Endometriosis develops when tissue resembling the uterine lining grows in places it should not, such as the ovaries, fallopian tubes, or pelvic lining, but no single cause explains why this happens. Decades of research have produced several credible theories, and the honest picture is that multiple biological pathways probably converge in any given person. Genetics, immune function, hormonal signaling, and environmental exposures all appear to play roles, and their relative importance likely differs from one person to the next.
Retrograde Menstruation and Why It Is Not the Whole Story
The oldest and most widely cited explanation is retrograde menstruation, first proposed by Dr. John Sampson in the 1920s. The idea is straightforward: during a period, some menstrual blood flows backward through the fallopian tubes and deposits fragments of endometrial tissue into the pelvic cavity. Those fragments then attach, grow, and form lesions. The theory has strong circumstantial support. People with structural abnormalities that block normal menstrual outflow, such as obstructive uterine anomalies, have a well-documented higher prevalence of endometriosis, which is exactly what you would expect if backward flow matters.1PubMed. Müllerian duct anomalies coincident with endometriosis: a review2PubMed Central. Müllerian anomalies and endometriosis: associations and phenotypic variations
The problem is that retrograde menstruation is extremely common. Studies using laparoscopy during menstruation have found it in the majority of people who menstruate, yet only roughly one in ten develops endometriosis. So backward flow alone is not enough. Other factors have to decide whether those stray tissue fragments survive, implant, and grow, or whether the body clears them.3Frontiers in Reproductive Health. Menstruation Dysregulation and Endometriosis Development That gap between how common retrograde menstruation is and how common endometriosis is has pushed researchers toward a web of additional explanations.
Other Ways Endometrial-Like Tissue Can End Up in the Wrong Place
Retrograde menstruation is not the only route. Several alternative theories explain how endometrial-like tissue appears in locations that backward flow cannot easily reach, such as the lungs, lymph nodes, or distant abdominal sites.
One theory, called coelomic metaplasia, proposes that the lining of the pelvic and abdominal cavities (the peritoneum) can transform into endometrial-like tissue under certain hormonal signals. Laboratory work has shown that peritoneal cells and ovarian surface cells, when exposed to estrogen, can undergo structural changes that resemble endometrial tissue, forming gland-like structures in experimental models.4PubMed. Coelomic metaplasia theory of endometriosis: evidence from in vivo studies and an in vitro experimental model This would explain why endometriosis sometimes appears in people who have never menstruated, including rare cases in premenarcheal girls and even assigned-male patients on estrogen therapy.
A stem cell theory takes a different angle. The endometrium contains stem-like progenitor cells that enable its monthly regeneration. According to this model, those stem cells can escape the uterus through the fallopian tubes, or travel via blood and lymph vessels, then settle in distant tissue and differentiate into the glandular and stromal components of endometriotic lesions.5PubMed Central. A Revised Stem Cell Theory for the Pathogenesis of Endometriosis Some evidence suggests bone marrow stem cells can also be recruited to lesion sites, potentially contributing to deep infiltrating forms of the disease.6PubMed Central. Endometrial stem/progenitor cells and their roles in immunity, clinical application, and endometriosis
Lymphatic spread is another pathway supported by clinical evidence. Endometrial cells have been found in uterine-draining lymph nodes, and one prospective study reported that spread to pelvic sentinel lymph nodes occurred in about 11 percent of people with ovarian or peritoneal endometriosis.7PubMed. Lymphatic spread of endometriosis to pelvic sentinel lymph nodes: a prospective clinical study People with endometriosis also show higher lymphatic vessel density in their uterine lining, which could make it easier for endometrial fragments to enter lymphatic circulation.8PubMed. The role of the lymphatic system in endometriosis: a comprehensive review of the literature
None of these theories is mutually exclusive. A comprehensive review of the pathogenesis literature concluded that retrograde menstruation, coelomic metaplasia, immune dysfunction, hormonal imbalance, stem cell involvement, and epigenetic changes have all been implicated, but the true origin remains poorly understood.9PubMed Central. The Main Theories on the Pathogenesis of Endometriosis The most likely reality is that different mechanisms dominate in different people and different subtypes.
