European Journal of Obstetrics & Gynecology and Reproductive Biology
Interleukin-1β gene polymorphism in women with vulvar vestibulitis syndrome
Introduction
Vulvar vestibulitis syndrome remains an unresolved problem for both patient and clinician. The syndrome is characterized by exquisite pinpoint tenderness when discrete regions of the vaginal vestibule are touched with a cotton swab. A consequence of this sensitivity is the inability to experience pain-free vaginal penetration. This severely limits the quality of life in affected women. The prevalence of vulvar vestibulitis has been estimated to be as much as 15% in a general gynecological practice; mostly women of reproductive age are affected [1].
Although, several theories of the mechanism(s) responsible for the physical symptoms have been proposed [2], [3], [4], the cause(s) of vulvar vestibulitis syndrome remains unidentified. In addition, treatments are aimed at alleviating symptoms and do not address the underlying pathophysiology of the syndrome. In women whose symptoms are not resolved following an initial treatment, the vulvar pain is characterized by a chronic inflammatory infiltrate into the vestibular area [5].
Prior studies have identified mononuclear cells [6] and pro-inflammatory cytokines [7] in the vestibule of vulvar vestibulitis patients. We hypothesized that a transient exposure to Candida, human papillomavirus, toxic chemicals, semen or laser surgery might have induced an acute inflammatory reaction in these women which did not promptly resolve after clearance of the triggering agent. Instead, the inflammation became chronic due to a genetic deficiency in the capacity to effectively terminate the pro-inflammatory immune response [8], [9]. In support of this hypothesis we demonstrated that homozygosity at allele 2 of the polymorphic interleukin-1 receptor antagonist gene, a genotype associated with a prolonged and increased severity of inflammation in other chronic inflammatory disorders [10] was also more prevalent in women with vulvar vestibulitis syndrome than in controls [8]. In addition, production of interferon-α, an inducer of anti-bacterial and anti-viral activity, was also shown to be reduced in women with vulvar vestibulitis syndrome [11]. Most recently, the production of interleukin-1 receptor antagonist, a natural competitive inhibitor of interleukin-1 biological activity, by whole blood cultures from women with vulvar vestibulitis syndrome, was demonstrated to be significantly lower than that synthesized by other women [9]. Thus, alteration in synthesis of this anti-inflammatory regulatory component could be a destabilizing factor in the regulation of inflammatory reactions.
Similar to the interleukin-1 receptor antagonist gene, the gene coding for interleukin-1β is also polymorphic [12], [13]. Individuals with the less common allele 2 at the +3953 locus have been shown to produce increased quantities of interleukin-1β than do individuals homozygous for allele 1 [12]. Thus, possession of allele 2 may also be associated with a more severe pro-inflammatory immune reaction. We, therefore, evaluated DNA samples and whole blood culture supernatants, from women studied previously [9], [11], for possession of the different interleukin-1β alleles and its relation to induced interleukin-1β production.
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Subjects
The 59 women with strictly defined vulvar vestibulitis syndrome, as well as the 48 age-matched control women subjects with no history of vulvodynia, have been described in previous reports [9], [11]. Briefly, the overwhelming majority of women in both groups were Caucasian, of European descent and from the middle class. Vulvar vestibulitis syndrome was defined as severe pain confined to the vulvar vestibule when areas were lightly touched with a cotton swab. Patients reported that vaginal
Results
The distribution of the individual interleukin-1β genotypes in the women with vulvar vestibulitis syndrome and controls, as well as the frequency of both alleles, is shown in Table 1. As expected, the 1,1 genotype was predominant in both groups. However, the frequency of this genotype was reduced in the vestibulitis patients (54%) as compared to the controls (75%) (P=0.02). In contrast, the frequencies of the 1,2 and 2,2 genotypes were approximately doubled in the vulvar vestibulitis patients
Discussion
This communication plus our previous report [8] demonstrates that women with vulvar vestibulitis syndrome have an increased prevalence of less common alleles of both the polymorphic interleukin-1β and interleukin-1 receptor antagonist genes. Each of these alleles, identified as allele 2 in both genes, have been associated with increased production of the pro-inflammatory cytokine, interleukin-1β, and with prolonged inflammatory responses [12], [13], [14], [15]. The findings, therefore, support
Acknowledgements
These studies were supported in part by a grant from the National Vulvodynia Association.
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Present address: Department of Obstetrics and Gynecology, University Hospital, Lausanne, Switzerland.