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This article is a CME / CE certified activity. To earn credit for this activity visit: http://www.medscape.org/viewarticle/877370

Vulvodynia: A Common and Under­Recognized Pain Disorder in Women and Female Adolescents ­­ Integrating Current Knowledge Into Clinical Practice CME / CE Jacob Bornstein, MD; Andrew Goldstein, MD; Ruby Nguyen, PhD; Colleen Stockdale, MD; Pamela Morrison Wiles, DPT

Posted: 4/18/2017 This activity was developed through a comprehensive review of the literature and best practices by vulvodynia experts to provide continuing education for healthcare providers.

Introduction

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Historical Perspective

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What we now refer to as "vulvodynia" was first documented in medical texts in 1880, although some believe that the condition may have been described as far back as the 1st century (McElhiney 2006). Vulvodynia was described as "supersensitiveness of the vulva" and "a fruitful source of dyspareunia" before mention of the condition disappeared from medical texts for 5 decades.

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Magnitude of the Problem

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Studies of women found that the incidence of symptom onset is highest between the ages of 18 and 25. Once thought to affect primarily white women, recent studies indicate that Hispanic women are significantly more likely to develop vulvodynia and may present with different vulvar pain subtypes.

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Because vulvodynia is rarely covered in medical school curricula and residency programs, symptoms mimic those of common vulvovaginal infections, and, in many cases, no abnormalities of the vulvar tissue can be seen upon examination, women are often misdiagnosed. In 2003, the first federally funded population­based epidemiologic study in Boston found that almost 60% of patients reported visiting ≥3 healthcare providers to receive a diagnosis, 40% of whom remained undiagnosed after 3 consultations.

Using prevalence estimates of 3% to 7%, Xie and colleagues demonstrated the significant economic impact of vulvodynia in the United States: $31 to $72 billion in direct and indirect costs.

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Anatomy and Neurobiology of the Urogenital Tract

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The vulva is the external female genitalia. It includes the mons pubis, labia majora, labia minora, prepuce or clitoral hood, clitoris, and vulvar vestibule. The vulva is the center of a woman's sexual response. The anterior and posterior boundaries of the vulva extend from the mons pubis to the anus, respectively. Its lateral boundaries lie at the genitocrural folds. The mons pubis is comprised of a fat pad at the anterior of the vulva and is covered in pubic hair. The labia majora are derived embryologically from labioscrotal swellings. They fuse posteriorly and attach anteriorly to the mons pubis. The labia minora, hairless folds of skin embryologically derived from urethral folds, lie within the labia majora. The labia minora fuse anteriorly, forming the prepuce (hood) of the clitoris, and extend posteriorly to either side of the vaginal opening. They fuse posteriorly at the vulvar vestibule, creating a fold of skin called the posterior fourchette. The mons pubis, perineum, and labia are derived from the embryonic ectoderm. Vulvar skin is a keratinized, stratified, squamous epithelial structure that contains sebaceous glands and sweat glands. The keratin thickness of vulvar skin decreases progressively from the labia majora, over the clitoris to the labia minora. The vulvar vestibule extends from the frenulum of the clitoris anteriorly to the fourchette posteriorly. Hart's line marks the juncture of nonkeratinized epithelium of the vestibule and the keratinized epithelium of the inner surface of the labia minora. The vulvar vestibule, derived from the urogenital sinus endoderm, contains the major vestibular glands (Bartholin's and Skene's) and the minor vestibular glands. The vestibular glands secrete mucous during sexual arousal and orgasm. The clitoris is located under the prepuce and is embryologically derived from the genital tubercle. It is formed of erectile corpora cavernosa tissue, which becomes engorged with blood during sexual stimulation (Farage 2006; Krantz 1977; Woodruff 1985).

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The vulva is innervated by the anterior labial branches of the (A) ilioinguinal nerve (L1); (B) genitofemoral nerve (L1­2); and (C, D) branches of the pudendal nerve (S2­4). Near the medial aspect of the ischial tuberosity, the pudendal nerve divides into 3 branches: (C) the dorsal nerve of the clitoris (shown deeper as dashed lines in muscles of the urogenital diaphragm), (D) the perineal nerve, which innervates the labia majora and perineum, and (E) the inferior rectal nerve, which innervates the perianal area. The pudendal nerve also innervates the external anal sphincter and deep muscles of the urogenital triangle (Peng 2009). For a thorough review of the neurobiology of the urogenital tract, see Wesselmann (1997).

