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Questions and Anwers 1

Questions and Anwers 1

Top International Faculty Convenes to Talk about Sex…and Endometriosis…Seriously!
At Endofound's Second Annual Scientific Symposium

“We are here today to exchange options and ideas.”
- Symposium Chair, Tamer Seckin, MD

In support of this event, Endofound acknowledges the generous gift made by the Leon Lowenstein Foundation, Inc. in behalf of Kim Bendheim, Co-Chairman and Director of the Foundation, along with the genorosity of our event partners, Ethicon Endosurgery, Simbionix, Karl Storz Endoscopy, Lumenis Lasers, Abbott Medical, endometriosis.org and the Endometriosis Research Center.

Speaker 1: As you know, we are webcasting live and we do have a couple Q and A interests from our audience that I'd like to get into before I open it to the floor. Particularly to Dr. Kodaman and all speakers and all panelists. Are there currently any tests available to physicians to predict the success rate of implantation, or is this the current research at this stage?

Speaker 2: Do you want me to come up? Currently, this is what's out there right now. People are looking at using the markers of implantation in women with endometriosis to be able to predict success rate of pregnancy, but it's certainly right now just in the investigational stages.

Speaker 3: Thank you.

Speaker 1: I open it to the floor at this time if there are any Q and A. Dr. Redwine?

Dr. Redwine: I enjoyed all the speakers very much. I have a question for Dr. Fazleabas regarding the baboons. Two questions. One, was it studied that if the endometriosis that had been induced was removed, did the endometrium go back to normal? And two, how are you sure that the endometrial implants that you saw at various stages weren't going to be something that was spontaneously developing as it can in natural baboons?

Dr. Fazleabas: So, in regards to first question, we tried that experiment. So, what we did was basically in our model, since we knew what was happening with between the early and the late stages, we went ahead and ablated lesions at one month, and then let the animals go for six months and ablated the lesions at six months. We haven't seen a really significant change in any of the markers of the eutopic endometrium except for a couple of them, but these are smaller numbers; we only did five animals in each group. What the data seems to suggest is that if you ablated at one month, and I think most of you would agree, that we saw a slight reversal in that the endometrium came to back to showing the genes that would be normally expected to see, but at six months, essentially, we didn't see any changes at all.
So, early intervention had a slight effect but it wasn't significant enough that we could really say it was definite. The one gene that I didn't talk about, but lysyl oxidases, which have been identified in implants, both rat, human, baboon, it seems to be a gene that's changing early. That one was one that we saw was significantly down-regulated if we ablated the lesions early.
In regards to your second question, I think that's a great question. Basically, if we continue to do surgeries on these animals independent of doing any kind of intervention, a subset of them will definitely develop endometriosis by the time you get up to the fourth and fifth surgery. So yeah, I cannot tell you that these are all developing with regards to ... and it's not a consequence of surgery.
But the only thing is, going back to the comment I made, is that if you ovariectomize the animals, once we inoculated them and then put them strictly on estrogen pellets or implants, which are about what you measure in a baboon in the late follicular stage, these lesions do not maintain. So, just estrogen alone after you inoculate these animals don't maintain the lesions, which seems to suggest that that needs to be this constant seeding and going back to what Caroline was talking about, that perhaps the development of stem cells and things like that are constantly initiating and keeping the disease going.

Speaker 3: Thank you.

Speaker 1: Dr. Griffith.

Dr. Griffith: I have a question for Caroline Gargett. In some other tissues, particularly in liver, there is a lot of evidence that the mature cells have a tremendous proliferative potential; up to 80 times, and that in certain models of injury in liver, you have the mature cells proliferating and other models you have the stem cell compartment, or the putative stem cell compartment proliferating. So ... I really don't know where she went, so I don't know where I'm looking to find her ... oh. So, I'm wondering, in the endometrium, what do you think about the balance between when mature ... you go to a liver facet meeting and people come to blows almost over how you studied this, and so on, but there is accumulating a lot of evidence that the differentiated cells have enormous proliferative potential; there may be bi-directional or coming back from the biliary cells.
So, what do you think about the endometrium, and the balance between these and different kinds of injury and disease?

