Bruno Lunenfeld, MD

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:  "Today on February 10, 2001 it is my  pleasure to interview Professor Bruno       Lunenfeld, the starter of the GnRH Analogue Conferences the sixth  of which we are holding at the present time in Geneva.  I would like to  ask him when these meetings started, what is the intention of the  meetings, and what is the future?  Let us start with the historical  part, please."
       
       

:   "As you know very well, this is the 6th GnRH meeting.  We started some  fifteen years ago, and in the beginning we were investigating the  possibility of the uses of GnRH agonists.  We were then investigating  the possibility of the use of GnRH agonists in precocious puberty; this  was indication number one at that time.  We were then already thinking  of the possibility of using GnRH in four different situations; in the  situation where we would like to intervene or to modulate diseases that  are dependent on sex steroids, which could be, endometriosis, uterine  fibroids, and you can name many more.  The second indication was to stop  sex steroid production if it is too early or too modulated like in  precocious puberty or in order to prevent an untimely LH peak as we saw  often in ART protocols.  The third situation was to look at situations  where there are hormone dependent cancers and whether we could intervene  by these situations.  We already knew by that time that castration was  one of the main treatment modalities for prostatic cancer and,  therefore, we thought we could use GnRH agonists for this kind of  purpose.  The fourth situation, which we're still debating today, is can  we use GnRH agonists or analogues in the modulation of cancer specific  areas not directly via the steroid patterns.  Now this all became clear  of course because we already knew at that time that GnRH agonists were  the first and only medication which could do exactly the same that a  surgically hormone specific type of vasectomy could do or what a  castration,       orchiectomy, or a male castration could perform.  We could do this  reversibly with GnRH analogues; this was the beginning and the  rationale of having these GnRH meetings.  The meeting was opened at that  time by Andrew       Schally, the discoverer of GnRH who also received the Nobel Prize  for this purpose."
       
       

:  "Let  us go now to the two different sides - agonists and antagonists.  At  this meeting we have for the first time clinical data on interaction of  antagonists so please differentiate the two, and how do you foresee the  future interaction of these two lines?"
       
       

:   "The main problem of the GnRH analogues was the flare up effect, and  because of the mechanism of action of GnRH analogues, you know that the  first situation is a flare up of the hormones (LH and FSH) and then  there is a desensitization.  This flare up effect, of course, can be  detrimental or has a negative effect in hormone dependent diseases like  prostate cancer.  It can have a negative effect in the uterine fibroid  situation, and it can have negative effects in many other situations.   Therefore, the moment we had antagonists, which worked by competitive  binding, we get a direct inhibition of the gonadotrophins and do not  have this flare up effect. This is with of course a major advantage.   The big problem with the antagonists was that the first generations had  histamine release and we needed a lot of work and many, many years of  work until antagonists could be used clinically without side effects."
       
       

:  "At the present time, which other fields are antagonists already used?"
       
       

:   "In the beginning I forgot to stress one of the most important uses of  GnRH agonists namely in assisted reproductive procedures.  As you know  and have heard in this meeting, 80% or maybe even 90% of assisted  reproductive cycles are used together today with GnRH agonists.  In this  area, the antagonists are playing a very important part as you have  heard in this meeting because they can reduce the time of treatment and  they reduce the number of ampoules of       gonadotrophins. This makes treatment more acceptable by patients.   It's a more friendly treatment for the patient and permits a more  flexible therapy than with the  use of  GnRH agonists.
       
       

:  "So in the area of reproductive medicine it's already an accepted concept.  How is it in the area of urology?"
       
       

:   "The main problem was that the GnRH antagonists available today, as you  have heard here, were mainly short acting antagonists. Only very  recently has a long acting GnRH antagonists been discovered.  It is now  in Phase II and Phase III clinical trials and it will be on the market  very soon, and this is Abarelix which has a very, very long action and,  of course, can be used then in diseases which need very long  suppressions of sex steroids like prostate cancer, uterine fibroids, and  endometriosis."
       
       

:  "In  the gynecological area the antagonists have also been discussed at this  meeting in uterine fibroids and endometriosis.  How many of these  products are available that are not given daily?"
       
       

:   "For the time being the only antagonists which is a long acting  antagonist is a product which is not yet on the market which is       Abarelix."
       
       

:  "Cetrorelix has a 3 mg compound from the Serono Company which is used in  reproductive medicine.  Has it also been used in clinical trials for  myomas and endometriosis?"
       
       

:   "Very limited trials in this respect, and very limited material with a  very nice potential I am not aware of large scale clinical trials.
       
       

:  "Professor Lunenfeld, my last question  goes to the field of cancer.  Cancer is still a threatening disease, how  is the future action of antagonists and agonists in the field of  cancer?"
       
