Endometriosis Is an Immune Disorder

If you have endometriosis, you have probably been told some version of this: periods hurt, you’re stressed, it’s IBS, it’s anxiety. On average, women wait seven to nine years between their first symptom and a diagnosis. That’s the standard experience. Part of why it takes so long is that we’ve been telling the wrong story about what endometriosis is.

Endometriosis is a condition in which tissue similar to the lining of the uterus grows outside the uterus. Most often it’s found on the peritoneum, the membrane lining the pelvic and abdominal cavity, on the ovaries, where it can form endometriotic cysts, and as deep nodules involving the bowel, the bladder, or the space between the rectum and the vagina. It can also be extra-pelvic (outside the pelvis), on the diaphragm, lungs, in cesarean section scars, on the liver or spleen, even along the sciatic nerve.

A closely related condition, adenomyosis, involves the same kind of tissue growing within the muscular wall of the uterus itself. It typically causes heavy, painful periods, a tender or enlarged uterus, and difficulty with implantation and pregnancy. The two conditions frequently occur together. Many women with endometriosis also have adenomyosis, and vice versa but adenomyosis is missed even more often, because laparoscopy cannot see inside the uterine wall. It’s identified on ultrasound or MRI, and for decades it was confirmed only after hysterectomy. If you’ve had endometriosis surgery and your heavy bleeding and cramping never improved, adenomyosis is worth asking about.

The question nobody asks

The textbook explanation is retrograde menstruation: during your period, some menstrual tissue flows backward through the fallopian tubes into the pelvis instead of out of the body, and implants where it doesn’t belong.

Here’s the problem with stopping there. Retrograde menstruation happens in the vast majority of women. Most women’s bodies push some tissue backward every single month. Yet only about 10% of reproductive-age women develop endometriosis (although this number might underestimate the prevalence)

So, the real question was never “how does the tissue get there.” It’s: why does that tissue survive and grow in some women and not others?

A 2023 review in Frontiers in Immunology by Siman Chen and colleagues at Fudan University makes the case directly. Their conclusion is that the immune environment of the pelvis plays a central role in causing endometriosis – not a side effect of it. Immune cells and the inflammatory signals they release are what build the blood supply and scar tissue that let lesions take hold and grow. And because hormonal therapy doesn’t address any of that, the future belongs to non-hormonal treatments aimed at the immune environment.

And I think there’s one immune cell at the center of this that the field hasn’t yet given proper attention.

Meet the mast cell

Mast cells are immune cells stationed throughout your body-in your skin, gut, bladder, uterus, lungs, in the lining of blood vessels, and clustered directly alongside nerve endings. They are first responders, positioned at every surface where your body meets the outside world.

When a mast cell activates, it releases a chemical arsenal: histamine, prostaglandins, cytokines, and growth factors. In the right amount, it can be protective. It’s how you fight infection and heal wounds.

When mast cells become chronically overactive, the same machinery turns destructive. That condition is called mast cell activation syndrome, or MCAS: inflammation that never resolves, and a body that reacts to seemingly everything, like foods, smells, temperature changes, hormonal shifts, and more.

Mast cell numbers are elevated in endometriosis lesions, particularly deep lesions, and those cells show evidence of having actively released their contents. They are not incidental passengers in this tissue.

What mast cells actually do in endometriosis

A lesion can’t survive on its own. It needs a blood supply to feed it, and as it establishes itself it drives scarring, inflammation, and nerve growth in the tissue around it. Mast cells release the signals behind every one of those.

They build the blood supply. A lesion cannot survive without one. Mast cells release VEGF, the primary signal that tells the body to grow new blood vessels, which helps the tissue take hold and grow.

They grow the nerves. This is the one that matters most for pain. Mast cells release nerve growth factor, which prompts nerve fibers to sprout and multiply — and mast cells sit physically adjacent to those nerves. The lesion doesn’t just grow a blood supply. It wires itself into your nervous system. That’s why endometriosis pain becomes constant rather than cyclical, spreads well beyond the pelvis, and persists when there’s nothing actively bleeding.

They lay down scar tissue. Mast cell enzymes activate the fibroblasts that produce fibrosis — the dense scarring that makes established endometriosis so hard to treat and so painful long after treatment.

They keep the inflammation running. Histamine, prostaglandins, and cytokines released directly into the pelvic environment maintain exactly the inflammatory state that promotes lesion survival.

Blood supply, nerve supply, scar tissue, inflammation. That’s essentially the entire disease process, and mast cells contribute to all four.

Why it flares on a cycle

Mast cells carry estrogen receptors, and estrogen can cause activation of mast cell. The same trigger that would produce a mild reaction at one point in your cycle produces a much bigger one when estrogen is high. Your mast cells can be more reactive at predictable points every month.

Progesterone normally has a stabilizing effect on mast cells. But endometriosis lesions are notoriously progesterone-resistant so that brake doesn’t engage properly where it’s needed most.

This is also why the same framework applies to adenomyosis. It is estrogen-dependent and progesterone-resistant in the same way, it involves the same inflammatory and nerve-related changes in the uterine wall, and mast cells have been documented in adenomyotic tissue as well. Two conditions, one underlying process.

So every month, as estrogen rises, mast cells become easier to set off while the signal that would normally calm them isn’t getting through. That is the mechanism behind something patients describe and are rarely given an explanation for: symptoms that flare on a predictable schedule, and that affect the whole body rather than just the pelvis.

