International Medical Conference Endometriosis 2025:
Endometriosis 2025: Your Mother Should Know, Your Doctor Should Know Better!
Adenomyosis-induced Heavy Menstrual Bleeding: Its Pathophysiology and Possible Intervention - Sun-Wei Guo, PhD
It's my great pleasure to introduce Dr. Sanga. We use a PhD from Shanghai OB GYN Hospital and Fundan University to talk about he's an expert in pathophysiology and specialize in endometriosis. And his work has significantly advanced the understanding of the genetics mechanism, the inflammatory mechanism for endometriosis.
Thank you again, thanks to Tamer and also Dan for organizing such a wonderful meeting. It's a great honor to be here. Now what I'm going to do is to share with you some of the work we've done. The pathophysiology of adeno mouse is induced heavy menstrual bleeding and it's possible intervention. Now, adeno mouse is actually fairly common, but it's also traditionally viewed as enigmatic disease simply because it is under researched. If you care to look at the PubMed, you can see that the number of publications on ad is only like 10% of those endometriosis, which is also under-researched disease compared with breast cancer and prostate cancer.
We often say this is actually, we don't know anything about this pathogenesis and pathophysiology, but I think that in the last five, six years things has been changing. And this moment I think that we do know some of the pathophys path, genesis and pathophysiology of alysis. For example, the endometrial myometrial interface disruption caused by e transgenic. The procedures is actually one of the etiology for adeno, and this is in fact it has been supported by ampo epidemiology data as well as by animal experimentations. And not just one group, but also several groups. And I'm anticipate more data were coming out not just from mice but also from rats. Now, unlike endometriosis, rodents can spontaneously develop adenomyosis and one of them actually the culprit is actually we found out there's a strong cells within the uterus. Of course there are some other causes and I think that we still have to investigate other pathogenesis.
And also over the years we have painted a picture probably in very broad strokes of the natural history of AdOne myotic lesions. Essentially it's just like the inmetro lesions. It undergoes repeated tissue injury and repair simply because of the cyclic menstruation, which is actually bleeding and then followed by a tissue repair and cultivating in tissue fibrosis. And what we have to do is to capitalize these findings and try to see how we can actually improve our diagnosis treatment and also the understanding of pathophysiology. For example, I think that when the tissues become fibrotic, they become stiff or rigid. So in this case, we can actually use emerging imaging technology, which is called ela. Now ultrasound graphic becomes available quite widely. It's been used for diagnosing breast cancers and also thyroid diseases. And it's in gynecologist, not very common, but I think it's going to be change.
Some of the diagnosis and the electrographic readings can not only help to better diagnose adeno lysis, but can also determine the best treatment modality, monitor the treatment response. And we also recently found that it can also determine what is the risk for recurrence if you discontinued hormonal drugs. Now this is essentially the big picture. You see that under the pathy leftmost is actually the MyUM normal bowel. The middle one is fibroids and also the right one is actually the adeno lesions. Essentially they show different stiffness, which is actually can be represented by the colorations. And with this we can also try to understand better the pathophysiology of, for example, pain and also the heavy menstrual bleeding. Now of course that we know some of the mechanism for normal endometrial repair and normal bleeding. And thanks to pioneering work by many giants, including researchers in Edinburgh, they actually figured out that after the progestin withdrawal, PG two signaling as well as hypoxic signaling involved, they're critical involved in tissue repair and then normal bleeding.
But in terms of aledo mouse is induced heavy menstrual bleeding, which is such a very common symptom or complaint from women with endometriosis. The exact pathology is actually at that time is essentially unclear. So what we did is actually to essentially use the first principle thinking because fibrosis will beget fibrosis, whether it's going to extend it to endometrial and if so, will that be the cause for heavy menstrual bleeding or HMB? And essentially this is what I thought. Essentially there's a lesion and because of a repeated tissue injury and repair, the lesions become more fibrotic. And so in this case more rigid and during the process some of the prefibrotic molecules will be seeped into neighboring junction zone and then to neighboring endometrium causing the fibrosis along the way. So in this case, I think that the first clue that I got is this hypothesis may have some validity, is that we actually found using ELA as a diagnostic procedure to find that the worm complaint of heavy menstrual bleeding, they actually had their lesions seem to be more stiffer than those complained with normal or light menstruation.