       

:  "I  think we've had a very nice symposium here on this respect.  Professor  Bartsch has given some very nice data, and I believe OBGYN.net already  interviewed him.  I think, again, the antagonists don't have the flare  up effect and they probably do much more than just decrease testosterone  on prostatic cancer.  I think they have a nice and big future in  prostatic cancer but it's only at the next Congress in two years that  we'll be able to tell."
       
       

:  "May I  finally allude to some personal aspects?  Your birthday is going to be  on Sunday and already OBGYN.net would like to congratulate you for all  your achievements in our field and wishes you a very happy birthday."
       
       

Articles

OBGYN.net Conference CoverageFrom the 6th GnRH Analogue ConferenceGeneva, Switzerland February 2001

The History of the GnRH Analogue Conferences

click             here for RealAudio/Video version

       "I'm here with Dr. Tulandi from McGill University in Montreal, and       we're going to talk about endometrial ablation versus hysterectomy."
             
             

       "The treatment of abnormal uterine bleeding could be medical       treatment or surgical treatment. Most people who elect to have a surgical       treatment do so because they want a long-lasting cure, but people who want       endometrial ablation do so because they want to avoid major surgery. In       selection of endometrial ablation, it is important to tell the patient       that this is not to eliminate the bleeding but to decrease the bleeding -       so patient selection is very important."
             
             

       "What other factors point towards successful surgery?"
             
             

       "Number one is patient selection. Number two is the surgeon's       expertise, if you're using a hysteroscopic technique."
             
             

       "There are a lot of new techniques that are out there; we hear about       microwave, cryoprobe ablations, balloon techniques, resection techniques,       or hysteroscopic vaporization techniques. What are your thoughts and       what's your take on this plethora of techniques? What should someone do to       figure out which technique is best?"
             
             

       "Again, it depends on the surgeon's familiarity with the technique.       If they know how to do a good hysteroscopic procedure, there's nothing       wrong with that. The technique is more difficult; it depends on the       expertise of the surgeon. The norm hysteroscopic technique is certainly       easier. There are many techniques, as you mentioned; one of them is       microwave endometrial ablation. There is a good randomized study conducted       by David Park in Aberdeen, showing the technique is as good and your       results are as good as resection. This is a good randomized study."
             
             

       "In failures, the patients who come back afterwards who are not happy       with the results, are they frequently candidates for another ablation       technique, or do they often go on to hysterectomy, or is medical treatment       considered again prior to another surgery?"
             
             

       "In general, they don't want to go back to medical treatment. Usually       our patients have been treated medically, and that's why they chose       surgical treatment. Now it depends, again, on the patients. Most of them       will go through a hysterectomy, some of them will say, "okay, why       don't you redo it" - and we have done two, three patients       successfully."
             
             

       "Have you seen any patients who've had pregnancies after this, and       have they been successful? How have you managed that, or are patients       generally too old?"
             
             

       "Luckily, I have never had any patient who got pregnant. But again,       it is important that we tell the patients before an endometrial ablation       you should not get pregnant."
             
             

       "Is adenomyosis a contraindication in your practice? Do you treat       those patients differently or advise them differently when approaching       ablation?"
             
             

       "At the moment, no, it's not contraindicated in my practice. I have       to admit that the failure rate is higher for women with adenomyosis. The       problem is we don't know which comes first - adenomyosis or the       endometrial ablation."
             
             

       "What about insurance companies - do you see them mandating this? In       our country, they quite often will mandate an ablation technique before       moving on to hysterectomy, even when the ablation technique may not be the       appropriate choice for that patient."
             
             

       "In Canada, we have social medicine. We're lucky that it's dictated       to us on what to do, so everything is based on medical decision or       indication."
             
             

       "Do you see new alternatives to management and dysfunctional bleeding       coming up in the near future?"
             
             

       "Like everything else, I think more and more medical treatment is       being instituted. We have been using a lot of Cyklokapron in the past two       or three years trying to decrease the amount of surgery but most of them       still come back for another procedure."
             
             

       "What sort of pre-treatment do you use before the ablation, and do       you feel that that plays a role in the success of the operation?"
             
             

       "I think most people will use GnRH analogue. Some people use danazol       or birth control pills. My favorite is GnRH analogue, but five weeks       before a procedure. Some other people will use suction curettage before       endometrial ablation, especially microwave - apparently the results are       the same."
             
             

 "I       have a colleague in St. Petersburg, Russia, who reported on 250 cases, and       that's the technique they used. They did not have the analogue available,       and they found that the suction was adequate preparation. We've used GnRH       analogues in our practice, mostly, and have been very pleased with the       results of that."
             
             

       "One thing which is important and interesting is that Dr. McCausland       from California has just published a paper - he called it "Partial       Endometrial Ablation," and he leaves the posterior wall intact. He       did not ablate the posterior wall. The purpose is so the patient can still       bleed. Again, he will tell the patient this is not to eliminate the       bleeding but to decrease the amount of bleeding. So basically, he wants to       prevent intrauterine adhesions."
             
