International Medical Conference Endometriosis 2025:
Endometriosis 2025: Your Mother Should Know, Your Doctor Should Know Better!
Diminished Estrogen Signaling Concordant With Increased Extent of Fibrosis in Ectopic Endometrium - Sun-Wei Guo, PhD
Alright, to introduce our next speaker, Sun-Wei Guo PhD is the leading researcher in gynecologic diseases specializing in the pathophysiology of endometriosis. His work has significantly advanced the understanding of the genetic epigenetic and inflammatory mechanisms underlying endometriosis, paving the way for new diagnostic and therapeutic strategies. He'll be speaking to us about diminished estrogen signaling concordant with increased extent of fibrosis and ectopic endometrium.
Thank you. First of all, I'd like to thank Tamer and Dan for inviting me over. And as a great honor today I'm going to try to convince you that there is a diminished estrogen signaling concordant with the increasing lesional fibrosis. Let's see here. Oops. Okay, now we all know that endometriosis as well as ID mouse, is actually estrogen dependent diseases and they also display chronic inflammation. When we say increased ESTRO signaling, that's actually usually manifested as an increased local production of estrogens. And the prevailing view is that there's a connection between inflammation and hypoestrogenism. In a sense.
This is actually a well known feedforward model proposed by a cedar balloon that I think key would be one of the speakers essentially that the prostaglandin E two actually stimulates the activation of the gene and proteins, the codes for the enzyme that they're critically involved in the estrogen biosis. And in turn they actually increase the local of production of estrogens and then in turn they increase, activate the estrogen receptor beta. And that in turn induces the activation of COX two leading to more production of prostaglandin E two. And that essentially forms a vicious cycle. Now as you can see that the PG two as well as the COX two, sits in very critical nexus in this feedforward loop. And as such that there is a several papers essentially regarded the PG two as a master of in osis and Cox two essentially is of vital importance.
So naturally they become the center, the target of the intervention. And actually there are several papers reported that the targeting these Cox two or PG two using COX two inhibitors seem to be a very effective strategy to treat endometriosis. But in reality, if you care to read PubMed papers, you still don't find any papers mentioned about the efficacy of using Cox two specific inhibitors. In fact, the Ashray guideline regarded that the non-steroid anti-inflammatory drugs, which mostly targets COX two to treat in evidence regarded as the weak. So the only study that did prove the Cox drug inhibitors is effective for treating in miosis is a study published almost, actually more than two decades ago. And essentially that they removed all the lesions and then they give the patients the COX two inhibitors and then they follow up patients for six months. But this study actually I would argue is not for treatment per se because they removed all the lesions.
So some of symptoms could be the residual lesions or less likely due to the de no lesions because it is given postoperatively. So this study should be regarded as the study aimed to reduce the risk of recurrence. And also the coap actually has some certain risks for increasing the cardiovascular disease risk and two drugs that's being pulled out from the market. And as such, there's a talking that we can actually, instead of targeting COX two, we should target the PG two receptors. There are two receptors that actually are expressed in the ectopic endometrium. One of'em is EP two, the one EP four. So the question, is it possible we can actually target these two receptors and achieve the therapeutic purpose? In fact, there is a study actually gave the evidence that the suggesting that yes, indeed these two inhibitors seem to be a novel drug, non hormonal drugs for treating endometriosis.
But if we look at real papers very closely, you can understand several things. One is actually this uses the immune deficient mouse. So it's not exactly real situation. And second of all, the induction period is two weeks. And we know that the two weeks is just way too short to see any fibrosis in the lesions. So in a sense, this model did not recalculate the human condition. And we also know that some other studies in fibrotic diseases, the PG two is actually antifibrotic. As the tissues become fibrotic, actually there's a diminished PG two signaling. So there's essentially something that we should consider. In fact, we did find that for women with ovarian end tumor and deep endometriosis, which actually two subtypes of endometriosis, deep INR lesions display higher fibrotic content, but also display lower COX two staining and also EP four staining. Now of course, these are two subtypes of essentially different things, but if we compare the same disease subtype, ovarian immune tumor, but in two different age group because one is the adolescences age between 15 and 19, the other one is 35 to 39.
So everything being core, the adolescent lesions are less likely to develop fibrosis because of a time constraint. So what we see is actually the adolescence ones display, again, higher fibroid content in the lesions, but also they have reduced COX two EP two and EP four sinis suggesting as the lesion become more fibrotic, actually PG two signal and become diminished. And it turns out that as the lesion become more fibrotic, it becomes stiff and rigid. And that will actually facilitate the fibrogenesis and also will actually suppress the expression of COX two, EP two and EP four. And also we extend it because COX two is just one key limiting enzyme to produce the PG two. There are several terminal enzymes that specifically to produce PG two, we actually looked at some of them. But before that we used several tissues, normal endometrium, ovarian endometrium, adenos, and also deep endometriosis.
