It’s 1927 and Mary Jones is  on her way to the hospital.

She’d had severe abdominal pain  when menstruating since puberty, and had just figured this was why  everyone says their “monthly curse” is such a nightmare. Yes, that’s real slang  for periods from back in the day.

But when she couldn’t get pregnant, she knew it was time to get a doctor involved. When she gets to the hospital, her doctor performs an exploratory surgery to see if there’s anything obviously  abnormal or obstructive in her abdomen. And they find a bunch of  unexpected tissue in there.

It’s scarred and hanging  off her reproductive organs for reasons they couldn’t explain. So Mary’s doctor removes the weird extra tissue and, after the surgery, Mary’s pain free! Sadly, the doctor had to remove her ovaries  along with all that mysterious tissue, so she wasn’t able to have  kids like she may have wanted.

Her doctors really didn’t know  much about endometriosis back then, nor did anyone else, really. And, honestly, we still don’t  know a lot about that diagnosis, despite decades of research in other areas. Mary Jones is a made up person based on  the real experiences of countless people. … And the thing is, we didn’t even have to make our  theoretical patient a woman, or even assigned female at birth.

Because the weirdest thing  about this uterine disease is that you don’t need a uterus to get it. [intro music] The problems associated  with endometriosis all begin when tissue starts growing  where it’s not supposed to be. Most of the time, your liver  tissue stays in the liver, bladder tissue stays in the bladder,  and uterine tissue stays in the uterus. When your uterine tissue starts  growing outside of the uterus, you have endometriosis.

And it’s not a good time. Not to be confused with "wandering womb syndrome" Which is not real but is a thing that we have a pin of and it's a cute little, angry uterus endometriosis is named after the endometrial  tissue from the uterus that goes rogue around your body. As you get more and more endometrial tissue accumulating in unexpected locations, it causes major problems, as you might imagine.

These errant cells end up sending out signals that cause inflammation, resulting in the formation of  lesions and causing abdominal pain that can be debilitating. On top of that, many people with  endometriosis experience infertility. But the thing is, we don’t know  why or how your endometrial tissue left the uterus in the first place.

And that’s a mystery that experts  have been mulling over for a century. In 1927, a researcher named John Sampson was one of the first to propose an explanation, arguing that endometriosis was caused by  something called retrograde menstruation. His idea was: when some unlucky  individuals get their period, their flow moves backwards  through the fallopian tubes.

In that process, it shuttles  tissue out of the uterus where it can attach to other organs and  start growing in new and unusual places. And, according to this explanation, it only happens to some menstruating people because the junction where the fallopian tubes connect to the rest of the uterus  has to be shaped just right …or wrong… to let that tissue through. There’s also a correlation  between endometriosis and patients with some kind of blockage  in their menstrual machinery, which could then be pushing menstrual fluid out through the only other available exit.

The retrograde menstruation  hypothesis does make intuitive sense, but it’s never really been confirmed. The true cause of endometriosis  has been tricky to nail down. And that could be because  endometriosis might not be one thing.

It might be three things. In 1997, Michelle Nisolle and Jacques Donnez proposed the idea that what we’re calling   endometriosis is actually  three distinct diagnoses. One is based in the ovaries, one in the abdomen and the last in either the rectum or vagina.

They’ve based this idea on the fact that  the three subgroupings of endometriosis result in tissue types that all look different. So if endometriosis is really  three different diseases, we may have been looking for one  smoking gun when we really needed three. Which would explain why it’s  been so hard to figure out!

And part of the problem may be that we  were only looking for that smoking gun in a specific population of people, when we needed to broaden the search to a whole other group of people as well. The retrograde menstruation hypothesis only makes sense if everyone who  has endometriosis menstruates. … Which isn’t true. One study looked at transmasculine  patients at Boston Children’s Hospital in various stages of transition, including some who’d started  testosterone treatment.

And Testosterone usuallty stops periods. They found that all seven who’d  reported a history of painful periods before their transition had endometriosis. And a 2019 study on transmasculine  adults who’d had hysterectomies found that of the 94 patients studied, 8 had endometriosis at the time of their surgery.

Now, that doesn’t immediately condemn  the retrograde menstruation hypothesis because those could have been  transmasculine people who menstruate. The 2019 paper noted that 12  people included in the study had breakthrough menstruation  while on testosterone therapy, but it didn’t say whether any of those  12 were among the 8 with endometriosis. And that doesn’t explain why cis women with no uteruses would have endometriosis, either.

If you were assigned female at birth, you could be one in roughly 4500 people diagnosed with MRKH syndrome, a condition where people are born without a uterus, cervix, or vagina, but do have ovaries. So you’d think, no uterus,  no endometriosis, right? Nope!

These people can totally still have it too. Okay, so that’s strike two on  the retrograde menstruation idea. Or it was, until researchers looked a bit closer.