             

       "Do you advise these patients any differently in the subsequent use       of hormone replacement therapy and menopause?"
             
             

       "I will still use estrogen and progesterone. I think it's important       to use progesterone."
             
             

       "Have you seen any malignancies in patients who've been treated with       estrogen alone after ablation?"
             
             

       "So far I have been lucky - I've never seen these patients, but we       are very careful. We do an endometrial biopsy in all patients before       endometrial ablation. If there is hyperplasia, especially in typical       cells, then we don't do it. So you might as well have resected."
             
             

       "Thank you so much. I appreciate it"
             
             

OBGYN.net Conference CoverageFrom First Congress on Controversies in Obstetrics, Gynecology & Infertility Prague CZECH REPUBLIC - October, 1999

Endometrial Ablation vs. Hysterectomy

       "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."
       
       

       "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."
       
       

 "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.?"
       
       

       "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."
       
       

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

       "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."
       
       

       "Are you doing that presently in your practice?"
       
       

       "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."
       
       

       "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."
       
       

       "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."
       
       

       "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?"
       
       

       "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."
       
       

       "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?
       
       

       "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."
       
       

       "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?"
       
       

       "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."
       
       

       "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."
       
       

       "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."
       
       

       "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?"
       
       

       "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."
       
       

       "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?"
       
       

       "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."
       
       

 "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."
       
       

       "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."
       
       

       "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?"
       
       

       "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."
       
       

       "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?"
       
       

       "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."
       
       

       "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."
       
       

       "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."
       
       

       "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?"
       
       

       "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."
       
       

       "And still for less costs than the IVF."
       
       

       "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."
       
       

       "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."
       
       

       "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."
       
       

       "Yes, it does. That would be exciting to see those results."
       
       

       "I'm sure we'd both want to participate."
       
       

       "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."
       
       

OBGYN.net Conference CoverageFrom First Congress on Controversies in Obstetrics, Gynecology & Infertility  Prague CZECH REPUBLIC - October, 1999

Treatments of Endometriosis Around the World

click             here for audio/video version

  "I       am here with Dr. Lunenfeld, and I remember the wonderful discussion and       breakfast we had back in Geneva. I am so excited that you let me know that       we will have an opportunity to meet in Geneva again. Can you tell us a       little bit about the conference that is going to be coming up in       Geneva?"
       
       

  "Dr.       Perloe, I am glad you enjoyed the meeting in Geneva and I am happy to       inform you that the 6th International Congress on GnRH Analogues in Cancer       and Human Reproduction will again take place in Geneva on February 8-11,       2001. It will be a very interesting meeting because at that time we hope       to be able to arrive at a consensus on the role of GnRH analogues in the       treatment options of endometriosis and in the management of uterine       fibroids. The use of cyclic 'add-back,' as well as adjunctive therapy in       patients treated with GnRH analogues for extended periods, will be       discussed. I am sure there will be long and heated debates on the use of       agonists via antagonists. We will learn the advantages and disadvantages       of agonists and antagonists, and I hope it will become clear when agonists       should be used and when to use antagonists.
       
       Furthermore I hope we will also come to a consensus on what the three most       important challenges for ART procedures are: to increase pregnancy rates,       decrease high-order multiple pregnancies, and avoid and manage       hyperstimulation. Also, concerning cancer and particularly prostate       cancer, new information will be made available in Geneva.
       
       The above are only a few topics to demonstrate to you why I think the next       meeting in Geneva in 2001 will be extremely interesting and will have a       very strong impact on our medical practices. Now, on to your question       concerning today's management of endometriosis with antagonists... For the       time being, there are no long-acting antagonists on the market. Since the       medical treatment of choice for hormone-dependent endometriotic lesions is       the administration of long-acting depot preparations of GnRH analogues,       long-acting GnRH agonists will remain the only therapeutic option.       Long-acting GnRH antagonists should become available for clinical use in       about three or four years, but for now, there is no question that the       long-acting GnRH agonists are the first line of treatment of any       hormone-dependent endometriotic lesion.
       
       As to your question concerning uterine fibroids, I think there is a       consensus - or at least I believe there will be after Geneva, 2000 - that       the primary treatment of most uterine fibroids will be with GnRH analogues       prior to surgery. I am sure most of my colleagues even today agree that,       following GnRH analogue treatment, there is a definite decrease in fibroid       size and decrease in blood loss. In many instances it will allow surgery       through the vaginal route. As I said previously, for the time being there       are no long-acting antagonists on the market and long-acting GnRH agonists       will remain the only therapeutic option."
       
