Endometriosis, hypermobility and EDS: where the connective tissue link holds up, and where it doesn’t

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Adam Foster is the founder of The Fibro Guy and one of the leading voices in hypermobility, EDS, and chronic pain rehabilitation. A former Reconnaissance Soldier, he developed chronic pain after an IED blast in Afghanistan and built his approach from the ground up when the medical system had no answers. Since 2009 he has worked with thousands of people across eight countries, drawing on pain neuroscience, motor learning, and sensorimotor rehabilitation. He co-authored "No Pain, No Pain" with trauma psychologist Dr Mairi Harper, directed the documentary "Invisible Monster," and has been featured in Forbes, BBC Radio 4, ITV News, LiveScience, and The Telegraph.

What endometriosis actually is

Endometriosis is tissue resembling the lining of the uterus sitting in places outside the uterus, and where it hurts depends as much on the surface it landed on, as on the tissue itself.

Line the inside of your abdomen with a thin, slippery membrane and you’ve got the peritoneum. It wraps the organs, lets them slide past each other while you move, bend and digest, and it’s densely supplied with nerves. Those nerves are no good at telling the brain where anything is. Irritate a patch of peritoneum and the pain arrives in your back, your hip, your rectum or the top of a thigh instead of at the spot being irritated, which is why endometriosis pain so rarely behaves like a period, and why people spend years being told it must be their bowel, their bladder, or their spine.

It appears on that peritoneal surface, on the ovaries, and sometimes deeper into the tissue behind the uterus. It responds to the hormonal cycle, which is part of why symptoms track the calendar for some people. And it does one thing the lining of the uterus never has to do, which is sit somewhere with no way out. Instead of being shed it bleeds where it is, provokes inflammation, and over months and years, the body builds around it.

What starts it has a clearer answer than it usually gets credit for. The best supported initiating mechanism is retrograde menstruation, where menstrual tissue travels backwards up the fallopian tubes and into the pelvis instead of all of it leaving the body ^[1][2]. The reason to believe it, is what happens when that tissue has nowhere else to go.

Where the outflow is blocked by a structural difference in how the reproductive tract formed, endometriosis pops up far more often: pooled across those studies, 47% with an obstruction against 19% without one ^[3]. The people who did the pooling rated their own estimate low certainty, so hold keep that in mind.

The same pattern shows up somewhere rarer though. In Mayer Rokitansky Kuster Hauser syndrome, where the uterus is absent or underdeveloped, endometriosis is far more common when there’s functioning endometrium, the lining itself, sitting in a uterine remnant, than when there isn’t ^[4].

Retrograde menstruation can’t carry the whole thing on its own though, and the reason is arithmetic. Refluxed menstrual material is common. Endometriosis that causes trouble is not ^[1][2]. So, something decides which refluxed tissue takes hold and which gets cleared, and the model the literature has settled into comes in two parts: seeding first, then a setting that lets it stay, built out of immune function, hormonal signalling, inherited and acquired molecular variation, and the local tissue conditions that let a lesion persist and invade ^[3][5].

Is endometriosis a connective tissue disease?

Yes, and the yes is a good deal more specific than either version of it you’ll have been told

Pull together 142 studies on what endometriotic lesions are made of, and fibrosis comes out as an important feature of every lesion subtype: driven mainly by myofibroblasts ^[6]. Fibrosis is scarring. Myofibroblasts are the cells that lay it down and then contract it, which is how a wound pulls itself together as it closes. In a lesion, that process doesn’t switch off. The tissue piles up extracellular matrix, the scaffolding that sits between cells, along with collagen, stiffens, and starts behaving like scar. ^[6][7].

That scaffolding is collagen, elastin and a long list of glycoproteins, holding the structure together and telling the cells sitting in it how to act. So a lesion laying down excess matrix and then tightening it, is doing something to the neighbourhood it appears in. The stiffening and tethering , is part of why deep disease hurts the way it does, and why it drags organs towards each other.

The genetics are similar. Earlier genome wide work put heritability at around 50% and found the inherited risk concentrated in several signalling pathways, and for the more severe disease specifically, in the genes that build and maintain that scaffolding ^[8]. A more recent multi ancestry analysis widened the picture to 80 genomic regions and tied the risk to tissue remodelling, immune regulation, hormonal regulation and inflammation ^[9].

So, yes. Connective tissue biology sits at the centre of what an endometriotic lesion is, and of which version of the disease somebody ends up with. What it doesn’t tell you though, is whether or not the connective tissue you were born with made the lesion more likely. Those two questions get run together constantly, including by people who should know better, and the second one has a far less neat and tidy answer to it.

