Superficial Dyspareunia and Localized Provoked Vulvodynia

As described in the title of an editorial in the journal Pain, female dyspareunia represents more than painful sex.¹ Defined as recurrent acute pain experienced primarily during penile–vaginal intercourse, dyspareunia is a common symptom that can affect a woman's quality of life in many ways. For many women with dyspareunia, it can be a source of frustration, because she may find herself going from a gynecologist to family doctor to therapist in a search of answers to the etiology of her symptoms and of possible treatments. In addition, a delay in finding an effective treatment has significant impact on a woman’s quality of life and intimate relationships. For health care providers, patients with chronic dyspareunia may represent a daunting challenge, particularly if easier interventions fail. However, for many women with dyspareunia, effective treatments will often alleviate their symptoms. An increasing number of publications are giving providers greater insights into localized provoked vulvodynia (LPV), previously known as vulvar vestibulitis syndrome (VVS).

Dyspareunia can be classified in many different ways. Some authors categorize this symptom as being primary, occurring ever since the first attempt at vaginal intercourse, or secondary, beginning spontaneously after previous pain-free and enjoyable intercourse. It may also be characterized as superficial, in which the patient notices pain primarily during vaginal penetration, or deep, in which the pain is worse with deeper penetration or thrusting. This chapter focuses on the evaluation and treatment of women with superficial dyspareunia, with a particular emphasis on what may be its most common cause, LPV.

Although most experts feel that dyspareunia is a common problem, the incidence of this symptom is difficult to estimate. A community study by Danielsson and colleagues estimate that one in five women between the ages of 18 and 29 report chronic dyspareunia.² In a study of five primary care practices in North Carolina, Jamieson and Steege found that 46% of sexually active respondents reported dyspareunia during or after intercourse.³ Of these women, 17% described pain near the opening of the vagina, 64% reported pain with deep penetration, and 8% had both. For most of these women, dyspareunia was only occasional, but 10% avoided sex and 3% had tried different sexual positions to avoid the pain. In terms of pelvic pain symptoms, dyspareunia ranked second only to dysmenorrhea in this study population. In another study, a phone survey contacted 2127 households and identified 100 symptomatic women and matched 325 asymptomatic controls for age and time. Vulvar pain lasting at least 6 months in duration was reported in 3.8% of respondents.⁴ Forty-five per cent of women reported an adverse effect on their sexual function and affected women reported a higher incidence of urinary tract infections, yeast infections, irritable bowel syndrome, depression, chronic fatigue syndrome, and fibromyalgia.

Classically, much of the discussion of dyspareunia has focused on whether this is a psychological problem or a physical one.⁵ As discussed by Meana and colleagues, dyspareunia is one of the few pain syndromes to be classified as a psychiatric illness in DSM-IV, and the psychiatric view has been that dyspareunia is primarily a sexual dysfunction. It is my personal observation that this perception of dyspareunia as a sexual dysfunction makes many women too embarrassed to mention this problem to their health care provider, and that many health care providers may give such symptoms scant attention. A recent study revealed that women saw an average of five physicians before an accurate diagnosis was made.⁶ However, detailed studies of women with dyspareunia show that such attitudes are unwarranted. In a study of 105 women with dyspareunia and 105 matched controls, Meana and colleagues performed an extensive standardized gynecological and psychological evaluation.^7, Women with dyspareunia had higher frequencies of LPV and vulvovaginal atrophy. In terms of psychological symptoms, patients with no physical findings reported more symptoms such as obsessive–compulsive sensitivities, interpersonal sensitivity, depression, and phobic anxiety. However, women with LPV were similar to controls in terms of psychopathology. These women, however, reported lower frequencies of intercourse, lower levels of desire and arousal, less success at achieving orgasm, and more erotophobia; these findings could almost be expected to be a result of having chronic pain with intercourse. It is worth emphasizing that only 27% of the women in this study had no abnormalities on a gynecological examination.

Identification and evaluation of a woman with dyspareunia

As mentioned previously, many women with dyspareunia are reluctant to volunteer their concerns about the symptoms. As described by Bachmann, simply asking “Are you sexually active?” and “Are you having any sexual difficulties or problems at this time?” is an effective way of identifying sexual problems.⁸ In a patient presenting with vulvovaginal problems, we routinely will ask about dyspareunia as part of the symptom complex that brings a patient to the office. Frequently, women with dyspareunia will attribute it to a vaginal infection and will not discuss this as a specific presenting symptom. Surprisingly, in some of these women, dyspareunia turns out to be the primary and only symptom.

