Understanding Neuroproliferative Vestibulodynia and the Connection with Endometriosis

Understanding Neuroproliferative Vestibulodynia and the Connection with Endometriosis

A few weeks ago, we delved into the intricacies of vestibulodynia and its potential association with painful intercourse in individuals with endometriosis. We presented an overview of vestibulodynia subtypes in general and discussed one of the more common presentations we see in those with endometriosis – hormonally mediated vestibulodynia which in many is caused from the side effects of the birth control pill, which are offered as first line “treatments” for endometriosis. Today, we will focus on another subtype, neuroproliferative vestibulodynia (NPV), and the fascinating connections are are seeing in these two conditions, including the role of mast cells.  

If you missed our previous discussion on painful sex and vestibulodynia, you can find the detailed information here. 

Recent research endeavors have yielded valuable insights into the fundamental causes of these conditions, unveiling a shared mechanism involving neuroproliferation, characterized by an increase in nerve cells. Furthermore, an elevated presence of mast cells—integral components in immune function—has been observed both in endometriosis tissue and the vestibule of individuals diagnosed with neuroproliferative vestibulodynia (NPV).

Individuals diagnosed with NPV undergo a surgical procedure which is excised to remove the problematic tissue, sound familiar? 

This surgical approach has demonstrated notable success in alleviating pain for individuals affected by NPV. Dr. Paul Yong, an OBGYN, endometriosis surgeon, and researcher based in Canada, addressed the parallels between these two conditions during his presentation titled ‘Neuroproliferative Dyspareunia’ at the ISSWSH’s annual conference in March 2022. Dr. Yong’s insights laid the foundation for subsequent research, with Dr. Irwin Goldstein initiated further exploration earlier this year.  We were lucky enough to be able to speak directly with these two on our podcast iCarebetter: Endometriosis Unplugged, available on Spotify (linked here) and Apple Podcasts.

A Quick Overview

Vestibulodynia

Vestibulodynia is a condition characterized by pain in the vestibule, the area of tissue within the vulva that surrounds the opening of the vagina. This pain can be described as sharp, stinging, burning, or hypersensitive, and can occur spontaneously or be provoked by touch or pressure, and many people will report superficial dyspareunia (or pain upon insertion) which is not limited to penis in vagina sex. Vestibulodynia is a subcategory of a broader condition called vulvodynia, which refers to chronic pain in the vulva.

Endometriosis

On the other hand, endometriosis is a condition where tissue similar to the lining of the uterus grows outside the uterus, often causing pain and fertility issues. This condition can cause deep dyspareunia, or pain with deep vaginal penetration. Like vestibulodynia, the pain associated with endometriosis can be chronic and can significantly impact the quality of life.

The Concept of Neuroproliferative Dyspareunia

Both vestibulodynia and endometriosis can lead to pain during sexual intercourse and the term neuroproliferative dyspareunia, is in reference to the source of the pain.  Both tissues have been shown to have neuroproliferation, or increased growth, of nerve endings in the areas affected by these conditions and we are now seeing an aberrant amount of mast cells as well also contributing to inflammation. This overgrowth of nerves, and presence of excessive mast cells, can lead to heightened sensitivity and pain during vaginal penetration, both superficially, as well as deep.

Neuroproliferation in Vestibulodynia

In the case of vestibulodynia, research has shown that there are too many nerve endings in the vestibule tissue. This overgrowth of nerves, or neuroproliferation, is still under investigation. However, it is believed that this could be due to a congenital birth defect, with the excess nerve endings developing very early. There are two types of neuroproliferative vestibulodynia: primary (congenital) and secondary (acquired). In primary vestibulodynia, individuals have experienced pain their entire lives though usually identified shortly after menses or with first attempts at penetration (sex, tampons, speculum exams) while in secondary or acquired vestibulodynia, pain develops later in life usually after an event such as an allergic reaction, chronic yeast infections or other infection, and there has typically been a period of normalcy prior to these event. 

Neuroproliferation in Endometriosis

In endometriosis, nerve fibers have been found around endometriosis lesions in the pelvic peritoneum. These nerve fibers are more numerous in individuals with endometriosis compared to those without the condition. The increase in nerve fibers is believed to be driven by the immune response to infection or allergy, leading to nerve proliferation.

