What Causes Endometriosis?

Exploring the Drivers Behind Endometriosis

Much of the information you’ll find online, in books, or in articles tends to state something along the lines of: “The cause of endometriosis is unknown, but we have several theories, some more plausible than others.” But what does that actually mean for you personally? If you are searching for answers—whether for pain relief, infertility, a diagnosis, or an explanation for why your endometriosis came back—you’re likely looking for practical guidance rather than abstract theories. Clear, actionable answers can feel surprisingly hard to come by. Adding to that frustration, you may also encounter a whirlwind of “controversies” about the most effective treatments, making your search for clarity even more confusing.

To put it simply, endometriosis is a chronic and often painful disease that affects at least 10% of women (XX) of reproductive age and is driven to a significant degree—though not exclusively—by sex hormones, particularly estrogen. It is extremely rare in men (XY), but cases have been documented when high, long-term doses of estrogen are used for prostate cancer or comparable medical conditions. As a result, the number of people who may experience endometriosis could shift. There may be growing relevance for trans women undergoing prolonged estrogen therapy.

This article provides an introductory overview of the latest research on the origins, biological mechanisms, and potential treatment approaches for this highly complex and widespread condition. In other words, it aims to link current knowledge with useful, practical insights you can apply when making decisions, including awareness of options that may become available in the future. This might or might not influence your choices right now.

At the conclusion of this article, we will offer practical guidance and strategies to help you move toward your goals. However, it’s essential to understand the foundational information first—otherwise, the recommendations won’t have context or meaning.

What is Endometriosis?

Endometriosis is a medical condition in which tissue resembling the endometrial lining of the uterus grows outside the uterus. This statement appears frequently, but what does it actually mean? It means that, although these cells look very similar under a microscope, they are molecularly quite different.

Gene expression: Endometriotic cells typically show increased expression of genes linked to cell survival, inflammation, the formation of new blood vessels (angiogenesis, which provides nutrients), and invasive behavior when compared to standard endometrial cells. Prominent examples include genes that code for COX-2, VEGF, MMPs, and various cytokines, all of which are often upregulated. Together, these contribute to highly aggressive behavior.

Epigenetics (which you will read more about below): Epigenetic distinctions—such as differences in DNA methylation and histone modifications—have been identified between endometriotic and endometrial cells. These changes influence gene activity without altering the actual DNA sequence.

Hormonal responses: Endometriotic cells frequently behave differently in response to hormones like estrogen and progesterone. For instance, they often contain higher amounts of aromatase, the enzyme responsible for producing estrogen. They may also be less sensitive to progesterone than normal intra-uterine endometrial tissue, due to altered progesterone receptor expression.

Immune response: Endometriotic lesions commonly include immune cells such as macrophages and T cells and generate pro-inflammatory cytokines. This indicates a persistent inflammatory reaction, which may play a role in the symptoms of endometriosis and in helping endometriotic cells survive outside the uterus.

The presence of these abnormal, endometrial-like tissues in ectopic or atypical locations frequently leads to chronic pelvic pain, gastrointestinal issues such as bloating, fertility challenges, and a wide range of other symptoms that can seriously affect quality of life.

The Prevalence Endometriosis and its Impact

In addition to affecting at least 10% of XX women—and potentially a growing number of XY trans-women—endometriosis is also found in up to 50% of women undergoing evaluation for fertility problems. Further, epidemiological data indicates that women with endometriosis may face an elevated risk of developing other health conditions, including (but not limited to) asthma, rheumatoid arthritis, intestinal dysbiosis, additional immune dysfunction, cardiovascular disease, and even cancers such as ovarian, breast, and melanoma. While endometriosis does not account for every symptom a person may experience, many of these symptoms and signs may still be closely connected and stem from a shared underlying cause related to endometriosis.

Unfortunately, diagnosis is often significantly delayed—by as much as a decade—because standard medical assessments and testing typically fail to consider these interrelated factors. In practical terms, this means that issues like intestinal symptoms are frequently evaluated on their own, while their potential relationship to painful periods, pain during intercourse, or infertility is missed. 

