept. Therefore, are we going to do conscious pain mapping, then anesthetize a patient in a general anesthetic sense and try to operate on the areas that we thought the pain originated from? That argument, I don't think, has been resolved yet to be honest."

Dr. Mark Perloe: "We have done this in a hand full of patients, and it's been of limited use in that about half the patients are unable to tolerate the procedure and everything hurts. In those that you find the source of pain, it's usually confirming where you thought the pain might be. Another controversy that comes up is the issue of what sort of energy source do you use - and whether endometriosis should be excised or vaporized. What are your thoughts on that?"

Professor William Ledger: "Working in the U.K. National Health Service, we invariably are offered the cheapest. So although I appreciate the science that's gone into trying to decide on these questions of how best to do the surgery, in practice we get electrodiathermy with monopolar and bipolar, again, depending on the nature of the disease we're approaching. My practice is now going along with what I think is a European group management of endometrioma is to drain an endometrioma, cauterize it's base looking for the site of active disease but no longer trying to strip away the pseudo-capsule. Again, from the point of view of preserving fertility, it seems that that capsule contains follicles which would be lost if we surgically remove them reducing that woman's chances of pregnancy."

Dr. Mark Perloe: "I think it's important if one is going to use an electrical energy source on the inside, that a bipolar or laser will be less damaging than using a monopolar energy source which will have more tissue penetration and more likely to take out an ovary. I'm sure we've all seen patients who end up amenorrhea secondary to ovarian failure after aggressive or too aggressive surgery."

Professor William Ledger: "That's absolutely right, and again, there are big issues of consent here that you have to be very careful to explain to the patient - what it is we're trying to achieve and what the potential dangers are. You know you see someone without endometriosis and you try your best to remove all visible deposits, and yet at the same time try not to damage an ovary. That is very difficult."

Dr. Mark Perloe: "It certainly is, and I think the management of large endometrioma is certainly one of the challenges we face. It's certainly a challenge we face in managing our IVF patients too. What are your thoughts about the management of endometriosis? It seems that overall, having endometriosis or not - doesn't effect the outcome of IVF. Do you see the endometrioma as a special case though?"

Professor William Ledger: "Yes, there was an interesting presentation yesterday saying exactly that, that patients with endometriosis seem to do just as well as any other group of patients having IVF. I'm still doubtful I have to say. I think it's clear that mild, moderate disease probably does not impact an IVF outcome. I just think from the basic view of how does the ovary function in IVF if both ovaries are occupied by large cysts which will have an effect on blood flow, and which probably will contain substances which can be toxic to this development. It is almost impossible to believe that those cysts will not have a negative impact on the IVF outcome. The studies that have been done have not included many women with severe disease in the IVF context because thankfully it is less common in the milder form of the disease. So I think probably there's still some work to be done there. As to treatment, I think the evidence would suggest that if a lesion is over five centimeters in size, it should be dealt with before the IVF cycle is started. Secondarily, if a smaller cyst is there, one should make every effort to avoid it. There's always a temptation with a needle in the pelvis and a cyst full of fluid to put the needle into the cyst and drain it. And again, those presented here and elsewhere, the risk of infection in that drained cyst because of the multiple needle punctured IVF is not small and can cause great damage."

Dr. Mark Perloe: "Absolutely, that's certainly our finding. One of the other things that has been interesting is that there has been some authors who have suggested that antiphospholipids are a problem in patients who are faced with endometriosis. I think that data has really been gone over and would lead one to think that it's not a factor in IVF. What is your belief, do you think that data's conclusive?"

Professor William Ledger: "No data's ever conclusive, but I think that it is much more solid now than it was a year or two ago. But again, evidence presented yesterday of increased rates of miscarriage in women treated with IVF after endometriosis are quite striking in a very small series, and suggest that maybe there's more work to be done looking at links between having positive endometriosis in the pelvis and pregnancy outcome. The data is there. All our IVF units monitor their patients through pregnancy meticulously. I just wonder if there's a need for a real analysis of big data bases looking for links between endometriosis and miscarriage."

Dr. Mark Perloe: "One of the problems with this is that you get the diagnosis, you have the surgery, and the physician generally would have treated the disease at the time of that surgery. The diagnosis is made - so whether there's significant disease present at the time, and it's the endometriosis that's causing the problem or the underlying premise that brings about endometriosis that would interfere - I think is an answer."

Professor William Ledger: "It's a fascinating question, and maybe you could use it as an argument to explore the hypothesis that it is a defect in endometrium itself which is leading to endometriosis, and secondarily, is causing problems with implantation and pregnancy failure. For as you say - there's no signs there, there's nothing more than an idea that would be interesting to explore."

Dr. Mark Perloe: "Many physicians in our country see the patient with endometriosis and believe that that's an indication to move on to in-vitro fertilization. They don't feel that that's an appropriate patient for ovulation induction and insemination. What do you think about that?"

Professor William Ledger: "Again, I think you must look at the severity of the disease. There are people with severe endometriosis who've had multiple pelvic surgeries who are unlikely to conceive with something as simple as superovulation IUI. On the other hand, in my practice the cost of superovulation IUI is so much less than IVF, and the human cost of doing IUI is also low. It's an easy treatment for most women to undergo without all the rigors of the IVF process. But I think the data would suggest that in mild or minimal disease, superovulation IUI has a clear place to pay. In your country, the dollar cost of IVF is even greater than in mine, and I'm sure there must be many couples who cannot afford that cost perhaps for more than one occasion. If you look at key success rates with IUI, maybe on a cost benefit analysis, three or four attempts at IUI would actually perform one cycle of IVF."

Dr. Mark Perloe: "And still for less costs than the IVF."

Professor William Ledger: "And still for less costs, yes. Many centers do IVF, they're only there for IVF, and other things are seen as old fashion or less effective. They are less effective on a cycle-per-cycle basis but they still make plenty of babies. But I think a good fertility center should have a range of treatments at their disposal, then again, reach a decision as an individual basis with the couple concerned."

Dr. Mark Perloe: "There's been data presented that pre-treatment with GnRH analogue is more important even in the patient who's undergoing IVF with endometriosis and that perhaps, even a three months pretreatment period improves the results."

Professor William Ledger: "Yes, but there's evidence on both sides of that, isn't there. Again, a good study is waiting to be done. Sam Marcus and Rob Edward several years ago now produced a paper showing that long term suppression of patients with severe endometriosis had a dramatic effect on IVF outcome. More recently there have been small landmark studies better designed than Markus and Edwards that seem to contradict that conclusion. There are some nice pilot pros in long term suppression which might give some theoretical basis to a benefit. It's not easy for them to be suppressed for many months at a time, I think you must be careful not to offer these treatments without some reasonably good scientific basis that's going to help. So again, I would encourage those out there that can put studies together to maybe think about running a proper multi-center study of one month versus three or four month suppression. It needs to be done but it needs to be done with big numbers."

Dr. Mark Perloe: "Yes, it does. That would be exciting to see those results."

Professor William Ledger: "I'm sure we'd both want to participate."

Dr. Mark Perloe: "I'm excited, we have a new program starting in Atlanta, and hopefully, we'll have the numbers to participate in those kinds of trials. Thank you so much Professor. It's been a pleasure talking to you."

Professor William Ledger: "Nice talking to you."