       
       

  "It       appears that the initial protocols in the initial results from Dr.       Felderbaum's study suggest that while you are using less FSH, you may       shorten the number of days by using an antagonist and lower the risk of       hyperstimulation. I'm not yet convinced that the pregnancy rates will be       better. Is that enough to get us to switch from a analogue to an       antagonist?"
       
       

  "You       are perfectly right. I agree that both Felderbaum (multiple-dose protocol)       and Olivienne (single-dose protocol) have clearly demonstrated that GnRH       antagonists such as cetrorelix and ganirelix prevent premature LH surges,       are safe and effective, and reduce treatment time and the amount of       gonadotropins necessary for successful ovarian stimulation. Fertilization       rates obtained are comparable to those obtained with GnRH agonists       protocols. If GnRH antagonists will be replaced in the future, all GnRH       protocols remain an open question. We have insufficient data, for example,       on the use of GnRH antagonists in PCOD patients."
       
       

  "Markus       and Edwards have suggested in their early work that a three-month trial or       three months pretreatment with analogue may improve the outcome in IVF.       What are your thoughts on that, and is there more data available now that       clarifies that picture?"
       
       

  "In       my opinion, this is true only for PCOD patients and this is probably one       of the reasons that you get similar effects if you pre-treat for one or       two months with some of the oral contraceptives. I know we will get some       more good data in Geneva in February of 2001."
       
       

  "I       think one of the things that's exciting to me in the PCOS patient is the       difference in vascular flow patterns. There's increased stromal flow,       there's decreased follicular flow, there's increased VEGF, there's       diminished blood flow in the endometrium, and these may all be factors.       Many people are utilizing metformin for ovulation induction, and we've had       in our program a number of successes in deliveries. Some people are even       suggesting that we continue using metformin to lower insulin levels and       maintain it during the pregnancy, suggesting that the diminished blood       flow or the destruction in blood flow associated with hyperinsulinemia may       be a factor in miscarriage. Do we need to look at that in the IVF patient,       and do you believe that insulin may play a role? Are you aware of any       other studies that are working on that role right now?"
       
       

  "Thank       you for enlightening me. I have heard about some of these studies, but I       have no personal experience. But the results make sense - they're logical.       We know, for instance, from a study done by Dr. Steve Frank in London that       when we reduce weight in some of the obese patients, insulin levels go       down and pregnancy rates are improved. We are planning a symposium on this       subject in Geneva during the GnRH meeting. I hope it will       materialize."
       
       

Endometriosis and Infertility

       "One of the confusing things that we see headlines on is male       menopause and the cause. I'm confused about what I ought to be calling it,       and what really is going on with males as they age. Do we need to be       concerned about this?"
       
       

       "Yes, I think so because I think it's quite clear today that there is       no male menopause. Males don't have menstruation - there is no stopping of       menstruation - and I'm very surprised why even the term "male       menopause" came up. To me there's nothing clinical, I just think it's       the wrong term. I also think andropause is really responsible for creating       this term which is wrong, because it's not only the androgens which go       down, we know it's dehydroepiandrosterone sulfate, the adrenal androgen       that goes down. We know that hormone secretion, melatonin secretion, and       estrogen secretion goes down. So I think with what we actually have is a       partial endocrine deficiency syndrome of the aging male, which I would       call "PEDAM" - partial endocrine deficiency of aging male. This       I think would be the correct scientific name. Today people like to call       it, "PADAM" - partial androgen deficiency or andropause because       actually the only product on the market today are testosterones. We know       very little about dehydroepiandrosterone although I'm quite sure it is       very important. We know very little on the condition of cortisol, which we       know is very important on this whole effect and bad on muscle composition       on osteoporosis. We know very little about melatonin. We know that all the       medicines used today in food additives are used less because the half life       is very, very short. We need well-standardized melatonin, which can remain       eight hours and really simulate the physiological effects to get a good       sleep. Because we know that under melatonin we have this slow wave sleep,       which is a sound sleep, and during that sound sleep we get secretion of       cortisol hormone. So I think a good sleep with secretion of cortisol       hormone could be the solution but for the time being there is no       standardized melatonin available. Cortisol is expensive but I think in       many countries it is forbidden for athletes which is a mistake - so many       studies have to be done in order to prove this. Now why do many countries       like the word hypogonadism in their aging male because all these products       - the testosterone products - are set for hypogonadism so if you go back       to the word hypogonadism in the aging male, you've less problems in the       registration of products which are readily available."
       
       

       "The other factor is dealing with insurance companies. A normal       physiological condition may not be one that they want to cover and coming       up with a CPT or ICD-9 code that warrants the condition or diagnoses it.       Is this the sort of thing that men are coming to physicians and       complaining about or do you see this as a standard part of the physician's       evaluation of the male? I mean, with women we have good evidence that we       can prevent heart disease, that we can prevent osteoporosis, and we can       improve sleep and do a little on hot flashes. A man doesn't have hot       flashes to come in that immediately disrupts his life, and we don't have       the obvious indication that we are improving health."
       
