Abstract
The objectives of this chapter are as follows: (1) to understand the current classification system for vulvar pain; (2) to explore the various causes of vulvodynia, including the histopathologic findings of patients with vulvodynia; and (3) to gain knowledge about the treatments used for localized and generalized vulvodynia. A review of the basic science of vulvodynia will be provided. New thoughts on potential causes will be discussed. Routine and some investigative treatments for vulvodynia will be explored. A number of subcategories of vulvodynia exist. Treatment for the various subcategories differs. Vulvodynia is a condition that is challenging for patients and health care providers. The pain and discomfort of vulvodynia affects the quality of life of many women. Pain can be continuous or intermittent, often aggravated by activities such as sitting at a desk, bicycle riding, and sexual intercourse. Although research in this topic has expanded over the past 40 years, further investigation is needed to optimize the care of women with vulvodynia.
Keywords
vulvodynia, localized, vestibulodynia, clitorodynia, pain
Chapter Outline
HISTORY OF VULVAR PAIN TERMINOLOGY
CAUSATIVE THEORIES OF VULVODYNIA
Introduction
Vulvodynia is defined as a chronic discomfort or pain, consisting of burning, stinging, irritation, and rawness on the vulva. It was once believed to be a rare condition, but is now known to affect millions of women. It can be a chronic pain disorder, at times associated with other chronic comorbid pain conditions. The prevalence of vulvodynia is 8.3%. The prevalence remains stable through age 70 years and has been shown to decline thereafter. The pain can be generalized—diffuse vulvar burning or irritation—or localized—pain at a specific area, such as the vestibule or clitoris. Localized vulvodynia that was previously termed vulvar vestibulitis is currently termed vestibulodynia . The vestibule is defined as the area between the hymen and Hart’s line ( Fig. 3.1 ).
History of Vulvar Pain Terminology
Vulvar pain discussion first appeared in the literature in 1861 in an article by Sims. He described a patient he saw in 1857 with vaginismus, but on further analysis of her history, she appeared to have vulvodynia. Thomas has described the condition as “excessive hypersensibility of the nerves supplying the mucous membrane of some portion of the vulva.” In 1889, Skene depicted a condition “characterized by a supersensitiveness of the vulva. … When, however, the examining finger comes in contact with the hyperaesthetic part, the patient complains of pain, which is sometimes so great as to cause her to cry out.” In the same year, Kellogg wrote about a patient with “sensitive points about the mouth of the vagina.” The topic was not readdressed until 1928, when Kelly saw a woman with “exquisitely sensitive deep red spots” that were a “fruitful source of dyspareunia.” In 1983, Friedrich reported on 13 patients with “vestibular adenitis.” Terminology has continued to change with time. The International Society for the Study of Vulvovaginal Disease (ISSVD) popularized a definition of vulvar pain in the 1980s (essential or dysesthetic vulvodynia), describing patients with a chronic discomfort and burning, stinging, irritation, and rawness of the vulva. In 1987, Friedrich proposed the term vulvar vestibulitis syndrome . There are two major forms of vulvar pain: hyperalgesia (low pain threshold) and allodynia (pain to light touch). The terminology of pain localized to the vulvar vestibule continues to undergo changes. Table 3.1 demonstrates the changes in terminology for vulvar pain that have occurred with time, up to the 2003 terminology. Concerns with the terminology were present. Recently, a new vulvodynia terminology has been approved ( Box 3.1 ).
| Vulvar Dysesthesia (1999) | Vulvar Dysesthesia (2001) | Vulvodynia (2003) |
|---|---|---|
| New Mexico, United States, ISSVD World Congress | Lisbon, Portugal, ISSVD World Congress (N ote : This was a provisional terminology system.) | Salvador, Brazil, ISSVD World Congress |
| Generalized vulvar dysesthesia | Provoked vulvar dysesthesia Generalized Localized (vestibule, clitoris, other) | Vulvodynia, generalized Provoked (sexual, nonsexual, both) Unprovoked Mixed (provoked and unprovoked) |
| Localized vulvar dysesthesia Vestibulodynia (formerly vulvar vestibulitis) Clitorodynia Other localized forms of vulvar dysesthesia | Spontaneous vulvar dysesthesia Generalized Localized (vestibule, clitoris, other) | Vulvodynia, localized (vestibulodynia, clitorodynia, hemivulvodynia) Provoked (sexual, nonsexual, both) Unprovoked Mixed (provoked and unprovoked) |
- A.
Vulvar pain caused by a specific disorder a
a Women may have both a specific disorder (e.g., lichen sclerosus) and vulvodynia.