Symptoms and Diagnosis of Endometriosis

Although discussion about the potential causes of endometriosis may persist for quite some time—and the origins may vary or overlap from one person to another—the first priority is obtaining an accurate diagnosis. That is what enables the most personalized and well-informed treatment plan.

Endometriosis symptoms can differ widely depending on where the disease is located in the body, the degree of inflammation it triggers, and any related conditions. Still, the most common symptoms include bloating, chronic pelvic pain (both cyclical and non-cyclical), painful menstrual periods, pain during intercourse, and pain with bowel movements and urination. Beyond physical pain, endometriosis is frequently linked to fatigue and depression, which further intensify the overall impact of the condition.

Diagnosing endometriosis is difficult because its symptoms overlap with those of more common health issues. This can lead to many years—up to a decade—of emergency room visits and appointments with multiple specialists, each examining symptoms only through their own specialty’s narrow perspective. For example, a gastroenterologist focuses on the digestive tract, a general gynecologist focuses on the uterus and ovaries, a neurologist targets nerve-related issues, and a urologist looks at the bladder—each searching for the usual conditions seen in their field. Those common diagnoses are usually not endometriosis. In addition, there are still no specific blood tests and current imaging techniques lack high accuracy. However, certain inflammatory markers and other lab tests can assist an endometriosis specialist in narrowing down the diagnosis. Similarly, imaging such as ultrasound or MRI may help detect clear signs like endometriomas (ovarian cysts containing old blood and endometriosis tissue) or deep infiltrating endometriosis. This information assists with surgical planning when disease involves areas such as the sciatic nerve, bladder, or rectum. But even if imaging appears normal, the surgeon and/or surgical team must still anticipate and be prepared for unexpected findings.

At present, the only way to confirm endometriosis with certainty is through biopsy, typically performed during minimally invasive diagnostic surgery. Ideally, the surgeon performing the procedure should also be skilled enough to remove any endometriosis discovered—by excision—during the same surgery rather than scheduling an additional operation. This is where diagnosis intersects with the most effective established treatment: excision surgery. The level of expertise required for this goes beyond that of most general gynecologists unless they have pursued additional training to develop advanced surgical skills. If possible, both diagnosis and any necessary treatment should be done correctly the first time to reduce misdiagnosis, lower complication risks, and avoid repeat surgeries.

As you will learn further in this article, diagnostic methods will likely be improved in the near future, and accurate blood tests for both diagnosing and monitoring endometriosis are expected to become available. These will rely on proteomics and miRNA signatures, meaning endometriosis correlates with certain measurable proteins and specific types of ribonucleic acids (RNA) circulating in the bloodstream. Significant research has already been conducted in this area, and the next step is determining which combination of these markers provides reliable accuracy.

Unraveling the Cause(s) of Endometriosis

It is very unlikely that a single, definitive cause of endometriosis will be identified any time soon—if ever discovered at all. That said, a unifying cause at the genetic level is still possible and remains an active area of research. When seeking practical, actionable answers, it is helpful to put this uncertainty into context. Much more realistically, the causes (plural) of endometriosis are polygenic (involving multiple gene abnormalities), multifactorial, and most likely vary from one individual to another. This is similar to what we see with other conditions. There is no single cause of cancer, high blood pressure, various forms of diabetes, and so on. Yet treatment options continue to expand because research is now focusing on identifying contributing factors and developing targeted therapies at the molecular, genetic, epigenetic, and genomic levels. That may sound complex, but these microscopic molecular components regulate everything in the body—both normal processes and disease.

