A Systems-Level Hypothesis of Endometriosis

Watch the original video on TikTok

Full transcript of the original video, lightly edited for readability.

So you have seen, I haven't gone from social media for a couple of weeks, and it's due to some heavy research I've been working on behind the scenes. And I'd like to share it with you guys because I believe it's going to change the way the endometriosis community thinks about this disease. So let's get right into it. For years, endometriosis has been explained through some handful of words. Right here we have estrogen, inflammation, immune dysfunction, has been reclassified over and over again.

It's an estrogen disease, it's a autoimmune disease, it's an insulin disease. It's just, it keeps getting reclassified. And all of these are real aspects of endometriosis, but for me, this is not a good focus. So the deeper that I went into my research, the more I realized there's something much more important. These are not the first event. These are aspects, but they are not the origin, they're not the Genesis of what the disease has already done, how it has survived. So I start to ask a different question.

Not why does endometriosis grow, but rather, why does endometriosis survive to begin with? Because when you think about that, how it happens when an endometrial like cell or an endometriotic cell lands outside of the uterus, they enter a hostile environment. Low oxygen, immune attack, inflammation, iron and heme exposure, which result in oxidative stress. They lose their normal attachment. There's a lack of nutrients. By all reasons and theory, these Cells. These cells should not survive. They should be cleared. They should not be able to implant.

They shouldn't be able to remodel the tissue and inflame the nerves to become a chronic disease. That right there has been my focus. The real mystery is the survival, not how they grow. You can see how they grow, and that's where my hypothesis begins. And bear in mind, this is a hypothesis. This is something I'm actually publishing to a couple of. A few journals here. So let's talk about it. Well, do a brief overview of what I like to call selective redox survival state, or in plain English, it means that the cell is not globally healthy, just globally protected.

It means that it preserves just enough antioxidant responses to avoid dying, while leaving enough oxidative signaling to keep the active disease machinery turned on. So let's kind of talk about that. The lesion has to find a dangerous middle ground because too much oxidant stress and it dies. Too much antioxidant control and the pathological signals shut down. But in the middle is where the cell survives and stays activated in a disease state. So endometriosis lives in that middle state. One of the key pieces here is GPX4.

GPX4 helps protect the cells from something known as ferroptosis. This is iron driven cell death. And that matters because endometriosis lives in an iron rich environment. There's bleeding, heme, oxidative stress, lipid peroxides, peroxides. If a Cell is going to survive that environment, it needs GPX4. And that's why GPX4 is not the opposite of oxidative stress. GPX4 may be one of the reasons endometriotic cells can survive in that oxidative stress. And this is a major shift, because instead of saying endometriosis is just oxidative, we're saying the disease may preserve the exact antioxidant systems it needs to avoid death while still allowing damaging signals to continue.

As we will talk here, there's a selected part 2 that. There's literature out there that points that superoxide dismutase 2 helps buffer mitochondrial oxidative stress. So now we have the possible survival pattern. The cell may preserve GPX4 to avoid ferroptosis, and then may prefer. May preserve SAW 2 to protect mitochondrial function. It may have other weaknesses, but in this case, these are our focus. You know, GPX 1, GPX 3, all of that matters because hydrogen peroxide is not just damage. Hydrogen peroxide is a signal.

Hydrogen peroxide signaling stays active. It can affect hypoxia. Inducible one factor one alpha. And. Sorry, that. That can affect inflammation, mind you, that can affect angiogenesis. Hypoxic cells behave long term. So when we look at that, we're looking at something known as pseudohypoxia. Hypoxiainducible factor one alpha is normally activated when oxygen is low, but the body also has machinery that degrades it when it's no longer needed. That degradation depends on enzymes called Phds and VHL recognition. So the question becomes, what If the problem is not simply hypoxia inducible, one fact, hypoxia inducible factor 1 alpha, that that it's high.

What if the problem is that the redox stress makes a cell less able to degrade it properly? That will create a pseudo hypoxic state. The cell then behaves like it's under low oxygen, even though it's not. And when the situation is more complex than oxygen alone, then that's kind of where we start to see an issue. Because hypoxia inducible factor 1 alpha helps the cell survive. It promotes vascular endothelial growth factor, blood vessel growth, metabolism. It helps invasion and adaptation under stress.

And that is perfect for an early lesion and trying to survive outside of the uterus. So now that model starts to come together. A displaced stromal cell enters the pelvic cavity, and it faces hypoxia, iron, oxidative stress, immune pressure. Most cells are going to die. But a susceptible subset of cells that preserve GPX4 and sod2 so they can avoid ferroptosis. Ferroptosis and mitochondrial collapse keep peroxide signaling active. They can stabilize hypoxia. This will factor survival programs. And they begin to build a blood supply.

That is the early survival game. Now, this is kind of where it goes into gata2 and gata6. This is where they become important. We've talked about it in the channel, how gata2 is connected to normal progesterone resistance and stromal identity right here. The research does show that endometriotic cells. In endometriotic cells, GOTA2 becomes hypermethylated So it comes, becomes shut off, repressed. Well, GOTA. GOTA6 becomes hypomethylated and abundant. So it's turned on. Or in simple terms, the normal progesterone response get shut down and more lesion like identities get opened up.

And that matters because endometriosis is not just an estrogen disease, it's also progesterone resistant. There's a lot of mechanisms here at play. So in my model, early redox survival comes first. Redox is just your antioxidant oxidant mechanism. So redox comes first, then hypoxia, then redox stress is going to help shift these epigenetic changes of GATA2 closing and GATA6 opening. Progesterone response weakens, estrogen linked survival programs increase aromatase inflammation. And each time the loop gets stronger and stronger and stronger. And that's why this disease seems to kind of continue growing out of control.

This is what I've been working on.