March 8: Q&A with Panel & Closing Remarks
Endometriosis Foundation of America
Medical Conference 2019
From Biomarkers to Precision Surgery
March 8-9, 2019 - Lenox Hill Hospital, NYC
This detail that you people know, the facts, it blows me away. Having said that, I wanna ask a little bit more about dysmenorrhea. I think Dr.Saldano and Dr.Gregersen had mentioned it. Dysmenorrhea has both, potentially, a uterine component and a more general pelvic pain component. I believe it's important to try to separate out the uterine component from the pelvic pain component. Not just from a scientific basis, but also because the main therapeutic effect of both Lupron and Elagolix is on dysmenorrhea. If these medicines are actually treating uterine pain, rather than endometriosis pain, I think that would be a significant differential. So, I guess my question is, do we have anyway, short of questioning the patient about, 'Do you have uterine cramps with the menstrual flow?', is there any way to separate out dysmenorrhea coming from the uterus versus dysmenorrhea coming from endometriosis in the pelvis?
Can I just ask one clarifying thing? Because adenomyosis could muddy the picture here, which is common. It's common in a lot of patients.
Right. Yeah, it is, it is. But that's uterine also in a sense.
Yeah, I'm just saying Lupron wouldn't be expected to affect that.
If you do the sonogram, you can identify that the patient has adenomyosis very easily.
I'm stuck on the clinical symptom of dysmenorrhea. How do you differentiate uterine versus pelvic source? Cause it's an important question for therapeutics.
Let me approach Frank Ling's paper really quickly. For those of you who think that Frank Ling's paper showed that Lupron can help you diagnose endometriosis, the statistically significant observation Frank Ling had looked at Lupron and pain was comparing Lupron to placebo. Okay? If you read that first abstract, Lupron to placebo. If you dig inside the paper and find Lupron in patients who did not have endometriosis, versus Lupron who had no endometriosis. 10% difference, P values 0.7. Lupron worked for all pain, whether there is or is not endometriosis, in that paper.
Well yeah. It's
It's irrelevant, Lupron works for pain. And it looks like it's all estrogen-sensitive pain. It is not specific, in spite of all the stuff that came out from ACOG.
That's why it might be really important to-
I have a question.
Have a screening tool or a diagnostic that you can use to follow patients that are on therapies that don't require an invasive approach.
I think that was a great question. I'd like to add as a clinician, there is laterality also as a component to the uterine pain. Uterine pain, as a clinician, it might offer more crampy pain. Where the other pain is sustainers as detach from bleeding. A sustain pain usually may have some laterality even radiation to leg or other parts of the elements that have been discussed. In my clinical observation or the way, I process it.
Well, in my clinical observation, uterine pains seem to radiate to the lower back down the front of the legs and up towards the umbilicus. I mean, those are crude measurements to ask a patient about but many times they will say, yeah I have those things, and for me that kind of points to the uterus more than endometriosis.
Yes, it is but it's an important question.
Question to Linda Griffith. What makes your setup or the cheap environments synthetic basal membrane style, extracellular membrane style environment different than Bullen's environment? I believe she said they developed glands stroma, what is the difference the media that he uses to get the stroma gland to produce? Is it the technique or the environment?
Sorry, I don't know what you're asking the comparison to which?
What kind of environment does Dr. Bullen use?
He's actually producing uterine cells from induced pluripotent stem cells. So the kind that if you took the patient's stem cells and put them in culture and you make them into the pluripotent stem. Take their fiberglass, make a pluripotent stem cell, and induce them in. When you do that there's a lot of emerging ideas about how you can use those to study disease. I think he's proposing that those could be used for therapeutics. You have to go through a whole lot of things to kind of prove that they're all the way differentiated to an adult version of any of these cells. That's true with all IPS cell derived. So they have a lot of the markers, they're from stem cells and they're the patient's cells, but they wouldn't necessarily have all the epigenetic markers that a patient has.
I take patient cells so, endometrial biopsies, where it is endometrium by all the standards we would have and then say, "This captures things that happened to the patients." So she's got all these kind of dysregulations that have been discussed all day today by the folks up here on the stage with me and others. And can we learn from all the things that happened to that patient, whether it was environmental toxicants or inflammation, whatever can we learn about the nature of her cells? So, I'm looking at the patient. Capture the patient's entire experience whereas he's making them out of IPS cells, which would then lose most of the epigenetic changes that are hallmarks of the disease. Two different applications though because he wants to use them for regenerative medicine.