C. Gargett: Thank you for that question, that's a really important one, and in fact we've done some work in mice using a different technique, which we started, called the label retaining cell technique, when we didn't have any markers. We've looked at which cells drive endometrial proliferation after regressing the endometrium, so it's really thin, and then giving it just a single estrogen injection when it regenerates, and we got two very different results, depending on the age of the mice.
What we found, was that if we had ovariectomized the mice prepubertally, that the cells that really regenerated the endometrium, or the first epithelial cells to proliferate, were indeed the label retaining cells. But, when we had the [inaudible 00:06:17] mice and we had ovariectomized those, and then regressed the endometrium until it was very thin, and then gave back estrogen, many cells proliferated.
And so we really have some ongoing studies using reporter mice, where we can conditionally label epithelial cells to look at populations, because I do too, think that maybe it's so rapid, the proliferative response, and such rapid growth, I do think that there may be different kinds of populations of adult stem cells, so maybe a really ... perhaps the most primitive one that doesn't divide very often and is very rare, and a lot of the cells may proliferate quite easily, and that maybe these [inaudible 00:07:10] cells that have that capacity. But how much proliferative capacity is [inaudible 00:07:17] we don't know, because it may be shared, and then need to be regenerated again from this other population.
So, it is a really important question, and at the moment we really can't fully answer it, but I do think that what you've raised is an important consideration, and we're working on it in different ways. We really have to use mice, which don't menstruate, but you can induce menstruation in mice; we do have a model that does that. And there is really quite a disconnect, or different response between the luminol epithelium and the glandular epithelium in that type of response, in recovering from a menstruation-like event.

Dr. Griffith: [inaudible 00:08:02]

C. Gargett: Yes. There's quite a lot involved there.

Speaker 1: Thank you both very much.

Speaker 8: Dr Rodgers, you're just talking about atypical endo, and I was wondering if you considered microscopic endometriosis to be in that category.

Speaker 3: Sorry.

Dr. Rodgers: No I don't, I think atypical endometriosis, as it's now understood, simply represents a dysplastic change that's occurring in otherwise typical endometriosis, that often is observed when endometriosis is physically associated with, in the same patient, endometrial or more often now, ovarian cancer. So there's a hypothesis or a theory that atypical endometriosis may be a precursor lesion to some forms of ovarian cancer.
These days, ovarian cancer really refers to cancer of particular types that arises within the female pelvis. A fairly significant number of ... some types of ovarian cancer don't arise from the ovary. The origin of ovarian cancer is something that's being very actively investigated now and studied, and even the origin of different types of ovarian cancer and their relationship with the ovary and the Fallopian tube, and the Mullerian tissues that are present in the pelvis is a very area of study, as is endometriosis.
Microscopic endometriosis, I think is a very controversial issue. There are believers, or clinicians that believe that microscopic endometriosis is very significant, and I personally believe that it is, because of the association of microscopic endometriosis with, for instance, in fertility. But, if the patient's problem is one of mass lesions or painful menstruation or pain in intercourse, the lesion may be more related to inflammatory changes around larger masses of endometriosis in a particular location, mainly in the cul-de-sac.
So what I meant by needing different classifications of endometriosis, the clinical syndrome is associated with the presence of endometrium in the abdomen, may have different causes and treatments, and in some cases, microscopic endometriosis may just be a normal phenomenon that occurs in women, and what occurs in women that are symptomatic with endometriotic disease is that they just have a little bit more of it. It may not be you have a disease or not, it may be an issue of whether you have a lot of it, and whether it's more than the normal physiologic systems in the body are able to deal with appropriately, so it's very complex, very challenging.

Speaker 1: Thank you.

Speaker 3: [inaudible 00:11:31] in the back.

Speaker 1: [inaudible 00:11:36].

Speaker 10: Thank you. This is a question for Dr. Fazleabas, and the primate model, and the notion of the importance of retrograde menstruation on the development of lesions. Have you or anyone else had a chance to examine whether in these primates, removal of the uterus affects, or halts the development of new lesions in the peritoneum, and given what you stated about the communication between eutopic and ectopic endometrium, whether the removal of the uterus actually halted the progression of existing lesions or not.