Before performing a detailed history and physical examination on a patient reporting dyspareunia, it is important to realize that any of the organs in the pelvis, if affected with a problem, can lead to this symptom. Furthermore, as summarized in Table 1, a broad array of pathological conditions can cause pain. Thus, when evaluating a patient with dyspareunia, the clinician should perform a very detailed history and physical examination, along with appropriate laboratory evaluation, to obtain as specific a diagnosis as possible. Once a specific diagnosis is ascertained, a treatment plan can be established. In turn, this plan should be constantly re-evaluated as the patient returns for follow-up visits to ensure adequate progress and also to treat intervening conditions in a timely manner. For example, a patient with lichen sclerosus may initially find that her pain with intercourse resolves with ultra-potent topical corticosteroid therapy but then returns a few months later when she has an episode of vulvovaginal candidiasis (VVC).

Table 1. Etiologies of superficial dyspareunia

When a patient has dyspareunia, asking her further details about the pain is an important first step in history-taking. Women can be asked about the duration of the pain, its severity, and its location. In terms of measuring severity, many researchers will measure pain with intercourse as mild (able to enjoy intercourse but painful), moderate (able to have intercourse but not enjoyable), or severe (affects her ability to have intercourse). Specific questions about frequency of intercourse will give added insight into the severity of symptoms; the woman with “severe” pain who can still have intercourse three times per week is different than the one who has not been able to have intercourse in 3 years! Patients who primarily report pain with penetration are more likely to have a vulvar or vestibular etiology, whereas those who also describe pain with thrusting are more likely to have a vaginal, cervical, vesical, or rectal problem. Other questions to ask in terms of a sexual history include those about number of previous partners (and whether dyspareunia was present with them) and whether patients feel that they achieve adequate lubrication during sexual activity or if they use lubricants and report irritation in association. 

Once an adequate history about the dyspareunia has been taken, attention should be given to other associated vulvovaginal symptoms, such as itching, burning, irritation, or an abnormal discharge; positive answers to these questions suggest the possibility of an infectious or dermatological cause to the pain. Postpartum or postmenopausal women, especially if they note vaginal dryness, may have atrophic vaginitis. Finally, one should keep in mind that dyspareunia may be a symptom attributable to a systemic disorder. In a study of women with systemic sclerosis, Bhadauria and colleagues found that they were more likely to report dyspareunia (56%) or vulvar ulcerations (23%) than a control group with systemic lupus erythematosus or rheumatoid arthritis.⁹ In a prospective study of 11 women with chronic dyspareunia and musculoskeletal symptoms, Raynaud's phenomenon, or symptoms of ocular or oral dryness, Mulherin and colleagues found that they had some form of Sjögren's syndrome.¹⁰ Thus, a thorough review of systems is important to possibly uncover a more serious underlying disease.

When examining a woman with dyspareunia, one should attempt to evaluate the vulva, vulvar vestibule, hymen, vagina, cervix, bladder, and rectum, because any of these structures, if affected by a pathological condition, can be the source of the patient's pain. Thus, one should begin with a careful inspection of the vulva and vestibule. When evaluating the vulva, the clinician should pay close attention to the structures of the external genitalia and look closely for abnormal areas of erythema or edema. Patches of white epithelium, labial atrophy, phimosis of the clitoris, or other evidence of vulvar scarring may suggest the presence of lichen sclerosus or lichen planus. Palpation of the vulva and the vestibule with a cotton-tipped applicator will serve to localize the symptoms. Evidence of fissures or ulcers should lead the examiner to suspect a herpes simplex virus or yeast infection. Examination of the hymen may reveal a stenotic hymen. In addition to assessing the qualities of the vaginal secretions, inspection of the vagina should include a careful search for areas of erythema, erosions, and atrophy. Similarly, the cervical examination will assess for evidence of edema, erythema, friability, and mucopurulent discharge. On bimanual examination, the clinician can focus on each separate area and try to reproduce the patient's dyspareunia. On internal bimanual examination, one can get a sense of whether there exists any stenosis in either the introital or the deeper vaginal areas, as well as whether there is increased muscle tone in the bulbocavernosus or levator muscles. 

