The prevailing cause of chronic vulvovaginal candidiasis (CVVC) is an excessive, dysregulated immune response to low levels of candida organisms —just like an allergy (1). It is a loss of tolerance to the organism in otherwise healthy individuals, and is regulated by polymorphisms (gene variations) that control inflammation and immune response. Similar to allergies that occur in other parts of the body, this is an exaggerated reaction to even the tiniest amounts of candida and can produce the symptoms of redness, burning, pain, swelling, painful sex, and more. The presence of estrogen is also a very important factor in CVVC, as estrogen stimulates the storage of glycogen in vaginal cells, which converts to glucose and provides an energy source to candida species (1). Antifungal medications like fluconazole will control the symptoms, but do not cure this genetically-based dysfunctional immune response (1). Therefore, continuous suppression of candida is often required to keep levels below the threshold for inflammation (2).

Because of these polymorphisms, women with CVVC have a very hard time fighting off yeast infections and this leads to increased production of mast cells. Mast cells are white blood cells that mediate inflammatory responses in allergic reactions and persistent infections. When stimulated by an allergen, the mast cells release chemical mediators such as histamine into the surrounding tissue. This causes inflammation, swelling, itching, pain and other symptoms. If the candida is not cleared, these mast cells stay activated and cause worsening of pain (3).

Numerous studies have examined the vaginal epithelial (wall) cells of women with CVVC, and shown that these cells are highly intolerant to the presence of candida, which generates the exaggerated immune response to very low levels (4). This vaginal hypersensitivity response to candida may be associated with increased levels of prostaglandin E2, a key mediator of inflammation which is capable of suppressing localized vaginal cell-mediated immune responses. The loss of localized vaginal defense mechanisms can result in colonization of candida and the associated inflammatory symptoms (5). This inflammatory response can continue despite negative cultures for candida after an acute culture-positive infection, because the standard treatment does not clear 100% of the candida (2). When compared to control groups (i.e., women without CVVC), it’s been shown that the controls can tolerate much higher amounts of candida before inflammation is triggered — and protection from symptoms is associated with a lack of inflammation (2, 4). So, CVVC is caused by a woman’s individual genetic susceptibility to an organism that is tolerated by most other women. CVVC is not about differences in the candida organism itself — the same candida cells can cause zero symptoms in one woman and terrible pain in another woman. It is estimated that 15-20% of women are asymptomatically colonized with yeast — meaning their vaginal swab may register “positive” for a yeast infection, but they do not have any symptoms (6). This comes down to their genetics as well, where asymptomatic culture-positive women do not have the polymorphisms that CVVC patients do, and therefore are protected from inflammation and other symptoms. Yes, this is SO unfair!

The Falsetta Lab at University of Rochester Medical Center has run several studies on this genetic susceptibility and dysregulated immune response to candida in women diagnosed with “vulvodynia” (vulvar pain). Vestibular cells taken from women with “vulvodynia” had an inflammatory response to extremely low doses of candida albicans — as few as 100 colony forming units — while pain-free external vulvar cells failed to respond (7). Therefore, the vestibule tissue of these women is inherently sensitive to yeast, and unfortunately, today’s testing technology often cannot pick up such low levels. This leads to many women with CVVC getting diagnosed with “vulvodynia” and prescribed incorrect treatments (e.g., estrogen cream, antidepressants) — even when 70% of vulvodynia patients report a previous history of chronic or recurrent yeast infections (8).

Women with CVVC tend to be otherwise completely healthy. The problem is specific to the vagina, and no studies have shown systemic immune deficiency in these women. The candida hypersensitivity only occurs in the vaginal microbiome, which is why CVVC patients typically do not also have oral candidiasis (2). However, atopy (a genetic predisposition to develop allergic diseases) has been shown to be more prevalent in women who are susceptible to yeast infections than in the general population (9).