What Cause of Endometriosis?

Actionable Insights into the Cause of Endometriosis and Evidence-Based Treatments on the Horizon

Most of what you read online and in books or articles says something like “The cause of endometriosis is unknown, but we have a number of theories, some of which are more likely than others.” But what does this practically mean for you as an individual?   As someone who is looking for answers for pain relief or infertility solutions or a diagnosis or why your endo recurred, you probably want practical answers not abstract theories. Actionable answers seem remarkably elusive.  To add to your frustration, you may also find yourself stumbling upon a storm of “controversies” regarding the best treatment options, further muddying the water in your personal quest for answers.

Basically, endometriosis is a chronic and often painful condition that affects at least 10% of women (XX) of reproductive age and significantly, but not entirely, fueled by sex hormones, mainly estrogen.  It is exceedingly rare in men (XY) but has been reported with high doses of prolonged estrogen therapy for prostate cancer and similar conditions.  Thus, the scope of how many people with endometriosis may be changing. Endo may have increasing implications for trans women who might be prescribed prolonged estrogen therapy. 

This article is an introductory overview of the most current research on the etiology, pathobiology, and potential therapeutic strategies for this extremely complex and prevalent condition.  In other words, it attempts to connect what we know with some practical insights for you to base decisions on, including factoring in what may be coming as options down the road. This may or may not alter your decision-making today as well.  

At the end of this article, we will introduce some practical tips and strategies for getting you to where you want to go. But you must understand the basis for these first, or it won’t make sense.   

What is Endometriosis?

Endometriosis is a medical condition characterized by the growth of endometrial-like tissue, similar to the internal lining of the uterus, outside the uterus. You see this mentioned a lot, but what does it mean exactly?  It means that the cells look quite similar under the microscope, but molecularly they are very different.   

Gene expression : Endometriotic cells often express genes associated with survival, inflammation, angiogenesis (blood vessel formation to have access to nutrients), and invasion more highly than typical endometrial cells. Major examples include genes coding for COX-2, VEGF, MMPs, and various cytokines, which are often upregulated. These all encode for aggressive epigenetics (something you will read about below): Epigenetic differences, including DNA methylation and histone modification differences, have been observed between endometriotic and endometrial cells. These changes can alter gene expression without changing the DNA sequence itself.

Hormonal responses: Endometriotic cells often show altered responses to hormones, including estrogen and progesterone. For example, they usually contain higher levels of aromatase, an enzyme that produces estrogen.  In addition, they may be less responsive to progesterone compared to normal intra-uterine endometrial tissue due to changes in progesterone receptor expression.

Immune response: Endometriotic lesions often contain immune cells, such as macrophages and T cells, and produce pro-inflammatory cytokines. This suggests an ongoing inflammatory response, which may contribute to the symptoms of endometriosis and the survival of endometriotic cells outside the uterus.

The presence of these aberrant endometrial-like tissues in ectopic or unusual locations often results in chronic pelvic pain, intestinal symptoms like bloating, fertility problems, and a lot of other symptoms that can significantly impact the quality of life. 

The Prevalence and Impact of Endometriosis

Beyond affecting at least 10% of XX women and potentially an increasing number of XY trans-women, the condition is detected in up to 50% of women seeking treatment for fertility issues. Moreover, epidemiological studies suggest that women with endometriosis may be at a higher risk of developing other health conditions including, but not limited to, asthma, rheumatoid arthritis, intestinal dysbiosis, other immune dysfunction, cardiovascular disease and even cancers like ovarian, breast and melanoma. So, while endo cannot explain all symptoms, these symptoms and signs may still be very related and due to a common root cause of endometriosis. Too often, an endo diagnosis is extremely delayed, up to a decade, because medical evaluation and testing do not explore these connections.  In other words, for example, intestinal complaints are looked at in isolation, and connections to painful periods, pain during sex, or infertility are overlooked.   

Symptoms and Diagnosis of Endometriosis

While debate concerning possible causes of endometriosis may continue for some time and the etiologies may overlap or differ between individuals, the first step is to get a correct diagnosis. That leads to the best personalized and informed treatment plan. 