Dr. Fazleabas: That's a really good question. I don't think anybody's done a hysterectomy independent of that as far as the animals are concerned, I think part of it is just the expense of doing experiments of keeping those animals around, but I think that's a good question with regards to whether removing that will help the disease go away.
No, we haven't done those experiments and I'm not aware of anybody else that's done them.

Speaker 1: Thank you. Dr. [inaudible 00:12:46] do you have a question?

Speaker 11: This is the time to ask questions. You're never going to get these experts in the same room. There are many questions obviously, it's endless, and we really don't care about the time at this moment, but we will probably come to it.
My question about the endometriosis and cancer issue. In my clinical practice, in my limited affiliation with endometriosis, I have over ten cases, and this is only me in there, and I want to ask the question, who wasn't speaker, but one of the podium members, my colleague, which I failed to ask this question before, Dr. [inaudible 00:13:26], and others can join.
Dr [inaudible 00:13:27] does a lot of prophylactic ovariectomies, which I'm a firm believer on patients with a history of ovarian cancer in the family, and is post breast cancer. Two questions, whether you have any opinion about endometriosis' role in ovarian cancer, and in the ovariectomy group practice that you have, I know, how much of when you look back when you removed, or how much of peritoneal pathology you see in these patients, which they probably don't even complain. I'm very curious to hear you peritoneal observation in those ovariectomy patients.

Speaker 12: I think we all know that there is an epidemiologic association with a history of endometriosis and an elevated risk to develop ovarian cancer. Dr. Rodgers can certainly talk about clear cell carcinomas that arise in areas of endometriosis. But that actually brings up a question, because as I sit here in the audience having been a former cancer researcher, I'm looking at the same genes that actually we studied in our laboratories, associated with, expressed in endometriotic implants.
So, that actually brings me to ask a question to Dr. Fazleabas, and the other investigators. How much cross talk do you have with the oncology researchers at your institutions? Because I think that's tremendously interesting, I mean it's not a completely benign disease, it's not a malignant disease; it almost makes you think of a borderline tumor of some sort. I mean, it doesn't grow completely out of control.
So, I think that the dialogue between the cancer researchers and the endometriosis researchers is a tremendously, probably, important question. In terms of peritoneal disease at the time of prophylactic surgery, pretty uncommon actually. Asymptomatic peritoneal disease for other patients that I ended up operating on, certainly so. But certainly by happenstance I occasionally will find some peritoneal pathology with endometriosis and individuals who are at elevated risk to develop ovarian cancer with endometriosis. Actually we just did a case recently, but I can't comment on the percentage per se, it seems to be quite low, actually.

Speaker 1: Thank you.

Dr. Fazleabas: Just to respond to your question. I've been fortunate with my new institution that that is really significant, because right next to me is sat [inaudible 00:16:03] from gynecological oncology research, and we really got thinking about this and some of the work that we've done, where we've seen metastatic markers coming up early, and what has really triggered one of our discussions is a recent paper that came out in the New England Journal of Medicine and Science with Vogelstein's group with regards to the role of ARID1A, and I think that's certainly significant. And we went back and simply looked at our array data, to look to see if ARID1A was even there, and lo and behold, yes, it's down-regulated as you would expect, in our baboons, at three months after we've induced the disease.
Now, what the association of that is, what the polymorphisms are, I mean it's extremely complicated in terms of the numbers of polymorphisms that are associated with this, and what does ARID1B do now, but a paper came out just recently, again suggesting that the ARID1A gene might also be involved in endometrial cancer. So, this might be sort of a common component that oncologists and biologists like me can talk about, because here's a gene that seems to be associated with something that's of epithelial endometrial origin. And I'm fortunate in my current situation there, we do a lot of cross talk.

