Bowel Endometriosis - Ted Lee, MD

I just moved to New York just over January, so my slides deal. Say I'm in Pittsburgh. So talking about laparoscopic management, rectal Sigma endometriosis and the objectives to go over the diagnosis of invasive recals endometriosis and apply current management of invasive rectals endometriosis and discuss outcomes and complications following the treatment and demonstrate different techniques of treating recals osis. So this is a large nodule, a transmural nodule that's about four or five centimeters in size. That's through and through. You can see the nodules is cut by a valve at this point and it's typical of patient with severe rectals. Endometriosis diagnosis. Most patients going to have typical endometrial symptoms of pelvic pain, dysmenorrhea, dystonia, and dys. And DYS can be either constant intermittent or cyclic. Patient may have intermittent constipation and diarrhea or have cyclic constipation or cyclic hemato Keysia examination is on pelvic exam. On inspect exam, miss a deviation of cervix suggesting evidence of infiltrated miosis and some of them might even have miosis in a posterial vaginal phonic. On recal vaginal exam, you feel nodularities and tethering. In terms of imaging, you can do transvaginal ultrasound MRI or rectal ultrasound.

So frequently most of the ultrasound done in more centers in the United States are not very specific for endometriosis, so most of the time they'll be able to just detect endometriomas. But when the patient has endometrioma, it would suggest that they're very, very high risk of having some level of bowel endometriosis as well as operation cul-de-sac. In specialized centers. Ultrasound is very useful in assessing deep endometriosis. In places like in Brazil it's very common as well as in Europe. You can have people who are very good with vaginal ultrasound for detections of rectal similar endometriosis with sensitivity of 83%, specificity of 94%. And it's useful in preoperative planning and counseling MRI, which is much more common in this country. So typically I don't order MI on every patient, so if patient have nodularity eye exam, I would order MRI. If a patient has endometrioma on ultrasound, I'll order MRI and it's best done with both vaginal and rectal contrast. And the poor sensitivity of most MI studies can show sensitivity of the 90% and specificity of 96%. When the tricity involved in the upper rectal sigmoid colon, it's not as sensitive. It's frequently missed those disease as a lot of rectal contrasts cannot reach the upper rectum or upper sigmoid. And obviously for MRI you with a much better perspective from anatomic standpoint of where every other organ is. Unlike a vaginal ultrasound where you only look at a specific place at one time with an MRI, you have a much better perspective with a rest of the anatomy.

So this is a patient who had endometriosis in the rectal vaginal septum invading through the rectal wall. So the Y here is the vaginal gel, the vaginal vagina, and the Y here is the rectum. You can see this nodule right here in the same patients. You can see the endometriosis over here on the left side of the rectal vaginal septum with superficial invasion into the rectal wall. And you can see here in another view here as well. In this patient you have the mushroom sign of very large nodules involving a length of probably of three four centimeter length of the rectals colon and basically the rectum or the rectal colon kind of wrap around the nodule. And then this is the type of patient who end up with the bowel resections. You can see the glandular tissues here, the white part within the nodule here. And then this is a patient who has endometriosis on the upper rectal, similar colon. You can see that right here it's very thickened and it's very long. The lesions are quite long. So this patient was also likely to end up with the resection anastomosis. Again, another patient with a mushroom sign. You can see that all this lesions here, so basically it's just a loop of bowel with a nodule within the loops of a bowel. You will see that in a lot less patient with severe rectal osis and nine frequently this type patient with a heid keysia, they'll have bleeding during their period, rectal bleeding during their period.