Laboratory evaluation depends to some degree on the findings of the examination. A vaginal pH and saline and 10% KOH microscopy are mandatory tests in any woman with dyspareunia. Because the sensitivity of microscopy to detect yeast is only 50% and because VVC is a frequent cause of dyspareunia, I routinely perform yeast cultures. Ancillary tests such as gonorrhea, chlamydia and trichomonas nucleic acid amplification testing (NAAT) are helpful in situations where the history is suggestive of a sexually transmitted disease or the wet mount reveals significant polymorphonuclear leukocytes. Any ulcer in the vulvar or vestibular skin should be evaluated with a herpes simplex virus (HSV) culture, HSV-1 and HSV-2 type specific IgG antibodies, and a rapid plasma reagent (RPR). Furthermore, vulvar or vaginal biopsy may be the appropriate diagnostic test if some sort of dermatological condition or a neoplasm is suspected. In women with bladder pain or other urinary symptoms, a urinalysis and urine culture are indicated. If these are negative, evaluation by a urologist may be helpful. Finally, in patients in whom some type of underlying systemic illness such as Sjögren's syndrome is suspected, referral to a rheumatologist for a more detailed evaluation is in order.

As a final consideration, the clinician may find that in some women with severe dyspareunia, perhaps in part secondary to vaginismus, a full examination may be next to impossible. In this situation, one should have no hesitation to recommend an examination under anesthesia to ensure that no anatomical problems are adding to the patient's pain.

Therapy for dyspareunia

To a great degree, successful treatment of dyspareunia will depend on the establishment of an accurate diagnosis and subsequent therapy. Apart from the treatment of LPV, the reader is referred to other chapters for more detailed management of the many causes of dyspareunia.

No matter what the cause, certain adjunctive maneuvers may help alleviate the patient's symptoms. Avoiding soaps and chemical irritants may help to decrease vulvar or vestibular inflammation. I will recommend routine use of a water-based lubricant with intercourse with avoidance of alcohol-based as they can tend to contribute to vaginal dryness and exacerbate symptoms. Because chronic pain may lead to decreased lubrication as a secondary phenomenon, it is easier to have patients use a lubricant rather than have them worry about this issue. In women who use latex condoms and who may be latex-sensitive, use of a polyurethane condom or some other method of birth control may avert a reaction to the condom. Finally, as noted earlier, dyspareunia is a symptom that may have many psychological ramifications, ranging from decreased libido to relationship difficulties to vaginismus. Women with chronic dyspareunia who feel that the pain is having a significant impact on libido or psychosexual self-image should be referred for counseling. Multimodal sex therapy, consisting of individual and couples therapy and other interventions such as cognitive–behavior techniques, is an important part of the multidisciplinary approach to these disorders.¹¹

Vulvodynia is defined as chronic vulvar burning condition of unknown etiology and is thought to represent a broad umbrella group of conditions that cause vulvar pain. Classically, vulvar vestibulitis syndrome (VVS), a condition where women exhibit specific point tenderness in the vestibule, has been considered the most common form of vulvodynia. It is characterized by feelings of vulvar rawness, stinging and/or burning. The nomenclature for this condition is currently in flux. In 2003, the International Society for the Study of Vulvovaginal Diseases (ISSVD) proposed a new terminology and classification system for vulvar pain, which is summarized in Table 2.¹² Provoked vulvodynia means that discomfort is triggered when physical contact occurs, as opposed to unprovoked situations where pain occurs spontaneously. Because the presence of inflammation (i.e. -itis) in VVS has been repeatedly debated, the term has been eliminated. With the new system, most patients with VVS would be classified as having localized provoked vulvodynia (LPV). Although both terms have been used in this chapter, providers should be aware of the current recommended nomenclature. 

Table 2. ISSVD terminology and classification of vulvar pain

Although there are descriptions of LPV dating back to more than a century ago, LPV became more clearly described in the early 1980s in articles by Woodruff, Parmley and Friedrich.^{13, 14, 15} In their articles, they described a condition in which women reported a burning pain on contact with the vestibule and in which examination revealed foci of tender inflamed areas in the vestibule. Twenty years later, despite hundreds of articles on the subject, this remains a condition in which there remains a wide spectrum of opinion about possible causes, accuracy of diagnosis, and optimal treatment approach.

LPV is a condition whose primary hallmark symptom is dyspareunia with intromission. Although exact data on the prevalence of LPV in the general population remain scarce, certain studies suggest that this is a common condition. In a mail and telephone survey of 4915 Boston area women, Harlow and colleagues found that 16% of surveyed women reported a history of chronic knife-like or excessive pain on contact with the genital area lasting for at least 3 months or longer, and 7% were experiencing it at the time of the survey.¹⁶ Similarly, Nyirjesy and colleagues found that up to 15% of patients referred to a tertiary care center for the evaluation of chronic vaginal and vulvar symptoms had LPV.¹⁷ These studies suggest that LPV is a fairly common cause of vulvar pain.