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http://www.medscape.org/viewarticle/877370_print 11/69 21/4/2017 www.medscape.org/viewarticle/877370_print The pelvic floor muscles are divided into 3 categories. The superficial pelvic floor muscles (bulbocavernosus or bulbospongiosus, ischiocavernosus, superficial transverse perineal/perineus muscle) are collectively known as the urogenital diaphragm. The function of the urogenital diaphragm muscles includes a role in sexual function (eg, clitoral engorgement, vaginal closure, reflexive response to enhance sexual pleasure, and facilitating closure of the urethra and anus for continence). The middle layer is comprised of the deep transverse perineal muscle and sphincter urethra. The deep pelvic floor muscles, sometimes called the anal triangle, include the levator ani (pubococcygeus, iliococcygeus, and puborectalis), and coccygeus. Other associated pelvic and hip muscles include the piriformis, obturator internus muscles, and gluteus maximus. The perineal body is the central tendon and attachment site for the superficial, middle, and deep pelvic floor muscles.

The internal pudendal artery, vein, and nerve, which pass through Alcock's canal, provide neurovascular function to the pelvic floor musculature. Alcock's canal is comprised of fascia or connective tissue from the obturator internus. Although the pudendal nerve is known to innervate the levator ani muscles, there have been more recent studies describing innervation by the levator ani nerve and direct nerve roots S3 and/or S4 (Barber 2002, Grigorescu 2008). Specifically, the pubococcygeus muscle is innervated by the levator ani nerve S3­5 and the perineal branch of the pudendal nerve S3­4. The iliococcygeus is innervated by the levator ani nerve S3­4, and the puborectalis is innervated by the inferior rectal branches of the pudendal nerve S2­S4. The coccygeus is innervated by direct nerve roots S3­4. The function of the deep pelvic floor muscles includes supporting the abdominal viscera or organs, providing pelvic and spinal stability, assisting in respiration, and providing sphincteric closure for bowel and bladder function. They also play a role in sexual function. For a thorough review of the anatomy and physiology of the pelvic floor, see Herschorn 2004.

Terminology and Classification

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The current classification differentiates: vulvar pain due to a known cause vs idiopathic chronic vulvar pain (ie, vulvodynia).

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Pain is first classified by location, ie, generalized (several areas of the vulva), localized (a specific area of the vulva), or mixed; secondly, it is classified by provocation (provoked, spontaneous, or mixed). It is also described by onset (either primary or secondary) and temporal pattern (intermittent, persistent, constant, immediate, or delayed). The 2 most common forms of vulvodynia are: generalized vulvodynia and provoked vestibulodynia (formerly Vulvar Vestibulitis

http://www.medscape.org/viewarticle/877370_print 13/69 21/4/2017 www.medscape.org/viewarticle/877370_print Syndrome). It should be noted that women may have both a specific disorder (eg, lichen sclerosus) and vulvodynia. Please see Slide 26 for potential associated factors.

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Since 1975, many terms have been used to describe the 2 most common vulvodynia subtypes, causing confusion among the medical, scientific, and patient communities.

Pathophysiology

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The pathophysiology of vulvodynia remains inconclusive. (See vulvodynia pathophysiology references 1–50.) However, research to date supports the theory that multiple mechanisms predispose, trigger, and perpetuate symptoms.