Potential Theories

One of the most commonly cited explanations for the origin of endometriosis is Sampson’s long-standing concept of “retrograde menstruation.” This theory has been both overly praised and heavily criticized—and often misunderstood. It proposes that fragments and cells from the endometrial lining flow backward through the Fallopian tubes during menstruation, escape the uterus, and then implant in the pelvic cavity, directly forming endometriosis lesions. However, since retrograde menstruation occurs in a very high percentage of women (at least 70–90%, according to laparoscopic observational studies), why do the vast majority of women with a uterus not develop endometriosis? Additionally, from a molecular standpoint, eutopic endometrium and ectopic endometriosis cells display many differences. These contradictions raise the possibility that this theory is either outdated and incorrect, or that most women have bio-molecular or immune defenses that prevent spilled endometrial cells from implanting, while some do not. It is also possible that, given the existence of somatic stem cells in the endometrium, only a specific subset of these stem cells can implant and differentiate if they reach the peritoneal cavity—not typical endometrial cells. Therefore, before dismissing this theory entirely, more advanced research using modern scientific tools is needed. Our scientific knowledge has progressed tremendously since this idea was first put forward more than a century ago.

What is certain, however, is that for endometriosis to grow and create problems, it must arrive at the site and successfully implant. So aside from retrograde menstruation, how else could this occur?

Other proposed theories for the development of endometriosis include:

1. Müllerianosis: This concept describes an organoid structure known as a “choristoma,” consisting of Müllerian-derived tissue—endometrial, endocervical, and endosalpingeal cells—deposited in abnormal locations during embryonic development. Sampson also proposed this as a possibility.

2. Coelomic metaplasia: First suggested about a century ago, this theory proposes that the peritoneal mesothelial lining could transform into endometrial-like tissue.

3. Endometrial somatic stem/progenitor cells: These may contribute to endometriosis lesions by reaching the peritoneum through retrograde menstruation (a variation of the original theory) or by traveling through lymphatic or small vascular channels.

4. Benign metastasis: This suggests that endometrial cells are transported outside the uterus via the lymphatic system.

5. Bone marrow pluripotent stem cells: These circulating cells, capable of differentiating into any cell type, may reach the pelvis or other areas through the bloodstream, implant in a favorable environment, and grow.

Additional theories exist, and combinations or modified versions of the above have also been proposed.

As is true in many areas of medicine, the reality likely lies somewhere among these theories—and may differ somewhat from person to person. Modern molecular evidence supports aspects of most of these theories, often showing areas of overlap.

Endometriosis Growth and Progression

Understanding how endometriosis develops may eventually lead to prevention strategies, which will likely need to be highly personalized. For now, the more practical question is: once the initial cells are present, what drives them to grow, recur, and progress at different speeds? It is the growth itself that leads to symptoms by causing inflammation, fibrosis (scar tissue), and pain. Remember that endometriosis generally appears in three forms: (1) superficial, (2) deep infiltrating, and (3) endometriomas. These types may overlap or appear independently, making it unlikely that a single universal treatment approach will ever apply to everyone.

What truly matters in day-to-day life is what triggers progression, when it occurs, and why. By addressing these questions, useful insights and actionable strategies can be developed. The following represent mechanisms or pathways through which endometriosis cells can be sustained and driven to grow. As such, they offer potential points for intervention—both currently and in the future—as more treatment targets are identified.

This leads us to the practical focus: what can be medically or surgically acted upon today, and what proactive steps might you personally take now to influence your situation? The latter falls within lifestyle and dietary choices—but rooted in science. While there is a great deal of “alternative” advice that lacks credibility, there are also many evidence-informed holistic and natural approaches that may be beneficial.

Genetics and Genomics

Evidence from epidemiologic studies, twin studies, single-gene research, and genome-wide association studies (GWAS) makes it clear that the risk of developing endometriosis is strongly rooted in multiple genes (polygenic) and their polymorphisms (variations of different degrees). Genes can also interact with one another, either increasing or decreasing disease risk. However, inheriting unfavorable gene polymorphisms or mutations is not the final determining factor, because whether these genes become activated or suppressed depends on various multifactorial influences—such as environmental exposures, including nutrition, toxins, and lifestyle choices. Put simply, you may inherit “good” or “bad” genetic cards, but how they ultimately play out can still be influenced. These influences fall under the fields of genomics and epigenetics, along with related sciences such as proteomics, metabolomics, nutrigenomics, and others. In essence, these disciplines explore how genes are switched on or off.