Genetics and Heritability
Endometriosis runs in families, but it does not follow a simple one-gene pattern. A large twin study found that roughly 47 percent of the variation in endometriosis risk could be attributed to genetic factors, with the remaining 53 percent coming from individual environmental influences.10PubMed. Heritability of endometriosis That is a moderate genetic contribution, comparable to conditions like asthma or type 2 diabetes, where genes load the gun but environment and chance pull the trigger.
If your mother or sister has endometriosis, your risk is roughly doubled compared to someone with no family history. One case-control study found that about 6 percent of first-degree relatives of endometriosis patients had the condition, compared to 3 percent among controls.11PubMed Central. Family incidence of endometriosis in first-, second-, and third-degree relatives: case-control study The researchers noted that this modest increase suggests genetics is a contributing factor but may play a less dominant role than previously thought. Inheritance appears to be polygenic, meaning many genes each contribute a small amount of risk rather than one gene acting as a switch.12PubMed Central. Genetics and genomics of endometriosis
Epigenetic Changes and Why Identical Genes Can Produce Different Outcomes
Even when two people carry the same DNA sequence, their genes can behave differently depending on how those genes are switched on or off. These switches, controlled by chemical modifications to DNA and its surrounding proteins, are called epigenetic changes. In endometriosis, researchers have found widespread differences in which genes are active in lesion tissue compared to normal endometrium. These alterations affect genes involved in hormone signaling, immune regulation, and cell identity.13PubMed Central. Epigenetic Dysregulation in Endometriosis: Implications for Pathophysiology and Therapeutics
One notable example involves a family of genes called GATA factors, which help determine what type of tissue a cell becomes. Researchers found that the chemical modifications controlling these genes were significantly altered in endometriotic tissue, and that those modifications correlated inversely with gene activity. Since the different GATA genes sit on separate chromosomes, the changes are not a single event spreading along a chromosome but rather a coordinated shift happening across the genome.14PLOS Genetics. Genome-Wide DNA Methylation Analysis Predicts an Epigenetic Switch for GATA Factor Expression in Endometriosis Epigenetic changes are influenced by hormones, inflammation, and environmental exposures, which is one reason these different risk factors are so hard to study in isolation.
When the Immune System Does Not Clean Up
If backward-flowing menstrual tissue lands in the pelvis, the immune system should recognize it as out of place and clear it. In people who develop endometriosis, that cleanup process appears to fail. Several types of immune cells behave abnormally. Natural killer cells, which normally destroy misplaced cells, show reduced activity in people with endometriosis. Research indicates that these cells express higher levels of inhibitory surface receptors and that excess estrogen interferes with their ability to mature and function properly.15Frontiers in Immunology. From local lesion to multisystem disease: integrated crosstalk among the gut microbiota, immune system, and host metabolism in endometriosis
Macrophages, T cells, B cells, neutrophils, and dendritic cells are also implicated. Rather than eliminating the misplaced tissue, these cells contribute to an inflammatory environment that actually supports lesion survival and growth.16PubMed Central. Exploring the Immune System’s Role in Endometriosis: Insights Into Pathogenesis, Pain, and Treatment This chronic inflammation is not just a bystander. It drives the pain associated with the disease and helps explain why endometriosis behaves as a systemic inflammatory condition rather than a strictly pelvic one.
Estrogen Dependence and Progesterone Resistance
Endometriosis is fundamentally an estrogen-dependent disease. Estrogen fuels the growth and survival of endometriotic tissue, and most medical treatments work by suppressing estrogen levels. But the hormonal picture is more nuanced than just “too much estrogen.” Endometriotic tissue is also resistant to progesterone, the hormone that normally counterbalances estrogen’s growth-promoting effects. This resistance means that even when progesterone is present at normal levels, the tissue does not respond to it the way healthy endometrium would.17PubMed Central. Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms
What causes this progesterone resistance? Multiple factors converge: abnormal receptor signaling, chronic inflammation, altered gene expression patterns, epigenetic changes, and possibly environmental toxin exposure. The result is a hormonal microenvironment that strongly favors tissue growth and inflammation at lesion sites, even when circulating hormone levels look normal on a blood test.