The symptoms of endometriosis  can vary greatly based on where it is located in your body, the inflammation it is causing and all of the related conditions. But, the most common symptoms include bloating, chronic pelvic pain (both cyclical and non-cyclical), painful menstrual cycles, painful intercourse, and pain during bowel movements and urination. In addition to physical discomfort, endometriosis is often associated with fatigue and depression, further compounding the impact of the condition.

Diagnosing endometriosis is challenging due to the overlap of its symptoms with more common conditions. This can result in up to a decade of visiting emergency rooms and various specialists, who look at the symptoms through their specialty’s diagnostic lens with somewhat of a tunnel-vision result.  So, a gastro will focus on the gut, a general gynecologist will focus on the uterus and ovaries, a neurologist will focus on nerves, a urologist will focus on the bladder, and so on, all looking for common diagnoses within their specialties. These more common diagnoses are usually not endometriosis.  Further, there are no specific blood tests yet and imaging is not very accurate. However, inflammatory markers and other tests can help an endo specialist hone in on the diagnosis.  Similarly, imaging via ultrasound or MRI may be helpful in finding obvious signs of endometriomas (ovarian cysts filled with old blood and endometriosis tissue) or deep infiltrating type of endometriosis.  This simply helps preparation for surgery in the event of findings like disease near the sciatic nerve or growing into the bladder or rectum. However, if negative, the surgeon and/or team must still expect and be ready to handle the unexpected.

Today, a definitive diagnosis of endometriosis can only be achieved by biopsy, usually during a diagnostic minimally invasive surgery.  Ideally, the surgeon who is operating should be capable of removing any endo that is found by excising it, at that time and not at a subsequent surgery.  This is where the diagnosis overlaps with an effective known treatment, excision surgery. The skill base for this is usually beyond most general gynecologists unless they have devoted extra time and training to acquire more advanced surgical skills.  If possible, this diagnosis and possibly therapeutic surgery should be done correctly the first time to minimize misdiagnosis, complications and repeat surgeries. 

Based on some of what you are about to read, diagnostics will likely soon be enhanced, and accurate blood tests will become available for diagnosis and monitoring.  These tests will be based on proteomics and miRNA signatures, which means that endometriosis is associated with various measurable proteins and ribonucleic acids (RNA) of a specific kind, circulating in the blood.    A lot of research has already been done on this, but it is a matter of finding a combination of these that is accurate.  

Unraveling the Cause or Causes of Endometriosis

It is highly unlikely that there will be a discovery of “THE’ unifying cause of endometriosis any time soon, if ever. However, this is still possible on a gene level and is a focus of ongoing research. But when you are looking for actionable, practical answers, this uncertainty should be framed a little better.  Far more likely than not, the causes (plural) of endometriosis are polygenic (multiple gene aberrations), multifactorial, and most likely differ between individuals. The same situation exists in other diseases we treat.  There is no single cause of cancer, blood pressure problems, different types of diabetes, and so on.  Yet, treatment options are increasing because we are now searching for causative factors and targeted therapies at a molecular, genetic, epigenetic and genomic level.  That is a mouthful, but these subcellular molecular factors control everything in your body, normal and abnormal. More on this below. 

Theories

One of the most widely accepted theories for the origin of endometriosis is the very old concept of “retrograde menstruation”, proposed by Sampson. It has been both overly glorified and vilified and certainly misunderstood often. This theory suggests that endometrial tissue fragments and cells escape from the uterus during menstruation, being forced backward through the Fallopian tubes, and implant in the pelvic cavity, directly forming endometriosis lesions.  But since retrograde menstruation is very common (at least 70-90% of all women based on laparoscopy observational studies), why do most or all women with a uterus not have endo?  Also, from a molecular point of view, eutopic endometrium and ectopic endometriosis cells differ in many respects. The answer to these disconnects is that perhaps this theory is indeed totally wrong and outdated.  Or perhaps there are factors in most women that can bio-molecularly or immunologically repel the growth of spilled endometrial cells, while some can’t. Or perhaps, since we know somatic stem cells exist in the endometrium, only a fraction of a certain type of stem cell may grow and differentiate if dropped into the peritoneal cavity and not all endometrial cells.  So, before completely retiring this theory, more sophisticated studies are required with today’s scientific tools. We have come a long way since the limited science that was available more than 100 years ago, when this was initially proposed.   

