Azoles May Target Underlying Mechanism(s) of Localized Provoked Vulvodynia. (1st August 2022)

• Record Type: Journal Article
• Authors: Flores, B; Falsetta, M
• Is Part Of: Journal of sexual medicine. Volume 19(2022)Supplement 3
• Page Start: S35
• Page End: S35
• Publication Date: 2022-08-01
• Subjects: Sexual disorders -- Periodicals; Sex -- Periodicals; Sexual health -- Periodicals; 616.69005
• DOI: 10.1016/j.jsxm.2022.05.121
• Languages: English
• ISSNs: 1743-6095

Abstract

ABSTRACT: Introduction: Vulvodynia is a crippling disease that drastically reduces the quality of life in women. Chronic, otherwise unexplained pain localized to the vulvar vestibule is the identifying symptom associated with this disease, in which pain lasts greater than three months, often significantly longer, on the order of years. Vulvodynia is difficult to diagnose and assess, let alone deliver adequate treatment due to the disease being poorly understood. We have evidence that suggests the cytochrome P450 (CYP450) family of enzymes is involved in the vulvodynia mechanism and may represent a new therapeutic target. Objective: Our goal is to identify underlying mechanisms of disease in vulvodynia to develop improved therapeutic strategies. For this investigation, we focused on CYP450 and specifically aimed to narrow down the list of possible enzymes within this nearly 50 member family that might relieve vulvar pain if targeted. Methods: We used a validated primary human fibroblast culture system where each woman serves as her own control. In this model, fibroblasts are cultured from affected and unaffected sites in patients. In addition, fibroblasts are cultured from the same sites in women without the disease. Pro-inflammatory mediator production, specifically prostaglandin E2 (PGE2) and interleukin-6 (IL-6) are surrogate measures of pain, which we measured via ELISA assays. We evaluated the role of CYP450 in vulvar pain by antagonizing specific family members to (1) determine if CYP450 is a reasonable target for therapeutic intervention, (2) pinpoint family members of interest, and (3) evaluate if azoles used to treat vulvovaginal yeast infection, which are known to target CYP450, would have therapeutic effect for vulvodynia. Results: We found that azoles commonly used to treat vulvovaginal yeast infection (e.g. miconazole and terconazole) reduced pro-inflammatory mediator production in fibroblasts. Miconazole and terconazole target a similar group of CYPs, suggesting that CYP2C9, CYP2C19, CYP3A4, and CYP3A7 may be involved in the vulvodynia mechanism. Global inhibition of the CYP family with 1-aminobenzotriazole also reduced pro-inflammatory mediator production, which may mean that targeting any one CYP or group of CYPs could be effective. This is potentially promising information as it could mean that any azole approved for vulvovaginal use would address vulvodynia symptoms. We are currently investigating this possibility. Conclusions: As we uncover additional pieces of the vulvodynia mechanism, we identify new avenues for improved patient care. Based on published clinical data and our in vitro findings, azoles may have a role in treating vulvodynia. Disclosure: No