And also we know that the PG two is actually antifibrotic. That's actually was well documented in other fibrotic diseases. And actually I mentioned that yesterday and PG two and lo behold is found to be diminished as the mitosis. As the lesion become more fibrotic, actually the signaling become diminished or even vanished. So in this case, the thinking is that if the endometrium become fibrotic, maybe the PG two signaling will also diminished. So that will actually impair the endometrial repair so that the actual cause heavy menstrual bleeding, it turns out that we can see that over there that the lesional fibrosis or stiffness actually as measured, essentially there's a noninvasive quantification of the lesion of fibrosis correlated very nicely with the amount of menses. And also we did a very careful study secure the tissue column containing the stiffest of the lesion along with neighboring junctional zone and also the endometrial.
And what we found, yes indeed lesion, we actually looked at two groups of patients. One is with the excessive bleeding defined as the amount of blood loss exceeding 100 ml, the moderate and heavy defined as the 60 to 100 mil. So in this case we can see that the woman complained of excessive bleeding. They actually, they had their lesions, stiffness of fibrosis much higher, significantly higher than those moderate or heavy. And the junction foam essentially the same and also but the H one alpha staining and also COX two EP two EP four. The receptor for PG two actually is the reverse. So this is actually more, it's a graphical summary and you can see that the in the fibrosis is actually, the brown one is actually the bottom and this is the black ones actually the lesions, they had a higher fibrosis and so it's a neighboring junction zone.
And the endometrium, they essentially highly significant higher than those with the complaint of moderate to heavy bleeding. But on the other hand, in terms of he one RFAs Cox two EP two EP four, essentially they become reversed suggesting yes indeed, as the endometrial become lesion become fibrotic endometrial because also become fibrotic and the endometrial signaling for hypo hypoxia and also PG two actually goes down. And then actually we can see that some of the signalings actually correlated with the lesional fibrosis. And also we are thinking along this way what else we need for proper endometrial repair aside from COX two and also hypoxia. Now we do know for any tissue repair, there's a well calibrated inflammation. So all tissue repair needs inflammation. And one of them actually the transcription factor called NF CAB, is actually that modulate the inflammation. So when there's inflammation that's N caba B is activated, they actually would show many it's downstream genes and proteins so that they can actually mediate inflammation.
So one, the mechanism to activate the in caba B is the HD three or histone dase three. It's actually involved, it's been demonstrated, it's actually been involved in NCA B activation. And surprisingly that the X stack three has been reported by asis group that actually it's been downregulated in endometrium from with infantile women with the endometriosis. So one thing is, well, if endometriosis patients endometrium have a downregulated HD three, well that also happened to woman with alysis. And lo and behold, I think this is actually true. The hypothesis is endometrial expression of HD three is reduced and woman with adino masses could complaint of heavy menstrual bleeding. And the loss of HDAC three endometrium from women with adeno masis is due to the propagation of lesional fibrosis to endometrium and loss of endometrial HDAC three, suppressing copper B activation using diminished inflammation, endometrial repair, and consequently causing HMB.
And that's we actually found yes indeed in woman also, again, the same group of patients. One is the control, the other one is heavy menstrual bleeding, moderate heavy 60 built to 100 versus excessive. And we can see every respects of the Maru faces. The H stack three staining or expression actually is reduced in woman complaint of excessive bleeding. And on the other hand, the endometrial fibrosis is actually much higher in the excessive group. And also we can see that again, this is another set of patients and essentially validation of our previous observation. Again, the lesional fibrosis is higher excessive group injunction zone and the neighboring endometrium, which is also higher than the contr endometrium and the endometrial expression of HDAC three staining actually correlated negatively with the amount of masses and the extent of endometrial fibrosis correlated positively with the amount of masses. And also we use the sonography to measure the stiffness noting at thes, sorry, noting the lesions but also the junction zone, we actually found indeed consistent with the extent of fibrosis.