One thing is for certain, for endo to grow and cause problems it must get there somehow and take root first.  Other than retrograde menstruation, how else might that happen? 

Other theories as to how endo originates include: 

1/ Müllerianosis, which means an organoid structure called a “choristoma” composed of Müllerian rests which are islands of tissue of endometrial, endocervical and endosalpingeal that are deposited in unusual areas during the growth of an embryo. This was also suggested by Sampson.   

2/ Coelomic metaplasia: this theory suggests that peritoneal mesothelium (lining) could transform into endometrial-like tissue (also proposed about 100 years ago) 

3/ Endometrial somatic stem/progenitor cells may play a role in the formation of endometriosis lesions, getting to the peritoneum either by retrograde menstruation (a variation of the original theory) or via lymph or tiny vascular transport channels 

4/ Benign metastasis, meaning that endometrial cells are transported by the lymphatic system beyond the uterus 

5/ Bone marrow pluripotent stem cells (i.e. can turn into any cell imaginable), which we know circulate in the blood, can reach the pelvis or other areas directly, implant due to a favorable local growth environment and grow.  

There are others, and variations or mixtures of the above have also been proposed. 

The truth, as almost always, is likely in between all these theories and likely differs between individuals to some extent. Today, we have molecular evidence that supports most of the above in varying degrees and tends to overlap.  

Endometriosis Growth and Progression 

Finding out how endometriosis develops will eventually lead to prevention strategies, which may be highly individualized.  But for now, the more actionable question is, once the initial cells are there, what causes them to grow and regrow, and at different rates?  It is the growth that gets you into trouble with symptoms by triggering inflammation, fibrosis (scar tissue) and pain.   Keep in mind that there are three general types of endo: 1/ superficial 2/ deep infiltrating and 3/ endometrioma.  These can overlap, or not. So, most likely, there will never be a one-size-fits-all solution. 

However, what happens with progression, when it happens and why it happens is where the rubber meets the road. In answering these questions, insights and actionable strategies can be developed.  The following are avenues or pathways by which endometriosis cells can be fueled to grow.  Therefore, they present actionable intervention possibilities, now and into the future as we identify more targets.  

So, the following is where we are going with all this.  What is medically/surgically actionable now and what you can do proactively today that may influence your personal situation?  The latter is in the realm of lifestyle and diet but grounded in science.  There is a lot of woo-woo “alternative” stuff out there but also quite a bit of holistic natural options that is evidence-informed and can be helpful.  

Genetics and Genomics

From epidemiologic, twin, single gene, and genome-wide association studies (GWAS) there is little doubt that risk factors for developing endo is largely grounded in multiple genes (polygenic) and their polymorphisms (alterations of various magnitudes).  In addition, genes can interact with each other, either amplifying or reducing disease.  But inheriting less desirable gene polymorphisms or mutations is not the be-all end-all because how these genes are activated or suppressed is dependent upon other multifactorial influences (e.g. your environment, including nutrition, toxins and lifestyle choices).  In other words, you may inherit good cards or bad cards, but how they play out can be influenced.  These influences are based on  genomics and epigenetics  and related sciences like proteomics,  metabolomics, nutrigenomics, and so on. Basically, these sciences all study how genes are suppressed or expressed.

