What is endometriosis?

Act 1The seeds

Every month when you menstruate, some of that blood flows backward through your fallopian tubes into your pelvis instead of out through your cervix. This is called retrograde menstruation, and here’s the wild part: it happens in about 90% of women. Most of them never develop endometriosis.

So retrograde flow isn’t the disease. It’s just how the seeds get planted.

The disease is what happens next.

Act 2The immune failure

In a healthy body, the immune system sees those wayward endometrial cells in the pelvis and clears them. Natural killer (NK) cells patrol, macrophages clean up, and that’s the end of it.

In endometriosis, that clearance system breaks down. NK cells in the peritoneal fluid are dysfunctional. They see the invaders but don’t attack. Macrophages switch from “clean this up” mode to “tolerate this” mode. The immune system essentially waves the ectopic cells through. The seeds land, and nobody removes them.

That’s why you can have endometriosis with perfectly normal anatomy. The problem isn’t structural. It’s immunological.

Act 3The fuel

Once those cells implant, they do something normal uterine tissue doesn’t do: they start producing their own estrogen.

Ectopic endometrial cells express an enzyme called aromatase (CYP19A1). Aromatase converts androgens into estradiol locally, right at the lesion site. That estradiol then upregulates COX-2, which produces prostaglandin E2 (PGE2). And PGE2 further induces aromatase.

It’s a self-sustaining feedback loop. The lesion makes its own fuel. It doesn’t need your ovaries to survive.

This is why women who are surgically menopausal can still have active disease. This is why simply suppressing ovarian estrogen doesn’t fully eradicate it. The lesions have gone off-grid.

Act 4The escape from progesterone

Normally, progesterone is the hormone that keeps the uterine lining in check. It drives programmed cell death, limits estrogen’s effects, and keeps things balanced.

In endometriosis, this system is broken too. There is a striking loss of a progesterone receptor subtype called PR-B, the one that actually mediates most of progesterone’s effects. What remains is PR-A, which not only fails to respond to progesterone but actively blocks any residual PR-B from functioning.

This is called progesterone resistance. The receptor is present. The hormone is present. The lock and key are both there, but the key no longer turns anything.

This is why progestins help manage symptoms but don’t cure the disease. The mechanism driving that resistance? Epigenetic silencing: the PR-B gene gets methylated and shut off in endometriotic lesions, permanently, at the DNA level.

Act 5The firestorm

With no immune clearance, autonomous estrogen production, and progesterone resistance all running simultaneously, the pelvic environment becomes chronically inflamed. Cytokines like IL-6 and TNF-α drive further implantation. VEGF builds new blood vessels to feed the lesions. Matrix metalloproteinases (MMPs) allow the tissue to invade deeper structures.

Over time this creates adhesions that glue organs together, obliterated anatomy, ovarian cysts called endometriomas (chocolate cysts, filled with old blood from cyclical bleeding), and in severe cases deep infiltrating disease invading the uterosacral ligaments, the space between the rectum and vagina, the bowel, and the bladder.

Why it hurts so much

Pain in endometriosis isn’t just inflammation. The lesions develop direct nerve fiber ingrowth: sensory nerve fibers and sympathetic fibers actually grow into the lesions themselves. Over time, the central nervous system upregulates its pain processing through a phenomenon called central sensitization, where the brain becomes hyperresponsive to pain signals from the pelvis. This is why pain often persists even after surgical removal of visible lesions, and why the same amount of disease can cause wildly different levels of pain in different women.