Infectious (e.g., recurrent candidiasis, herpes)
Inflammatory (e.g., lichen sclerosus, lichen planus, disorders)
Neoplastic (e.g., Paget disease, squamous cell carcinoma)
Neurologic (e.g., postherpetic neuralgia, nerve compression or injury, neuroma)
Trauma (e.g., female genital cutting, obstetric)
Iatrogenic (e.g., postoperative, chemotherapy, radiation)
Hormonal deficiencies (e.g., genitourinary syndrome of menopause [vulvovaginal atrophy], lactational amenorrhea)
- B.
Vulvodynia—vulvar pain of at least 3 months’ duration, without clear identifiable cause, which may have potential associated factors
The following are the descriptors:
Localized (e.g., vestibulodynia, clitorodynia) or generalized or mixed (localized and generalized)
Provoked (e.g., insertional, contact), spontaneous, or mixed (provoked and spontaneous)
Onset (primary or secondary)
Temporal pattern (intermittent, persistent, constant, immediate, delayed)
IPPS, International Pelvic Pain Society; ISSWSH, The International Society for the Study of Women’s Sexual Health
ISSVD, The International Society for the Study of Vulvovaginal Disease.
Patients with vulvar pain localized to the vestibule have a normal-appearing vulva, other than occasional erythema ( Fig. 3.2 ). The erythema tends to be most prominent at the Bartholin’s, Skene’s, and vestibular duct openings. The other form of localized pain is clitorodynia. Pain associated with an abnormal vulvar appearance does not qualify for the diagnosis of localized vulvodynia ( Box 3.2 ).
Podophyllin overdose
Condylox (podofilox) overdose
Behçet disease
Aphthous ulcers
Herpes (simplex and zoster)
Candidiasis
Trichomonas
Chancroid
Sjögren disease
Contact dermatitis
Endometriosis
Pemphigus
Pemphigoid
Atrophy
Lichen sclerosus
Lichen planus
Crohn disease
Bartholin’s abscess
Trauma
Imperforate hymen
Prolapsed urethra
Vulvar intraepithelial neoplasia
Carcinoma
Causative Theories of Vulvodynia
Many theories have been proposed for the causes of vulvodynia, including abnormalities of embryologic development, infection, inflammation, genetics, immune factors, nerve sensitization, and increased muscle tone. The exact cause of vulvodynia is unknown; there likely is no single cause.
Embryologic Development
McCormack and Fitzpatrick et al. have linked vestibular pain with interstitial cystitis, another idiopathic inflammatory syndrome of the urogenital tract. They have speculated that the tissues from two distinct anatomic sites have a common embryologic origin and therefore are predisposed to similar pathologic responses when challenged. Additional studies have found an association between vulvodynia and interstitial cystitis.
Infection With Candida
Infection with Candida has been suggested to be associated with vestibular pain. Frequently, patients with vulvar pain mention a history of recurrent Candida infections. Studies have compared the frequency of Candida infections in patients with vestibular pain to a control population. Patients with pain reported more Candida infections than normal controls; however, this association is based on patient self-reports of past infections, not verified with culture tests. Meana et al. and Bazin et al. did not find a high prevalence of culture-documented Candida infection. Additionally, Marinoff and Turner did not demonstrate a hypersensitivity to Candida in patients with vestibular pain. A lack of certain lactobacilli species that protect against yeast infections has been reported. In a study by Ventolini et al., Lactobacillus crispatus was found only in control patients. None of the patients with symptomatic vulvodynia had Lactobacillus crispatus.
A recent study involving a murine model of vaginal infection with Candida albicans found an abnormal inflammatory response and heightened sensitivity of the vaginal opening. Falsetta et al. have suggested that a fibroblast-mediated proinflammatory response to C. albicans contributes to the induction of pain in patients with localized provoked vulvodynia. Enhanced, site-specific, innate immune responsiveness to yeast pathogens by fibroblasts may be an early step in localized provoked vulvodynia pathogenesis. The low fibroblast interleukin-6 (IL-6) immunohistochemistry-positive count may result from IL-6 produced by fibroblasts existing in a secreted extracellular state.
Inflammation
The role that inflammation plays in the development of localized vulvodynia is unclear. Various papers that mentioned inflammation and inflammatory cytokines have shown inconsistent results. The suffix “-itis” (as in vestibulitis) has been excluded from the vulvodynia terminology because studies found a lack of association between excised tissue and inflammation. Bohm-Starke et al. found a low expression of the inflammatory markers cyclooxygenase-2 and inducible nitric oxide synthase in the vestibular mucosa of women with localized vestibular pain, as well as in healthy control subjects. T cells have also been investigated. Biopsies from women with primary provoked localized vulvodynia have shown significantly more CD4 + T cells than those from women with secondary provoked localized vulvodynia (PLV) and unaffected controls.