Epigenetics

Epigenetics studies how genes are controlled or expressed without changing the inherited DNA sequence.  “Epi-” means on top of the genes.  These are modifications that attach to the DNA, like methyl groups (from diet and supplement sources), which can suppress or help activate genes. Environmental factors such as diet, hormones, stress, drugs, chemical toxin exposure alter methylation.  Directly related to endo, alterations in DNA methylation patterns in endometriotic lesions have been described.  The epigenome harbors other ways that this gene to environment interaction occurs.  This includes histone modification, which is regulatory mechanism that controls unraveling of DNA so it can be read or transcribed.  This is also subject to lifestyle and dietary influence today and is a major potential therapeutic target for the future.

Hormonal imbalances

Endometriosis is often described as a “steroid-dependent” disorder, reflecting the significant role of steroid hormones, mainly estrogen, in its pathogenesis. 

This is a VERY complex influence and defies logic in some cases.  It is not as simple as therapeutically adding or taking away estrogen or progesterone.  Rather, it depends on tissue levels of estrogen and progesterone as well as the number and sensitivity of estrogen and progesterone receptors. The hormones and their receptors work like a lock (receptor) and key (hormone).  And that is just the beginning, because there are different components of receptors and additional molecular pathway influences, before and after estrogen binds to its receptor. 

For example, there is more estrogen circulating when someone is significantly overweight, because there is production from the ovaries AND estrogen from fat cell interconversion AND from environmental xenoestrogen endocrine disruptors that are stored in fat. So that would mean the people who are overweight are more likely to have endo, right?  Wrong.  Endo is more common in women with a healthy BMI. In fact, problematic deep infiltrating endo and endometrioma types, is more prevalent in those who are very thin (BMI less than 18.5).  Why?  This is unknown, but various homeostatic mechanisms like estrogen receptor upregulation can hypothetically lead to higher estrogen sensitivity. Also, hormonal signals are not the only molecular influence on endo.

As another example, after  menopause , estrogen levels drop and endometriosis does tend to regress, but not in everyone. That is partly because endometriosis lesions can produce their own estrogen and there are likely other molecular growth factors in play.  There are also more ERβ receptors on endometriosis cells, and this causes higher prostaglandin production (which contributes to pain at any point in life).

In general, lowering “estrogen-dominance” to some degree suppresses endometriosis, but ideally not using synthetic progestins to “balance” hormones.   Progesterone (natural) and progestins (synthetic) do downregulate and limit the mitogenic (growth) influence of estrogen but progestins can also be a mitogenic in some tissues (e.g. breast).  In addition, overall progesterone or progestins exert less of an effect on endometriosis than on eutopic endometrial tissue normally found inside the uterus.  Likewise, dropping estrogen levels radically via GnRH agents for a relatively short period of time does not achieve the desired result and causes side effects and harm.  The risk vs benefit is particularly precarious here. Potentially, chronic gentle suppression might be more effective, and at least safer.  This can be achieved by using progesterone.  Synthetic progestins like norethindrone acetate can be used but with the caveats above. Alternatively, you can also help “balance hormones” by consuming seaweed, regular exercising and other lifestyle choices, like active xenoestrogen toxin avoidance.

Inflammation 

Endometriosis may be partially a product of inflammation and is also characterized by generating an inflammatory response itself.  So, it can snowball and contribute to the development and persistence of symptoms. Immune cells, such as macrophages, NK and T cells, are found in abundance in endometriosis lesions, and their interactions with endometriosis cells can promote the formation and growth of these lesions. Additionally, the peritoneal fluid of women with endometriosis often exhibits an altered composition, with increased levels of pro-inflammatory cytokines and growth factors.  

Inflammation can be from various sources, including infection which may be clinical (in other words you feel sick) or chronic subclinical.  For example, it is well established that chronic endometritis (infection inside the uterine lining) is present in endometriosis patients more often than those without endo. This is an association, and the cause-effect is not well worked out, but more recently various bacteria have been implicated.  At least in animal models, antibiotic treatment targeting those bacteria have produced regression of endometriosis lesions. Bacteria from the uterus or cervix can easily travel, either directly through the Fallopian tubes or via the bloodstream, to cause inflammation in the peritoneal cavity.  This inflammatory response is postulated to lead to progression of endo. 