Dr. Griffith: One thing, as I've come into endometriosis research, if you do research in breast cancer or if you have breast cancer, patients are incredibly stratified, and there are different protocols, if you have triple negative or ER positive or HER2 positive, because people have been studying it for a long time and have found that unlike a lot of the blood cancers, the leukemias, there's not a single gene. There are many, many different origins. So, in leukemias you can find this cancer stem cell that gives rise to almost clonal things where you can have something like Gleevec be fantastic drug, but in breast cancer, non-small cell lung carcinoma, et cetera, there are many, many different origins of these cancers and different patients respond differently. And I'm fascinated by the relative lack of stratification of patients, because what we think of as appearing as morphologically similar diseases in various patients, may in fact be very different molecular origins, and yet we lump patients together.
So, one of the things that I'm very interested in, that we're trying to do, because we do have a lot of crosstalk between cancer research and endometriosis at my institution, is thinking about these stratifications, and it requires an enormous interface with a clinical side from the basic scientists like us. So, I'm eager to hear about that later at the breaks and lunch, or whatever later today, opinions from people. You can just come up and tell me things.

Speaker 1: Thank you Dr. Griffith.

Dr. Rodgers: There's a related comment I'd like to make. In cancer studies, typically, when a cancer researcher is searching for unique gene expression patterns, or patterns of epigenetic modification that are unique to cancer, they're comparing that expression to other normal tissue that is not proliferative. The endometrium is uniquely proliferative in the body, and when you compare endometrial tissue, normal endometrial tissue, to ... or use the same assays that many cancer researchers use, you find that the genes or gene products, or signal transduction pathways that are activated that are associated with cancer and a cancer researcher is studying to explain cancer, are also activated and are active in normal endometrium. In fact, I'm not aware of any real pathways that are absent in endometrium. It's as active and proliferative as the most proliferative cancers; it does it a letter better, it's more organized, but cancer is proliferative and so is endometrium, so it's hard to draw the line. If you use those as definitions of cancer, you would consider endometrial tissue, normal endometrial tissue, a cancer. And where endometriosis fits into that is really an interesting question.
So, I think you're right. I think the stratification is very important, I think, in endometriosis.

Dr. Griffith: [inaudible 00:20:16]?

Dr. Rodgers: Well, there are and there aren't, and also inflammation seems to trigger in tissues most of the same things that are found in cancers, but you're right, invasive property is very important.

Dr. Griffith: [inaudible 00:20:31].

Dr. Rodgers: Exactly.

Dr. Griffith: [inaudible 00:20:32].

Dr. Rodgers: Endometriosis is more than just one thing. Inflammation is ... these are all very, very complex biological processes.

Speaker 1: Thank you, Dr. Rodgers. Gentleman behind Dr. Rodgers.

Speaker 13: Good morning. Dr. [inaudible 00:20:45] from Puerto Rico. Hello Dr. Rodgers, I'm a reproductive endocrinologist in Puerto Rico, and a few months ago or a year ago we had a patient with a peritoneal biopsy and a mucin-like material that we sent to the pathologist, and they reported that we had a malignancy. A mucin-producing malignancy somewhere in the pelvic cavity. I have seen that for a long, long time, my [inaudible 00:21:17] has seen that for a long, long time, a mucin-like material in the peritoneum of patients with endometriosis, with several degrees, is that something that you see at your department with frequency?
We sent those slides to [inaudible 00:21:36] pathology department and they also asked us to look for the malignancy. The patient was explored, and nothing was found, but it's something that we have found over and over, and we don't even know whether the link was something we have to be more careful about. Mucin-producing malignancies.

Dr. Rodgers: I can't really ... it isn't my experience that it happens often. There's a disease called pseudomyxoma peritonei that's associated with mucin-producing tumors, usually the appendix and sometimes of the ovary, but usually with exploration you can find something that explains it. I don't believe that it has anything really to do with endometriosis.

Speaker 1: Thank you. And with that I would like to close our first session with a special thanks to Dr. Caroline Gargett, our honoree, all our session chairs and panelists, I want to thank you very much, everybody who contributed to the Q and A cross talk, a very engaging, very important dialogue, and I want to thank you for that. If everybody would like to take a five or a ten minute break to visit our event partners, and have some refreshments, please do so now. Thank you.