And the rectal ultrasound is for nodules higher up on the sigma colon. That's frequently missed by MRI. So in a patient who complain of cyclic rectal bleeding and on exam you don't feel any nodule on exam, so you say what's going on, there is no nodules and frequently their nodules are much higher up. You cannot even reach them on exam. So they will do a sigmoidoscopy and do an ultrasound circumferentially. And you can see a large nodule here on the, probably from four o'clock to seven o'clock region. There's not large nodule. They can measure the size of nodules and they can see the bulging and the sigmoid can see the bulging into the rectal sigmoid colon. So this is in patient who have rectal bleeding who he couldn't explain on exam. And most patients with rectal miosis are going to have ablation of the cul-de-sac. And so it's very, very unusual for patient to have endometriosis of the rectum without ablation of the cul-de-sac. It's very, very rare to see. So typically in a patient who has schematic drawing, the yellow lines here is the ureter and then this is a uterosacral ligament and this is just sort of points of entry into the per rectal fossa and the rectovaginal space. So in a lot of patients this area is obliterated, for example, on the left side and the rectovaginal space is obliterated. Sometime you'll find patients with obliterations on the right side and at times you get entire CORs obliterated. So you'll have to find entry into those spaces.

So here is a video of a patient who has a basically position of cul-de-sac and will be able to enter the rectal peral fossa medial to sacral ligand and lateral to the rectum. And once you enter the space, you can able to develop the per rectal fsa, the AYA space fairly easily. And next it can be done on both sides. I'm going to fast forward here.

Okay, perfect.

And then you basically, once you develop a space on either side and you basically sharply dissect the rectum of the posterior vagina cervix and the uterus and it's done with sharp dissection with scissors. And then a lot of times with this kind dissection, you basically you are feeling the weakness in the pathology. It can feel okay this is some space there and can cut there. And so a lot of times you are using blunt dissection as an investigation tool, like an interrogation tool to allow you to know where to go next.

And once you probe and feel where the potential spaces are, you can then open it up, there's some weakness there. And then so it began to work from numb to unknown and begin to open up all the spaces here and some weakness there. And basically other heart area will cut it sharply with scissors. And now we are in the rectal vaginal space and so we can see all the known spaces on either side, even known space in the middle. The rest that we can take down very, very quickly at this point with sharp dissection using electrosurgery, this is very, very routine for most people who do this type of surgery all the time. So the rectal vaginal spaces then develop and then you can go on to palpate the nodule on the rectum and be able to remove the nodule.

Alright,

And so would be a similar kind of situation here. So here would be where you enter the per recal sal cobi space, which is medial to the atrial sacral ligament. And then once you develop space laterally on both sides, then you can take down the dense fibrotic lesions in the midline. So on the left side you can open the same space and you can plunge a space all the way to the elevated anai muscles actually. And then you sharply dissect the middle part of the dense adhesions with both coal and hot scissors in areas where you're not sure where the rectum is and usually use a cold cut. And again, a lot of times when you cut through it, you can actually hear audible sounds, you hear like crunch sun outside of the body because the tissue is so fibrotic at times. Once you feel for get into the space per recto, FOSS on either side is developed on the right side and the left side already. We'll go ahead and take down the dense adhesions in the middle and frequently that you would have end miosis on both the cervical side, vaginal side as well as the rectal side. So the nodules, the materials is split in two halves and then after that you address each half separately. Okay, so the rectal vaginal spaces then develop at this point.

And I'll skip this one just for sake. So surgical management of rectal sigma endometriosis, it can be quite variable from center to center. Shaving techniques is applicable for superficial disease only. I do mostly antidisciplinary rectal recession with two layer suture repair and many centers in the world. And this is popularized by hair ridge with here today was the disco recession with the circular staplers. And for patient who have a larger disease, you can do signal resection and primary asims without divesting ileostomy. So typically there are different criteria that we use to decide to do disco resection versus segmental resections.

