International Medical Conference Endometriosis 2025:
Endometriosis 2025: Your Mother Should Know, Your Doctor Should Know Better!
Discussion - Science in Endometriosis Part I
Linda, go ahead. Oh my god, this is such a fantastic session. All of you are great. I'm going to ask you kind of out of left field question. And Katie, your talk was great. Your neutrophil and macrophage data from the menstrual fluid was really, really super interesting. And it brings up a question that there are these emerging data suggestions, not great data yet about links between endometriosis and infection. And so there was that fuso bacteria nucleo paper, which maybe wasn't super convincing, but could some kind. And we've gotten interested in this because we found or just getting ready to submit a paper, and this was the collaborator mical, that a prior history of infection with Lyme disease predisposes you to certain gynecology diseases. And certainly in mice, if you infect with Borrelia, they get these huge uterine phenotypes. And so right now everything is sort of suggested interesting and so on. But do you think that these phenotypes that you're seeing could be another piece of suggesting that maybe there's some kind of infectious, very, very lingering occult or whatever stimulation of the immune system?
I think yes and no. I think there's the potential, but one of the things that we do see is we often see bacteria in all of our samples to some degree, but the differences are so strong that we're continuously seeing over and over in endometriosis
And
It's actually stronger on day two. I didn't mention that, but we see a stronger phenotype on day two than day one. So I mean it could be, and that's one of the questions that we want to ask as we do more research. Is this related to just endometriosis or is this something else to do with other endometrioid type diseases or uterine diseases? Excuse me. Or is there an infection? I don't know.
And one last on your patient populations, because again, the data are so interesting and provocative, are the controls in endo patients matched for comparable bleeding patterns? Because if you have heavy menstrual bleeders versus life bleeders and some patients with endometriosis, I hear this from actually a lot of students, they'll bleed really heavy for two days, have nothing for a day, and then it starts back up again. And so it'll be a gap and then another three or four days. And so when you do your patient versus control, do you match for comparable sort of bleeding rates to the extent that it's possible?
We don't have enough patient population yet to do that, but we have compared them from day one to day two to see what their changes within the patient population. And we don't have enough to say anything at this point. We only have about 20 patients.
This is for all the panelists. This is the first time I've been in a meeting of this sort where I've not heard the term stem cell mentioned at least once. So I'm very curious as to why. Thank you. They're hard to find.
There's a small population in menstrual fluid. We do have that on our panel, but we haven't completely analyzed it at our level.
Yeah, I mean certainly stem cells play a major role. I just figured you guys have heard me talk about stem cells too much and want me to talk about something different. But certainly stem cells we found contribute to endometriosis and play it in a very important role in normal uterine physiology as well and uterine repair and remodeling of the uterus of pregnancy at postpartum remodeling in therapeutic use in asman syndrome. It's all there. Nothing's changed. But you've heard, I think that was last time I was here I talked about stem cells, so I just thought I'd give you something new.
I have a question. Hi. So do you have a sense for anyone, r and I had this discussion before, but do you have a sense that day one, day two, day three even matters? Is it that people who have shorter periods, do they have the same arc? Is it the same physiological process, basically start medium end and for some people it's lighter and abbreviated and for some people it's heavier and longer, or is it actually different biology that's happening?
Is that for me prior?
It kind of is, but I'm like if anybody else says of you.
Yeah, I mean the data that we're finding indicates that there is different menstrual dynamics both by day meaning day one looks different from day two. Day two looks different from day three and that within day one, endometriosis patients seem to have certain modules super activated. So even in the modules that you're looking at, that would be classic day one indicators, endometriosis patients, the way we refer to it internally is they're gassing. They're constantly gassing the entire menstrual process. And so if you look at day three, normal bleeders will start winding down. There is angiogenesis and repair starting again. They've started the next cycle and you see endometriosis patients still gassing and it might be related to the fact that they have longer periods, heavier periods, what have you. But I think it's both. Both that there is a difference by day and within that that endometriosis patients have different menal dynamics.
Got it. And you missed my talk. Sorry, we already talked about this, but what I'm asking is this idea that are there these key pillars that have to be unlocked to have endometriosis? Similarly, I'm just wondering if we think about menstruation, are there five fundamental, here are the pillars of menstruation. First you have to do this, then you have to do that, then you have to do that. And do we yet understand that enough to be able to say, and someone with endometriosis is someone who either over unlocks this one or doesn't clamp it down in time. Do you know what I mean? How close are we to actually even defining the normal physiology to be able to understand people who have menstrual abnormalities?
I think we're over the halfway mark. I don't know if I could give you with confidence a sense of how close we are to unlocking every variable that adds enough noise to understanding typical menstrual dynamics such that you then feel confident saying everything's been accounted for. But the reason I spent this entire time talking about tissue and timing is we think that that accounts for over 60% of the noise that we're seeing. I threw in that bacteria at the end of the talk. I think that that actually probably is another component that could confuse signaling downstream. We look at things like sample degradation and maybe some of these things are very specific to us because we do tampon collection, the sample sits in the body for a while. There are specific features of collecting and tampons that require us to control for introductions of noise through that route. But I think we're past that halfway point.
Well, thank you very much all of you for excellent presentations. I have a question for all of you, but individual answer. How do you define your control of patients who don't have endometriosis? How do you find them? How do you define them and then please explain.