Epigenetics

Epigenetics examines how genes are regulated or expressed without altering the DNA sequence itself. The prefix “epi-” means “on top of” the genes. Epigenetic changes involve modifications that attach to DNA—such as methyl groups (sourced from diet and supplements)—which can either suppress or activate gene expression. Environmental factors, including diet, hormones, stress, medications, and exposure to chemical toxins, influence methylation. Specifically related to endometriosis, altered DNA methylation patterns have been identified in endometriotic lesions. The epigenome includes additional mechanisms for gene–environment interaction, such as histone modification, a regulatory process that determines how DNA unwinds so it can be read or transcribed. This, too, is affected by lifestyle and diet today and represents a major potential therapeutic target for the future.

Hormonal Imbalances

Endometriosis is frequently referred to as a “steroid-dependent” condition, highlighting the substantial influence of steroid hormones—primarily estrogen—in its development.

This relationship is extremely complex and, in some cases, counterintuitive. Managing endometriosis is not as simple as adding or reducing estrogen or progesterone. The effects depend on the levels of these hormones within the tissues, as well as the number and sensitivity of estrogen and progesterone receptors. The receptors function like locks, while the hormones act as keys. And this is only the starting point, because receptors have different components, and additional molecular pathways influence activity both before and after estrogen binds to its receptor.

For example, individuals who are significantly overweight often have higher circulating estrogen levels. This is because estrogen is produced by the ovaries, converted within fat cells, and also released from environmental xenoestrogen endocrine disruptors stored in fat. Using that logic, one might assume that people with higher body weight would be more likely to have endometriosis. Not so. Endometriosis is more common in women with a healthy BMI. In fact, the more problematic deep infiltrating forms and endometriomas are more frequently seen in very thin individuals (BMI under 18.5). The reason remains unclear, but possible explanations include homeostatic mechanisms—such as estrogen receptor upregulation—leading to increased estrogen sensitivity. Additionally, hormone signaling is not the only molecular factor influencing endometriosis.

Another example involves menopause. Post-menopause, estrogen levels decline and endometriosis usually regresses, but not for everyone. This is partly due to the fact that endometriosis lesions can generate their own estrogen, and additional molecular growth factors are likely involved. There are also more ERβ receptors on endometriosis cells, resulting in increased prostaglandin production, which contributes to pain at any age.

Overall, reducing “estrogen dominance” to some extent can suppress endometriosis, but ideally not by using synthetic progestins as a form of hormone “balancing.” Natural progesterone and synthetic progestins both decrease and counter estrogen’s growth-promoting effects, yet progestins can also promote growth in certain tissues (such as the breast). Furthermore, progesterone and progestins generally have a weaker impact on endometriosis than on normal intrauterine endometrial tissue. Likewise, using GnRH agents to drastically lower estrogen levels for a short time does not produce the intended benefit and leads to side effects and potential harm, making the risk–benefit balance particularly problematic. A more effective—and safer—approach may be long-term gentle suppression, which can be done using progesterone. Synthetic progestins such as norethindrone acetate remain an option, with the above cautions. Another route to support hormonal balance involves lifestyle approaches, including consuming seaweed, exercising regularly, and actively reducing exposure to xenoestrogen toxins.

Inflammation

Endometriosis may partly result from inflammation, and it simultaneously triggers an inflammatory response of its own. This means it can become a self-perpetuating cycle, contributing to the onset and persistence of symptoms. Immune cells—including macrophages, NK cells, and T cells—are commonly found within endometriosis lesions, and their interactions with endometriosis cells can help drive lesion formation and growth. In addition, the peritoneal fluid of individuals with endometriosis often shows altered composition, with elevated levels of pro-inflammatory cytokines and growth factors.

Inflammation can arise from various origins, including infection—either clinical (meaning you feel ill) or chronic and subclinical. For instance, chronic endometritis (infection of the uterine lining) occurs more frequently in patients with endometriosis than in those without it. While this is a correlation and the causal relationship remains unclear, multiple bacteria have recently been implicated. In animal models, antibiotic treatments aimed at these bacteria have led to regression of endometriosis lesions. Bacteria from the uterus or cervix can easily travel—either directly through the Fallopian tubes or via the bloodstream—to the peritoneal cavity, where they can trigger inflammation. This inflammatory response is thought to contribute to the progression of endometriosis.