So the disco resections that you have less bladder dysfunction because a lot of times with a segmental resection, some of the nerve going to the bladder are damaged along the way is a disco resection is shorter. Operative time is typically limited to smaller lesions, usually less than three centimeters. And of course there's some concern about risk of residual disease with the disc resection. With a segmental resection you have higher bladder dysfunction because disruption of the nerve going to the bladder, your longer operative time, obviously it can take very large nodules with atory resections is also potentially have more complete removal of the disease. You have higher risk for stenosis and obviously if the lesions are very low, the similar recession is very, very low closer to the annual verge. Many of those patients will end up with diverting ileostomy. So this is an algorithm that was developed by Mauricio Braille center in Brazil. So they basically in patient with pain, rectal pain as well as who also have a lesion that's increasing in size, they basically can be go to shaving lesion, extend up to the external muscularis. And then or if it's a disco, they say it's a smaller nodule less than three centimeters and it's no deeper than the inner layer of the muscularis. But segmental is a large nodules and it is deeper into the inner muscularis. And all there multiple nodules on the rectal colon are also indication for segmental.

So this is the discoid resection, the squeeze technique. So this is both applicable for a patient with a smaller nodules. So I use the N seal device and basically N seal device doesn't have to go through heart tissue, so it go around the nodules. And so in this case I happen to spare the mucosa, but I basically remove as much as I need to, but no more as the idea is that if I get into the lumen, I get into the lumen. If I don't, I don't. And so then obviously I move the bowel away, then at this point there's no more endometriosis so I just remove what's necessary to remove that and I'll close the defect on the muscularis of the rectum with sutures and I can be down fairly straightforward. And this is another nodules that we are using a squeeze technique that it bounces off the nodule basically because this particular device doesn't like to go through heart tissues. In this particular case, the small nodules again through the rectum into the lumen. And we just repair that in two layers and we just close that. Any other, when you close a vaginal cuff after hysterectomy, this is basically the same thing. There's not much difference in terms of your technique of closing

And close in two layers it'll implicate the first layer

And this nodule is only probably like 1.5 centimeter in size. It's very small. Many places will do the secure stapler and dunk the nodule in and the fire stapler, it's much faster that way. But in my institution I just don't have access to the stapler because the general surgeons won't let me use it. So I just close this primarily and myself into layers. And after we close the defect, then we basically do basically air leak test, we fill the pelvis with water and then we will pump the air into the rectum with the proctor scope. And as long as we don't have any bubbles going through that means we have air tight closure.

So that's for the small nodules. And you can also remove fairly large nodules as well. So this patient's had nodules that I was actually bigger than I had expected that normally I probably should have done a segment, had my general surgeon come into the segmental resections. But obviously I was not prepared because I didn't expect the nodule to be that big, the defect to be lot large and the general surgeon wasn't around. So I had to basically close this in some one way or the other. So it can see by the end when I remove the nodule that basically the top two thirds of the bowel is missing on the top and you see one to put the rectal probe in, you'll see that this is a very large nodule, the probe is everything is uncovered, the probe is uncovered. So we have to close this in two layers, but because defect was so big that we basically split into two halves.

So we basically close the middle and then just close one half, then the other half and put them back together that way it's almost like a zplasty basically. So we placed the interrupted sutures in the middle line and then we tie them together and we split the defect into two halves. And so we use the probe as a template so when we close it, we don't end up with a stricture. So that's really the key is that we keep the probe in there so that way we don't end up creating a narrowing of the bow.

And so we basically close one half and then the other and both sides, we have it close in two layers so you can see that the configurations, it become a V shape closure basically. But then we kept the probe there to minimize the risk of strictures on this patients. So basically just a very extensive suture on this point. So like I said, normally nodule this size would've been done with the sigmoid, a resection anastomosis. Again, we do it like two layer closure, just like what we did with the smaller nodules. So it's basically the same

Use the barbed

Suture, we use barbed suture for both bowel and bladder. We've been doing that for many, many years. We publish our case series of using clo bowel and bladder with the barb sutures.