Leaky gut, which may be related to an unhealthy low microbiome diversity, can lead to bacterial fragments, called lipopolysaccharides (LPS), seeding the peritoneal cavity as well.  This in turn causes inflammation and the same potential effect on endo growth.   

Inflammation is not all due to infection.  It can be due to a myriad of other non-infectious factors including stress, autoimmune disorders, obesity, systemic diseases like diabetes or pre-diabetes, mast cell activation, toxin exposure and so on.  

Most of these inflammatory conditions are molecularly actionable and are the target of research. For now, general anti-inflammatory strategies can be effective, both pharmacologic and integrative.   

Dysbiosis

Dysbiosis of the gut has a direct negative effect on the gut-endocrine axis and can impact endometriosis growth.  There are three significant ways this happens. 

Estrobolome: This term refers to the fraction of gut microbiota capable of metabolizing estrogens. In healthy individuals, the estrobolome helps maintain a balance of estrogen levels by contributing to the enterohepatic circulation of estrogens, thereby affecting the overall circulating and excreted amounts of these hormones. Dysbiosis, however, can disrupt the functioning of the estrobolome, leading to alterations in the metabolism of estrogens. In the context of endometriosis, this dysbiosis may lead to excess circulating estrogen, which stimulates the growth and survival of endometrial cells outside the uterus, contributing to endometriosis. 

Gut-Endocrine Axis: The gut microbiota also influences the gut-endocrine axis, which refers to the complex interplay between the gut microbiota, gut cells, and endocrine organs. Dysbiosis can result in changes in gut permeability (also known as “leaky gut” introduced above), leading to increased inflammation and immune dysregulation. This can, in turn, disrupt normal hormone regulation, potentially exacerbating conditions like endometriosis.

Gut-Brain Axis: Dysbiosis can also influence the gut-brain axis, a bi-directional communication system that links the central nervous system with the enteric nervous system. Changes in the gut microbiota can affect this axis and lead to altered pain perception and increased stress responses, both of which can affect the experience and progression of endometriosis.

Cancer molecular shared growth drivers

It’s important to note that a very small fraction of women with endometriosis might develop an  endo-associated cancer  (<1%), and gene mutations probably drive that.  Having said that there is overlap of these genes with more aggressive variants of endo, like deep infiltrating and endometrioma.  Meaning, they may not lead to cancer but may still fuel a more aggressive form of endometriosis.  This has led some researchers to propose that endometriosis is a pre-cancerous condition in a small percentage of those with endo.  The most studied gene in this regard is ARID1A, but the following have also been associated: KRAS, PTEN, HOXA10, VEGF, ESR1 and ESR2, and FN1.  Since there is a lot of research on these in the cancer world, there may be targeted therapies for more aggressive variants of endometriosis arising from this research.

Current Treatment Strategies for Endometriosis

Current effective treatment for most endo patients is built upon a personalized evaluation, correct diagnosis, and expert excision surgery to reduce the amount of inflammation and triggering of pain and other symptoms.  This is followed by some degree of medical suppression in many patients, usually on a hormonal basis.  Personalized guidance is key, which does not go overboard by either over or under-treating. 

Excisional surgery is today’s cornerstone because it yields an accurate diagnosis and removes all visible disease if possible.  But surgery should not be performed indiscriminately.  It should be done by an expert if the index of suspicion for endo justifies the surgical risks.  It seems prudent to reserve consideration of medical suppressive treatments for use after an accurate diagnosis is made vs. use of potentially very dangerous hormonal therapies based on a suspicion of endo only.   

Before and after surgery there are quite a few optimization strategies, including pelvic floor physical therapy (PFPT) and a pain management plan which consider what the pain triggers are.   These can differ between people. Both supportive therapies are complex but integral to treatment in most cases. This helps you get ready for surgery and go through surgery more smoothly and then transition to a life without endo.  