Is endometriosis more common if you’re hypermobile?

If you’ve been anywhere near Instagram on this subject you’ll have met the claim that these two come as a pair, usually delivered with a good deal more confidence than anything in this field has earned.

The largest clinical cohort in hypermobile type Ehlers-Danlos syndrome put reported endometriosis at roughly 3% to 6%, which is about what you’d expect in the general population, and it came out that way despite very high rates of period pain, heavy bleeding, and painful sex in the same group ^[10]. So: an ordinary rate of confirmed endometriosis sitting alongside an enormous amount of gynaecological pain. Both halves of that are the finding, and the second half is the one nobody quotes.

Other work has reported higher numbers still. Surveys of people with EDS and hypermobility spectrum disorder, HSD, have put self reported endometriosis at anywhere from about one in seven to one in four, but those studies ran on questionnaires or on samples of people who were already symptomatic, so they’ll overestimate confirmed disease ^[10][11]. That isn’t a dismissal of them though, and it certainly isn’t a comment on anybody who filled one in. Put a question to people who have spent years hunting for an answer and you’ll hear back from the ones who found something.

Looking at it the other way round, from endometriosis towards hypermobility, one survey of people having pelvic floor physiotherapy for endometriosis had about one in five reporting Ehlers Danlos syndrome, in a self selected group that was never designed to estimate prevalence ^[12].

What you’re left with is substantial symptom overlap that can hide the diagnosis both ways, and no established excess either way ^[13][14]. The authors of that large cohort were blunt about the consequence: symptom based over diagnosis is plausible here, because hEDS on its own commonly produces period pain, painful sex, chronic pain, and abnormal bleeding ^[10][15].

Careful with that sentence though, because on a bad night it reads like an accusation, when really it’s not. It’s a statement about how a label gets arrived at, and everybody in that cohort was in real pain. The question being raised is which drawer it got filed in.

It’s a less satisfying answer than the one circulating I know, but a much more useful one at that, because the interesting part was never whether these two turn up in the same people. It’s what happens when they do.

Explore the course

Is it the endo or is it the hypermobility?

This is the question you probably came here with, and the reason nobody answers it cleanly is that a hypermobile pelvis produces pain in the same places endometriosis does, albeit by a different route.

A joint is held in place by two things: the passive restraint of its ligaments and capsule, and the moment to moment work of the muscles around it. Where the passive restraint is more compliant, the muscles take on more of the job, and they have to keep doing it rather than stepping in now and then. Around the pelvis that falls to the deep hip muscles, the abdominal wall, and the pelvic floor (which is already busy holding organs up, managing continence and absorbing pressure every time you cough, laugh or even stand up).

A muscle that never gets to stand down gets sore. It becomes tender to pressure and it starts referring pain away from itself, which in the pelvis means pain felt low in the abdomen, deep inside, at the tailbone, or during sex. None of that needs a lesion anywhere. It’s what an overworked muscle in an awkward job does, and it’s why a bad pelvic day can follow a thoroughly ordinary one.

Now, put a gynaecological condition on top. Pain during or after sex gets reported by somewhere between four and six in ten people in these hypermobility groups ^[10][11], and in endometriosis it’s common, often severe, in the same place, with the same reluctance to localise.

Endometriosis isn’t the only other candidate either. Adenomyosis, where endometrial type tissue sits inside the muscular wall of the uterus itself, produces heavy, painful periods that feel much the same from the outside. A pelvis can carry more than one of these at once, which is what makes a neat answer unavailable.

The waiting is the other thing these two have in common. Endometriosis diagnosis is often delayed by 4 to 11 years ^[16]^[17]. In hEDS and HSD the delay gets measured in decades ^[18]^[14]. So if you have both, you’ve waited twice over, and each wait has been explained to you with reference to the other condition.

It’s worth knowing what the test physically is as well, because people get told they’ve been ruled out by something that was never going to rule anything in. A laparoscopy is a camera passed through a small incision near the navel, with the abdomen gently inflated so the surgeon can see the peritoneal surfaces, the ovaries, the outside of the uterus and the space behind it. It’s a direct look at those surfaces. An ultrasound is a different test answering a different question, and the two aren’t interchangeable, so a clear scan doesn’t settle it, regardless of what you were told on the way out of the appointment.

It does change the question though. Which of the two it is turns out be matter less than which kind of pain you have, because the treatments don’t divide along the lines of the diagnosis. They divide into things aimed at a lesion and things aimed at an overworked, sensitised pelvis. Plenty of people need both.

