Getting to the Cause of Vulvodynia

Even light that touches in certain areas of the vulva causes severe, prolonged pain for women who have vulvodynia. Recently, the disease has been linked to immunomodulatory stimulus. And more than 70% of women with localized provoked vulvodynia (LPV), the most common form, report having had frequent vaginal yeast infections—sometimes > 4 a year.

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To better understand the inflammatory pathways involved, University of Rochester researchers used tissue biopsies from women with and without LPV. No participants had used corticosteroids or nonsteroidal anti-inflammatory medications, and none had chronic inflammatory illnesses other than LPV. Pain levels at the vaginal vestibule ranged from 7 to 9 (10 being the maximum score); pain-free controls scored 0. All the women had negative yeast cultures at the time of study entry.

Vulvar fibroblast strains produce interleukin (IL)-6 and prostaglandin E₂ in response to challenge with yeast components. The researchers compared the fibroblast responses with zymosan, a mixture of yeast cell wall mannoproteins and β-glucan purified from nonpathogenic Saccharomyces cerevisiae (S cerevisiae) and Candida albicans (C albicans).

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On stimulation with zymosan, vestibular fibroblasts of LPV cases produced as much as 5 times more IL-6 transcript than did the vestibular fibroblasts from healthy women. In patients with LPV, vestibular fibroblasts responded strongly to even low infectious doses of C albicans—as few as 100 colony-forming units. (That is, cell numbers that fall within the normal range, the researchers note.) External vulvar cells, not typically associated with pain, responded less, even to higher doses. The results suggest that LPV patients are “exquisitely sensitive” to components of the yeast cell wall, the researchers say, namely β-glucan and mannoprotein.

The researchers pinpointed 2 possible targets for resolving proinflammatory signaling and pain: the NFκB pathway and Dectin-1-mediated signaling. Infection with live C albicans activated the NFκB inflammatory pathway more effectively than did S cerevisiae. Findings from their earlier studies and other research demonstrated that vestibular cells possess an “immunological memory,” the researchers say, where repeated infections with C albicans predispose those cells to produce higher levels of proinflammatory mediators even after the stimulus is removed. They suggest that NFκB inhibitors, which are used in cancer therapies, may have a role in LPV treatment.

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Dectin-1, a surface receptor that binds C albicans cell wall glucan, was significantly elevated in vestibular cells in both patients and controls and was most abundant in LPV patients. Blocking Dectin-1 significantly reduced pain-associated IL-6 and PGE₂ production during the response to C albicans.

The discovery that vestibular fibroblasts are equipped to sense yeast and yeast products, the researchers say, is a significant and new finding.

Source
Falsetta ML, Foster DC, Woeller CF, et al. Am J Obstet Gynecol. 2015;213(1):38.e1-38.e12.
doi: 10.1016/j.aj0g.2015.02.002.