Comorbidities: painful bladder syndrome, fibromyalgia, irritable bowel syndrome, and temporomandibular disorder are significantly associated with vulvodynia Genetics: Some women with vulvodynia have a genetic predisposition that increases the risk of candidiasis or other infections, prolongs inflammatory responses, or affects their response to oral contraceptives Hormonal factors: In some women, the use of combined hormonal contraceptives has been associated with an increased risk of vulvodynia Inflammation: Based on either histologic, immunologic, or biochemical studies, inflammation has been associated with vulvodynia. There is an increase in the number of mast cells and degranulated mast cells Musculoskeletal: Pelvic floor overactivity is frequent Neurologic mechanisms: Higher sensitivity to stimulation in non­genital areas is seen and brain imaging studies depict function changes Neuroproliferation: Increase in the density of nerve endings in the vestibule (ie, nociceptors with increased density of the vanilloid receptor VR1) leading to increased sensitivity Psychosocial factors: Anxiety, depression, childhood victimization, posttraumatic stress, and mood or anxiety disorder Structural defects: There are reports that repair of pelvic floor prolapse is associated with the resolution of vulvodynia

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Our understanding of the pathophysiologic mechanisms of vulvodynia is in its infancy. This diagram compares the mechanisms of normal pain transmission to the proposed pathophysiologic transmission of pain in women with vulvodynia. It is likely that different mechanisms, influenced by several predisposing, triggering, and maintaining factors, as well as genetic and environmental factors, will be identified.

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One possible pathophysiologic mechanism of vestibulodynia is neuroproliferation. A special nerve fiber staining, PGP 9.5, was used to depict small nerve fibers in patients with vestibulodynia and women without vestibulodynia undergoing http://www.medscape.org/viewarticle/877370_print 16/69 21/4/2017 www.medscape.org/viewarticle/877370_print vestibular biopsy for other conditions. Subepithelial and intraepithelial nerve fibers were detected only in patients with vestibulodynia. The fibers penetrated the basal membrane and continued vertically for more than half the distance to the epithelial surface. Branching of the nerve fibers within the epithelium was rarely seen (Bornstein 1997, Bornstein 2008).

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In vestibulodynia, there is frequently an increase in mast cell number and activity. In Bornstein et al, mast cells, stained by Giemsa, showed degranulation. The discharged granules contained tryptase, histamine, serotonin, bradykinin, heparanase, nerve growth factor, etc. Some of these enzymes may participate in the pathogenesis of vestibulodynia (Bornstein 2004).

Differential Diagnosis

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Preliminary findings of research on factors associated with the risk of developing vulvodynia indicate that there may be multiple risk factors involved, but larger studies are needed to confirm these findings. Multiple studies suggest that vulvodynia patients experience more frequent vaginal infections; however, in most cases, prior vaginal infections were either self­reported or unconfirmed by the treating clinician. Research demonstrates that patients and clinicians are poor at accurately diagnosing vaginal infections (Ferris 1996, Ferris 2002, Ledger 2004, Schwiertz 2006). The only population­ based case­control study to date that compared the frequency of self­reported urogenital infections before the onset of vulvar pain demonstrated that a history of genital warts (OR 3.4), trichomoniasis (OR 5.7), urinary tract infection (OR 2.0), http://www.medscape.org/viewarticle/877370_print 18/69 21/4/2017 www.medscape.org/viewarticle/877370_print or yeast infection (OR 2.1) was associated with increased risk of vulvodynia. The researchers also found that women with multiple infections prior to the onset of vulvar pain were at highest risk; a combination of urinary tract infection and sexually transmitted infections (STIs) was associated with a 10­fold higher risk (Nguyen 2009). Recent pathophysiologic studies have demonstrated a relationship between vulvodynia and Candida albicans (Babula 2004, Foster 2007, Ramirez De Knott 2005, Farmer 2011).

Research to date appears to implicate oral contraceptive (OC) use in the development and/or maintenance of vulvodynia in some subgroups. Some clinicians propose that the use of OCs, particularly at an early age, down­regulates estrogen receptors in the vulvovaginal tissue, causing the vestibular epithelium to become thin and fragile. In a study of women using Yasmin, Battaglia (2012) found decreased labial thickness, introital area, frequency of intercourse and orgasm during intercourse, as well as increased pain with intercourse and pulsatility index of the dorsal clitoral and posterior labial arteries. In another study, quantitative sensory testing of the vestibular mucosa in healthy women revealed significantly lower mechanical pain thresholds in the OC group, with the most sensitivity in the posterior vestibule. The investigators concluded that OCs may induce increased sensitivity in the vestibular mucosa in healthy women, possibly contributing to the development of vulvodynia (Bohm­Starke 2004). Heddini (2012) found that provoked vestibulodynia patients carrying a polymorphism in the guanosine triphosphate cyclohydrolase (GCH1) gene and using OCs had higher pain sensitivity compared to noncarriers. Several studies have demonstrated increased risk in this patient population (Sjoberg 1997, Greenstein 2007, Bazin 1994, Bouchard 2002), although a population­based study did not (Harlow 2008).