Diagnosis

Women with LPV present with a primary report of dyspareunia, particularly with intromission. Most of the time, these symptoms occur in women who have previously had comfortable, pain-free intercourse and then gradually or acutely noticed this problem. Other activities that involve contact with the introital area, such as tampon insertion, wearing tight clothes, or bike riding, may cause pain. Patients also note variable amounts of burning, irritation, and itching in their daily activities. Symptoms are almost completely localized to the vulvar vestibule.

A clinical diagnosis is made by fulfilling Friedreich's criteria, which consist of a history of vulvar pain with attempted intromission during intercourse, finding focal areas of erythema confined to the vulvar vestibule, and eliciting tenderness on palpation of these areas with a cotton-tipped applicator. In most cases, patients are required to have duration of symptoms of more than 6 months before their symptoms are diagnosed as LPV. Although most clinicians agree on Friedreich's criteria, fulfilling these criteria may not always be straightforward. For example, vestibular erythema is relatively common in many women and of itself may be a normal finding. Furthermore, tenderness to pressure on examination may depend on the technique of the examiners and their ability to elicit the appropriate response. Finally, although the diagnosis of LPV entails an exclusion of other conditions that can cause vulvar inflammation and pain, such as candidiasis or vulvar non-neoplastic epithelial disorders, the role of ancillary tests such as vaginal evaluations for causes of vaginitis, fungal cultures, or even vulvar biopsies varies tremendously within the published literature. Nevertheless, Bergeron and colleagues, in trying to assess the reliability of diagnosing LPV when performed by two independent gynecologic examinations, did find substantial inter-rater agreement, particularly when it came to the criterion of tenderness.¹⁸ 

In carefully performed controlled studies, investigators have successfully demonstrated that there are measurable physical differences between women with LPV and healthy women. Laser Doppler perfusion imaging to map the superficial blood flow in the vestibular mucosa has shown significant increases in perfusion values, particularly at the posterior fourchette.^19, Bohm-Starke and colleagues were able to demonstrate increased tenderness to punctate mechanical, thermal, distension but not vibrational stimuli in the vestibules of LPV patients.²⁰ The finding that these women may have increased pain perception elsewhere (i.e., the forearm) raises the possibility that LPV may represent some sort of systemic pain condition.²¹ In another study by Gupta and colleagues, the investigators demonstrated that patients with LPV have different alterations in intrinsic connectivity of regions comprising sensorimotor, salience and default mode networks compared to healthy control subjects and in subjects with other pain disorders such as irritable bowel syndrome.²² A cross-sectional study further examined the relationship between the presence of vulvodynia, fibromyalgia, interstitial cystitis, and irritable bowel syndrome.²³ Of the 1940 women included, 27.1% screened positive for multiple conditions and the presence of vulvodynia was associated with the presence of each of the other comorbid conditions. These findings suggest that while chronic pain disorders have similar mechanisms, there may be a role in functional connectivity related to pain pathways that show disease specificity. However, future research is needed to further establish the details of such pathways.

Epidemiology of localized provoked vulvodynia

It is estimated that approximately 14 million women in the United States are affected by LPV.²⁴ A population-based study suggests that the lifetime incidence occurs in approximately 16%, with the majority of women affected under the age of 30.^25, In their 1986 study of 67 women with LPV, Peckham and colleagues found that this condition predominantly occurs in white women. Although the age range of affected women was broad (14–67 years), most women were in their 20s and 30s, with a median age of 25 years.²⁶ Eighty per cent described an acute onset of symptoms; however, once they acquired the condition, the duration of symptoms extended months to years. An “in-depth” evaluation of nine women for concurrent conditions, allergies, or extra-genital physical findings did not find any notable findings. Compared with controls, women with LPV were more likely to be using oral contraceptives and to have been using them for a longer time; the association was strongest for those women who were using pills with high-progestin, high-androgenic, and low-estrogenic potency.²⁷

Danielsson and colleagues, in a case-control study of Swedish women with LPV, sought to focus on differences in medical, psychosexual, and psychological aspects of this disease. Women with LPV were more likely to report back, neck, and shoulder pain, gastrointestinal symptoms, headaches, urinary tract infections, and other skin problems.²⁸ In terms of gynecological history, they were more likely to report dysmenorrhea, a history of vulvovaginal candidiasis, and human papillomavirus (HPV) infection; the study could not ascertain the accuracy of diagnoses of infectious factors. Before their condition, these women had similar satisfaction scores regarding their sexual relationship; not surprisingly, they reported lower satisfaction scores after LPV, less frequency of vaginal intercourse, and more instances of participating in sexual activity without really wanting to. There were no significant differences between cases and controls in terms of social network and psychological factors. Other studies comparing women with LPV to control women and those with chronic pelvic pain have yielded fairly similar results.^{29, 30} Women with LPV had not experienced abuse more often than controls in their study.

