A review of the available clinical therapies for vulvodynia management and new data implicating proinflammatory mediators in pain elicitation

Abstract

Localised provoked vulvodynia (LPV) is a common, chronic, and disabling condition: patients experience profound pain and a diminished quality of life. The aetiologic origins of vulvodynia are poorly understood, yet recent evidence suggests a link to site-specific inflammatory responses. Fibroblasts isolated from the vestibule of LPV patients are sensitive to proinflammatory stimuli and copiously produce pain-associated proinflammatory mediators (IL-6 and PGE2 ). Although LPV is a multifactorial disorder, understanding vulvar inflammation and targeting the inflammatory response should lead to treatment advances, especially for patients exhibiting signs of inflammation. NFκB (already targeted clinically) or other inflammatory components may be suitable therapeutic targets.

Tweetable abstract: Vulvodynia is a poorly understood, prevalent, and serious women's health issue requiring better understanding to improve therapy.

Keywords: PGE 2; Dectin-1; IL-6; NFκB; fibroblast; inflammation; vestibulitis; vulvar pain; vulvodynia.

Conflict of interest statement

of Interests: No conflicts of interest to disclose. The ICMJE disclosure forms are available as online supporting information.

© 2016 Royal College of Obstetricians and Gynaecologists.

Figures

Figure 1. The fungal cell wall and its paradigm receptors

This illustration depicts the C. albicans cell wall, which is comprised of four major components: mannoprotein, β‐glucan, chitin, and the plasma membrane. Although, the mannoprotein layer is primarily exposed, β‐glucan and chitin are accessible at bud scars during cell division, and β‐glucan is actively secreted by C. albicans during chronic infection. We have focused on receptors involved in mannoprotein and glucan recognition (listed on the left), as they are major components of zymosan, which has also been established to elicit a strong response in human vulvar fibroblasts.

Figure 2. Inflammatory PPR-mediated mechanisms implicated in vulvodynia

This illustration depicts the transcriptional activation of pro-inflammatory mediators when Dectin‐1 and other PRRs (e.g. TLR‐2 and TLR‐4) signal through the NFkB pathway. Dectin‐1 senses live yeast and zymosan to elicit the production and release of pro-inflammatory mediators (IL‐6 and PGE2). Signaling through Dectin‐1 results in phosphorylation of NFkB inhibitors, which are subsequently degraded via proteolysis to allow NFkB subunits (associated with canonical pathway) to translocate to the nucleus to activate transcription of IL‐6 and Cox‐2 (rate-limiting enzyme in PGE2 synthesis). We have discovered the presence of TLR‐2 and TLR‐4 on vulvar fibroblasts; these PRRs have been shown to signal through NFkB in other cells types, although their function in vulvar fibroblasts has not been confirmed. We are investigating the role of these and other PRRs in sensing and responding to subclinical levels of yeast and other stimuli that may contribute to chronic vestibular inflammation.