Sun-Wei Guo, PhD - Adenomyosis and Pain: The Hidden Drivers of Uterine Pain—From Myometrium to Nociceptors

Is actually under researched disease and actually no drug has ever been developed exclusively for this condition. So as a result, management is actually a challenge. Now, although we always say we don't know much about this disease, I think that in the last few years, I think that the landscape has been changing. One thing is that we know that the uterine procedures is one cause for causing this disease. And in this case, along the way, we actually did establish mouse model for this condition. And also this has been proven validated independently by other groups. And of course, there's other causes and actually in the process to find other causes. Also, we had a fairly good grip on the natural history of adenomyotic lesions, although it's probably on the bigger strokes, but still I think that essentially it goes through several molecular processes, epithelial medicine chemical transition fibroblasts to mild fibroblast transdifferentiation and smooth muscle plasia and fibrogenesis.

And so in this case, I think that the lesion become more fibrotic and that along the way, some of the lesion stromal cells become smooth muscle cells that actually that will create the enlarged uterus. And also there's increased uterine contractility and also the increased new fiber density and reduced progestin receptor expression and cancer associated mutations along the way. And we can actually use these findings to understand the pathogenesis of pathophysiology of this one. For example, to improve the diagnosis. In this case, we can actually use the increasing stiffness of the lesions and use the elastosomography to diagnose this disease. So in this case, actually the lesional stiffness correlates very nicely with the extent of lesional fibrosis. And we can also have a better understanding of how adenomyosis causes heavy menstrual bleeding. It turns out that when the lesion become more fibrotic, actually some of the fibrosis will somehow permeated into the neighboring junctionism or mild mutual interface and to the endometrial.

So in this case, the meteorum become more fibrotic. That will actually cause the lot of things. For example, in this case, the reduce the PG2 signaling and also here are hypoxia signaling and also glycolysis and also the reduction of the HDAC-3 and actually causes the muffling of the inflammation. So in this case, when all the signaling is actually impaired, the endometrial repair actually was impaired. So that's actually will cause the heavy menstrual bleeding. But what about adenomyosis associated dysmenorrhea? And this is something that not much work has been done and conceivably that there's several things can happen. One thing is the hyperinnovation that's actually that probably the nerve-centric view will be very helpful here. And also that there's the increased uterine contractility. And of course, some pain mediators will be actually derived from adenomatic lesions that also essentially causes the perception of pains. But when we looked at the uterine hypercontractility in adenomyosis, again, not much work.

One thing we do know is actually is some of the oxytocin receptors overexpression, and also this actually correlate with the uterine contractility as well as the severity of dysmenorrhea, and also decrease the contractile frequency in velocity, but increased amplitude. And also the PG-2 PGF-2 alpha may be aberrantly expressed and ves suppressing receptor, actually there's some service work that could be involved, and probably the arrangement of the potassium channels may also be involved.

But the thing is the clinical trials using some of various inhibitors, for example, oxytocin receptors, actually the trial has been withdrawn, simply because I think that the exotorsin has many involved in many normal physiology. I think that for one thing is it's actually the recognized as love hormone, and of course we have to think if there are any other corporates. And one thing is the nitric oxide, and we know that the nitric oxide is a potent smooth muscle relaxant and hydrolytic agent. It is actually synthesized by the synthesized ENOs or INOS or NOS. But the data in that these proteins actually conflicting in adenomyosis. One paper says there's an increased monutral expression of NOS, but another paper said that actually ENOS is reduced, but there's an increase of INOS, but the nitric oxide levels in the junction zone is reduced. So using the first principle as a guidance, I think that aside from the fibrosis permitted to the junction zone, it could also permit it to the neighboring monometrum.

And when this happens, they will actually change this tissue stiffness and mechanobiology, which is actually not being adequately investigated. So that would cause a lot of aberrations. So one thing we actually looked at the PSO channels. PISO one and two, actually two newly discovered mechanical sensitive casing channels that transduces mechanical stress into calcium-dependent signals. It's actually the two discoveries of these two channels actually won the Nobel Prize in 2021. And we do know that PSO-1 is activated in uterus by stretching. And if you depress the PSO-1, that will actually cause labor problems. So the question we asked this is what roles, if any, that does do PSO-1 and PSO-2 play in adenomyosis. So we actually collect some of data. We looked at the mild metrums, control myelometrum, and also the modmutrium that in proximity laboring the lesions as well as distal that we call it contralateral metrum.

It turns out that in normal myometrium, there's no fibrosis, but the mildmetrium that closer lesions, the fibrosis is actually increased and to a less extent, the distal mildmetrium. Oxytoxin receptor, same thing that's increased in apilateral mildmetrum, but less so in the contralateral. PSO-1 is actually surprisingly is actually decreased. PSO-2 is actually increased ENOs is actually decreased, but one of the active form is the phosphorophorated ENOs is actually even more depressed in myometrium nearing the lesions. I know essentially there's no change. It's just like the control endometrium. And one thing is we actually found that the severity of dysmenorrhea correlated very nicely with the extension of fibrosis in myometrum. And also the severity correlated with the PC lateral PSO2 expression and the OTR expression, same thing. There's a positive correlation and negatively with the ipse lateral PSO1 expression, and even more so with the PNOs, PINOS.

And then again, same thing, that there's some correlation between the PSO1 and PR2, in this case, the negative correlations. And we also did some in vitro experiment, essentially found that the yes protein levels, same thing that for the ENOs, the ipsilateral MR metrium is actually significantly reduced compared with the controls, especially PENOs. And INOS is actually essentially no difference. PSO1 expression actually seemed to be dependent on the matrix stiffness. So essentially, if there are more fibrosis, expression is going to be going down more. Okay. Oh, okay. I'm running out of time.

So actually this mouse experiment essentially replicated what we found in humans, essentially found that there's a lesion progresses, the myometrium appears one and ENOS expression actually decreased progressively with the increased uterine contractility as well as the uterine contractility irregularity and according with the severity of pains. So I guess I'm running out of time. So with this, we also find that the PS01 is actually hypermethylated, it's actually silenced. So in this case, that actually echoed what we've reported years ago that the using valproate acid actually seemed to be has some therapeutic value, and essentially that's what we proposed. So with this, we don't know about hyperinnovation, but I guess I have to skip this. Okay. Thank you very much.