However, more recent studies provide some evidence that psychosocial factors may play a stronger role in the development of persistent vulvodynia. A population-based survey of adult women reported that all types of abuse were linked to a four to six fold increase of vulvodynia.^{31, 32,} Subsequently, another large-scale study conducted by Landry and Bergeron, also demonstrated that adolescent girls who experienced dyspareunia reported more sexual abuse.³¹ Furthermore, a community-based study which evaluated women with depression or anxiety, showed that the odds of vulvodynia were four times more likely among that particular cohort of women.^33, Such studies demonstrate the complex and intimate relationship between vulvodynia and psychological factors. This knowledge can empower the physician and aid in the identification of women who may be more at risk for the development of LPV based on their psychosexual and psychologic history. 

Studies of LPV patients have attempted to further our understanding of this syndrome by approaching it from a number of different aspects. Patient histories suggest that an infectious process may play a role in the development of LPV. As noted earlier 80% of women with LPV describe an acute onset that then leads to the more chronic pain. However, the multiple treatments that the typical LPV patient has received before the establishment of a proper diagnosis make it difficult to identify the precipitating cause in these women.

When efforts began to identify an infectious cause for LPV, attention rapidly turned to HPV. In 1988, Turner and Marinoff described seven women with LPV who all had HPV DNA in tissue specimens.^34, Subsequent studies also found HPV DNA in 30–100% of patients with LPV.³⁵ However, more recent studies, which used PCR as the tool for detecting HPV, have led to a re-evaluation of the link between LPV and HPV. Wilkinson and colleagues found HPV types 6, 11, 16, and 18 in only three of 31 biopsy specimens of women with LPV.³⁶ Marks and colleagues found that LPV patients with HPV DNA by PCR were clinically identical to women with LPV who tested negative for HPV DNA; their findings suggest that HPV, if present, may be an innocent bystander.³⁷ A study from Israel found HPV in 54% of LPV and only 4% of control women, but the control group consisted of women undergoing vaginal operations for various benign causes or undergoing repair of an episiotomy.³⁸ Hybridization tests for HPV types 6, 11, 16, 18, and 33 were negative in 39% of women, and no one HPV type was consistently found in the other positive samples. It is not clear that the control group was appropriately matched for potential confounding factors. However, a Canadian study comparing women with LPV to controls found similar rates of HPV in cases (29.6%) and controls (23.9%).³⁹ Finally, in a study meant to evaluate clinical symptoms and signs associated with detection of HPV, no association was found between HPV and symptoms of vulvovaginal burning or pain.⁴⁰ 

Studies that have sought other infectious etiologies for LPV have generally found microbes present at an expected prevalence, although control groups were not always used. For example, although no controls were included, culture identified an expected prevalence of microbes in 57 cases of LPV that included Ureaplasma urealyticum (18%), Gardnerella vaginalis (14%), and Candida spp. (9%); Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, and Mycoplasma hominis were not detected.^41, In situ stains for candida, gram-positive bacteria, and mycobacteria have uniformly been negative, although these techniques are relatively insensitive.^{42, 43}

In 1989, Ashman and Ott noted that Candida albicans antigens cross-react with certain antigens in vulvovaginal tissue.⁴⁴ As proposed by these authors, they suggested that an effective immune response against C. albicans is aborted by this cross-reactivity and that, after repeated infections, susceptible patients become hyperreactive to the cross-reactive antigens, and the patient has LPV in the absence of active candidal infection. Candida, a commensal microorganism known to cause the most common clinical infections of the vulva and vagina, is certainly a likely candidate as a possible cause of LPV. 

Until recently, epidemiological studies of the relationship between LPV and VVC have yielded conflicting results. Earlier studies of VVS patients did not look for the presence of yeast by microscopy or culture or did not explore the issue at all. While Candida spp. were found in 9% of women in one report,⁴¹ Nyirjesy and Halpern found Candida spp. by culture in 24% of women with LPV.⁴⁵ In two case–control studies, LPV was strongly associated with a history of physician-diagnosed VVC with an odds ratio of approximately 5, as well as physician-diagnosed bacterial vaginosis (BV).^{46, 47} The discrepancies in findings may be related to the small number of patients in all three studies, but are also caused by the methods used to detect yeast. For example, candida was diagnosed by a culture performed only once, multiple times, and by a patient history of physician-diagnosed VVC.^{41, 45, 46, 47} Finally, in a prospective cohort study of 996 Swedish women, more women with vulvar pain had VVC (22.8%) than those without pain (12.4%).⁴⁸ More recent studies have further demonstrated a relationship between LPV and VVC.