Interleukins have also been studied in association with vulvodynia. Baker et al. found that the level of IL-8 was significantly increased (1.7 times; p = 0.00021) in vestibulodynia patients versus controls. Levels of IL-1α, -1β, -2, -4, -6, -6sR, -15, -16, and -17, regulated on activation, normal T cell expressed and secreted (RANTES), transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), induced protein 10 (IP-10), eotaxin-1 and -2, monocyte chemoattractant protein-1 (MCP-1), granulocyte-colony stimulating factor (G-CSF), tissue inhibitor of metalloproteinases 2 (TIMP2), platelet-derived growth factor BB (PDGF-BB), I-309 protein, and macrophage inflammatory protein-1β and -1δ were significantly decreased ( p < 0.001 or p < 0.005) in vestibulodynia patients when compared with healthy volunteers.
Mast cells have also been studied, with conflicting results, in their relation to vestibulodynia. Bornstein et al. found a significant increase in inflammatory infiltrates, number of mast cells, and degranulated mast cells in vestibulodynia patients compared to normal controls. In the study by Reaguer et al., most mast cell–rich biopsies with more than 40 mast cells/mm 2 were classified as a secondary mast cell disorder, reflecting an activated immune system in 75% of vulvodynia patients. In contrast, Papoutsis et al. and Tomolla et al. did not find an association between mast cells and vestibulodynia. In these two studies, similar amounts of mast cells were present throughout the vestibular mucosa of patients and controls. There appears to be an age-related finding in mast cell density. Compared with premenopausal primary and secondary vestibular biopsies, postmenopausal tissues had more mast cells.
Genetic and Immune Factors
It may be that there is an association with other factors involved in the inflammatory response, rather than inflammatory cells alone. Goetsch was one of the first researchers to question a genetic association of localized vulvar pain and found that 31 gynecology patients (15% of the total) questioned over a 6-month period were found to have localized vestibular pain; 32% had a female relative with dyspareunia or tampon intolerance, raising the issue of a genetic predisposition. Genetic polymorphisms and the immune system may be involved. Emerging evidence has demonstrated that microRNAs (miRNAs) regulate the expression of pain-relevant genes. In a recent study, vestibulodynia patients differed from controls in expression of 10 miRNAs of predicted importance for pain and estrogen signaling.
Another genetic connection has been suggested by Gerber et al. Allele 2 in the IL-1β gene was found to be more common in women with vestibulodynia than in other women. Allele 2 of the IL-1β gene was identified in 27 women (46% of the total) with vestibulodynia as opposed to 12 (25%) control women. Susceptibility to vestibulodynia might be influenced by carriage of this polymorphism. Persons homozygous for allele 2 of the IL-1RA gene (IL1RN*2) have a more prolonged and more severe proinflammatory immune response than those with other IL-1RA genotypes. The role for defective immune regulation in this patient population has been proposed. A relative inability to downregulate proinflammatory IL-1β activity by IL-1 receptor antagonists may contribute to the pathophysiologic features of localized vulvodynia. Another theory about the immune pathway is that patients with vestibulodynia have a reduced capacity for TNF-α production in response to microbial components. It has been suggested that polymorphism in the CIAS1 gene may play a central role in the triggering of vestibulodynia in a subset of patients.
A recent study has analyzed data on cytosine-adenine-guanine (CAG) trinucleotide repeats on an androgen receptor (AR) gene among a select group of vulvodynia cases and nonaffected controls. Women with vulvodynia who had started combined oral contraceptives (COCs) prior to pain onset, and whose pain resolved after COCs were discontinued, were more likely than controls to have a greater number of CAG repeats in the AR gene and were also likely to have a lower free testosterone level. However, it was pointed out by Reed et al. that the study compared two groups who differed in a number of ways, making interpretation of the results problematic.
The serotonin (5-hydroxytryptamine [5-HT]) receptor gene (5HT-2A) polymorphism and its association with vestibulodynia has been studied. It was found that the probability of provoked vestibulodynia was elevated in participants carrying the 1438G and 102C alleles of the 5HT-2A gene.
Clinically, genetics may play a role in those undergoing vestibulectomy for localized pain. The relative risk of vestibulectomy has been found to be elevated in first-, second-, and third-degree female relatives.
Neuropathways
Krantz was instrumental in examining the nerve characteristics of the vulva and vagina. In this study, the region of the hymeneal ring was richly supplied with free nerve endings. No corpuscular endings of any form were observed. Only free nerve endings were observed in the fossa navicularis. A sparsity of nerve endings was noted in the vagina as compared with the region of the fourchette, fossa navicularis, and hymeneal ring. Additionally, an association with age was noted. Interestingly, there were more free nerve endings in the genitalia of young patients than in older patients.