And what we found is actually as actually consistently with the published studies, the extent of lesional fibrosis, the highest in deep lesions followed by adeno masis and then by ovarian tumor. But all the enzymes involved in the terminal, the synthesis of the PD two, they're all increased in ovarian tumor tissues, but less so in denino analysis, essentially very much diminished in deep lesions. But one of the metabolic enzyme PG two is actually increased in deep INR lesions. So this essentially says that the yes, all the enzymes involved in producing the PG two is actually highest in ovarian tumor, but much lower and adenal analysis essentially that the no difference between deep inmetro lesions and control tum, essentially PG two signaling is diminished or vanished in deep lesions. This is actually the gene expression data, protein data were consistent. And also in terms of animal model, we can actually see that we actually use the induced endometriosis in mouse for two weeks and also for four weeks to see any difference. And also we looked at the routine endometriosis and also a mouse model of deep endometriosis. But this lesions are quite different in terms of the fibrotic content. What we see is that essentially that there's a pain behaviors actually is worsened for deep endometriosis. There's a progressive but deterioration in the pain response suggesting that the as lesion become more progressive, the pain actually is worsened.
And also that we can see that this is actually for the endometrial essentially in terms of fibrosis, they essentially stay the same for Cox two two EP four in different cellular components, essentially status constant. But for the deep lesions it's actually, it's higher. And also the four weeks old lesions is much higher than two a week old lesion. And also there's a crossover. So if we look at using lesion, the two weeks is actually you did see heightened cox a PG two signaling, but if you look using the lesion samples, harvest it at four weeks, when the lesion fibrotic content is higher, you can actually see that all the PG two signaling actually depressed. So that's again proves the point.
And we also looked at the effect of using EP two EP four inhibitors to treat a mouse model of deep mitosis. And what we found is that although they dis suppressed all the P two signaling proteins, but in terms of the one, the proxy measure for lesional development, which is actually the lesional fibrosis, it's actually there's those dependent increase suggesting that using EP two and EP four for this mouse model, deep endometriosis is actually exacerbated the endometriosis. And the pain behaviors also kind of become worsened as you can see that the higher doses actually has the shortest, the hot plate latency. And also their body weight is actually, they reduce the most simply because the pain suppressed food intake and resulting the reduced body weight. And so in summary, I think that the EP three, EP four inhibitors do not seem to work well for deep endometriosis. And so in humans we do know there's a diagnostic delay and also a lesion are likely to be more fibrotic if they actually the lesion have more time to progress. And we also, there's a clinical impression that there's an increasing difficulty in that order for treating adenyl mouses. And deep endometriosis is actually using hormonal therapies.
And most of studies actually reporting higher estrogen signaling, actually they used ovarian in tumor tissue samples. Similar study didn't even mention what kind of material. But presumably because more abundance of ovarian in tumor tissues, actually I would presume that you actually use the in tumor tissue samples. A few studies that did use deep lesion than samples, they actually reported lower signaling. And there's also some conflicting results. For example, the well-known study by she etal, they actually reported hypomethylation for ER beta, but later studies from Brazil, they actually looked at deep image, deep lesions, actually didn't find any such evidence, Japanese studies, and also didn't find such evidence. So I think that the one thing that's missing is they fail to measure the lesion of fibrosis as a potential confounding factor. So we also looked at theum and also ovarian tumor ID mouses and deep in mitosis. And we actually looked at some of the genes and proteins involved in estrogen bio synthesis and also the estrogen action beta R alpha and also decoupled estrogen receptor. And it turns out actually in terms, the severity of dysmenorrhea is usually the highest in the woman with the deep endometriosis followed by adeno mouses and then by ovarian tumor. And also the lesion of fibrosis is the highest in deep lesions followed by adeno, mouses, ais and ovarian in tumor.
And lo and behold, all the proteins involved in estrogen bio synthesis is actually the elevated in ovarian tumor, but much less in Aden lesions. And for a deep end lesions, essentially it's no difference as compared with ome. So it's also for the estrogen beta, but for ER alpha, they all kind of reduced expression and GPE, same thing. That's actually as the ER beta. And we can see all these proteins actually correlated with the extent of lesion of fibrosis. And also that this is gene expression, essentially confirm this is protein or joint attention to the last one. So for the ovarian end, oma, the estrogen concentration is the highest followed by the adal lysis. And for deep endo lesions, essentially it's no different from the canum in theum. So essentially the estrogen signaling is completely vanished for deep EMR lesions. So in summary, estrogen signaling is elevated in ovarian MI tumor, but much less so in adenomas and in deep lesions, the signaling is actually essentially vanished.
So in conclusion, estrogen signaling diminishes a concordant with the extent of lesional fibrosis. This is actually consistent with the clinical impression that the treating deep mitosis or adeno analysis seems to be more challenging than Ian MI tumor unless it's actually, if the drug actually induces amenorrhea. And most if not all studies, estrogen signaling actually used tissue samples from ovarian tumor. So we know that not all ectopic endometrial equal and reduced signaling is due in part due to the reduced PG two signaling. And of course the more proximate mechanism will awaits for the investigation. And this actually can explain a lot of things. For example, some of the wireless controversy or conflicting results in the literature. And also there is hormonal treatment actually has no cyto reductive effect for deep INR lesions. And the addition of aromatase inhibitors to existing hormonal drugs actually does not seem to be associated with more better outcomes. And with all this, I think that it's time we need to appraise our treatment strategies for With this, I'll thank my collaborators and thank you for your attention. Thank you.