VVC is the most commonly reported genital infections associated with LPV. In a study by Farmer et al., the investigators developed a vulvodynia animal model to evaluate the relationship between vulvar hypersensitivity seen in LPV and abnormal sensory processing secondary to chronic inflammation resulting from recurrent VVC.^49, In their study, female mice were subjected to recurrent vulvovaginal infection with C. albicans. This cohort of mice demonstrated mechanical allodynia localized to the vulva and also exhibited hyperinnervation. The presence of hyperinnervation was demonstrated by the presence of increased protein gene product 9.5, calcitonin gene-related peptide, and vesicular monoamine transporter 2 immunoreactivity. The investigators also observed that the hypersensitivity was present for 21 days even after the resolution of active infection. Additionally, only a subset of infected mice developed mechanical allodynia, which mirrors the clinical correlate in female patients, because only a small subset of women develop LPV after RVVC. 

Other studies of women with vulvar vestibulitis have sought to further delineate some of the histological changes that occur with this condition. Preliminary studies have suggested that women with LPV have a local elevation of inflammatory cells and proinflammatory cytokines, suggestive of a hyperimmune response.^{50, 51} The histopathology from the vestibular area of women with VVS has demonstrated a chronic, predominantly lymphocytic, inflammatory infiltrate.^{42, 52} A moderate-to-severe level of inflammation is present in 60–100% of women with LPV. The degree of inflammation seems to be greater beneath the squamous epithelium than beneath the vestibular glands.^52, From two studies that examined controls without LPV, it is less clear whether such inflammation may also occur in normal women.^{43, 53} Although Pyka and colleagues observed mast cells in only 21% of patients with LPV, others have noted increased numbers of mast cells in LPV compared with controls.^{42, 50} However, other findings consistent with allergic reactions, such as increased numbers of eosinophils, are not usually present.^50, In terms of local cytokine production, Foster and Hasday found that vulvar and vestibular tissue obtained from women with vulvar vestibulitis contained twice the tissue concentrations of IL-1β (p = 0.02) and TNF-α (p = 0.07) as compared with tissue from women undergoing rectocele repair.⁵¹ Of interest, both the degree of inflammation found on histology and the concentration of IL-1β and of TNF-α in the tissue were higher in the vulvar area than the vestibular area of both patients with LPV and controls. The authors felt that the higher levels of these two cytokines are responsible for the localized pain and tenderness that LPV patients exhibit. More recently, vestibular fibroblasts have been implicated as the potential source of these proinflammatory cytokines, particularly when provoked with Candida albicans and alpha-melanocyte-stimulating hormone.^54,  Furthermore, a subsequent study by Foster et al. identified higher levels of IL-6 and PGE₂ production in vestibular fibroblasts after C. albicans and C. glabrata infection, compared with external vulvar fibroblasts.⁵⁵ The findings of their study potentially indicate that site-specific enhanced responsiveness to innate immune mediators may precede LPV onset and promote early pathogenesis in combination with additional factors stated earlier in this chapter.

Taken in aggregate, these findings of a hyperimmune response are consistent with some sort of infectious or postinfectious process. It is possible that some of this response occurs because of genetic factors. LPV seems to occur predominantly in a white population.^{26, 46} Additionally, women with LPV are more likely to have a homozygous form of allele 2 of the gene encoding for the IL-1 receptor antagonist than control women.⁵⁶ This allele is associated with greater biological activity of IL-1β, a proinflammatory cytokine.⁵⁷ In vitro, these women may also demonstrate an inability to produce interferon-α, a cytokine that may limit chronic inflammation.⁵⁸ 

Given the preceding studies, one could speculate that LPV represents a multistep process. Some initial injury, such as a localized infection, may trigger inflammation in the vestibule. In the susceptible woman, once this inflammation develops, there are qualitative differences to her inflammatory pattern, differences that might be genetically predetermined, that prevent adequate resolution of the inflammation. These localized changes could over time also lead to changes in peripheral nerve structure and function leading to peripheral sensitization. Such changes were observed by Bohm-Starke and colleagues who noted increased numbers of intraepithelial nerve endings in women with LPV compared with healthy controls.⁵⁹ Additional psychological or psychosexual factors such a depression, anxiety, can furthermore predispose these susceptible women to develop LPV.