Just one comment from a clinical perspective. We all come to the idea it's the fibrosis that's the evil part of the whole endometriosis progression. It's the fibrosis that gets harden then and leads to organ dysfunction. So, is there any way of measuring glands versus stroma component and
We can measure-
Instrument sensitive, in a way that that really designates the aggressiveness of the clinical, maybe sentimentality too, realistically speaking. It's not the gland really, it's the reaction to the glands presence or the whole fight going on there that brings out the fibrosis and almost ossifying the tissues around it becomes frozen pelvis in the end. Not every lesion goes to that direction. Not at all. Only some group goes aggressively and why some reason they are all under medical treatment for ten years, fifteen years, nonstop everything is given to these patients. Somehow, their periods are not there, their ovulation is not there, but the disease is going on and on and on.
So this is why we want to model it. We can measure fibrosis and you can certainly measure it by using second harmonics in the exact[inaudible 00:08:07] system I have and we've done that. I didn't show you that data today, but progression to fibrosis through repeated cycling, repeated recruitment of the immune cells and inflammation is something that exactly what we want to study. I didn't show that today, but clearly trying to decern how you progress down that path versus others is a point of trying to build these kind of models and why I hope we can make them simple enough that we could get them out into the community so that OSGi and you and everybody else can use them. So, you can definitely do it in the in vitro model. I don't know how you look at it in Vevo except by the methods others have discussed.
I have a question for Katie Burns. Katie you over here? Fabulous talk. It's a technical question. Have you tested your system with anti-ERA and anti-ERB, and anti-GP30 to see which pathway of estrogen this is going down?
My other question-
But thank you yes
For OSGi, is when you inoculate baboons, you have to inoculate them twice in order to get the endometriosis to take. Does that give us any clue about human endometriosis and how it's established?
Why I guess in humans, of course, it's constant. The one thing with the baboon model is that we overpower the system, we overpower the immune system essentially any of the clearing mechanisms. You're putting in menstrual tissue at each time point that probably the animal would not see in a lifetime. And we do that purposely, the expense in models and want to really induce the disease. I think part of that is what we found is that again as other peoples talked about is that if you follow these animals over time they are always building new lesions. And it will only build them as long as their cycling. If you ovariectomize the animals and just even give them estrogen. The lesions disappear over time. So it's a seeding mechanism I think that's really important.
I had a question about immunological warfare. The cells come out they're fought off or not fought off, develop endometriosis or not develop endometriosis. In women who don't have endometriosis, is there actual evidence of this immunological warfare going on? 90% of women don't have endometriosis so there should be lots of evidence of this immunological warfare that's keeping the cells from attaching. Is there evidence of that going on?
I think its also the balance. We've also talked about that even the early insults what clinicians describe as maybe endometriosis that you can't see or there's some kind of effect outside that could be having an impact on the eutopic endometrium. So, is it possible besides some of the other genetic alterations and epidemic changes we've seen that there's something inherently different about the uteri of these women? And if they have, we'll call it a disease as its known or termed, its already starting imprint changes in the endometrium itself. So perhaps those cells are escaping or have changed their phenotype to some extent and they escape that immune cell balance. They can attach, they can grow, they can innovate.
Well is there evidence of the immune surveillance in women without endometriosis? How does that work? Cause 90% of them-
There are a few pieces of evidence, several pieces of evidence that the endometrium of women with endo is different with respect to cytokines and pro-inflammatory mediators, prostaglandins, aromatase, increased estrogen, but there's also we have found... we didn't present this data today, that there is a decrease in the number of uterine and K cells in the menstrual affluent of women with endometriosis and uterine and K cells are those cells that take care of senescent cells and they're very involved in immunosurveillance. So there's clearly a defect in that capacity in women with endometriosis.
What I'm interested in, is there positive evidence of those NK cells killing reflux in the endometrium in the 90% of women who don't have endometriosis?