Why your pain doesn’t match what they found

Two people can come off the same operating table with the same findings written in the same notes and have very different lives afterwards, because the pain and the lesions are only loosely tied to each other.

In endometriosis, pain severity often correlates poorly with how much disease is there, and the pain frequently involves central sensitisation, cross-organ sensitisation and myofascial dysfunction ^[19]^[20]. Three terms worth having properly, because between them they explain how a clear scan and a successful operation can leave you exactly where you were.

Your nervous system isn’t a set of fixed wires carrying a fixed amount of traffic. It adjusts. When something hurts repeatedly the nerve endings in that area get easier to set off, so less pressure is needed to produce anything at all. Further up, the spinal cord passes more of it along than it used to, and it starts letting through input from neighbouring structures that would normally be filtered out on the way. That’s the cross organ part, and it’s why the bladder, the bowel and the pelvis end up sharing symptoms that started in only one of them. And the brain, which has been running a continuous prediction about what’s going on down there off several years of evidence that something usually is, starts treating ordinary input as something worth reporting on.

The result is a system doing exactly what it’s evolved to do with the volume turned up, so an ordinary amount of input produces a genuinely large amount of pain.

If you’ve been told the scans were clear, or that the surgery went well, and you’re still in pain, this is probably the most useful thing int his entire article for you. You’re not misjudging it. The pain is doing what the system is built to do, and that’s a separate problem from the lesion ,with separate things aimed at it.

It’s common, too. Across endometriosis cohorts, central sensitisation has been reported in something like four or five in ten at specialist centres, with the review estimates running from about one in ten to nearly six in ten depending on where you look and how you count ^[21][22][23]. If you carry a fibromyalgia diagnosis alongside the hypermobility one, you’ve already met this mechanism under another name.

The myofascial side sits right next to it. Fascia is the connective tissue sheeting that wraps and connects muscle, so myofascial pain is pain coming from the muscle and its wrapping instead of from an organ. It’s the tender, achy, hard to point at kind, and it refers. Myofascial dysfunction is one of the things endometriosis pain often involves ^[20], and myofascial problems are described as common in connective tissue disorders as well ^[24]^[20]. That’s the one place these two conditions genuinely meet, and they meet in the muscle rather than in the prevalence figures. Two different starting points, one overworked, tender, sensitised pelvic floor.

What’s actually shown to work for the pain

Everything below is treatment evidence for endometriosis, so the obvious thing first.

Hormonal suppression, the first thing you’ll be offered

Combined hormonal contraceptives and progestins sit first line in most guidelines ^[25]. Progestins, also written progestogens, are synthetic versions of progesterone, and what they and the combined pill have in common, is that they suppress the cyclical hormonal signalling the lesions respond to. That quietens the tissue without removing it.

The effect is moderate though^[26][27]. Roughly two thirds of people get adequate relief and roughly one third don’t, through either failure or intolerance, which often gets labelled progesterone resistance ^[28][29]. That’s the term for a drug not doing the thing it’s meant to, so if you’re in that third.

In a large randomised comparison after surgery, long acting progestogens and combined oral contraceptives each improved pain by about 40% over three years ^[30].

These treatments are suppressive, and symptoms commonly come back once they’re stopped ^[31]. People usually phrase that as whether the pill is treating the problem or hiding it, and the worry underneath it is a fair one. What it tells you is what the drug is for. It holds the symptoms down while you’re taking it, and it isn’t removing the disease while it does that. Whether anything else needs doing about that is a conversation for a gynaecologist.

When the first thing doesn’t work

The next step is deeper suppression of the hormonal signal, with GnRH agonists or the newer oral GnRH antagonists, which guidelines put second line ^[32]. GnRH is the hormone at the top of the chain, the one that starts the sequence ending in a cycle, so both act earlier than the pill does. An antagonist blocks the signal. An agonist floods it until the system stops answering. Opposite routes, same destination.

The trial evidence behind them is actually fairly strong. Relugolix combination therapy is the clearest example: three in four responded on period pain against under a third on placebo, while on non menstrual pelvic pain the gap was much narrower, roughly six in ten against four in ten ^[33]. Elagolix and linzagolix land in similar territory, elagolix with period pain response somewhere between a half and three quarters against about a fifth on placebo ^[34], and linzagolix at the higher dose with add-back therapy, meaning a small amount of hormone given alongside, getting about seven in ten against under a quarter ^[35]. Pooled across the oral antagonists, two people need to take one for one extra person to respond on period pain, and about five for one extra response on the non menstrual pain ^[36].