       

       "I thank you very much for this question because I think I have the       exact answer which you need here. Women go for prevention, they have       gynecologists who are their confidant, and they can discuss with him all       kinds of things. They are geared for prevention, they go to the ob-gyn       when they are healthy and when they are pregnant. They are geared for       prevention, when they have a child, they immunize the child - they will       try to keep it well. They will maintain health. Men only go for       operations. They don't have a physician, and they don't have men's health       physicians. We have to go to the urologist, and we have to teach the       urologist - don't put your finger in only like this for the prostate, also       put the finger in straight to look for colorectal cancer. So I think we       have to teach awareness to men that they should go also for prevention. We       know that in Western Europe, nearly 20% of women have a clinical breast       examination, self-examination, or mammography - but something - to check       for breast cancer. Only 0.3% of men make a PSA - a prostate specific       antigen - examination which we can predict cancer expression five years       before. So why shouldn't men from fifty onwards have at least one digital       examination a year together with a PSA - this would prevent things. So I       think here we need to create awareness, and we need to create a men's       health physician, and this exam and the International Society of the Study       of the Aging Male are really doing this. I very much hope you would come       to Geneva, and you will see how much data exists already but it's spread       all around. I think Geneva in February 2000, the 9th through the 13th, may       be one place where the gap will start closing itself, and you will be able       to see a little bit clearer picture."
       
       

The Aging Male

       "I'm here with Dr. Genazzani and Dr. Carp. Can you tell us about your       practice and where you're in practice?"
       
       

       "Yes, I am a Professor of Gynecology and Obstetrics in the University       of Pisa in Italy."
       
       

       "Yes, I'm senior lecturer in Obstetrics and Gynecology and Embryology       and Teratology at the University of Tel Aviv in Israel."
       
       

       "Thank you. Dr. Genazzani, you spoke earlier on menopause, and I hear       that you have a conference coming up. Can you tell us a bit about the       conference?"
       
       

       "Yes, we will organize for the 8th World Congress of Gynecological       Endocrinology in Florence in December of 2000. This is a conference, which       came after our previous venues in Buenos Aries, Barcelona, and others. We       expect to have more than 2,000 people and all the areas of gynecological       endocrinology will be analyzed starting from the embryonic function to the       counsel of the other function to the placenta in pregnancy and then also       we will move on to the effect of hormones on cancer tissues and how to       manage the postmenopausal woman, how to take care of the pelvic floor       disorders and as you can see a series of items will be covered."
       
       

       "Professor Genazzani, I was very interested to hear your lecture       which you gave just a little while ago in the conference in which you were       speaking about hormone replacement therapy after menopause. I think one of       the things you mentioned was what are the indications. Is hormonal       replacement therapy indicated for all patients, is it a preventative       measure, is it just for some patients, and is it treatment for       symptoms?"
       
       

       "I think that it's difficult to give a general answer. Certainly the       hormone replacement therapy after menopause is treatment for symptoms but       it's also very efficient therapy to prevent diseases later on then for       it's positive effect on cardiovascular levels, for the prevention of       osteoporosis, for the measure effect on the brain. I think it's       conceivable for a woman without symptoms to start the therapy to prevent       possible diseases later on. Mostly women are coming in from the symptoms,       and their symptoms are not only the hot flashes or insomnia but are also       other symptoms of the changes in the hormonal age that affect the female       population. They don't accept having to watch their weight and the changes       in the quality of their skin, and the quality of the mucosa. I think       better attention from the general practitioner or the specialist should be       on how the female body acts in regard to hormone deprivation right after       menopause. This is considerable now, and I think a woman can start therapy       and the therapy can be changed throughout the years because as long as       she's under therapy, her body is changing so she will need different       amounts of hormones at different times. There are also other therapies       that can be done after the first year after menopause. They are considered       to not only treat a woman for the preventative effect on the womb and on       the cardiovascular but also to prevent some possible problems that she has       by the fact that she has taken the estrogen therapy for ten years."
       
       

       "We've had a lot of new estrogen replacement therapies and routes of       administrations and protocols that have come in front of us. I think it's       a bit confusing for physicians to understand both the safety and the       efficacy of each of these various methods in relieving these symptoms.       What are your comments on that?"
       