No, not at this moment. There's no evidence for that. There's a great paper by Brighton and Brosons who describe uterine NK cells as very important for removing the senescent cells that are involved in endometrial remodeling and when that does not occur they do not decidualize properly. Its believed promote uterine factor and fertility for women with endometriosis. And they have some pretty compelling evidence in their paper and I would point to that as some evidence for that.
Two things are dominant in my mind. One is the frequency and the quantity quantification of the material that escapes if it deters greatness or effluent that is different that has properties to fight against and win the war in a peritoneal battlefield. That quantification is more important because these women characteristically have heavy bleeding. They bleed tremendously. The menorrhagia is there. There they have uterine anomalies. They have in the uterus. One observation we have we published in a hysteroscopy book we have three hundred cases we looked at biopsy-proven endometriosis early in advanced. 30% of them their endometrium cavity had detected along with direct observation and I think that's important.
Also, the damage on the peritoneum is more than we see, its not only the lesion we see the classically defined lesion, pigmented lesion and non pigmented lesion that's mounted in red wine for years, early ninety on til then. Its been defined so well. Since that nobody really... there's not a single article for twenty years, how that really look. According to classic definition what they tried to do every millimeter divided into thousands micron two hundred microns you and I even less. We can see and we can detect endometriosis. It's true they were right on that. In that group, for that definition, that is endometriosis very little in that sense. Even one or two if you get it right that's endometriosis. On the other hand, there's a huge mass infiltrating frozen to the sciatic nerve in volume one kilogram of mass exaggerating. That's endometriosis too. There's a huge difference the amount of horsepower the nuclear genetic machine exerting on the way it goes and the timeline achieves that purpose is different from one person to another and they also the genetic power of the disease process is different. Many plays are going on here.
I would like to ask OSGi a question that follows up on that question I think I asked him five years ago when we first got involved in this. Which is, how important are the particular subsets in the menstrual affluent that were menstrual blood that you put into the perineal cavity and I was asking you about red cells are they really important to be there and I think neutrophils which are about half of the white cells that are in a menstrual affluent are probably really important? Have you actually asked whether the lesions are more easy or harder to develop by depleting some of those elements?
So we haven't but Thomas Dehoomp did a really nice series of experiments in Kenya using the baboon model. So essentially what he did was he took the menstrual tissue just like we do and inoculated the animals, but if he started depleting, centrifuging it out just using only the menstrual, just the fluid without any cells. Those animals didn't get the disease. They have to have the cells and the tissue to get the disease
Right. The question is what cells? Can you just do stromal cells or epithelial cells? Do you need the neutrophils at all to induce the lesions? That's basically my question.
And that's my aim in one of my RO1s so I hope that I can
I mean one of the comments I made towards the end in terms of using genetically modified mice. It looks like with the epithelial cells that overexpress at least in the context of N1ICD and some of the other genes that we were looking at. If they're specifically overexpressed in the epithelial cells they tend to be-
Does it promote their survival?
I never looked at it. They're just
In our specimens we have very few epithelial cells. Very very few, but they die, very very quickly.
Maybe they need to get into the perineal cavity in order to survive.
It seems like we're concluding the day. Are there any more questions? There's one more. One more in the back.
Hi, thanks. As a long term sufferer, I would like to just say thank you to everyone who's doing some incredible work by the sounds of things. It's given me faith as well we are going somewhere, so thank you for that. Because I think that for a lot of us it's felt like we're not, but a lot of us aren't in these rooms. So, I would like to say thank you to everyone who is doing something.
A few kinds of comments, which would lead down to a question is the menstrual affluent you are talking about and the blood from lesions elsewhere. I'm presuming they are both being studied in a similar light and today seemed very pelvic focused, but we're all in agreement that endometriosis is a body-wide disease, I hope. I'm 40, symptomatic since 14. Nine surgeries, allodex, hysterectomy, still symptomatic in all the ways that you were describing earlier, even though I have no womb anymore. So, I'm just wondering if we are properly looking at things with regards to the body wide aspect. Cause I've been saying to doctors for years, I am systemically inflamed, but to get that listen to has been really difficult, which is why I'm here because I saw the heading and I was like, "Yes, finally. Here we go. Brilliant."