Okay, so basically closing the second layer, the implicating layer, and just similar to the earlier smaller nodules that we basically do a air leak test on both sides at the end of our closure. So we don't want to repeat that. Basically we do the same thing on the other side in two layers. And then we do the air leak test just like we have done before. And we clamp the bow and we pump air into the rectum and there's no air bubbling through. So that's good. So that is our way of doing discovery resections. And I'm not going to show the segmental resection because everybody does that and it's typically done by the general surgeons in the United States, but I know in other countries sometime the gynecologist will do that themselves. And that is my talk. Thank you. Our next speaker is Dr. Hugh Taylor. He's going to talk to about systematic nature of S Is he here? No,

It's

Prerecorded. Oh, it's prerecorded. Okay.

Recording stopped.

Well

Yeah, you want me to

Feel some questions right now while we are waiting for your thing going on?

Just second. I think it's going to pick up, where's the delay?

So the next pop, do we have any questions for the first three speakers?

I have a question for you. What kind of

Suture used to be

90 or question from? So you said that the presence of endometrial would be measured probably bowel

Involvement, five times risk for,

So that's surgery and bowel end shows up five years later. And would you still say that there's probably bowel movement at that point too or are you talking more about

The first? Well I don't, I mean they actually have just removed at that time. It's possible, but obviously they already high risk group already and so obviously

Can we start? Yeah.

I'm Kim Taylor from Yale School of Medicine and it's a pleasure to be here remotely with you today. I wish I could be there in person to see all of my friends, but today I'm going to talk to you about endometriosis and what I want to stress today is that endometriosis we think of as a gynecologic disease, but there are many systemic manifestations of endometriosis. This is really not just the disease. We've traditionally defined endometriosis as atopic endometrial glands and stroma that is in the pelvis. And you see multiple types of lesions. That simple histologic definition of endometriosis really belies the complexity of this disease. Sometimes we see the blue or brown lesions, the powder burn lesions, sometimes we see red lesions, white lesions, clear lesions are the big endometriomas. This is a complex disease that is more than that simple histologic definition would imply.

Not only that we know the clinical presentation is quite buried. Sometimes we see patients who present with horrific pain, sometimes they have no pain at all and we find that we diagnose it and we see them for in treatment. Sometimes they gotten pregnant, have no pain and we find it completely asymptomatic. It seen as an incidental finding on an imaging technique for some other purpose or surgery for some other reason. So the clinical presentation is quite varied and doesn't point into this just being simply a localized disease to cause. Further, we know that the pain varies considerably rather, doesn't vary by stage of the disease that whether we look at dysmenorrhea or non menstrual pelvic pain or dysuria at any stage of the disease, we're just as likely to see pain. So what's going on, what we see in the pelvis doesn't explain the entirety of this disease.

And finally, endometriosis is associated with many other symptoms outside the pelvis. We see of course the infertility, pain and the classic things we think of, but we know that be bladder dysfunction, that can be whole body inflammation, bowel dysfunction. We know that anxiety is more common in women with endometriosis that they can have a lower BMI, that they can have depression or fatigue and that in the long run they're even now we know more likely to develop cardiovascular disease. So what I want to stress is what you see in the pelvis is really just a part of this disease. Endometriosis truly is a systemic disease that affects the entire body in multiple organ systems and reference. There is a review wrote a few years ago that really summarizes much of this concept of all the different organs that are affected. Well we think of traditionally of endometriosis as being due to retrograde menstruation Sams today, but this absolutely cannot explain all of endometriosis.

It cannot explain systemic effects. It can't explain endometriosis outside of the pyramid and it can't explain those rare cases where we find endometriosis. For example in men in the old days, men with high dose estrogen from prostate cancer somewhat develop endometriosis. There have to be other etiologies in endometriosis, we've championed the stem cell theory against stem cells from bone marrow and other sources differentiated to endometrium in other locations. To summarize this data from many years ago now, about 20 years ago, we first started looking at chy stem cells in the bone marrow. These multimode stem cells in the bone marrow that could differentiate to multiple cell types and solid organs. The reason certainly that should be able to give rise to endometrium one of the cell types with the most dramatic turnover. Well we look first in a mouse model. We took cells from male mice and bone marrow derived cells and we transplanted them into females.