Environmental Exposures
Some environmental chemicals, particularly those that disrupt hormone signaling, have been linked to endometriosis risk. The best-studied class is dioxins, persistent industrial pollutants that accumulate in the body. Animal studies showed that dioxin exposure increases the incidence and severity of endometriosis in primates and promotes endometrial tissue growth in rodent models.18PubMed Central. Dioxins and endometriosis: a plausible hypothesis
In humans, the evidence is less clear-cut. Some studies have found higher blood dioxin levels in people with endometriosis, while others have not confirmed the association.19PubMed Central. Environmental Factors and Endometriosis Polychlorinated biphenyls (PCBs), a related group of pollutants, have a somewhat stronger signal. An Italian case-control study found that people in the highest exposure categories for several PCB congeners had roughly three to five times the risk of endometriosis compared to those with the lowest levels.20PubMed Central. Endometriosis and Organochlorinated Environmental Pollutants: A Case–Control Study on Italian Women of Reproductive Age These chemicals may act through multiple pathways, including direct hormonal mimicry and epigenetic modifications that alter gene expression.
The practical takeaway is that environmental exposures are likely one piece of the puzzle for some people, but the research has not reached the point where you can point to a specific chemical exposure and say “this caused your endometriosis.” These pollutants are widespread and impossible to completely avoid, making it difficult to separate their effect from the many other factors at play.
The Gut Microbiome Connection
An emerging area of research links gut bacteria to endometriosis through estrogen metabolism. Certain gut bacteria produce enzymes that reactivate estrogen that would otherwise be excreted from the body. The collection of genes encoding these enzymes is called the estrobolome. When the gut microbiome is out of balance, it can lead to higher levels of circulating estrogen, which in turn could fuel endometriotic tissue growth.21PubMed. The role of gut and genital microbiota and the estrobolome in endometriosis, infertility and chronic pelvic pain
Studies comparing the gut microbiome of people with and without endometriosis have found differences in specific bacterial populations. One study reported that people with endometriosis had higher levels of the bacterial class Erysipelotrichia and higher concentrations of estrogen metabolites in their stool, though overall microbial diversity and gut enzyme activity did not differ significantly between groups.22PubMed Central. Gut Microbiome-Estrobolome Profile in Reproductive-Age Women with Endometriosis This is an early-stage finding and does not mean that gut bacteria cause endometriosis. But the connection between gut health, estrogen cycling, and endometriosis is generating real research interest.23PubMed Central. Unraveling the Contribution of Estrobolome Alterations to Endometriosis Pathogenesis
Can Endometriosis Start Before You Ever Have a Period?
One of the more surprising theories suggests that some cases of endometriosis may originate at birth. Newborns experience a hormonal withdrawal when they lose exposure to their mother’s estrogen, and this can trigger a mini-menstruation in the neonatal uterus. Occult vaginal bleeding happens in a majority of newborns, while visible bleeding occurs in an estimated 5 percent. If the cervical canal is functionally plugged in a newborn, that uterine shedding could flow backward through the fallopian tubes, seeding endometrial cells in the pelvis long before puberty.24Human Reproduction. Neonatal uterine bleeding as antecedent of pelvic endometriosis
This theory is supported by the observation that endometriosis occurs in premenarcheal girls, particularly those with cervical outflow obstruction and open fallopian tubes. If neonatal retrograde bleeding seeds dormant lesions, those lesions could be activated years later when puberty brings rising estrogen levels. It is a speculative but thought-provoking framework that reframes endometriosis as something that, in some cases, may already be set in motion before the first period ever arrives.
Different Subtypes, Different Environments
Endometriosis is not one uniform disease. It takes at least three recognized forms: superficial peritoneal lesions, ovarian endometriomas (cysts), and deep infiltrating endometriosis. These subtypes look different under a microscope and behave differently in the body, which has led researchers to question whether they all develop through the same pathway.
Superficial lesions tend to have well-organized, differentiated glandular patterns, while deep infiltrating lesions and ovarian endometriomas show more disorganized, undifferentiated tissue.25PubMed. Histologic classification of specimens from women affected by superficial endometriosis, deeply infiltrating endometriosis, and ovarian endometriomas Deep lesions undergo more extensive tissue transformation and develop more fibrous scar-like content, while ovarian endometriomas tend to be more vascular. The two forms share many similarities, suggesting a common starting point, but the differences in their tissue makeup appear to be driven by the local environment where the lesion develops rather than a fundamentally different origin.26PubMed. Histological and Immunohistochemical Characterization of the Similarity and Difference Between Ovarian Endometriomas and Deep Infiltrating Endometriosis
This matters because it means a person could potentially have multiple subtypes simultaneously, each influenced by its local tissue environment. Treatment and symptoms vary across subtypes, and the fact that a lesion on the ovary differs from one embedded in the bowel wall may come down to the surrounding tissue rather than a different biological cause.