Therapy for localized provoked vulvodynia

As can be expected when the cause is unknown and has been attributed to such a wide variety of diseases, many treatment options have been proposed for LPV. Given the increasing number of potential therapies for LPV and the need to develop an organized plan for treating women with LPV a consensus panel of experts proposed guidelines in 2005.⁶⁰ In brief, the options can be classified as either medical or surgical.

With medical therapy, attention is initially focused on eliminating factors that may contribute to vulvovaginal irritation. At our center, patients receive extensive counseling about soaps and laundry detergents, choice of pads or panty liners, and the use of lubricants with intercourse. Much of this counseling is geared toward having the patient minimize the number of interventions that she is using in the area. For example, it is not uncommon for patients with LPV to engage in overzealous hygiene to “keep the area clean,” which in turn exacerbates her symptoms. If an infection such as VVC is encountered, we will often choose to prolong courses of therapy in an effort to prevent relapse and gain better insight into the amount of symptoms that can be attributed to the infection.

In those women whose symptoms remain, as outlined in Table 3, there is an extensive list of potential treatments. In some women, use of topical lidocaine before coitus may successfully control symptoms. Topical corticosteroids or some other anti-inflammatory therapy seems a logical step to treat the local inflammation regardless of etiology. Although conversations with health care providers who regularly treat LPV reveal that many will empirically attempt a trial of corticosteroid therapy before more aggressive attempts at therapy, published data with regard to outcomes after corticosteroid therapy are sparse. Nyirjesy and Halpern reported a positive response, defined as a response in which the patient felt that her symptoms had diminished to an acceptable or non-existent level, in 34% of 68 patients treated with 0.25% desoximetasone cream used topically twice daily for 4 weeks.⁴⁵ Murina and colleagues, using three weekly methylprednisolone and lidocaine injections in 22 women, found that 32% had complete resolution of their symptoms and 36% showed marked improvement.⁶¹ In a pilot study of 11 patients treated with 4% cromolyn cream applied three times daily, 10 had marked improvement. However, in a prospective double-blind placebo-controlled study, there was a similar response rate between cromolyn and placebo groups.⁶² The finding that 42% of patients experienced a 50% or greater reduction in symptoms highlights the need for more placebo-controlled study and a better understanding of this disease. Even more recently, similar levels of improvement in patients receiving oral desipramine, topical lidocaine and respective placebo groups in another double-blind study underscore the lack of any treatment approach which is superior to placebo. In this trial, Foster and colleagues evaluated 133 vulvodynia-afflicted women over a 12-week period and assigned women to four treatment groups: placebo tablets-placebo cream, desipramine tablets-placebo cream-placebo tablets-lidocaine cream, and desipramine tablets-lidocaine cream.⁶³ Using the tampon test as the primary endpoint in treatment goal, it was demonstrated that oral desipramine (t = 0.90; p = 0.37) and topical lidocaine (t =1.27; p = 0.21), as monotherapy or in combination, failed to reduce vulvodynia pain more than placebo. Furthermore, given the improvement seen with active and placebo treatments, past trials lacking placebo controls must now be re-evaluated.

Table 3. Possible therapies for localized provoked vulvodynia

Because tricyclic antidepressants block the reuptake of norepinephrine and serotonin, neurotransmitters that are involved in pain pathways, they are used extensively in women with LPV. However, few studies have evaluated this therapy. Nyirjesy and Halpern reported that 20 of 35 (57%) LPV patients had significant improvement with amitriptyline in doses up to 100 mg daily.⁴⁵ In a larger study of 148 women who received 75 mg amitriptyline daily, Pagano reported a response rate of 60%.^64, Other drugs for neuropathic pain, such as gabapentin, an antiepileptic and structural analogue for the neurotransmitter gamma aminobutyric acid (GABA), and venlafaxine, can be used in situations where patients cannot tolerate amitriptyline. With gabapentin, in particular, in a group of 17 patients, 14 (82%) improved with doses up to 1200 mg daily.⁶⁵ Although these drugs carry their own side effects, successful treatment sometimes depends on a trial and error approach to finding a drug which works and which can be tolerated. Further studies have evaluated the use of topical gabapentin with less systemic side effects. Women were treated with 2–6% topical gabapentin and after 8 weeks of therapy, 80% of subjects reported at least a 50% improvement in their pain scores.^66,

Similar results have been reported with a compounded cream containing 2% amitriptyline/2% baclofen (ABC). In a retrospective study by Nyirjesy and colleagues, 38 women with LPV and who received treatment with ABC were identified from a database of 505 women with chronic vulvovaginal disorders.⁶⁷ With a median follow-up of 33 weeks, 29% of patients reported no or little improvement, 18% reported moderate improvement, and 53% reported significant improvement in their symptoms. However, no change was noted in the reported frequency of sexual intercourse, sexual desire, or satisfaction with sexual life. No patients reported systemic side effects. With topical treatments, the absence of systemic side effects may be mitigated by local side effects such as burning in about 10% of patients. With other topical agents such as capsaicin, even higher rates of burning can be expected.