Other risk factors reported in the literature include a history of allergies (Harlow 2009); vulvar dermatoses (Coombs 2011); autoimmune disease (Driul 2011) and an altered immuno­inflammatory response (Breshears 2011); early age of menarche (Harlow 2001); dysmenorrhea (Granot 2004); difficulty or severe pain with first tampon use (Harlow 2003, Landry 2009, Legocki 2011); early age of first intercourse (Bazin 1994, Berglund 2002); pain with first intercourse (Legocki 2011); pain with/after sex (Reed 2012); nulliparity (Edgardh 2007); childhood nocturnal enuresis (Greenstein 2005); urinary burning (Reed 2012); nocturnal urination, pain with wiping, and bike riding (Legocki 2011); genetic variability (Babula 2008, Foster 2004, Gerber 2003, Jeremias 2000, Lev­Sagie 2009) and altered gene expression, particularly in genes implicated in osteoarthritis (Breshears 2011) and with an altered immuno­inflammatory response (Bornstein 2004, Bornstein 2008, Foster 1997, Foster 2007, Gerber 2002, Harlow 2009, Lev­Sagie 2009); and chronic pain in other areas of the body (Falik­ Zaccai 2011, Arnold 2006, Heddini 2012). (See differential diagnosis references.)

Although one study supports some degree of association (Harlow 2005), several studies have refuted the notion that prior sexual and/or physical abuse is a risk factor for vulvodynia (Dalton 2002, Plante 2008, Edwards 1997, Reed 2000). Khandker (2011) is the only population­based epidemiologic study to demonstrate antecedent depression and anxiety as risk factors for vulvodynia. Plante (2008) demonstrated that women with vulvodynia reported more adverse life experiences. See Bohm­Starke 2010 for additional information.

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According to the International Society for the Study of Vulvovaginal Disease (ISSVD) (Bornstein 2016), known causes of chronic vulvar pain are: (1) infectious, (2) inflammatory, (3) neoplastic, (4) traumatic, (5) iatrogenic, (6) hormonal deficiencies, or (7) neurologic. If the cause is unknown, it is classified as vulvodynia. Conditions falling into the first 7 categories must be ruled out prior to making a diagnosis of vulvodynia. Examples of some of these prevalent conditions follow, with references to journal articles that provide information on diagnosis and treatment since this is beyond the scope of this program.

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http://www.medscape.org/viewarticle/877370_print 20/69 21/4/2017 www.medscape.org/viewarticle/877370_print The image on the left is a vaginal smear identifying Candida albicans, using a gram stain technique. In­office diagnosis can be made with microscopy using a potassium hydroxide prep, and vaginal culture can be used for speciation and sensitivity. C. albicans is a component of the normal flora in many women. Under certain conditions, such as a hormone imbalance, antibiotic treatment, or transient localized immune suppression, C. albicans can multiply, resulting in a symptomatic condition known as vulvovaginal candidiasis. Recent studies have implicated recurrent or chronic vulvovaginal candidiasis as a causative factor in vulvodynia.

It should be noted that the microbiome of the vagina is very complex and many species of bacteria, which may be considered pathogens in other parts of the body, are not pathogens in the vagina. Bacterial species such as Group B strep, Klebsiella, and Escherichia coli are common in the vagina and should not be treated.

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The image on the left is a phase contrast wet mount micrograph of a vaginal discharge revealing the presence of Trichomonas vaginalis protozoa. Trichomoniasis is an STI that causes itching, irritation, and abnormal discharge.