       

       "I agree completely with you but you know human beings are so       different from one to another. So it's considerable, you don't have the       same therapy for everybody. It would be impossible to treat all women with       the same therapy. Some of them need other therapies, some need smaller       doses, some higher doses, some may prefer the patches of administration or       they prefer to have them by administration by any kind of gel or any other       therapy. I think gynecologists now can provide general practitioners and       the other specialists a variety of therapies because they are facing a       variety of individuals. Not only do we now have hormonal replacement       therapy with estrogen and progesterone but also it's conceivable now that       after ten years of hormone replacement therapy, the woman can start with       selective estrogen receptor modulators or other kinds of therapy when       she's no longer symptomatic, and when she wants again to prevent the       possible risk acquired and linked to the estrogen administration for a       long time and also to prevent the bone deterioration and cardiovascular       irregularities. I think we are facing forewarnings of the scientists to       women to try not only to prolong their lives but to reduce the period of       validity they have in the last five years of their life when the       osteoporosis, the cardiovascular changes, and all the problems that a       woman has, that can give absolute deterioration of the quality of       life"
       
       

       "You mentioned in your lecture some of the problems a patient       complains about, some patients might have bleeding during the time or       after a course of hormonal replacement. Do you think women are getting       enough supportive therapy when the side effects come up but they will       still continue with treatment, particularly you mentioned the SERM,       sometimes the symptoms such as hot flashes may come back. Is there still       enough support in your opinion?"
       
       

       "I think we have to personalize the therapy. Concerning the bleeding,       we have to change the therapy to correct the regular bleeding, such as       menstrual bleeding, or in any case to correct the irregular bleeding.       These are the things that women don't accept. Concerning the SERMs, for       that reason I sustain that some are useful later on after menopause but       not at the moment of the menopause because they activate in some subjects       the hot flashes, and the hot flashes are symptoms. I think we have the       experience from many studies that even though the woman start again, after       a few months the hot flashes will disappear, The entity is absolutely not       putting out some of the therapy for the patient, this was our experience.       But certainly I believe that the woman has to ask the doctor when she's       under therapy to personalize the therapy and she needs measure       control."
       
       

       "Many of the women that we see either have had thrombotic events in       the past or as part of their screening for recurrent pregnancy loss or       pregnancy complications. People have looked at various clotting factors       such as Factor X Leiden and the like and have said that if these clotting       factors are abnormal or there's been a past history, then estrogen is       contraindicated. The only one hormone replacement that I'm aware of now       that is not contraindicated is tibolone in that environment. Have you had       experience with this or how do you redress the needs of that patient       population?"
       
       

       "Yes, we also have an analogue of PSA tibolone for many years. First       of all, the women who have real clotting problems, it's not so big and       certainly estrogen that also serves to activate their clotting system. For       that reason, they remain a risk factor, and tibolone doesn't seem to       effect the clotting system in the same way even though tibolone also has       estrogenic effects. I think it's very important that doctors make some       kind of screening, mostly on an annual or periodic basis. We don't need to       at each exam but certainly as a screening exam. But when on an screening       basis you can be aware that it can be a possible risk, then I agree that       you can measure those parameters which can indicate easy activation of the       clotting system. In such a case, you have to try to correct it, and don't       use therapies while there's an estrogenic effect on the vessels. Even with       this genic effect on the vessels, they are very positive in another area       because they are positive from the endothelial sense. They can give a       better endothelial function, and they can show antiagonist sporadic effect       on the arterial wall. Then I think you have to balance this impossible       situation."
       
       

 "I       think in the states it will be hard to do those studies but I'd like to       see in the low risk group maybe coming in with low estrogen and baby       aspirin or some effective factor but I don't think those studies are going       to happen in the states."
       
       

       "There's a chance only one of the major concerns of estrogen       replacement therapy of course, is the effect on the breast and sometimes       also on the endometrium where there also may be a constant genetic effect.       What is current thinking on the effect of the breast?"
       
       

       "The effect on the breast, first of all, they have never shown from       the estrogen any cardio-genetic effects on the breast. They have shown the       promoting effect, this is what we believe more now, that we can activate       the replication of the cells and then this can have some negative impact.       But you know the figures are in 1,000 women followed for twenty years and       who are not treated with estrogen - they have thirty-five with new breast       cancer. If they are treated for five years, you move this forty-five to       forty-seven, and for ten years you move this thirty-five to fifty-two.       These are the figures, the figures also sustain that the mortality in       these same groups are more or less the same, indicating that the quality       of the tumors that they had, this seven in omission, are of a more curable       kind. I think in another size and a series of studies that show that       having a baby prior has shown that the positive effect of vascular levels       are so deep, but if we make a mean of the pull and counts, the pull still       remains more than the count. A record should be kept of any anomalies,       it's very important for the woman to share any personal history regarding       breast cancer in her family history to make an adequate screening       protocol. I think at least now we can believe that our hormonal therapy       can be given for ten years and probably can be a full load by certain       therapy just to counteract the effect on the breast. This I think should       be a good general strategy but as I was sustaining, this is on the breast.       Concerning the endometrium, on the endometrium you know If we give a       progesterone together with estrogen it has been shown that they have a       reduction of naturally expected cancer or smaller - more or less 50%. It's       the same from colon cancer, and speaking about cancers, I think that the       dollars are in favor of the therapy. It may be adequate screening if we       follow the woman, if we do mammograms as they have to be done, and then if       you maintain a close connection between the patient and the doctor."
       