And then we looked at Y chromosome by fluorescent incy hybridization, and this is what we saw. The A, it shows you a control male, the blue is the nuclei, the red dots, the white chromosome. You can see that almost every cell we can see that Y chromosome B is a female to female bone marrow transplant. We're picking a uterus, there are none. But in C and D you can see those Y chromosome cells that came from the bone marrow that we transplanted into these mice in the uterus. The C shows the epithelium and the dark strike. Down the middle is the lumen of this uterus is the epithelial cells on either side and that's a bone marrow derived cell and D is the stromal disease. We also humans with the women who had bone marrow transplant in the old days when we took whole bone marrow transplanted the bin.

And here we looked at a woman who had a single HLA mismatch in the bone marrow donor and the brown hair stands for the HLA type of the bone marrow donor. So you can see on the left the bone marrow cells that can interate into this endometrium. The epithelial cells that are bone marrow donor origin on the right, the arrows point to the stromal cells that are bone marrow donor origin. The arrowhead point to the cells that are the endogenous resident stromal cells that don't have that HR mismatch. Those are the cells that have the same agility type as the recipient. And of course we looked at multiple other markers that prove that these cells really are endometrial cells that have differentiated from bone marrow, not just leukocytes. We also show that they contribute to the ectopic divisions. This is a busy slide, but I want to show you in the right you can see that those red cells or cells coming in from bone marrow, this was a bone marrow transplant with they cells that have red forest of protein.

You can see not only do they contribute to the endometriosis lesion itself, but outside of that endometriosis lesion to help propagate it elsewhere and contribute to the blood vessels that come in and support that lesion angiogenesis. So this is a novel origin for endometriosis. Stem cells contribute to endometriosis. They likely account for endometriosis outside the herital cavity and truly a novel mechanism, not just endometriosis but any disease. And I imagine we'll find some other diseases are due to stem cell inappropriate ectopic differentiation. Not only that, these stem cells from the endometriosis that go there, some of 'em remain a stem cells that alter and then they can come back into the circulation. And this is a mouse experiment. We see these peaks of endometrial or endometriosis derived in stem cells that travel then in the circulation and they can go to other organs. Is this a way that, so different organs that are affected not only by endometriosis, either coming from bone marrow stem cells or from the endometriosis lesions themselves and then going to distant organs where they may have an effect.

And this is some cell sorting experiments with the greater endometriosis lesions with red fluorescent protein. You can see on the left the panel there looks at four different organs, lung, clean liver brain, and the left shows the host organism from which we derive the endometrial cells of the transplant. The middle column shows the negative control where we do not use the red fluorescent animals. And then the third column shows the endometriosis created from those animals with the red fluorescent protein. And we look at those four different organs and to the right of that line, you'll see a few cells in each of these that had that red fluorescent protein in the lung, in the spleen, in the liver, in the brain. They're rare, small numbers, nothing you would ever clinically recognize the endometriosis, but could they be altered to function of these different organs in women with endometriosis?

Again, this looks at the percent cell cap. You can see it's tiny, but in every mouse we looked at, every organ we looked at here show the brain four we looked at, you can see some of these DS cells, red forest and cells in these organs. So when we think about cell trafficking in endometriosis, this really is a disease of cells moving around the body. We've always thought of it that way from the old theories of retrograde menstruation where cells come out of the uterus traffic to the peritoneal cavity. But now we know that cells from bone marrow go both to the uterus and feed the endometriosis. I draw that line much thicker going to be endometriosis because that inflammatory environment in the endometriosis attracts more stem cells and then those cells can lead the endometriosis and contribute to or influence a host of other organs throughout the body.

