Adenomyosis on the Endometriosis Spectrum — Part 2

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

Now let's talk about the article inside the study. They found phenotypes that are immune, hormonal, vascular, inflammatory and tissue remodeling. The overall spectrum. This study looked at roughly 1.4 million women, including over 105,000 cases of endometriosis and adenomyosis. And the researchers found 80 genomic regions associated with endometriosis risk. Thirty seven of those were new. They also found five genome wide significant points for adenomyosis. That matters because it tells us endometriosis is not controlled by one gene, one hormone, one inflammatory molecule or one theory.

It is polygenic. Meaning many genetic regions contribute to the type of endometriosis manifestation. Now let's make this simple. So let's go back to our analogy. Think of your genes like a shoelace. One long shoelace running through the biology of the body. That shoelace passes through hormone regulation, it passes through immune signaling, it passes through inflammation, it passes through vascular development, it passes through cell adhesion, it passes through tissue remodeling. It passes through pain sensitivity, it passes through the uterus, ovaries, bowel, nerves, immune system and even systemic symptoms like fatigue, migraine, anxiety and nausea.

Now imagine a knot, fray or weak point somewhere on that shoelace. Where that weak point happens helps shape what phenotype you see. If the disruption is near hormone regulation genes, the disease may look more hormone driven. If it is near immune regulation genes, it may look more inflammatory or systemic. If it is near vascular remodeling genes, the lesions may be better at Building blood supply. If it is near tissue remodeling genes, the disease may become more adhesive, fibrotic, invasive, or deep.

If it is near pain or neuro immune pathways, the symptoms may be severe even when the visible surgical stage looks mild. That is the shoelace analogy. The shoelace is the endometriosis. Genes where the disruption lands help shape the phenotype. Meaning adenomyosis, thoracic endometriosis, deep infiltrating endometriosis. They all fall under the endometriosis umbrella. There is no separation but a spectrum, and this article gives us a genetic map of that concept. Let's talk about some of the genes. One major gene is WNT4.

WNT4 is important in reproductive track development, uterine biology, and tissue patterning. If WNT signaling is altered, it can affect how tissues develop, repair, and respond to injury. That helps explain why endometriosis is not just misplaced tissue. It may involve abnormal tissue identity and repair behavior. Another major gene is GREB1. GREB1 is connected to estrogen receptor activity. This matters because estrogen does play a role in endometriosis, but not in the shallow way people say online. Estrogen is not the root villain. The issue is that the lesion environment can become rewired to use estrogen pathologically.

So when G R E B 1 and estrogen regulated pathways show up, that supports the idea of abnormal hormone response, not simply too much estrogen. Then we have ESR1 and PGR ESR1 is the estrogen receptor alpha gene. PGR. Is the progesterone receptor gene. This is huge because endometriosis is often described as estrogen responsive and progesterone resistant. The article's drug repurposing analysis was partly driven by ESR1 and PGR, reinforcing that estrogen and progesterone signaling are central biological nodes. But again, this does not mean the disease is only hormonal.

It means hormone signaling is one major branch of the network. Another important gene is KDR. KDR. Encodes VEGFR2, a receptor involved in blood vessel formation that connects directly to angiogenesis. Endometriosis lesions need blood supply, they need oxygen, they need nutrients, they need vascular access to survive. So when vascular development genes like KDR. Show up, it supports the idea that lesion survival depends on the ability to build or hijack blood vessels. Then we have VEZT. VEZT. Is connected to cell adhesion and tissue organization.

That matters because endometriosis is not just cells floating around. Cells have to attach, they have to invade, they have to survive in the wrong location, they have to interact with the extracellular matrix. Genes involved in adhesion and cellular morphogenesis help explain why some cells implant, stick, remodel, and become persistent lesions. The article also highlights genes and regions like S Y N E 1, G D A, P 1, H R H 1, FSH B R S P O 3, FN1, SEMA3F H O X A 3, SKAP1, TFPI, and others.

Each of these points toward a different biological layer. HRH1 is especially interesting because it connects to histamine signaling, inflammation, and pain sensitivity. That fits with what many women experience mast cell like flares, histamine symptoms, nerve irritation, and inflammatory pain. FN1, or fibronectin, connects to extracellular matrix and tissue remodeling. That matters for adhesions, fibrosis, and the structural side of the disease. SEMA3F connects to cell guidance and neurovascular behavior. That is important because endometriosis is not just inflammatory, it is also nerve related and vascular.

SKAP1 points toward immune regulation. TFPI. Points toward vascular and coagulation related biology. RSPO3 connects to WNT. Signaling and tissue development. FSH B. Connects to reproductive endocrine regulations. So when you put all of this together, the picture becomes clear. Endometriosis is not one pathway, it is a network disease and that is why phenotypes develop differently. One woman may have mostly bowel symptoms because the disease expression is affecting tissue remodeling, inflammation, and posterior pelvic anatomy. Another woman may have severe bladder symptoms because local inflammation and nerve sensitivity are affecting that compartment.

Another may have adenomyosis because the uterine muscle and junctional zone are involved. Another may have migraines, nausea, fatigue, and anxiety because the disease overlaps with systemic, neuro, immune, and neuroendocrine pathways. Another may have infertility because the disease is affecting ovarian environment, inflammation, adhesions, follicular health, or endometrial receptivity. Another may have severe pain with minimal disease because pain is not only about lesion size. Pain depends on nerves, inflammation, immune activation, histamine prostaglandins, fibrosis, central sensitization, and where the lesion is located. That is why staging has failed.

Women. Stage 1 does not mean mild suffering. Stage 4 does not always mean the worst pain. Surgical stage tells you what can be seen anatomically. It does not fully tell you the genetic, immune, neurological, hormonal, metabolic, or epigenetic state of the disease. For this reason, we revamped endometriosis grading and have one of the most accurate grading systems available. Check our profile to take our test. Adenomyosis is shown on this article to share similarities in this architecture as well. That matters because a woman with adenomyosis may have heavier bleeding, uterine enlargement, cramping, clotting, and pressure symptoms, while another woman with endometriosis may have more peritoneum, bowel, nerve, or ovarian involvement.

Same broader family of disease mechanisms, different phenotype expression. So what does this article mean? The same thing we've been saying for the last seven years. The old model is breaking. Endometriosis is not just retrograde menstruation. It is not just estrogen. It is not just inflammation. It is not just pain. It is a genetically influenced multisystem disease. Involving hormone signaling, immune dysfunction, inflammation, vascular remodeling, cell adhesion, tissue invasion, epigenetic regulation, and pain biology. The machinery is broken. Estrogen was never the bad guy here.

This study gives scientific weight to what patients have been living for years. Endometriosis is a spectrum. The phenotype depends on which part of the shoelace is pulled.