It also explains why hormonal suppression works partially and unsatisfyingly. Lowering estrogen does reduce mast cell reactivity but it does it by shutting down your reproductive system, with all the side effects that follow, while leaving the overactive mast cells themselves untouched.

Why surgery so often isn’t the end

Mast cells and nerves talk to each other in both directions. Mast cells release chemicals that make nearby sensory nerves more excitable. Those activated nerves release their own signals back onto the mast cells, triggering further release. Immune cell excites nerve, nerve excites immune cell, and the loop sustains itself.

Once that circuit is established, it can keep generating pain independent of how much lesion tissue remains. Pain returns in 40 to 50% of patients within five years of surgery. You can remove tissue. You cannot excise a sensitized nerve–immune loop.

This is also why the amount of disease a surgeon sees doesn’t predict how much pain you’re in. Someone with minimal disease can be debilitated; someone with extensive disease can feel relatively fine. If inflammation and nerve involvement generate the pain, then counting lesions was always measuring the wrong thing.

Why this matters beyond the pelvis

In my practice, endometriosis almost never arrives alone.

It shows up alongside PMOS (Polyendocrine Ovarian Syndrome), POTS, hypermobility, interstitial cystitis, IBS, migraine, fibromyalgia, lipedema, and/or venous compression. Patients describe reacting to foods, medications, smells, heat, and hormonal shifts and many other triggers. They describe flares that are cyclical but whole-body.

A model confined to the pelvis and considered gynecologic cannot explain that pattern. Mast cell activation can explain it because mast cells are present in every tissue those diagnoses involve: bladder, gut, blood vessels, brain, connective tissue, skin.

When these conditions cluster this consistently in the same patient, the simplest explanation isn’t a run of bad luck across five separate diseases. It’s one upstream driver.

What actually helps: Mast Cell Targeted Therapy

The research is pointing toward non-hormonal, immune-targeted treatment. And some of the most interesting evidence there involves a drug class nobody saw coming.

GLP-1 medications

You know these as diabetes and weight loss drugs. What’s less widely known is that GLP-1 receptors sit on mast cells themselves, as well as on other immune cells, the nerves of the gut, and the lining of blood vessels. Engaging those receptors quiets inflammatory signaling, an effect entirely different from anything to do with appetite or weight.

In July 2025, our group published the first case series of GLP-1 receptor agonist therapy in mast cell activation syndrome (Afrin, Weinstock, Dempsey, et al., American Journal of the Medical Sciences). Among 47 patients who had already failed standard, layered mast cell treatment, 89% showed overall clinical benefit across skin, gastrointestinal, neurologic, and general systemic symptoms.

Two details matter enormously. Benefit occurred in patients who were not overweight, and at doses well below those used for weight loss. That combination is the strongest argument that what we’re seeing is an anti-inflammatory effect on mast cells, not a downstream consequence of losing weight.

I want to be straightforward about the limits. This is a case series, not a randomized controlled trial. It tells us that a high proportion of very difficult patients improved; it does not yet tell us how much benefit to expect or precisely who will respond.

This also is not a medication to start casually. Highly reactive patients need low starting doses, slow titration, and close monitoring and it requires a physician who understands both the drug and mast cell disease.

Other Mast Cell treatments

If the mast cell picture fits you, there are approaches worth discussing with your physician today: H1 and H2 antihistamines often used together, mast cell stabilizers, and natural stabilizers such as quercetin and luteolin . None of these are cures, and none replace appropriate care by endometriosis specialists. In the right patient, they lower the inflammatory baseline that everything else sits on top of.

Additional considerations

Get your iron checked. Undiagnosed iron deficiency is common in endometriosis and likely accounts for a meaningful share of the fatigue. It’s easy to test and easy to correct. Ask specifically for a ferritin level since a normal hemoglobin does not rule out iron deficiency.

Consider pelvic floor physical therapy. If you’ve been bracing against pelvic pain for years, you have very likely developed muscle spasm and guarding that generate pain of their own. That’s a second, separate, treatable problem layered on top of the endometriosis and no amount of treating the endometriosis will resolve it.

The bottom line

Almost every woman has tissue travel backward during her period. Only some develop endometriosis. The difference isn’t the tissue but rather the immune environment that either clears it or feeds it.

That’s why hormone suppression alone so rarely resolves this, and why surgery so often isn’t the end of the story.

If every specialist you’ve seen found nothing wrong in their own area, that doesn’t mean nothing is wrong. It means the problem doesn’t live in any one area.

And if your symptoms flare on a cycle, if you react to foods, medications, smells, temperature, bariatric pressure or other trigger, or if you also deal with POTS, hypermobility, PMOS (formally PCOS), fibromyalgia, IBS, interstitial cystitis or other multisystem inflammatory condition, ask about mast cells. That conversation isn’t standard yet, but it should be.

Dr. Tania Dempsey is a physician at the AIM Center for Personalized Medicine specializing in complex chronic illness, mast cell activation syndrome, and multisystem inflammatory disease.

Key references:

Chen S, Liu Y, Zhong Z, Wei C, Liu Y, Zhu X. Peritoneal immune microenvironment of endometriosis: Role and therapeutic perspectives. Front Immunol. 2023;14:1134663.

Afrin LB, Weinstock LB, Dempsey TT, Aschenbrenner K, Blitshteyn S, Schofield JR. Utility of glucagon-like-peptide-1-receptor agonists in mast cell activation syndrome. Am J Med Sci. 2025;370(4):377-382. doi:10.1016/j.amjms.2025.07.006