Research Linking Organic and Physiological Factors with Vulvodynia

By Marek Jantos Ph.D.

Various potential pathophysiologies have been researched in an attempt to identify possible dermatological, infectious, neurological, or muscular causes. The physiological-organic findings reported include:

low grade chronic inflammation (due to possible up-regulation of local mast cells),
viral, bacterial and fungal infections,
proliferation of local pain fibres (indicating upregulation of the local pain system),
dysfunctional pelvic muscle states (mostly up-regulation of pelvic muscle tone).

These pathologic findings are acknowledged in the recent state-of-the-art consensus statement on vulvodynia (Bachmann et al., 2006) and will form the basis of the discussion that follows.

Inflammatory factors
The search for inflammatory and skin related causes of vulvodynia produced inconsistent findings. This ultimately led to the conclusion that, by the very definition of vulvodynia, the condition and any positive dermatological findings would automatically result in a medical diagnosis, and exclude the diagnosis of vulvodynia (McKay, 1985; McKay et al., 1991; Byth, 1998; Willsteed, 1995).

Vestibular inflammation, even though reported by patients and noted in some studies (Pyka et al., 1998; Peckham et al., 1986), was not a consistent feature and failed to differentiate between vulvodynia patients and controls (Landquist et al., 1997). Because inflammation was not found to be a reliable factor in the differential diagnosis of vulvodynia, the term “-itis”, as in vestibulitis was excluded from ISSVD terminology in relation to vulvodynia (Moyal-Barracco & Lynch, 2003). The presence of erythema, when present, was predominantly confined to the posterior fourchette (Lynch, 1986; McKay, 1988).

Several studies have looked at the potential role of genetic factors in the etiology or susceptibility to vulvodynia symptoms. Some patients were found to possess an uncommon genotype (IL-1RA) that is associated with chronic inflammation (Witkin et al., 2002) and prolonged and intensified inflammation was seen as a potential trigger of other events, including the autonomic nervous system alterations, resulting in increased sensitivity to pain and chronic localized inflammation (Gerber et al., 2003). Women who carry the proinflammatory genetic variants were found to be 4-8.5 times more likely to develop vestibulodynia (Foster et al., 2004). Further studies are required to improve the current understanding of the relevance of genotypes and the pro-inflammatory response at the tissue and cellular level.

Infections
Research also focussed on potential links between sexually transmitted diseases and vulvodynia but no evidence was found to support the link (Marinoff & Turner, 1986). The role of candida infections had been suspected and studied as a possible trigger in the development of vulvodynia (Friedrick, 1988; Peckham et al., 1986, Mann et al., 1992). Although a history of candida is reported by many women with vulvodynia (Witkin et al., 2002; Jantos & White, 1997) no causal relationship or hypersensitivity to candida has been demonstrated (Marinoff & Turner, 1986). A link between the human papillomavirus (HPV) and vulvodynia was proposed (Marinoff & Turner, 1991) but subsequent research found no evidence linking HPV in the etiology of the disorder (Bergeron et al., 1994).

Neuropathic causes
A suggestion was made that vulvodynia may be a form of neuropathic pain in the form of pudendal neuralgia (pain along the distribution of the pudendal nerve), caused by compression or entrapment of the nerve by the sacrospinous and sacrotuberous ligaments (Turner & Marinoff, 1991). Even though such entrapment can occur, there is no evidence of pudendal neuralgia being a primary cause of vulvodynia.

Further studies focussed on the role of superficial nerves in the vulva. Since the primary symptom of vulvodynia is evoked by touch and pressure application to the vaginal introitus, a number of studies explored the role of superficial nerves in vulvar pain. Morphological studies examining the neural content of biopsied vulvar tissue found evidence of increased density of superficial intraepithelial free nerve endings in vulvodynia (Bohm-Starke et al., 1998). To assess the impact of increased density of nerve endings on pain thresholds, a study of 19 patients diagnosed with vestibulodynia (in the study referred to as vvs), examined the reactivity of patients to heat, cold, mechanical stimulation, vibration and distension of the mucosa (Bohm-Starke et al., 2001). All of the patients demonstrated significantly greater hypersensitivity to mechanical stimulation, temperature, and distension but not to vibration. The study provided some evidence supporting the view that sensory abnormalities in these patients were best explained by peripheral noxious mechanisms involving sensitization and/or proliferation of various types of C-nociceptors (pain fibres know to cause a burning sensation). The authors concluded that, from a clinical perspective, treatment should focus on destroying superficial nociceptive nerve endings, or reducing their hyper-excitability by suitable ion channel blockers. In the opinion of the authors, the sensory abnormalities associated with vulvar pain had a clear organic basis and could not be explained on the basis of psychological factors.

A further study examining a neuropathic link with vulvodynia used quantitative sensory testing (QST) with vestibulodynia patients (in the study referred to as vvs), to demonstrate that symptom severity was directly related to mechanical and thermal pain thresholds (Lowestein et al., 2004). In this study, sensory tests effectively discriminated between patients and controls, and between levels of pain severity. The evidence was seen as favouring a neuropathic explanation of chronic vulvar pain. However, the significance of this finding was partially called into question by a subsequent study of pain thresholds, in which tests were carried out applying noxious stimuli, not to the vulvar region, but the forearm (Granot et al., 2002). It was noted that enhanced pain perception in patients was not just localized to the genital site but also evident in other regions of the body. The severity of pain was found to be related to patient’s anxiety and provided evidence of a generalised pain disorder. Patients demonstrated higher trait and state anxiety, lower pain and unpleasantness thresholds, an increased autonomic reactivity. This study provided evidence that secondary hyperesthesia may be modulated by psychological attribute such as anxiety.

