For a woman with vulvodynia, everyday activities—sitting, walking, even standing—can evoke burning or knife-like pain. This common condition involves chronic pain in the vulva, especially the vaginal opening, which often makes intercourse exquisitely painful. That kind of pain is not easy to talk about. And when a woman does seek medical care for the problem, she may find there are no good answers. That is because, as yet, there is no known cause, and no reliable treatment.
Now, investigators have developed the first animal model of vulvodynia, and in doing so, find evidence for a cause. They showed that in mice, repeated or extended yeast infections produce a condition that closely mimics vulvodynia in women. In the most common form of vulvodynia, provoked vestibulodynia (PVD, also known as vulvar vestibulitis syndrome), pain is evoked by pressure. Likewise, the researchers found that following infection, animals became hypersensitive to touch, and the pain persisted long after infection and inflammation had cleared up. Vulvar tissue from the mice, like tissue from women with vulvodynia, also contained a higher-than-normal density of sensory nerve fibers. The findings, from Melissa Farmer, Jeffrey Mogil, and colleagues at McGill University in Montreal, Canada, may help in determining whether, and how, infection leads to vulvodynia in women, and advance the search for treatments. The paper appeared in the September 21 issue of Science Translational Medicine.
A variety of puzzling pain conditions—irritable bowel syndrome, chronic prostatitis, and others—are associated with previous infection, leading researchers to suspect that recurrent or long-term infection might somehow be involved in long-lasting pain (e.g., see Spiller and Garsed, 2009). In the case of vulvodynia, some women with the condition have a history of yeast infections (Witkin et al., 2002), but whether past recurrent infection could have a causal role in chronic pain was not known. The McGill researchers, directed by Yitzchak (Irv) Binik, a psychologist who studies genital pain syndromes in people, and Mogil, who develops rodent pain models (and is a PRF science advisor), teamed up to investigate the issue using mice.
Farmer, who is now at Northwestern University in Chicago, Illinois, infected female mice with the fungus Candida albicans, the most common cause of yeast infections, by pipetting a culture onto the vaginal opening. During active infection, the mice developed allodynia, becoming hypersensitive to touch in the area. After four days, the researchers treated the mice with the antifungal drug fluconazole, the infection cleared up, and allodynia disappeared. When the mice were infected and treated a second time, the pain once again came and went. However, after a third round of infection and treatment, pain persisted in some mice. Of 15 mice infected, six continued to show signs of allodynia three weeks after the infection had resolved. This matches what clinicians see frequently: Women with a history of yeast infections often experience vulvar pain even when they do not have an active infection.
The investigators found that prolonged infection was especially likely to produce persistent hypersensitivity. After a single 14-day infection, most of the mice remained profoundly hypersensitive seven weeks after the infection had resolved. In addition, vulvar injections of the yeast cell wall glucan zymosan, prepared from Saccharomyces cerevisiae, elicited lasting allodynia. That indicated that the vulvodynia-like response did not require a live pathogen, and could perhaps be caused by other fungi besides Candida.
The researchers saw no visible changes in vulvar tissue after infection cleared up; nor did they find elevated levels of inflammatory cells. However, they did detect a threefold increase in the density of nerve fibers in the lamina propria layer (beneath the epithelium) of vulvar tissue from allodynic versus non-allodynic mice, which resembled the increased nerve fiber densities observed in tissue from women with vulvodynia. Immunohistochemical staining for calcitonin gene-related peptide (CGRP) and vesicular monoamine transporter 2 indicated that the hyperinnervation involved peptidergic nociceptive and sympathetic fibers.
The mechanism by which pain outlives infection remains a mystery. “My intuition is that it’s inflammatory,” Farmer said, but given the lack of frank ongoing inflammation, that is hard to prove. However, inflammation might persist in some poorly understood form. “I don’t think we really know what chronic inflammation looks like,” she said. The researchers suspect that the infection-induced hyperinnervation may play a big part. “The pain that persists after the resolution of infection may be due to an abnormal persistence of the hyperinnervation evoked during the acute inflammatory response,” they write in the paper.
The new mouse model shows for the first time that recurrent infections can lead to chronic pain. If the same is true in women, “This is a testament to how important it is to try to aggressively treat these things as quickly as possible…and prevent the transition to the chronic state,” Farmer told PRF.
Importantly, infection is almost certainly not the only cause of vulvodynia. Recent estimates indicate that the condition is quite common; a just-published study concluded that approximately a quarter of women have experienced vulvodynia at some time (Reed et al., 2011, in press). “There are likely lots of different pathways” that all lead to vulvodynia, Farmer said. “I don’t think that vulvodynia is a unitary pain disorder.” In addition, factors such as genetic variation (Foster et al., 2004) shape a woman’s susceptibility. In line with that idea, Farmer found that recurrent yeast infection caused persistent pain in only a subset of mice.
Christin Veasley of the National Vulvodynia Association, which partially funded the study, said that this first animal model offers hope that researchers will also be able to develop models for additional potential vulvodynia triggers, such as nerve injury, altered hormone levels, and other types of infection including bacterial vaginosis.
Image: Candida albicans culture. Credit: Dr. William Kaplan, CDC.