Other studies have analyzed the nerve factors in women with vulvar pain. Westrom and Willen used S-100 stains for neural tissue protein and found that 44 of 47 patients with localized pain to the vestibule had more nerve fibers than control patients. Vessels in this patient population were found to have a proliferation of nerve bundles around the vessels, thus possibly contributing to the erythema that often occurs in this patient population. Women suffering from vestibular pain have also demonstrated lowered tactile detection and pain thresholds in the vulvar vestibule than a control population. Patients with vulvar pain localized to the vestibule have an increase in immunoreactive nerve fibers or sensitization of thermoreceptors and nociceptors in their vestibular mucosa. Central neural pathways may also be involved with vestibulodynia. The augmented brain activation in vulvodynia patients in response to a stimulus remote from the vulva suggests a central pathology in this disorder.
Human Papillomavirus
A previous area of confusion was the emphasis on human papillomavirus (HPV) in the causation of symptoms of vulvodynia. Although several studies initially supported the association of HPV with vulvar pain, other studies did not find an association of HPV and vulvar pain, particularly in pain localized to the vestibule, other than pain secondary to the treatments used for HPV-related conditions. *
* References .
Protease inhibitors, known for their antiviral properties, have been studied for their effect on pain. It has been suggested that in women with secondary vestibulodynia with constant pain, insufficient vaginal protease inhibitor production may contribute to increased pain sensitivity.
Steroid Receptor Pathways
Steroid receptor expression and morphology in vulvar vestibular mucosa in women with provoked vestibulodynia have been studied. Increased expression of estrogen receptor alpha in the vestibular mucosa of patients with vestibulodynia has been found. Animal studies have shown that estrogen receptor subtypes are important for vanilloid receptor function. The vanilloid receptor is expressed by nociceptive fibers and is triggered by a variety of noxious stimuli, such as capsaicin, with subsequent release of neuropeptides, which may then induce neurogenic inflammation. An increase of vanilloid receptor VR-1 has been observed in vestibular biopsies from patients with provoked vestibulodynia.
Increased Muscle Tone
Pelvic floor muscle dysfunction plays an important role in the pathophysiology of provoked vestibulodynia (PVD). There is evidence to support their involvement in the pathophysiology of localized vulvodynia.
Histopathology
The epithelium covering the vestibule of the vulva differs from extragenital skin because it is nonkeratinized, with a nonpigmented surface, and consequently is more similar to mucosal surfaces than to skin at an ultrastructural level. The vestibular surface has an epithelium of several layers of closely packed cells. These cells mature and differentiate as they approach the surface. Unlike keratinized skin, appendages such as hair follicles and sweat glands and the characteristic granular and cornified cells are absent from vestibular epithelium. The surface of the vestibular epithelium is characterized by microridges. The surface cells of perineum, a keratinized epithelial surface, do not show this type of microridge.
Vestibulectomy specimens in patients with vulvar pain have been analyzed and revealed several findings. On occasion, vestibular gland adenomas have been associated with pain. Glomus tumors have also been reported to cause pain on the vulva. The focus of this discussion, though, is on pain localized to the vestibule, with a normal appearance, excluding erythema. Findings described in vestibulectomy specimens include a mixed population of T lymphocytes, variable numbers of monocytes, and rare plasma cells ( Fig. 3.3 ). The microscopic findings are of a nonspecific inflammatory infiltrate, sometimes present around the minor vestibular gland ( Fig. 3.4 ). Squamous metaplasia in vestibular glands and their ducts has been reported ( Fig. 3.5 ). Epidermal hyperkeratosis and parakeratosis have also been described but may represent lichenification resulting from rubbing of the underlying condition. White blood cells may be seen in all layers of the epithelium. Small surface erosions (ulcers) may be seen, either acute or healing ( Fig. 3.6 ). These findings are not specific and can be seen in unaffected women. As previously discussed, many studies have supported the association of inflammation with diseases of the vestibule, whereas other studies lack support for this concept, having found inflammation to be present in the control population as well. Whether localized vulvodynia can be distinguished from the generalized form by pathologic parameters remains to be determined. Conceivably, a more discrete inflammatory response may cosegregate with the localized form, providing a morphologic correlate for the discomfort produced by point pressure . However, until this is proven, the pathologist is reminded that the previously stated histologic findings found in the setting of vulvar pain may or may not correlate with the clinical diagnosis of vestibulodynia. Additionally, histology is unable to predict which patients will respond to surgery. A format for pathologic reporting is outlined in Table 3.2 .