Symptoms of Neuroproliferative Vestibulodynia and Endometriosis

Vestibulodynia Symptoms

People with vestibulodynia typically experience pain at the entrance of the vagina, called the vestibule. This pain can be described in various ways, including as sharp, stinging, burning, or hypersensitive. This pain can also be classified by when it occurs, with provoked vestibulodynia referring to pain that occurs with touch or pressure, while unprovoked pain occurs spontaneously.

Endometriosis Symptoms

In endometriosis, the pain is typically experienced deeper within the pelvis, often during or after sexual intercourse. This deep dyspareunia can also be accompanied by other symptoms, such as painful periods (dysmenorrhea), painful bowel movements, and chronic pelvic pain to name a few. 

For more signs and symptoms, check out our blog Endometriosis Signs and Symptoms: Everything You Need to Know.

Causes of Neuroproliferative Vestibulodynia and Endometriosis

Causes of Vestibulodynia

The exact causes of vestibulodynia are still being investigated. However, research suggests that the overgrowth of nerves in the vestibule tissue could be triggered by signaling from immune cells in the tissue. This could be due to a congenital birth defect, resulting in excess nerve endings developing very early, or it could be an acquired condition, developing later in life possibly due to infection or allergy.

Causes of Endometriosis

The causes of endometriosis are also not fully understood though we have began to shift away from the narrative that it is caused by retrograde menstruation, and towards a genetic basis. We hope that in the future with new research, we will be able to fully understand the cause (or causes) and have optimal treatment methods to address the heterogeneity of this disease. 

You can read more about these theories in our blogs listed below:

  1. The History of Endometriosis: Unraveling the Theories and Advances [or lack thereof]
  2. Is Endometriosis Genetic? Understanding the Genetic Links in Endometriosis.

There has been limited research in the role of mast cells in endometriosis thus far, and Dr. Irwin Goldstein, MD has now successfully demonstrated in a case study of a patient with NPV, her endometriosis pathology also demonstrated similar findings, as well as a biopsy taken of her colon during a colonoscopy. 

Thank you to Paul Yong, MD for this information, here is a comparison of endometriosis and NPV and common mechanisms in each.

EndometriosisNPV
PrevalenceApprox 10%Approx 10%
DiagnosisHistological diagnosis(ectopic endometrial-like epithelium/stroma)Clinical diagnosis (but normal vestibular histology consists of epithelium/stroma)

NPV – mast cells and excessive nerve endings
Description of DyspareuniaDeep Superficial 
Nerve DensityIncreased local nerve density compared to controlsIncreased local nerve density compared to controls
NeutrophinsIncreased NGF expression by endometriosis stroma when higher nerve fibersIncreased NGF expression by immune cells in vestibulodynia in areas with more nerve fibers
InflammationIncreased IL-1b expression by endometriosis when higher nerve fibres

Endometriosis stromal cells, when stimulated by IL-1b, increase production of NGF and promote nerve fibre development in a PC12 2q13 polymorphism (adjacent to IL-1 family genes)

Mast cells

Tryptase
Increased IL-1b in tissues in vestibulodynia vs. controls; Not observed in another study (Eva)

Vestibular fibroblasts from patients with vestibulodynia expressed more IL-1b compared to external vulvar fibroblasts and to controlsIL-1b and IL-1R antagonist gene polymorphism

Mast cells

Tryptase

Heparanase

References

  1. Mwaura, A. N., Marshall, N., Anglesio, M. S., & Yong, P. J. (2023). Neuroproliferative dyspareunia in endometriosis and vestibulodynia. Sex Med Rev. https://doi.org/10.1093/sxmrev/qead033 
  2. Goldstein, S., Yee, A., & Goldstein, I. (2022). Severe Allergic, Inflammatory and Traumatic Reactions of the Vestibule Associated with Acquired Neuroproliferative Vestibulodynia. The Journal of Sexual Medicine, 19(8, Supplement 3), S3. https://doi.org/https://doi.org/10.1016/j.jsxm.2022.05.012

Bornstein, J., Goldstein, A. T., Stockdale, C. K., Bergeron, S., Pukall, C., Zolnoun, D., Coady, D., consensus vulvar pain terminology committee of the International Society for the Study of Vulvovaginal, D., International Society for the Study of Women’s Sexual, H., & International Pelvic Pain, S. (2016). 2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia. J Sex Med, 13(4), 607-612. https://doi.org/10.1016/j.jsxm.2016.02.167

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