In a follow up study the same research team showed that systemic pain perception was closely related to the choice of treatment and the rated success of treatment, irrespective of treatment modality used (Granot et al., 2004). Women who showed increased pain perception were more likely to choose conservative treatment options, but were less likely to report improvement. Those with a lower pain perception were more likely to choose surgery (vestibulectomy) and report more improvement. Pain perception was found to be related to autonomic dysregulation, with systolic blood pressure positively correlated with level of vulvar pain. Women with lower systolic blood pressure showed increased pain perception and reported less reduction in pain. Those with higher blood pressure showed lower reception of pain and reported more improvement with treatment.

In a study using functional magnetic resonance imaging, the heightened processing of tactile pain sensation was studied (Pukall et al., 2005). The goal of the study was to compare the neural response to mild and moderate pressure to the posterior portion of the vulva. Participants consisted of 14 women diagnosed with vestibulodynia (referred to in the study as vvs) and were matched with 14 age and contraceptive matched controls. All of the women with vestibulodynia described moderate pressure as painful and unpleasant, whereas only one of the control women found it to be painful and unpleasant. During pressure application described as painful by women with vestibulodynia, significantly higher cortical activation levels were noted in the insular and frontal cortical regions than that noted in controls. The results showed that women diagnosed with vestibulodynia exhibit an augmentation of genital sensory processing, which is similar to that observed in other syndromes characterised by hypersensitivity, including fibromyalgia, idiopathic back pain, irritable bowel syndrome and neuropathic pain.

A recent study on the effects of sexual arousal on genital and non-genital sensitivity in women with vestibulodynia (in the study referred to as vvs) offered further insight into the potential role of vulvar sensitivity in vulvodynia (Payne et al., 2007). Upon establishing baseline touch and pain thresholds, healthy controls and vestibulodynia women viewed erotic film segments while undergoing temperature sensory testing and monitoring their level of subjective sexual arousal. The findings showed that there was no difference between healthy and vestibulodynia women in terms of the level of physiological arousal, and increased sensitivity of the vestibule during the viewing of sexual content. However, in the case of the vestibulodynia group, arousal was associated with increased sensitivity to touch and pain. The results also showed a difference in sensitivity to touch as opposed to pain. The forearm, though more sensitive to touch, was less sensitive to pain than the labia and the labia were also less sensitive to touch then the vulvar vestibule. The results suggest increased sensitivity within the vulvar vestibule that may be the result of vasocongestion, increased muscle tension and heightened sensation associated with the orgasmic platform. From these findings it appears that “The vulvar vestibule may be a particularly unique genital area with sensory properties as different from other genital locations as other more distant peripheral locations, such as the forearm” (Payne et al., p. 298). However, at all locations tested, women with vestibulodynia experienced more sensitivity and pain than healthy participants at all locations tested. These data confirmed the existence of generalized sensory abnormality, as well as increased catastrophizing, hypervigilance, and fear of both intercourse and non-intercourse pain, as previously reported (Giesecke et al., 2004; Granot et al., 2002; Pukall et al., 2002). These findings imply the need to address issues related to fear, catastrophizing, and pain related hypervigilence as part of any pain management strategy.

Neuromuscular variables
Another area of research where a high degree of consensus has emerged relates to over-activation of the levator ani muscle, the primary muscle within the pelvic diaphragm. Through the use of SEMG, several studies have sought to evaluate the functional status of pelvic muscle in vulvodynia patients. Early studies found consistent SEMG characteristics that could differentiate between patients and controls (White et al., 1997). The SEMG characteristics included:

Elevated resting baselines in 71% of patients, with readings over 2.0 µV,
Poor contractile potential in 63% of patients with readings under 17 µV,
Elevated resting standard deviation greater than 2 µV in 93% of patients,
Poor recruitment and recovery times of over 0.2 sec in 86% of patients,
Spectral frequency of less than 115 Hz in 69% of patients.

Among vulvodynia patients, 88% showed at least three of the above criteria, thus providing objective confirmation for the diagnosis of vulvodynia. Subsequent studies confirmed that SEMG can differentiate symptomatic patients from asymptomatic controls (Glazer et al., 1998). Vulvodynia patients showed:

46% less amplitude during 3 sec phasic contractions,
49% less amplitude during 12 sec tonic contractions,
32% more amplitude during pre-test rest,
49% more muscle instability during pre-test rest.

Based on these findings, therapy focused on normalization of levator ani muscle function. SEMG assisted normalisation of pelvic muscle function resulted in an 83% reduction in symptoms (Glazer et al., 1995). It has been proposed that increased muscle resting tone in the pelvic floor can be a response to physical or chemical irritants, inflammation, trauma, or emotional tension (Hong et al., 2008; Hawthorn & Redmond, 1998; Flor et al., 1992; Gevirtz et al., 1996; McNaulty et al., 1994). Chronic over-activation of these muscles can progressively lead to painful decompensation of muscle tissue and peripheral sensitization associated with muscle ischemia (Burton, 1996).