In addition, evaluation of the related conditions covered in this article, like dysbiosis and possible small bacterial overgrowth (SIBO) and leaky gut is mandatory.  The symptoms can easily cross over from these conditions and endo, so it helps to sort out other related causes of pain and bloating. Finally, evaluation should also consider mast cell activation, chronic inflammatory response syndrome (CIRS), autoimmune hypothyroidism, fibromyalgia, irritable bowel syndrome (IBS) or disorders of gut-brain interactions, and interstitial cystitis (IS).  There are also conditions not directly related to endo but often associated, like Lyme disease and mold.  The latter two can accentuate inflammatory response and waterlogged damp buildings often have black mold.  The CDC is also warning that tick-borne disease like Lyme and Babesiosis is on the rise.    

Also, as you are now aware from reading this article, there are many other steps you can take to influence and limit the course of endo recurrence and progression .  None of this is magic and none of it is a quick fix but when guided by an expert it is also generally pro-health, not dangerous and not expensive by and large.  Again, best results are obtained with expert guidance. 

Emerging Therapeutic Approaches

Although we have some options today, there is a pressing need for novel, effective therapies for endometriosis beyond surgery and variations of hormonal therapy. For instance, immunotherapies that target specific cytokines or immune cells involved in endometriosis are currently under investigation. Other promising areas of research include therapies targeting the altered metabolic environment of endometriosis lesions and neuromodulator treatments aimed at disrupting pain pathways associated with the condition. This article is not intended to cover these future options in depth, but based on all the potential causes and influencing factors it becomes easier to see what is coming sooner than later.   

Some recent example animal studies and concepts which should get to human trials include: Targeted anti-inflammatory therapy,  antibiotic therapy targeting specific bacteria like Fusobacterium, antibody (AMY109) that binds IL-8, small interfering RNA for VEGF (siVEGF), epigenetic and histone modification targeting endo-related gene transcription including estogen and progesterone receptors, epigenetic modification of T-cell immune response in endo, ARID1A and related “cancer gene” targeting, and more. So, while we do not have these available in clinical practice yet, the research wheels are turning.  Certainly, that can be accelerated with more funding, but it is ongoing. 

Holistic Proactive Principles

While we await mainstream targeted molecular therapies you should know that the same molecular pathway targets are also influenced by natural  integrative approaches .  They may not be laser targeted on a specific molecular pathway but that can be a good thing.  Abnormal cells like endo know or learn how to work around blockades from therapy and the treatment can stop working. We know that from other diseases where molecular therapies are already quite common.   Mother nature has considered that problem, so to speak, and a lot of nutrients can have a synergistic favorable effect on multiple molecular pathways at the same time.  

Further, your microbiome, estrobolome, inflammation, oxidation, nutrition, stress, lack of exercise, and so much more, impacts your body on the basis of epigenetics that was introduced above.  More specifially, a significant part is related to nutrigenomic epigenetics.  This can be through food or well selected supplements and botanicals. 

It’s critical to note that this does not mean loading up on the weirdest supplements you never heard of that cost an arm and a leg.  The 80/20 rule, which says that you get 80% of your result from 20% of an action, suggests that you can get far with a personalized antioxidant anti-inflammatory diet.  This is often simply done via a whole food plant-based diet.  Combine this with an exercise plan and stress management and you are 80% of the way there. 

Conclusion

Endometriosis is a complex, multifaceted, polygenic and multifactorial disorder, and much remains to be understood about its causes and progression. As our understanding of endometriosis deepens, so too does our ability to develop accurate diagnostics and targeted, effective therapies. But for now, in expert hands and with your own proactive commitment to nutritional and lifestyle options, outcomes can be good to great. There is no disease or condition where everyone gets the benefit of a great outcome, but certainly in the case of endo it can be optimized by seeking out an endometriosis expert.  In addition, expert consultants, especially those with integrative or functional medicine training, can take it one step further.  

References: 

1. Endometriosis: Etiology, pathobiology, and therapeutic prospects
2. The Main Theories on the Pathogenesis of Endometriosis
3. Nutrition in the prevention and treatment of endometriosis: A review
4. Cancer-Associated Mutations in Endometriosis without Cancer

Updated Post: July 16, 2024