Autoimmune Overlap
People with endometriosis have higher rates of autoimmune conditions, and the overlap has fueled debate about whether endometriosis itself has autoimmune characteristics. Shared biological pathways seem to connect the two. Defects in T cell and regulatory cell function, along with abnormal levels of inflammatory signaling molecules, have been observed both in endometriosis and in several autoimmune diseases.27npj Women’s Health. Endometriosis and autoimmunity: a large-scale case-control study of endometriosis and 10 distinct autoimmune diseases
Whether endometriosis drives autoimmune disease, the other way around, or both stem from the same underlying immune dysfunction is not settled. A systematic review concluded that larger follow-up studies are needed to untangle the direction of this association.28PubMed Central. The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis What is increasingly accepted is that immune dysfunction likely contributes to endometriosis pathogenesis, regardless of its formal classification as autoimmune or not.29PubMed Central. Endometriosis and autoimmunity
Diet, Fat Intake, and Modifiable Factors
Lifestyle factors have received less research attention than genetic or hormonal ones, but a few findings stand out. A large prospective study following over half a million person-years of data found that total fat intake was not associated with endometriosis risk. However, people who consumed the most long-chain omega-3 fatty acids (found in fish and certain plant sources) were about 22 percent less likely to be diagnosed with endometriosis, while those who ate the most trans fats were 48 percent more likely to receive a diagnosis.30PubMed Central. A prospective study of dietary fat consumption and endometriosis risk
These associations are not proof of causation. People who eat more omega-3s and fewer trans fats differ from those who do not in many ways, and the study adjusted for known confounders but cannot eliminate them all. Still, omega-3 fatty acids are anti-inflammatory, and trans fats are pro-inflammatory, so the direction of the findings aligns with what we know about endometriosis biology. This is worth knowing if you are making dietary decisions, but it would be misleading to frame diet as a primary cause or a reliable prevention strategy for endometriosis.
Why Only Humans and a Few Other Primates?
Endometriosis occurs spontaneously almost exclusively in humans and certain non-human primates. This is because it requires menstruation, a trait that is rare among mammals. Most mammals reabsorb their uterine lining instead of shedding it. The few species that menstruate, including some old-world monkeys and great apes, are the only ones that develop endometriosis on their own without surgical induction.31The Tohoku Journal of Experimental Medicine. Primate Model Research for Endometriosis
This fact underscores how fundamental menstruation is to the disease process, even if retrograde menstruation alone does not cause it. It also creates a real challenge for research: most animal models require surgically transplanting endometrial tissue, which does not replicate the way human endometriosis naturally develops. Rodent and rabbit models have taught us about tissue behavior and treatment responses, but the spontaneous primate model remains the closest to the human disease. The rarity of suitable animal models is one reason why endometriosis research has been historically underfunded and understanding of its causes remains incomplete.
How Lesions Sustain Themselves
Once endometriotic tissue establishes itself in an ectopic location, it does not just sit there passively. Lesions recruit their own blood supply through angiogenesis, the growth of new blood vessels, and develop their own nerve fibers. Tissue adjacent to endometriosis lesions shows increased nerve density and vascular density, suggesting that the lesions actively remodel their local environment. Research into the signaling pathways involved has found that nerve growth factor (NGF) signaling through TrkA receptors appears to mediate the pain associated with endometriosis and may also influence lesion size. Blocking this particular signaling pathway in a mouse model reduced both pain behavior and lesion dimensions.32PubMed Central. Targeting NGF but not VEGFR1 or BDNF signaling reduces endometriosis-associated pain in mice
This self-sustaining behavior helps explain why endometriosis tends to be a chronic, progressive condition. The lesions are not just misplaced tissue waiting to be cleared. They actively modify their surroundings, build infrastructure, and generate inflammatory and pain signals that perpetuate the disease cycle. It also helps explain why surgical removal of lesions does not always prevent recurrence. If the underlying conditions that allowed the tissue to implant and thrive are still present, new lesions can form, or microscopic remnants can regrow.