The stiffness is actually much higher in the excessive group. And so did the junction zone. And this essentially the correlations, and this is a summary again, we show that there's a different set of data and excessive group displayed significantly higher tissue fibrosis and lesions, the neighboring junction zone and also endometrium. And in this case, endometrium is actually both the fibrosis is higher than the endometrium. And it turns out that the downregulation of HD three endometrium is due to the stiffness of the accuracy matrix. And once the edge deck three is suppressed, it actually inhibits Inca B activation and activity. And so if we induce end endometriosis in mice using the endometrial mal interruption disruption method, on top of that, we actually used a mouse model of simulated menstruation as actually angio just briefly mentioned it, and we can actually find that the yes in mouse with adeno mouses, actually they had lower edge deck three staining and higher endometrial fibrosis, which is essentially recalculated the foundings in humans.
And we also, well, the mouse also displayed impaired endometrial repair and also the increased amount of simulated menstruation, menstrual blood loss. And the menstrual blood loss actually correlated very nicely with the grade of endometrial repair, which actually we can score. And if we inhibit HD three by pharmacological means we use a low dose and high dose. And then we can actually see that in this case that the inhibition of HD three resulted in increased endometrial fibrosis, reduced NCAP B activity, and also reduced type one cytokines, which is usually inflammatory cytokines, and also M1 classically activated macrophages, which is essentially involved in inflammation, but increased type two, which is anti-inflammatory. And M two macrophages, which is actually involved in reparative process and also anti-inflammatory. So everything fits. And also inhibition of HD three resulted in impaired endometrial repair and also increased in a dose dependent manner of menstrual bleeding in mouth.
So along this thinking, what else? We do know that the, aside from the PG two hypoxia and also the inflammation, what else? Now we do know that in terms of tissue repair, it involves proliferation, inflammation, angiogenesis, and also they need to be available very quickly so that you can actually will not cause any oxidative stress. So in this case, glycolysis fits the bill. So we think that they will hypothesize that glycolysis actually may be also involved. It turns out many genes and proteins involved in in glycolysis are also the downstream targets of hypoxia. So things actually fits very well. So in this case, we actually use the simulated menstruating model and we actually suppress glycolysis. And lo and behold, that actually it got increased menstruating blood loss and also the repair, endometrial repair was impaired. And also in woman with adeno lysis, one of the proteins or enzymes involved in glycolysis HK two is actually a downregulated in this case, especially in those complaining of excessive bleeding.
And we also did experiment to try to see, let's see whether this is actually H stack three and the, I'll skip that for the interest of time. And if we reduce the glycolysis, actually some of the genes of proteins involved in glycolysis will be suppressed and the amount of manis will increased substantially. And also that they also somehow the type one inflammation cytokines actually be reduced. But that type two in cytokines actually increase, suggesting that there'll be attenuated or muffled inflammation. And these actually turns out to be dependent on the stiffness of these substrate essentially means that if the endometrium become fibrotic, actually these glycolysis actually will be suppressed. And also, I'll skip this. So the question is, given all this republic cannot increase the inflammation, try to rescue this kind of defect, what about increase glycolysis? Now one of the drug, it's actually for histamine receptor antagonist, which can be used for boing sickness. Okay, actually, it turns out that leasing, which has a very good safety file or profile, turns out that we can actually, we did most experiments essentially that the improved menstrual bleeding, first of all increased, improved the endometrial repair and reduce the simulator mainstream blood loss. And also without exacerbation of lesions, we can see that the lesional fibrosis is actually wet down.
And also, again, same thing that's improved the glycolysis. So in the interest of time, I think that essentially, this is briefly all the summary, not only the thing that the COX two and PG two and hip alpha cycling, but also HD three glycolysis and also inflammation, and that's actually involved in adeno SSIS induced heavy band stability. So in conclusion, lesional fibrosis can propagate into neighboring junction zone and endometrium diminishing the PG two and hypoxia signaling, reducing glycolysis and edge depth expression. And as a result, these changes each or individually or collectively disrupt endometrial repair causing HMB. And they also suggests as why developing non-hormonal drugs for treating adenyl mouse is so difficult because there's a very narrow corridor. Too much is bad, too little, it's also bad. And so enhancing glycolysis by leasing can actually alleviate adenyl mouse induced heavy menstrual bleeding in mouse, of course, in human data will await further testings. So with this, I think collaborators and thank you.
