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Nerves and Endometriosis: How neuroangiogenesis, nerve invasion, and nerve impingement contribute to excruciating pain

Many already know that endometriosis can affect the nerves, through growing directly on nerves, or through other mechanisms, such as nerve entrapment or nerve impingement.  The intense inflammatory milieu that usually occurs with endometriosis can also contribute to excruciating nerve pain and nerve damage throughout the entire body.  Through these various pathways alone,  endometriosis which affects the nerves has the potential to cause excruciating back, leg, hip, shoulder, and chest pain, whole-body symptoms of neuropathy, loss of bowel and bladder control, loss of leg function, breathing difficulties, severe shoulder and chest pain, severe functional damage to major organs like the bowel, bladder, ureter, lungs, and diaphragm, as well as incapacitating focal point and/or referred pain in surrounding areas.

In cases involving endometriosis of the sciatic nerve, the severe pain and loss of leg function can be especially debilitating, with potential to cause near paralysis or total loss of mobility.  Many are surprised to learn that endometriosis can cause severe symptoms in the extremities. Yet, such accounts of loss of leg function with endometriosis are not actually new. As our team reported on the ancient history of endometriosis, dating back approximately 4,000 years, ancient physicians described a chronic endometriosis-like condition (or adenomyosis-like), referred to as strangulation of the womb in some sources, which caused sufferers to suddenly lose leg function and collapse in extreme pain for several days each month, unable to move and drifiting in and out of consciousness.

Flash forward to modern time and the list of devastasting potential effects is only worsened when one considers that researchers now know endometriosis can also create its own new nerve fibers through the process of neuroangiogenesis / neurogenesis. This potentially helps explain the absolutely incapacitating pain, as well as the significantly increased level of nerve-fiber-density that endometriotic lesions can express.  

Given the excruciating pain so many endometriosis sufferers experience, at least some astute researchers (those who believed people’s endometriosis pain was real!) have been studying the potential connections to nerve dysregulation for several decades now, as can be seen from this 1973 article reporting on a case of right uterosacral ligament endometriosis invading the perineural space. Early 20th Century endometriosis experts from more than a hundred years ago were also already reporting on the numerous ways endometriosis could affect nerves.

Back in the early and mid-20th Century, these were working hypotheses, but today researchers now acknowledge that “A hallmark of endometriosis…is neuronal innervation of lesions.” Not all endometriotic lesions develop these features, but for those that do, the pain signaling can be absolutely unbearable. (Another reason why updating medical school curricula on endometriosis is one of the central missions of EndoMarch).

As we reported in a Nezhat et al blog post, for those suffering from endometriosis of the sciatic nerve, the level of pain when nerves are involved is devastating, with many losing the ability to walk without mobility aids like wheelchairs. Nerve sheath involvement has even been reported, including this case study involving endometriosis and a schwannoma, which is a benign nerve sheath tumor, growing in the chest area (mediastinal) of a 30-year-old patient with catamenial upper left chest pain.

No place in the body is immune to the invading properties of Endometriosis, including the spinal cord, as is reported in this case study on endometriosis of the conus medullaris (intramedullary spinal cord hematoma) causing cyclic radiculopathy. And it’s not just the intramedullary compartment that intraspinal endometriosis can involve; the subarachnoid, intradural-extramedullary, and extradural compartments can also be affected, including the vertebral bodies. In the case study involving endometriosis of the intramedullary compartment, the patient underwent three previously failed spine surgeries and had been suffering severe chronic back pain, radiculopathy, loss of bladder and bowel control, and motor and sensory weakness, all of which worsened during the time of menstruation. In other cases, endometriotic lesions mimic nerve sheath tumors, as occurred in this case of lumbar plexus endometriosis, causing similar debilitating symptoms.  