Leaky gut, which may be linked to low microbiome diversity, can allow bacterial fragments known as lipopolysaccharides (LPS) to enter the peritoneal cavity as well. This also leads to inflammation and may contribute to further endometriosis growth.

Not all inflammation stems from infection. It may be caused by many non-infectious factors, including stress, autoimmune disorders, obesity, systemic diseases such as diabetes or pre-diabetes, mast cell activation, toxin exposure, and more.

Most sources of inflammation are molecularly actionable and are currently the focus of research. For now, general anti-inflammatory strategies—pharmacologic and integrative—can be beneficial.

Dysbiosis

Imbalances in the gut microbiome (dysbiosis) have a direct negative influence on the gut–endocrine axis and can affect the growth of endometriosis. This occurs through three key mechanisms:

Estrobolome: This term describes the portion of gut bacteria capable of metabolizing estrogens. In a healthy state, the estrobolome helps regulate estrogen levels by contributing to enterohepatic circulation, which influences the amount of estrogen that circulates and is excreted. Dysbiosis, however, disrupts estrobolome function and alters estrogen metabolism. In endometriosis, this imbalance may lead to excess circulating estrogen, which promotes the growth and survival of endometrial cells outside the uterus, therefore contributing to endometriosis.

Gut–Endocrine Axis: The gut microbiota also impacts the gut–endocrine axis—a complex interaction among gut bacteria, gut cells, and endocrine organs. Dysbiosis can alter gut permeability (referred to earlier as “leaky gut”), increasing inflammation and causing immune system dysregulation. This can disrupt normal hormonal regulation, potentially worsening conditions such as endometriosis.

Gut–Brain Axis: Dysbiosis additionally affects the gut–brain axis, a two-way communication network linking the central nervous system and the enteric nervous system. Shifts in gut microbiota can influence this axis, resulting in altered pain perception and heightened stress responses, both of which can impact the experience and progression of endometriosis.

Shared Molecular Growth Drivers with Cancer

It is important to recognize that a very small percentage of women with endometriosis may develop an endometriosis-associated cancer (<1%), and gene mutations are likely the driving factor behind this. However, some of these same genes overlap with those linked to more aggressive forms of endometriosis, such as deep infiltrating disease and endometriomas. In other words, these mutations may not necessarily cause cancer, but they may fuel more severe variants of endometriosis. This overlap has led some researchers to suggest that endometriosis may function as a pre-cancerous condition in a small subset of individuals with the disease.

The most extensively researched gene in this context is ARID1A, though others have also been associated, including KRAS, PTEN, HOXA10, VEGF, ESR1, ESR2, and FN1. Because these genes are heavily studied in cancer research, there is potential for targeted therapies developed in the oncology field to be applied to more aggressive forms of endometriosis in the future.

Current Treatment Strategies for Endometriosis

For most individuals with endometriosis, effective treatment is based on a personalized assessment, an accurate diagnosis, and expert excision surgery aimed at reducing inflammation as well as pain and other symptoms. This is often followed by some level of medical suppression—usually hormonal—for many patients. The key is tailored guidance that avoids both over-treatment and under-treatment.

Excision surgery remains the cornerstone of care today because it provides a definitive diagnosis and removes all visible disease when possible. However, surgery should not be undertaken indiscriminately. It should be performed by a specialist when the level of suspicion for endometriosis justifies the surgical risks. It is generally advisable to consider medical suppressive therapies only after a confirmed diagnosis, rather than starting potentially risky hormonal treatments based merely on suspicion.

Before and after surgery, several optimization strategies can be beneficial, including pelvic floor physical therapy (PFPT) and a pain-management plan that takes into account each person’s specific pain triggers. These vary from individual to individual. Both supportive therapies are complex but essential parts of treatment in most cases, helping patients prepare for surgery, recover more smoothly, and transition toward life without endometriosis.