When it was thought that LPV was caused by HPV infection, intralesional injections of α-interferon were suggested as a possible therapy for LPV. A total of 12 one-million-unit injections are administered in the vestibule (three times per week for 4 weeks) in such a way as to inject the entire vestibule. Apart from the pain of the local injection, patients may report flu-like symptoms such as headache, myalgia, and fever. Initially, cure rates of almost 90% were reported.^68, However, other studies of α-interferon have shown a success rate as low 37–49%.^69, However, given that HPV is no longer speculated to be a major contributing factor to the development of LPV, α-interferon injections are no longer recommended for therapeutic use.

In the past 15 years, a treatment that has assumed more prominence in the medical management of LPV is electromyographic biofeedback of the pelvic floor musculature. As suggested by Glazer and colleagues, hyperirritability of the pelvic floor muscles is often noted in women with LPV.⁷⁰ They hypothesized that this hyperirritability destabilizes the pelvic floor muscles and thus perpetuates the vulvar skin disturbance. Pelvic floor muscle electromyographic biofeedback therapy, which consists of a series of exercises to strengthen the pelvic floor muscles with biofeedback assistance, allowed up to 79% of 28 women with LPV to resume comfortable coitus. Other studies of biofeedback therapy have had similar results.^{71, 72} Physical therapy meant to address pelvic floor muscle dysfunction is thought to provide similar and possibly superior benefits to electromyographic biofeedback treatment.

Surgical treatment for LPV has been well described as a viable approach to women with this disorder. The surgery that has been best described is a partial vestibulectomy with vaginal advancement (also known as perineoplasty).¹⁴ With this procedure, the entire posterior vestibule, along with the posterior hymen, is excised. Then, after mobilization of the vagina by dissecting it free from its underlying attachments, a flap of vagina is brought out over the denuded area and sutured into place. Although most procedures can be performed in an outpatient setting, it can take up to 3 months to get a sense of whether the disorder is cured. With this procedure, success rates of 63–100% have been described.^{14, 73, 74, 75} It is encouraging to note that even with a mean of 3.3 years of follow-up, Bergeron and colleagues still found a “positive” outcome in 63% of patients. Although complications such as hemorrhage, infection, and poor healing are of theoretical concern, they seem to occur surprisingly seldom. The development of postoperative Bartholin cysts also seems to be fairly rare.

In an effort to find a less extensive procedure, alternative surgeries for LPV have been proposed. In a prospective randomized trial, vestibuloplasty, consisting of a simple undermining of the affected areas, then closure, was ineffective in 10 patients, in comparison with nine of 11 women whose LPV was cured with vestibulectomy.⁷⁶ Local surgical excision of the inflamed vestibular areas may be effective as a more limited procedure, but it has only been described in a small series of 12 patients.^77, Finally, flashlamp-excited dye laser therapy yielded a complete and partial response rate of 62% and 30%, respectively, in a series of 175 women with LPV.⁷⁸

Faced with many different options in the treatment of LPV, it can be difficult to decide how to treat each individual patient. Whereas some experts advocate a limited role for surgery, others use it extensively.^{79, 80} In a randomized trial of group cognitive behavioral therapy, biofeedback, and vestibulectomy, all groups improved significantly, although the best response was seen in those women randomized to surgery.⁷² Finally, even in those patients whose LPV fail medical therapy, surgery is effective in up to 90% of women with persistent LPV.⁶⁴ However, the preceding statements are tempered by the observation that most of the data with regard to treatment of LPV are based on retrospective case series. Given the fact that no treatment has been shown to be clearly superior to others, it makes sense to try to tailor the therapy to the individual patient. For a woman hoping for a quick effective approach, surgery early on may be the best choice. For another woman who is averse to any type of surgery, a stepwise approach to medical therapy, such as described by Nyirjesy and Halpern, may be an appropriate way to begin, but the patient may need to understand that it may take quite a bit of time until she experiences an adequate level of symptomatic relief.⁴⁵ It is encouraging to note that, with all treatment modalities, there is a substantial chance of adequate improvement. It is my personal feeling that for women with LPV who are often frustrated with the previous lack of an adequate diagnosis and therapy, a message of hope and reassurance is clearly warranted.