In the field of oncology, it’s long been known that the peripheral nervous system plays an important role in cancer progression. Based on emerging research, it’s likely that a similar phenomenon may be at play with the progression of endometriosis. For example, one hypothesis suggests that endometriosis activates dorsal root neurons through peripheral nerve signaling pathways, which then initiates the development of a dense networks of new nerve fibers, while dysregulation of apoptosis, along with a multitude of other aberrant factors, impedes the body’s attempts to destroy diseased tissue. Some investigators also postulate that endometriosis exhibit a preferential proclivity for developing on or near existing nerve fibers, similar to the growth patterns of some cancers, though more research is needed to explore these potential connections further.  

Neuroangigenesis and perineural invasion would, of course, also be familiar to oncologists, as these are cellular pathways often seen in many cancers. Although endometriosis is not cancer,  there are shared neoplastic-like features which endometriosis researchers now acknowlegde exist. As well, some atypical forms of endometriosis are considered as likely precursor lesions, with potential to undergo malignant transformation. In fact, an estimated 10% of ovarian cancers (possibly more) are now recognized as deriving from endometriosis, and have been renamed with the new nomenclature of “endometriosis-associated” to reflect this origin. And it’s not just ovarian cancers, but endometriosis is now linked to a higher risk of developing other forms of cancer as well.

Stem cells may be one of many multifactorial drivers of disease development and progression in endometriosis, but these are still only hypotheses and more research is urgently needed. Whatever the etiological origins, what we do know is that this vicious cycle of severe, chronic inflammation, combined with the production of new nerve fibers and involvement in existing nerve networks, translates to incapacitating pain for Endometriosis Survivors. 

As you can see, then, endometriosis is not a period disease only affecting the pelvic area or reproductive tract, but rather is a whole-body (systemic) severe inflammatory chronic condition capable of destroying organs and causing severe symptoms throughout the entire body and at any time during the month. And so, when you start to truly understand the immense complexities of endometriosis, this is why it’s so upsetting to see endometriosis survivors gaslit and told that endometriosis couldn’t possibly cause whole-body severe symptoms: And, once one is gaslit into thinking these devastating symptoms are not real, it’s that much easier for unjust medical systems to outright deny referrals or access to gold standard excision surgery by qualified experts, which is currently the best hope for symptom relief and reducing the chance of disease progression through expert excision surgery to remove diseased, nerve damaging, inflammation causing lesions and subsequent fibrosis/adhesions. 

Sadly, medical gaslighting of endometriosis patients seems to be increasing in lockstep with increasing advocacy efforts. Specifically, there’s been pushback from entrenched interests who seem to prefer status quo thinking when it comes to the management of endometriosis. As as result, it appears that barriers to gold standard care are actually increasing, including through the clever tactic of promulgating patient guidelines which attempt to ration gold standard care only for extreme cases, while prioritizing the same old hormonal medications and devices over and over again (birth control pills, hormone-releasing IUDs, GnRH agonists, etc).

While adjuvant therapies to potentially help manage symptoms can play an important role in supporting pain management, these hormonal therapies were only meant to be taken for short periods of time, as long-term* use in particular, can lead to potentially devastating, permanent side effects, including permanent loss of ovarian function, tooth loss necessitating dentures, debilitating bone loss (including to the spine), pituitary tumors, seizures, and degenerative musculoskeletal disease. That’s a lot of potential risk and damage for medications that cannot cure or shrink or otherwise stop the progression of endometriosis.

And that’s why the EndoMarch Endo Justice Movement demands that true informed consent be required, which would include providing warnings about these and other potentially devastating outcomes that a large number of individuals with endometriosis experience. (*Note: short term use can also cause severe, permanent side effects).

So, the next time someone misdiagnoses the incapacitating symptoms of endometriosis as a simple case of frazzled nerves or anxiety, mention the 100-plus years of peer-reviewed literature demonstrating perineural invasion, neuroangiogenesis, and other forms of severe nerve pain and whole-body organ damage that nerve-related endometriosis can cause. As for frazzled nerves, yes, the fact that so many medical professionals are not even remotely familiar with this century-old foundational research is definitely an anxiety-inducing social pathology that needs immediate medical attention for sure.

Further Reading and Footnotes
1) This is a publication in progress, so references will be included after publication.