       

       "Dr. Carp, I'm interested and have been following your work in the       literature about evaluation of the immune system in patients with       recurrent pregnancy losses. What is the status of immune testing now? How       do you answer critics who say that there really isn't a place for this       because if you do nothing, 65% of the people are going to do quite well if       they've had three losses?"
       
       

       "I'm pleased that you mentioned that 65% of the people do well,       because the opposite side of the equation is 35% do not do well. But there       are people that actually seem to second that, now the first 35% will not       do well, that means they will come back again with a fourth pregnancy       loss, if you take as your basis three pregnancy losses. Those who come       with four pregnancy loses, 60% do not do well. That means that you're       talking about 20% or so of your patients who will come back after three       pregnancy losses with a further two losses. I think that our       responsibility as physicians is not to look at the 60% who do well but to       look at the 35% who do not do well or the 20% who come back with the       further two losses. That's why even though we treat patients with three or       more pregnancy losses, we try to limit our research to patients with five       or more losses because I think what tends to happen is that patients are       told 60% do well, therefore, go away and become pregnant again. On that       basis, when a patient comes to you with five or ten miscarriages, you may       be denying her investigation and treatment on the basis that the patients       with three loses do well. I really don't think that's fair to the       patient."
       
       

       "What happens to the patient who comes in with two losses and says,       "I've heard about this immune stuff, I don't want to lose       again."
       
       

       "You do have a very difficult clinical question because there are       patients who will look up sites on the Internet such as this one and       others, and they will come to you today and say, "I have heard about       immunization, I have heard about immunoglobulin, I have heard about other       methods of treatment. I want to be treated, I don't want another       loss." I think with these patients you have to explain to them that       the patient with two losses, 80% do well but we do not really have an       accurate enough diagnostic test to see who is the patient who will do well       and who will not do well. The patient has to realize that even if we       investigate the pregnancy loss, and we find a cause of pregnancy loss, it       will not necessarily be the cause of pregnancy loss, and that often       treatment of the moment is empiric. Immunotherapy is empirical treatment,       resection of the septum whether done hysteroscopically or in another way       is empirical, and immunoglobulin is empirical. Recent work on reduction of       LH levels has been empirical because patients with two pregnancy losses,       for example, most pregnancy losses will be due to chromosomal arrangements       in the fetus. I think it is still accurate, we can ask Professor Genazzani       as well, what is current practice in Italy but I think it's still       reasonable to say that in 90% of the world or 90% of the patients with       pregnancy losses where there is two, three, five, or ten losses, that       conceptus when it is lost is not karyotyped. We cannot even give the       patient an accurate diagnosis against that basis. We are being asked to       summarize treatment, to prove the treatment is effective, and that is       almost impossible."
       
       

       "So one of the things your suggesting when that second loss comes       along is to try to get the chromosomes to a consultant who may see the       patient after two or three losses for evaluation?"
       
       

 "I       say that most definitely, yes, because if you find the patient who has       lost an embryo which is chromosome 16 trisomy, x monosomy, you know that       he's elected to be chanced chromosome agents. You can then say to the       patient, "Your chance next time around is very, very good." You       can even give them figures depending on whether this is two losses or       three losses and discuss with them whether they want to spend the time for       other investigations or not. If however, you find that a patient is losing       normal embryos, then you have to investigate the other factors. Then I       think there's a place with immune investigation and other investigations       and probably treatment which is then much more directed at the cause of       pregnancy loss rather than the empirical fetus."
       
       

       "Do losses tend to cluster around the same indication so that if you       have patients who've had three or four losses, and you know that one or       two of them are chromosomal, is it in all likelihood that the others were       chromosomal or that future loses will be chromosomal? If per chance you       had someone with three losses, and you knew they were all chromosomal,       would your evaluation be different?"
       
       

