How is a connective tissue disorder linked to endometriosis?
Ehlers-Danlos Syndrome (EDS) is a connective tissue disorder caused by gene variations that affect how collagen is made or organised (1). Collagen is found throughout the human body — in skin, blood vessels, joints and ligaments — so when it doesn't form or hold together as it should, symptoms can turn up almost anywhere collagen does (1). This often includes joint hypermobility and frequent dislocations, skin that's unusually stretchy, fragile or slow to heal, easy bruising, and chronic pain, though the specific symptoms and their severity vary depending on the type of EDS someone has.
Because connective tissue plays a structural role in so many parts of the body, EDS also comes with a long list of conditions that commonly occur alongside it, touching everything from the gut and cardiovascular systems to the nervous system, and even brain functioning (neurodivergence is present at particularly higher rates in this community).
One of those comorbid conditions is endometriosis. A new study showed that those with endometriosis are seven times more likely to have an Ehlers-Danlos Syndrome (2). That is not a small overlap. But why are they so connected, when they’re such different conditions? A theory is that abnormal extracellular matrix (the scaffolding of cells that is made of mostly collagen) in EDS, makes it easier for endometriosis cells to migrate and implant, causing new lesion growth. But what is actually contributing to this? Here at the DITTO, we found some science that might explain it.
Your Body’s Molecular Scissors - MMPs
MMPs, or matrix metalloproteinases, are a group of enzymes whose job is to break down old tissue so your body can rebuild and remodel itself. Think of them as your body's molecular scissors: they cut through the extracellular matrix, the scaffolding of proteins (including collagen) that holds your tissues together, clearing the way for new tissue to form (3).
There are a few types of these "scissors," each specialising in a different part of that scaffolding: collagenases cut collagen specifically, while others, like gelatinases, stromelysins and matrilysins, break down other parts of the matrix (3).
Because they're so powerful, MMPs need careful control. Hormones, growth factors and inflammatory signals called cytokines all influence how active they are, and the body also has its own built-in brake: naturally occurring inhibitors called tissue inhibitors of MMPs (TIMPs), which help keep this cutting-and-rebuilding process balanced.
These Scissors Run Wild in Ehlers-Danlos Syndrome
In one study, researchers compared skin samples from women with hypermobile EDS (hEDS) to samples from healthy controls. MMP-1 stood out as the most elevated protein of all those measured - a whopping 53x higher in hEDS!
Meanwhile, TIMP-2, one of the "brakes" that normally keeps MMPs in check, was found at lower levels than in controls. Pathway analysis linked this combination - too much cutting, too little braking - to impaired extracellular matrix organisation and excess collagen breakdown.
When hEDS cells were treated with doxycycline, an antibiotic that also broadly inhibits MMP activity, their ECM organisation was restored and their matrix-degrading behaviour partly reversed (5). Take the overactive scissors away, and the tissue starts to hold together properly again. The authors flag this as a possible therapeutic target, though it's still early days, and long-term safety work remains to be done.
Endometriosis Lesions use MMPs to Cut Their Way In
For an endometriosis lesion to survive, it has to cut its way into surrounding tissue and anchor itself there. How does it manage that? You guessed it - using MMPs. In one study, women with endometriosis showed elevated levels of certain MMPs, notably MMP-2 and MMP-9, in their peritoneal fluid, alongside reduced TIMP-1 levels - a combination that creates an invasive microenvironment (4). In lesions specifically, MMP-2 activity was consistently higher, pointing to real dysregulation of this enzyme system. These enzymes also seem more active in early lesions, tapering off as the disease establishes.
Hormones tie this straight back to endometriosis biology. Estrogen drives MMP-2 and MMP-9 expression, while progesterone does the opposite: it suppresses MMP secretion, and boosts the TIMP inhibitors that keep them in check (4). Now remember that endometriosis lesions produce their own estrogen. That local estrogen supply keeps the molecular scissors sharp and busy, which is exactly what a lesion needs to keep invading.
There may even be a genetic thread here. Some studies link variants in the gene controlling MMP-1 production to a higher risk of endometriosis, hinting that MMP dysregulation isn't only a consequence of the disease, but could also be part of what predisposes someone to it in the first place (4).
Both conditions share a broken matrix-remodelling system
In endometriosis, MMPs are elevated and enable lesions to invade and anchor. In EDS, MMPs are elevated and degrade the very matrix that's supposed to hold connective tissue together. Same machinery, tipped the same direction - towards breakdown - with different consequences depending on the tissue.
It may not simply be that the EDS matrix is passively "easier to migrate through". The enzymatic system that remodels that matrix looks dysregulated in both conditions, which could help explain why they travel together so often. The extracellular matrix sits at the centre of both diseases.
This is a hypothesis from early research, not a settled mechanism. The EDS data spans different subtypes that may not behave in the same way. What we can say: MMPs are a plausible common thread,and they deserve far more research attention than they’re getting.
If one condition does set up the other, the more coherent hypothesis, given that EDS is absolutely present from birth (congenital), is that its underlying MMP dysregulation makes the extracellular matrix more permissive to endometriosis lesions establishing themselves — not the reverse. Alternatively, both conditions may trace back to a shared upstream driver: some common genetic or molecular vulnerability that independently pushes MMP activity in both toward breakdown, without either condition causing the other. Which of these is actually true is still an open question, and one for future research to settle.
Living with Two Ignored Conditions
EDS and endometriosis are already two of the most overlooked conditions in medicine on their own - both notorious for years-long diagnostic delays, symptoms dismissed as "just bad periods" or "just being flexible," and doctors who've had little to no training in recognising either one. Put them together, and that gap widens: despite how strongly these conditions overlap, there's still a striking lack of awareness, screening, or joined-up care connecting the two, even among specialists who treat one or the other.
If you have EDS, few doctors think to screen for endometriosis, and if you have endometriosis, almost none think to ask about joint hypermobility or connective tissue symptoms. Patients are often left piecing the connection together themselves, long before any clinician does. But this isn't just two unlucky diagnoses colliding - the mechanism connecting them is looking less like coincidence and more like shared biology.
If your symptoms have been treated as two unrelated problems, that response isn't keeping up with the science, and it isn't good enough. These conditions are connected, and that connection is mechanistic, not coincidental. Our hope is that research like this is the start of change: the more attention this gets, the sooner we’ll achieve care that reflects how these conditions work together in the body. Understanding the mechanism is the first step - turning it into better answers for the people living with both is the goal.
References:
1. Ravi U, Daley SF. Ehlers-Danlos Syndromes. [Updated 2026 Jun 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549814/
2. Khan et al. Comorbidity analysis and clustering of endometriosis patients using electronic health records. Cell Rep Med. 2025
3. Verma RP, Hansch C. Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorg Med Chem. 2007 Mar 15;15(6):2223-68. doi: 10.1016/j.bmc.2007.01.011. Epub 2007 Jan 17. PMID: 17275314.
4. Bałkowiec M, Maksym RB, Włodarski PK. The bimodal role of matrix metalloproteinases and their inhibitors in etiology and pathogenesis of endometriosis (Review). Mol Med Rep. 2018 Sep;18(3):3123-3136. doi: 10.3892/mmr.2018.9303. Epub 2018 Jul 23. PMID: 30066912; PMCID: PMC6102659.
5. Chiarelli N, Zoppi N, Venturini M, Capitanio D, Gelfi C, Ritelli M, Colombi M. Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target? Cells. 2021 Nov 19;10(11):3236. doi: 10.3390/cells10113236. PMID: 34831458; PMCID: PMC8621259.