Could this be a way where we see mechanism mediates those non pelvic manifestations of endometriosis? The other mechanism we looked at were microRNAs. These are the small RNA molecules that are in the genome, but they don't cook proteins. They're highly processed into small runs of 22 nucleotide RNA molecules that in general bind message RNA and block its transcription rather it's translation. We've shown some time ago that microRNAs, this looks at the seven family of microRNAs are decreased in endometriosis and in a more aggressive endometriosis, the red bars of essentially DEI, even lower levels of lead seven. What does lead seven do? I mentioned to you that lead seven is involved in locking the translocal messenger RNAs, including those of cycling dependent kinases, kras, Nick, there's genes involved in mitotic signaling genes involved in angiogenesis, cell adhesion, cell migration, all the things that go wrong in endometriosis generally let seven would block these processes.

And remember I said let's seven is lower endometriosis. So all of these processes go unchecked. Well these microRNAs not only have that local effect in the endometriosis, but we know that they're either secreted alone or in exosomes where they can travel in the circulation to distant organs. We looked at these potentially serving as biomarkers for endometriosis and indeed we showed that there's some microRNAs that are increased in endometriosis, some that are decreased. And we actually showed that you can use a pretty good diagnostic test for endometriosis using these microRNAs with a very high area under the curve of this receiver operated characteristic curve here. So potentially you could even use microRNAs as a diagnostic, but that's not what I'm here to talk about today. I'm talking about the whole body effects of endometriosis. So when we know from tumor biology and cancers, when these exosomes go in the circulation, they can reach shells far away from where they're made and have a hormone life effect influence gene expression block RNA translation and cells very far from where they're made.

So we look to see if that can be going on in endometriosis. First we looked at immune cells. This is macrophages in women and we treated them with the micro RNA compliments that commitment, what was happening in endometriosis, but two black bar show mimicking endometriosis and the gray bars control. So when we need increase microRNA 1 25, which is increased in endometriosis or we use an inhibitor to let seven B, which is decreased in endometriosis, we get an increased expression of T alpha IL one beta IL six L eight. These circulating microRNAs are affecting macrophages throughout the body to increase the production of these inflammatory cytokines that have been associated with endometriosis. So these microRNAs in the circulation, they're going to affect every macrophage throughout the body. And when we correlate the levels of these inflammatory cytokines, the amount of microRNA 1 25 in the circulation you can see is highly correlated as the endometriosis patients that at least for PHI and beta and IL six, a very close correlation between Mike burn one 20 five's inflammatory side we know is there's a metabolic phenotype in endometriosis.

We know women with endometriosis tend to have a lower BMI and a lower fat content. Well, we show the animal models that this is cause and effect. We create endometriosis in the animal models and the mice don't gain as much weight, so it's directly caused by the endometriosis. We're still see in some textbooks where it says the low body weight is a risk factor for endometriosis now is caused by the endometriosis. How does this metabolic effect happen? Well before all the details of this slide, but we looked at the liver of animals after we created endometriosis and you can see changes in a lot of the genes that would be predicted to lead to a lower body brain. So a metabolic effect on the liver is part of what produces this. We also looked at adipose tissue here. We directly treated with microRNAs to mimic what we see.

Endometriosis, different microRNAs here, 3 42 is one of the main players, but changes leptin, adiponectin IL six, hormone sensitive lipase in this adipose tissue contributing to this metabolic phenotype we see in endometriosis. So these microRNAs go to the liver, go to the adipose tissue and change metabolism. The other thing we looked at was brain. Now we know women with endometriosis can have central sensitization pain. We know they can have increased in anxiety and depression. And we show here in animal models where we can really get it causing the fact that these are not just simply patients that are more sensitive to pain or patients that are anxious and complain anymore. This is really a direct effect. These behaviors of creating endometriosis. Here we show that we create endometriosis in our animal model. The red bars and the endometriosis take out the brains and we do immunochemistry.