Okay, I guess I'll go first. So our controls were patients who were scheduled for a tubal ligation. These patients were patients that we didn't have that many of them in our first thing, and I try to go to all of them, but patients who have a laparoscopy, I will talk to the patient before the procedure and ask them if they've had any history of infertility or if they have any pelvic pain. And then I am there for the procedure because I'll collect the tissue and visually look to see that I don't see any obvious signs of endometriosis. That being said, we did have some patients in our study that were G zeros. I'm going to take it as by choice because they said that they didn't have any history of infertility, so I can't guarantee that, but that's how we did our controls and ours. I think that's an inherent problem in all of these studies is controls. Because we've seen patients like you showed that have no symptoms at all that unless you do a laparoscopy, you don't know that they don't have endo. And even if you do a laparoscopy, not everybody sees the endo, so it becomes more difficult.
Yeah, I'd agree with that. I'm not confident anybody is a control unless they've had a surgery to confirm that they don't have endometriosis. Unfortunately, those tubal obligations are getting more and more rare with great long ing reversible contraceptives. We see fewer people getting tubal obligations. That's the ideal control in my mind as well. So sometimes we'll expand to use other controls, but laparoscopic surgery with some, they've had their gallbladder out or some other surgery where they've documented not to have endometriosis because those tubal ligations are getting more and more rare also. That's why I like to work with the mice. You can define who's the control and who isn't, and when those correlate very nicely what we see in humans, then I feel much more confident about it as well.
The only thing I'll add to that is absolutely surgically controlled. Surgically confirmed negatives are the best. We have about a little over 20. There's so difficult to recruit,
It's very
I think if you're developing a biomarker, you really want some other real world examples of other disease that is not end endometriosis. So a completely healthy control may not be the ideal to make sure your biomarker distinguishes endometriosis from other reproductive diseases.
Two questions for Katie and one for, so Katie in the neutrophils, what I remember growing up is that there was a respiratory burst or an oxidative burst that was associated with neutrophils. Do you see an oxidative stress on the endometrial cells in those patients where neutrophils are recruited? That's question number one. And then you showed some cell ghosts in the patients with endometriosis cells that didn't look like they had any nuclei. I was just wondering if you could comment on what those ghosts were and then for you, Hugh, the data that you showed, you reported the type one or the pro-inflammatory cytokines for macrophages and we didn't hear anything about the other types of anti-inflammatory cytokines. So
Yeah, I think you're talking about those Tet three knockdowns where we see a change in flow. We reported the first couple predominant inflammatory cytokines, the first one we looked at, but we have gone back now and done some whole cytokine arrays and some RNA-Seq to see about levels. We're still analyzing that now, but I'm sure there'll be changes in those as well.
Hello, my question is for read. I wanted to find out how you guys account for dietary factors. For example, prior to periods. I know a lot of women tend to eat anti inflammatory foods and how that accounts for the inflammation that you see happening on day one, day two and day three.
We have a pretty intense survey instrument that we administer in addition to collecting path reports, OP reports for these patients. And so we do ask about their normal diet and we do have space on the actual kit where they can fill out any information that they want to provide. We don't specifically ask for what you were eating the day before or that day to try to take into account how the immediate anti-inflammatory effects might be impacting what we see downstream. But it's an interesting thought.
I have a question a bit for everybody, but I think mainly for red about progesterone resistance, it's something that I think we haven't heard a lot about today. I was wondering if you have the chance to collect any hormone levels that could be a way of timing cycle following the pattern of the hormones and see if there is any correlation with the changes that you see suggesting different responses to hormones and also more in general talking about infertility and implantation window. What's the role of progesterone resistance in all of this? Is it part of the story? Is it the whole story, something completely different?
I think I understood the first part. I'll offer up an answer and if I didn't get it, just let me know. I can either try again or find you afterwards to talk about it. We definitely try. We know birth control is one of the factors. Actually, to pariahs point, it's tissue, it, it's timing and birth control is the other one that absolutely impacts what you're seeing downstream from an expression perspective, especially progestin. The last slide that I showed you was just that there are clearly people who are on progestin that are not responding to progestin, and so I am imputing that they are progesterone resistant, but it's hard to ask a patient, are you progesterone resistant? They're not going to understand that even if at some point they had a conversation with their doctor that told them, here's why you're no longer trying this therapy.
It's fascinating from a infertility perspective, we ask a lot of questions about what could be leading to your infertility specifically go after infertility cases and controls so that we can have those symptomatic populations and be able to still make a diagnosis of endometriosis when you have so many comorbidities layered on. And in that infertility control population, we try to narrow down on exactly what we could be causing that infertility, everything from blocked fallopian tubes to fibroids to PID. We don't specifically ask a question about progestin except for were you on some sort of birth control prior that you had a negative effect on? But it's super interesting to think about and I'd love to find you later to find out how we can,
Okay, I'm getting the no more questions signal, so thank you everybody for
I just want to make one quick comment if I can. Just two minutes, just one minute. So clinically speaking, I really would like to hear the challenge that we meet. We meet towards frozen pelvis and that pro fibrotic cement like attitude that comes all of you're talking inflammation, inflammation, but in the end it's fibrosis and most important aspect of fibrosis contracture and that remember, we see at the limbs contracture that they have to have, it's the same thing happening here that cement like final episode, the inflammation in wound healing that never heals progressively. Are you thinking about that when you work on inflammation?
Thank you everybody.
