Available online 5 June 2023, 108467

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Localized provoked vulvodynia (LPV) affects ~14 million people in the US (9% of women), destroying lives and relationships. LPV is characterized by chronic pain (> 3 months) upon touch to the vulvar vestibule, which surrounds the vaginal opening. Many patients go months or years without a diagnosis. Once diagnosed, the treatments available only manage the symptoms of disease and do not correct the underlying problem. We have focused on elucidating the underlying mechanisms of chronic vulvar pain to speed diagnosis and improve intervention and management. We determined the inflammatory response to microorganisms, even members of the resident microflora, sets off a chain of events that culminates in chronic pain. This agrees with findings from several other groups, which show inflammation is altered in the painful vestibule. The vestibule of patients is acutely sensitive to inflammatory stimuli to the point of being deleterious. Rather than protect against vaginal infection, it causes heightened inflammation that does not resolve, which coincides with alterations in lipid metabolism that favor production of proinflammatory lipids and not pro-resolving lipids. Lipid dysbiosis in turn triggers pain signaling through the transient receptor potential vanilloid subtype 4 receptor (TRPV4). Treatment with specialized pro-resolving mediators (SPMs) that foster resolution reduces inflammation in fibroblasts and mice and vulvar sensitivity in mice. SPMs, specifically maresin 1, act on more than one part of the vulvodynia mechanism by limiting inflammation and acutely inhibiting TRPV4 signaling. Therefore, SPMs or other agents that target inflammation and/or TRPV4 signaling could prove effective as new vulvodynia therapies.

Section snippetsVulvar pain

Everyone with a vulva is likely to experience pain or discomfort in this area at some point in their life, even if only transiently, such as during pregnancy, after childbirth, or during menopause (Danby & Margesson, 2010; Simonelli, Eleuteri, Petruccelli, & Rossi, 2014). Despite the ubiquity of vulvar pain, our fundamental understanding of the mechanisms involved are limited, and epidemiological studies indicate it is both underdiagnosed and seldom discussed (Andrews, 2011; Bohm-Starke, 2010;

Yeast infections and vulvodynia

In patients with secondary vulvodynia, which appears more common than primary vulvodynia, there is a tipping point where patients go from pain-free to painful intercourse (Bornstein et al., 2016; Falsetta et al., 2017; Fischer, 2004; Haefner et al., 2005; Stockdale & Lawson, 2014). The most common warning sign is the occurrence of transient bouts of pain immediately following intercourse. It is difficult to discern a clear environmental cause for vulvodynia, as patients recall numerous factors

Why do the symptoms of vulvodynia persist?

For a long time, the resolution of inflammation was thought to be an inactive process mediated by a progressive tapering off of inflammatory signals as infection resolves and immune cells lyse and are no longer recruited to the site of infection (Buckley et al., 2014; Chiang & Serhan, 2017; Chiang & Serhan, 2020; Serhan, 2017a; Serhan, 2017b; Serhan et al., 2014; Serhan et al., 2015). However, with the discovery of SPMs, it became apparent that resolution is an active process governed by the

Pools of lipids involved in pain signaling are sustained in the painful vestibule

In exploring the mechanisms responsible for deficiencies in pro-resolving lipids using a targeted lipidomic analysis panel comprised of ~150 pro-resolving and inflammatory mediators, we made an unexpected finding. There are 4 EETs that are implicated in resolution: 5(6)-EET, 8(9)-EET, 11(12)-EET, and 14(15)-EET (Thomson et al., 2012; Yu et al., 2000). Since half of these were significantly less abundant in the painful vestibule, we became interested in their metabolism. EETs are produced by

Conclusion

There is considerable work to be done, but SPMs show promise for the development of new therapeutics for LPV. They are safe and naturally produced, although drug development steps are necessary for chemically synthesized SPMs. Natural products, such as purified fish oil could represent another option, although this may not be as potent as SPMs, especially considering the apparent dysregulation of lipid metabolism in LPV patients. Natural products also pose other challenges for drug development,

Current knowledge gaps and future directions

Although our mouse model of vulvodynia mimics the human disease in several key ways, it is impossible to recapitulate every aspect of human disease in an animal model, especially when the mechanisms of that disease are not yet fully elucidated. There is strong suspicion that vulvodynia is genetically inherited; a vulvodynia diagnosis is more likely if you have a first degree relative with this disease (Morgan et al., 2016). The data we have collected thus far points to a deficit in the

Declaration of Competing Interest

We do not have any conflicts of interest to disclose.

Acknowledgments

We have no conflicts to disclose. This work was funded by NIH-NICHD R01 HD092334 and R01 HD069313 and the National Vulvodynia Association. All figures were created with BioRender.com.

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