Turns out that a lot of people diagnosed with MRKH syndrome have something  called a rudimentary uterus. Although studies vary on how common this is, it seems like at least half  of MRKH patients have one. So you could have a little piece of uterine tissue that never developed into  a fully functional uterus, but there’s still something there.

And that turns out to be a really  important distinction across MRKH cases. A meta-analysis demonstrated that all of the people with  MRKH syndrome and endometriosis have at least a little bit of uterus, which might be where that rogue  tissue started its journey. Which means we’re back supporting  retrograde menstruation.

Except! Sometimes cis men have endometriosis too! There are 17 published case studies of  cis men with endometriosis as of 2024, which couldn’t be the result  of retrograde menstruation because they don’t have menstrual equipment!

And we’re pretty sure they checked this time. One alternate explanation has to do with hormones. See, a lot of the men who’ve  been diagnosed with endometriosis had been on estrogen therapy  to treat prostate cancer.

So maybe long-term exposure to estrogen can activate something in their  bodies to develop endometriosis. And to explain how that could happen, we need to go way back to when you were a fetus. Back in the good old days when you were a fetus, your whole body was pretty much a blank slate.

You had all these stem cells that could become an eyeball  or a kidney or whatever, depending on the hormones and  other factors they’re exposed to. So there was a point in your development where some of your cells could have  specialized into either ovaries and a uterus, or testicles and a penis, along with the other associated bits for each. This means that at one point in time, everybody had cells that  could have become a uterus.

Most of the time, any extra  cells that didn’t get used up making those organs end up  withering away and getting recycled. But this new endometriosis hypothesis suggests that the leftover would-be uterine cells might stow away in your body. And this wouldn’t be an issue unless  they were exposed to extra estrogen, which would cause them to start growing.

Suddenly, you’re a cis man  with endometrial tissue. It’s plausible enough. But not all of the men with endometriosis  had been on estrogen therapy.

There have been at least  two case reports of cis men who’d never been on estrogen therapy  and still got endometriosis anyway. Which isn’t a lot, but it’s  weird that it happened twice. So, it was back to the drawing board.

And to come up with a new explanation, researchers turned to a very old hypothesis, first put forth in 1919 by Robert Meyer. The idea was that sometimes, cells of one type might just turn into another, even in adults who are way past  the fetal development stage. He called this transition metaplasia.

In the case of endometriosis, this would mean that some of the mesothelial cells that cover your testis, could  turn into endometrial cells. In the metaplasia hypothesis for endometriosis, you wouldn’t need extra estrogen to  kick off the cellular switcheroo. Instead, the trigger would be inflammation.

Something like a surgery kicks  your immune system into hyperdrive, and all the resulting inflammation  could aggravate those cells and spin them up into endometriosis. I know. That sounds made up.

But in 2013, there was a case report of another cis man with endometriosis. His cells had the characteristic  estrogen receptors that endometriosis usually has, but they also had markers for mesothelial cells. Those mesothelial markers were probably left over from when the cells were mesothelial  before metaplasia happened.

At this point, it kind of feels  like we have too many hypotheses for what’s causing endometriosis,  which isn’t as bad as having too few, but also means we are a long ways  off from solving the whole puzzle. At the end of the day, even though it’s one of the most common  gynecological conditions humans face, we still don’t really know  what causes endometriosis. Retrograde menstruation is still  the most accepted explanation for how most people get endometriosis.

But now we know that it’s literally impossible for that to apply to everybody with this disease. So researchers may have been onto something when they suggested that maybe it can happen in more than one way or maybe we’re really talking about more than one diagnosis. Endometriosis is complicated,  and it affects 11% of cis women, plus those 17 cis men and counting.

And with so many people getting  this diagnosis every day, research has ramped up exponentially since the first publication in the 1920s. We’re way better at diagnosing it now, too. These days, you can often get  an idea of what’s going on through laparoscopy, ultrasounds, and MRIs.

So major surgery doesn’t have to  be the first step in diagnosis, like it was for Mary Jones. And once you get a diagnosis, we have a lot more ways to treat  this condition than we used to. There’s hormonal contraceptives, which regulate your hormones  and can stop menstruation, so there’s nothing to retrograde  up into the fallopian tubes.

And while Mary Jones wasn’t able to get pregnant, nowadays most people with endometriosis can still get pregnant through methods like IVF. There’s clearly a long way to go when  it comes to treating endometriosis. Or even, like, understanding it fully.

But research is always ongoing, and new treatments are always around the corner. If these case studies tell you anything, it’s that scientists are good at  updating their views with new evidence. When new publications poke  holes in one hypothesis, that’s how we form hypotheses that  explain even more about a condition.

And with enough time, we might  experiences the end of endometriosis. [ OUTRO]