Various genes that are associated with these phenomenon are in the brains of animals with endometriosis. On the upper right we show the electrophysiology is different, but most importantly when we look at behaviors as we show these behaviors are changed by creating endometriosis. You can see anxiety. You measure this in the open field test where you see how much time the mice huddle in the quarters. That tends to be a sign of anxiety in mice. And you could see that within about six weeks we see a statistically significant decrease in the amount of time they spent in the center of the box. We spent more time in the periphery of the box, again induced by the endometriosis. When we look at depression here in the bottom right, you can see here that depression was increased within the first week of creating endometriosis. And when we look at pain sensitization here, we use a hot plate test.

We put the mouse a warm surface, see how long it takes for that mouse to remove the pause, sensing that that's hot. And you can see that it was much faster in my endometriosis. It took about 12 weeks for that to become statistically significant. But it was. So all of these manifestations are due to the effect of endometriosis on the brain. We induce anxiety, pain, sensitization, depression, all from creating endometriosis. And then we looked at atherosclerosis. We took an APOE mouse is just generally don't develop atherosclerosis like we do. We took an APOE mouse and we created endometriosis. And you can see on the left the oil red standing, it stands for AIC sclerosis and this aorta of the spouse, it's much higher in the mice with endometriosis. And when we look at the luminal opening, the size of the opening of the blood vessel, it's decreased in mice with endometriosis.

And if we look at the thickness of the aortic wall can suggestive endometriosis much thicker in mice with endometriosis. Endometriosis is causing this atherosclerotic effect that is not due to medications we give our patients is not due to our surgeries on our patients. It's a direct effect of the endometriosis. What mediates this? Well, we didn't see any changes in lip levels with created endometriosis, but inflammatory markers were quite increased as was vegf. So we believe that's what's driving that atherosclerosis. So I hope I've convinced you that endometriosis really is a systemic disease that we're just seeing the tip of the iceberg and what we see in the pelvis. But there's many of these different effects of hyper RNAs of stem cells and inflammatory cytokines all drive change in other markets, but endometriosis really needs to be considered a chronic and systemic disease. The very presentation made it difficult sometimes for our colleagues, probably not.

Invite

Our

Speakers up to the podium here extra to actually

Nature barriers to start,

Need to start

Thinking about pain and ions, a psychiatrist, pain with bladder pain, with fatigue as all manifestations of the endometriosis and not think about multiple diagnosis. And I'm sure you've all had patients who come to you after seeing the urologist or the gastroenterologist or even the psychiatrist when they really just have endometriosis. I think we know, see that endometriosis is misdiagnoses majority of the cases and affects women. Half of women over five physicians before they get the right diagnosis. We can do, we can do better. And part of it's going to be understanding the systemic nature of the disease. It is a widespread systemic disease. The systemic nature explains these extent of symptoms often associated with endometriosis. You need to start thinking about this as one disease. Recognize all of these as just simply manifestations of endometriosis. And the mechanisms include stem cells, microRNAs, inflammation, all these circulating inflammatory cytokines. These are the mechanisms that mediate these long range effects of endometriosis. And there and acknowledge all of my collaborators that are endometriosis center, my laboratory members and funders that are listed here. Thank you

Live. No. Alright, so Fran, so if I have any questions directed at any of us Oh, he is here. Okay, perfect. He's live.

Alright.

Little bit of what you call it. Echos there. Echo. You can hear us? I guess. Not sure Can you? I'm not sure if has a lot of echoing right now. Anyhow, you just have to thank you. Yeah, well thank you. If we somehow can get this connected correctly, we'll reach back to you. Okay. Does anybody have any questions about any of here? Can you hear us here?

Do you hear me?

You. Hey. Okay, can you hear us? Just a second. Unmute a question for you

And for you, more and more speakers discuss about the presence of the stem

Cells.

I would like to know your opinion about the amount of stem cells in the mens field,

The among of stem cells in the menstrual. I dunno that anybody has quantify. I mean people have done close down and looked at stem cells, marker. They're

Present anyway, but we don't know exactly how are they survive, how many there are in the mens field. And I guess that should be a way of reserve for the future. Because

Mentally I think that's really in regards to stem cells being initiation. And that's change also

Your As discuss. I know.