But then that we are also in the realms of how we are treated as patients and the systems in various countries and I'm talking about England, France, America, all over the place. We get dissected into different departments. So I'm seeing my Gastroenterologist. I've got high gabaprotein, that's an inflammatory marker. I go with that to a Gyny and he doesn't wanna know. I go to a rheumatologists, she's like, "Yes, I'm looking at information, but go back to your gastro about that." I have a set examination gastro and he's like, "Well I'm not going to look at your ovaries because I'm not a Gyny." So I would just like to just put that out there really as comments to the Endometriosis Foundation of America and the world, that we've obviously got a long way to go, but it does fill me with confidence that there are conversations like this happening.
My main question, to get to that, sorry, was for the 200 million of us who hug hot water bottles and wear Thermacare heat pads all the time. Is there research being done into why heat helps? If not, why not?
I don't know if there's necessarily evidence into heat, but I actually am forty years old just like you and I've had endometriosis probably since I was 10 and I have had a very similar story to what you have had and heat does help. And I've actually studied why it helps and its the same kind of idea that we have a sympathetic nervous system, I think its the same idea with the cold as well. You cycle between hot and cold, if you sprain your ankle. So its kind of the same idea to confuse some of the nerves at least from what I've been able to understand. I'm sure there's much more specific nerve information that's from one of earlier speakers.
I would like to make a comment. You describe a lot of things in the body, I'm a man. I think for everything is an intelligence. There is a control it's my belief that all that what you describe is controlled by the nerves. When you asked why's the pain, dysmenorrhea, is different than the pain in the abdomen. The pain is always the same, the pain is going up. Using information going up to the brain, but when you have an irritation of the sympathetic nerve in a uterus. You will have all those irritation of the efferent fibers of the uterus. That mean you will have the bleeding, you will have more pain in the uterus, you will have the disfunction of the uterus and on. We saw your lecture, you said when we have no endometriosis, the patient, you used to word, "anti anticecelcyotisis," ET. It not an anti anticecelcyotisis, it's an irritation of the nerve of the blood and if and you have right, you send the patient to a urologist it will said, "Oh you are bleeding from the bladder," you have an anti anticecelcyotisis," so what we call adenomyosis is maybe anti anticecelcyotisis. By the urologist and when you send the patient to the gastrologist they will say, "Oh you have an over activity of the bowel, sometimes you have some bleeding." And its one pathology.
And just one further comment of the nerves. All patient with effective bio endometriosis have in really in common, is the stress. I was working twenty years in Germany, in Cologne. You know in Europe you have small cities, small countries and I saw a lot of patients coming from Turkey and this patient explain to me, its incredible what is going on this country in Germany. When I was in Turkey, I had no pain. Okay, we know about pollution, we know about coldness, there all the risk factor for endometriosis, but you have pollution and coldness in Turkey the same way as in Germany. But something changed externally in the life of this woman. They came to Germany and the have increase stress level and stress level that mean overactivity of the sympathetic nerve system. And my belief that the sympathetic nerve system will probably generate all this trouble. That mean endometriosis. Yeah.
And if I consider the patient with deep endometriosis. Maybe you will agree with me, my patient most of the patient effected by deep endometriosis with born with endometriosis, a woman, who was born in a family where very very frequently the women, the mother wanted to get a boy and she got a woman. So it's the first fight. We know that endometriosis develop in the fetus. Maybe that was the first fight of the woman, I want to live. Then very frequently, women working in the men world. In the world where they have to fight and do the most everyday day after day. I'm here I can do the same like you. That is stress too. It's really my beliefs that the stress, the sympathy nerve systems autoimmune cell nerve system maybe control all these things. Thank you
It seems like the time is up there. Are there any more questions? Well, we are here today, really to advance our knowledge and to help women with endometriosis and among us to develop a language of communication. I really appreciate patients coming here voicing their concern because those of you who have the disease will never understand I assure you, but we care. We genuinely care, look at these gentlemen, scientist, and surgeons and we see the disease differently. You can tell. Even in the same profession the same section for years they've been doing it they don't have the same opinion about things. You have to have empathy for us too, we don't have the answer, but I really appreciate you staying this long. I hope to see you tomorrow, we are starting at 8:30 it's going to be mainly surgery day, you can blast the surgeons and stump them, so it's going to be exciting tomorrow.