As seen on the right, genital herpes simplex (virus 1 or 2) infection typically presents as one or more blisters on or around the genitals or rectum. The blisters break, leaving tender ulcers that may take 2 to 4 weeks to heal the first time they occur. Frequently, genital herpes presents with more subtle signs, such as a small fissure or break in the skin. Viral shedding can also occur in the absence of visible manifestation.

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Lichen sclerosus (LS) is a chronic inflammatory condition of the vulva, most likely of autoimmune etiology. Both photos show cases of LS, but the photo on the left shows a severe case with a whitish color, itching, and fragile skin that may bruise or tear with contact or sexual intercourse. Diagnosis should be confirmed with vulvar skin biopsy evaluated by a dermatopathologist prior to initiating treatment with ultra­potent topical corticosteroids.

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Erosive lichen planus is another autoimmune skin disorder that can affect the vulva. As seen in these photos, lichen planus typically presents with white irregular lines and deep red areas of painful erosions. http://www.medscape.org/viewarticle/877370_print 22/69 21/4/2017 www.medscape.org/viewarticle/877370_print

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The photo on the left shows nondescript redness in a woman who has an irritant contact dermatitis from using a harsh soap. Contact dermatitis is a rash resulting from the skin's reaction to an external substance (eg, ointments, soaps, detergents, dyes, or sanitary pads). The rash may occur suddenly with blisters, itching, and weeping or it may be of slower onset with redness, burning, and some swelling. There are 2 types of contact dermatitis: irritant and allergic. Irritant dermatitis is the most common type causing burning, rawness, and/or irritation. Allergic dermatitis may be mild, with simply minor redness, swelling, and itching, or severe, with blistering, bright red swelling, and severe discomfort.

The primary symptom of lichen simplex chronicus (also known as eczema, atopic dermatitis, neurodermatitis) is itching. Pain and skin abnormalities result from rubbing or scratching, as can be seen from the rubbed and thickened skin in this photo. Lichen simplex chronicus frequently starts because of chronic inflammation from chronic/recurrent candidiasis, recurrent exposure to an irritant and/or allergen, or, less commonly, vulvar intraepithelial neoplasia (VIN). This chronic inflammation causes an itch­scratch cycle that leads to lichen simplex chronicus. Treatment consists of treating the infectious organism or removal of the allergen or irritant exposure. Application of ice and an antihistamine or tricyclic antidepressant are then used to stop the pruritus to break the itch­scratch cycle. Lastly, a potent topical corticosteroid is used to reduce the inflammation.

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These photos show vulvas with squamous cell carcinoma (SCC) on a background of LS. SCC can develop in 3% to 5% of women with LS. An additional cause of vulvar SCC is human papillomavirus (HPV) infection, which can cause vulvar intraepithelial neoplasia and then progress to SCC. Additionally, melanoma and Paget disease can occur on the vulva. Therefore, in any patient with persistent ulceration, a mass, or irregular pigmented lesion, the clinician should perform a vulvar biopsy to rule out malignancy.

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The MRI on the left shows a Tarlov cyst, a cerebrospinal fluid (CSF)­filled sac located in the spinal canal at the S1­S4 region of the spinal cord. Patients with Tarlov cysts are usually asymptomatic, but some do experience radiating pelvic and urogenital pain, persistent genital arousal disorder (PGAD), sexual dysfunction, and bladder dysfunction, among other symptoms.

The image on the right shows a labral hip tear, which can refer pain to the urogenital region.

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http://www.medscape.org/viewarticle/877370_print 26/69 21/4/2017 www.medscape.org/viewarticle/877370_print More than 130 million women across the world have undergone female genital cutting (FGC) and in some countries prevalence of FGC is >85% (UNICEF 2014).

Perineal trauma from a poorly healed or poorly repaired laceration or episiotomy may cause chronic vulvar pain or recurrent tearing (and pain) during intercourse. A recent review showed that 12.8% of women experience chronic vulvar pain at least 5 months after episiotomy (Turmo 2015).

Lastly, straddle injuries (most commonly from bicycles or falls from climbing) or injuries to the pelvis from motor vehicle accidents are uncommonly the cause of persistent vulvar pain.