Notice how large the placebo response is in those trials though first. That’s the reason to read the comparison and not the headline figure, and a response is a defined improvement rather than an absence of pain.

The cost is oestrogen suppression. With elagolix that showed up as more hot flushes and reduced bone density ^[34], which is what add back therapy exists for, and reviews support it as holding the benefit while improving safety ^[37]. In the relugolix combination trials, bone mineral density loss at the lumbar spine was kept under 1% over 24 weeks ^[33], and the benefit held out to two years in the open label extension, the stretch after the trial proper where everybody knows what they’re taking, with most people still responding and nine in ten off opioids by the end. There was no control arm on that part, so read it as durability ^[38].

If you’re hypermobile, bone is a fair thing to raise also, and something to raise at the start ,rather than at the point somebody suggests a second course. Ask what the monitoring is, and ask what the add-back is.

Surgery, and why pain can carry on afterwards

Surgery has a real place where the disease itself is anatomically important. In a prospective cohort of 4,721 people with deep rectovaginal endometriosis, meaning disease that has grown into the tissue between the rectum and the vagina, laparoscopic excision brought down cyclic and non cyclic pelvic pain, pain during sex, pain on opening the bowels and bladder pain, along with painkiller use. The benefit was maintained out to two years, and around one in fifteen had a complication ^[39].

What it doesn’t do is draw a line under the problem, and there’s a specific finding about who does less well out of it. Where pelvic floor myalgia, abdominal wall pain, depression or other pain conditions were there before the operation, quality of life afterwards was poorer ^[40]. Pelvic floor myalgia is that overworked, tender pelvic floor under its clinical name.

If you’re hypermobile, those are precisely the things already sitting in your notes. Which is an argument for getting at them beforehand, not an argument against the operation.

What the hormones and the surgery don’t touch

Hormonal treatment suppresses the lesion. Surgery removes it. Surgery on its own rarely ends the long term management, because symptoms and lesions commonly recur, and hormonal treatment on its own doesn’t address central sensitisation, pelvic floor dysfunction, the bowel and bladder contributors or the psychological side ^[41]^[42].

Care aimed at the pain mechanism is described as central to modern endometriosis care, not an optional add on for selected cases ^[43][42]. Pelvic floor physiotherapy, exercise, pain education, psychological care and centrally acting medication look most useful where the pain is sensitised or myofascial ^[43][44][45]. The support for that comes from cohort improvement data and systematic reviews, and controlled trials are limited ^[46][44], so treat it as a well reasoned approach and not a settled protocol.

There’s a direct reason to take the sensitisation side seriously as well . Central sensitisation predicts failure of hormonal therapy ^[47], and it predicts worse outcomes after surgery ^[40]. It’s one of the things that decides whether the other treatments work at all.

For our part, that’s where movement and strength work belongs in this picture, and it’s worth being exact about the claim. It doesn’t treat endometriosis. What decent rehabilitation can do is give an overworked, guarded pelvis a better strategy and give a sensitised nervous system better information, which is a reasonable thing to do alongside gynaecological treatment, but a terrible substitute for it.

One from the studios, as clinical pattern rather than evidence. People arrive having worked extremely hard at one half of this problem for years, and nobody has ever mentioned to them that there were two halves.

Does being hypermobile change any of this?

Partly, and in one specific place.

The gynaecological half doesn’t change. The lesion doesn’t care how far your elbows go back, and the hormonal and surgical evidence above is the evidence for endometriosis whatever else is on your problem list.

What changes is the other half. If you’re hypermobile the muscles around the pelvis are already carrying more of the stabilising job, myofascial problems are described as common in connective tissue disorders ^[24], and pelvic floor dysfunction is exactly the sort of thing the lesion directed treatments don’t address ^[41][42]. So the multimodal half of the plan isn’t an optional extra in your case. It’s probably the half with your name on it.

It changes what belongs in the appointment too. Worth mentioning at your appointmet: how your symptoms move through the month, what you’ve already tried and what happened when you did, your fertility plans if you have any, bone health if deeper suppression is being discussed, and every non gynaecological source of pain you’ve got, because that last one changes what to expect from the treatment.

And one thing to keep in mind. Having two conditions isn’t the same as having one condition that explains everything. The hypermobility explaining a good deal of your pain doesn’t make the endometriosis less real, and the endometriosis being treated doesn’t make your pelvis stop being a hypermobile one.

So, two plans, and they need to know about each other. The work on the second one is worth doing whatever happens with the first.

Adam

References

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