It is also necessary to evaluate related conditions discussed throughout this article, such as dysbiosis and possible small intestinal bacterial overgrowth (SIBO), as well as leaky gut. Symptoms of these conditions and endometriosis often overlap, so identifying other causes of pain and bloating is helpful. Evaluation should also consider mast cell activation, chronic inflammatory response syndrome (CIRS), autoimmune hypothyroidism, fibromyalgia, irritable bowel syndrome (IBS) or disorders of gut–brain interaction, and interstitial cystitis (IC). In addition, there are conditions not directly caused by endometriosis but commonly seen alongside it, such as Lyme disease and mold exposure. Both can amplify inflammatory responses, and water-damaged buildings can harbor black mold. The CDC has also issued warnings that tick-borne illnesses such as Lyme disease and babesiosis are increasing.

As highlighted in this article, there are many additional steps you can take to influence and reduce endometriosis recurrence and progression. None of them are magical or quick fixes, but with expert guidance they are generally health-supportive, safe, and usually not costly. Once again, the best outcomes occur when overseen by an experienced specialist.

Emerging Therapeutic Approaches

Although several treatment options exist today, there remains a significant need for new and effective therapies for endometriosis beyond surgery and variations of hormonal management. Researchers are currently exploring immunotherapies that target specific cytokines or immune cells involved in endometriosis. Additional promising research areas include treatments aimed at modifying the altered metabolic environment within endometriosis lesions and neuromodulator therapies designed to interrupt pain pathways associated with the disease. This article is not intended to explore these future options in depth, but when considering all the potential causes and contributing factors, it becomes clearer which advances are likely to arrive sooner rather than later.

Recent examples from animal studies—and concepts expected to advance to human trials—include: targeted anti-inflammatory therapy; antibiotic therapy directed at specific bacteria such as Fusobacterium; an antibody (AMY109) that binds IL-8; small interfering RNA targeting VEGF (siVEGF); epigenetic and histone modification therapies aimed at altering gene transcription related to endometriosis, including estrogen and progesterone receptors; epigenetic modification of T-cell immune responses in endometriosis; ARID1A and other “cancer gene” targeting strategies; and more. While these are not yet available in clinical practice, the research momentum is strong. Progress would certainly accelerate with increased funding, but development is already underway.

Proactive Holistic Principles

While we wait for mainstream, targeted molecular treatments, it’s important to understand that natural integrative approaches can also influence many of the same molecular pathways. Although they may not precisely target a single molecular pathway, this can actually be beneficial. Abnormal cells—such as those involved in endometriosis—can adapt or find ways around a blocked pathway, causing treatments to lose effectiveness. We see this in other conditions where molecular therapies are already widely used. In contrast, nature has, so to speak, anticipated this issue, and many nutrients can exert synergistic, positive effects across multiple molecular pathways simultaneously.

Additionally, your microbiome, estrobolome, inflammation, oxidation, nutrition, stress levels, lack of exercise, and more affect your body through epigenetic mechanisms, as discussed earlier. More specifically, a major part of this is driven by nutrigenomic epigenetics, which can be influenced through food, as well as carefully selected supplements and botanicals.

It is essential to emphasize that this does not mean stocking up on obscure, extremely expensive supplements. The 80/20 rule—which states that 80% of results often come from 20% of actions—applies here: significant progress can be made with a personalized antioxidant, anti-inflammatory diet. This is often achieved through a whole-food, plant-based approach. When combined with consistent exercise and stress-management practices, you are already 80% of the way toward supportive lifestyle change.

Conclusion

Endometriosis is a complex, multifaceted, polygenic, and multifactorial condition, and there is still much to learn about its causes and progression. As scientific understanding expands, so will the ability to create accurate diagnostic tools and targeted, effective treatments. In the meantime, with expert care—and your own proactive engagement in nutritional and lifestyle strategies—outcomes can range from good to excellent. No disease or condition guarantees a great outcome for everyone, but in the case of endometriosis, results can be optimized by working with an endometriosis specialist. Additionally, consulting with experts who have integrative or functional medicine training can elevate care even further.