       "My evaluation would be different, my advice would be slightly       different. It would depend on what sort of chromosome losses. The chance       for an assembly arrangement such as chromosomal 16 trisomy, which is the       most common, when we find in our series such as x monosomy, these do not       have high recurrence risks and an open chance is very good. You do       occasionally pick up a translocation, and when you pick up a translocation       then there may be a chance of that coming from one of the parents. You can       check the parents to see whether they have the same translocation, which       they have passed on. In most cases there is a very high recurrence risk,       and you can explain that recurrence risk to the patient. After that, you       may decide to investigate patients of those. The patient who loses the       chromosomally abnormal fetus may also have a septum present, similarly a       patient with septum may also lose chromosomally abnormal embryos. One does       not exclude the other and the fact that you have found one cause of loss       does not mean that you have found the cause, this is problem that we're       facing today. However, I do feel that much of the literature does depend       on finding one cause of loss, they don't find other causes of losses. I       think it also depends very much on the clinical presentation. If I give       you an example, we had one patient who had two pregnancy losses at twelve       weeks. She had septum within the uterus, she was advised of the       contraindication, she lost the third pregnancy also at twelve weeks. We       resected her septum, and she lost the third pregnancy at eight weeks. Now       this obviously sounds like a failure with treatment. Now if I give you       some more details about this patient and say that these three previous       losses were losses of live embryos at twelve weeks there was a fetal heart       present, the uterus started to contract, she started to bleed, and she       aborted a live embryo. The fourth pregnancy loss was ablated over at eight       weeks, now that sounds different because it doesn't sound quite so much as       it is a failure of treatment. If I now present the patient with even more       detail and say all pregnancy losses due to chromosome 16 trisomy, and that       the fifth and sixth pregnancies were induced labor each time at forty-two       weeks, you realize that the resection of the septum was not a failure of       treatment. It was in fact, a successful treatment and unfortunately these       things are not taken into account. As Professor Genazzani said about       hormone replacement therapy, patients are individuals, and if we stay with       this definition of assessing all patients with three or more losses,       that's one homogeneous basket we're never going to make any sense on this       subject."
       
       

       "One invariance being evaluated is again the clotting factors that       prothrombin gene mutations and Factor X Leiden in this area. Do you see       patients in Italy being screened for clotting factors as part of that       evaluation?"
       
       

       "Only if they have very special reasons to do this, and it's not yet       in the general practice also in the measures that we have to start in some       kind of screening problem but we also need to be concerned about pregnancy       loss. This is one area where we're defectors. It has to be taken into       consideration and we need to try to personalize all the screening project       and the screening problem. So it's not only bad for the patient but also       for the doctor who follows the patient when you have seen three to six       losses. Then you have to exam the embryo and there may be some genetic       defects in some and not in others and some others there might not be any       presence of the embryo. At the end of the study, you cannot know what kind       of therapy, if any therapy or what kind of approach you have to do. You       only have to hope that God will help us and that she can have live       children."
       
       

       "With thrombotic pregnancy loss, whether it's due to either       antiphospholipid antibodies or simply by a cyst or due to genetic       predispositions which is Factor X Leiden and prothrombin malformation and       so on. I think that first of all, clinically we have to define a certain       type of pregnancy loss. Now with antiphospholipid antibody syndrome, the       preponderance of second and third trimester losses is much higher than it       is in unselected patients in common pregnancy loss. Patients who receive       it, the current pregnancy loss, 90% were in the first trimester and about       10% in the second and third trimesters. Patients with antiphospholipid       syndrome, they're not 30-40% in the second and third trimesters so it may       be that in traumatic pregnancy loss, we have a normal embryo or fetus but       then due to the clotting, we get ischemia and the effects of retardation       and fetal death. Now certainly if you look at Preston's paper summarizing       the EPCOT study on thrombophilias, they did say that the chance of a       stillbirth - and they define stillbirth as being a fetal loss of about       twenty-eight weeks - is also much higher than the chance of what they call       the scavenge, which in their definition is a loss below twenty-eight       weeks. So I think there is a clinical picture starting to become clear,       when this becomes clearer and more accepted, I think we'll have a much       better indication as to who may need treatment for thrombotic pregnancy       loss."
       
       

       "Do you believe that placental evaluation is an important tool either       in determining patients who may be at risk for an immune basis or a       thrombotic basis for their loss?"
       
       

       "I can only say - what kind of placental evaluation? Maybe Dr. Carp       can give us a better, more precise results on what kind of placenta       screening and evaluation you would like to suggest to the standard       patient."
       
       

       "First of all, if we're talking about first trimester losses - there       is no placental evaluation. We're really in the hands of nature as to see       what comes out after that but you do have to access maybe not the       placental factors or the projected factors. Once we come to the second and       third trimester, unfortunately antiphospholipid antibodies have not proven       that good an indication of what goes on. So if you check 80% coagulum by       clotting factors whether it's either the activated PTT or Russell's viper       venom time, none of them has proven to be a good indication of what's       going on in with the pregnancy. Anticardiolipin antibody is notorious for       its intralaboratory/interlaboratory variation, you cannot trust antibody's       levels. Therefore, you can only trust placental assessment, and it's usual       to send for assessment, non-stressed cardiotopography, fetal growth on       ultrasound, flow studies, and they'll give you an indication that the       pregnancy is doing well or whether you may need to intervene and stand on       a sentry basis."
       
       

       "Dr. Genazzani, thank you."
       
       

       "I'm sorry, I thank you but I have to leave."
       
       

       "Dr. Carp, thank you so much."
       
       