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It has been recognized for decades that the tissues of the vulva and vagina are both responsive and dependent on sex steroids (hormones) for proper health and function. These sex steroids exert their effects through the nuclear receptors of estrogen, progesterone, androgen, and glucocorticoid. The hormone receptors are abundant in the epithelium of the outer vulva, endothelium of the vestibule, and mesothelium of the vagina. In addition, these hormone receptors are also found in high concentration in the deeper tissues of the vulva and vagina, including the glands and connective tissue, and adjacent to blood vessels and nerves. The hormones bind to the hormone receptors, which then leads to transcription and production of proteins that are essential for genital health and normal sexual function. Conversely, a deficiency in the sex steroids leads to dysfunction and, frequently, dyspareunia. It has been very well documented that a deficiency in circulating estrogen leads to anatomic and physiologic changes in the vagina. Anatomic changes include reduced collagen density and hyalinization, decreased elastin, thinning of the epithelium, altered appearance and function of smooth muscle cells, increased density of connective tissue, and fewer blood vessels. The labia minora thin and regress, the vestibule retracts, and the hymenal carunculae involute and lose elasticity. The urethral meatus appears prominent relative to the vestibule and becomes vulnerable to physical irritation and trauma.

Physiologic changes result in reduced vaginal blood flow, diminished lubrication, decreased flexibility and elasticity of the vaginal vault, and increased vaginal pH. Furthermore, decreases in vaginal tissue strength and increased friability may predispose to epithelial damage with penetrative sexual activity, leading to pain, burning, tearing, irritation, and postcoital bleeding. Epithelial thinning with decreased glycogenated superficial cells leads to changes in vaginal flora and loss of lactobacilli, increased pH, and a change in the microbiome. More recently, it has become apparent that deficiency in circulating free testosterone also adversely affects the tissues of the vulva and vagina. Decreased levels of androgens are associated with decreased mucinification, decreased nerve fiber density, and decreased vasodilation.

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As seen in these photographs, women who receive adjuvant endocrine therapy after the diagnosis of breast cancer (with an aromatase inhibitor or Tamoxifen), have a significant increase in dyspareunia (Baumgart 2013).

Prophylactic oophorectomy in women with BRCA mutations also increases the rate of dyspareunia (Finch 2011).

Sixty­seven percent of women who receive pelvic radiation therapy for anogenital malignancies develop dyspareunia (Stinesen 2015).

Repair of pelvic organ prolapse with synthetic vaginal mesh may have significant complications, including mesh contraction; mesh erosion into the vagina, bladder, and bowel; and dyspareunia. A meta­analysis of 71 papers showed that the overall rate of chronic dyspareunia after mesh placement is 9.1% (Abed 2011).

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After visible and/or neurologic causes of vulvar pain are identified and treated, one moves on to evaluate the patient for vulvodynia. Hyperalgesia and allodynia are present, with or without the presence of erythema. Although women with vulvodynia describe their pain in a variety of ways (eg, stabbing, aching, raw, searing, sharp, throbbing, knife­like, etc), burning is most commonly reported. If the pain is localized to the vulvar vestibule and provoked, the diagnosis is likely to be provoked vestibulodynia (PVD). PVD is further categorized as primary or secondary. PVD is the most common subtype affecting 80% of women with chronic vulvar pain symptoms (Harlow 2003). If the pain is generalized to multiple areas of the vulva and spontaneous, but exacerbated by touch/pressure, the diagnosis is likely generalized vulvodynia. Twenty percent of women suffer from this subtype or a mixture of both (Reed 2003, Edwards 2004).

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Based on data from a National Institutes of Health (NIH)­funded population­based study, these 4 questions have been found to be highly predictive of an office­based diagnosis of vulvodynia (Harlow 2009). These questions were validated against clinical examination with 80% specificity and 95% sensitivity. They should be included on screening forms to help healthcare practitioners identify women and adolescents who may be suffering from the condition.

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For more than a decade, gynecologists, dermatologists, vulvar pain specialists, and researchers have used the 2003 ISSVD terminology as a guide to diagnosing vulvar pain. This terminology evolved over years of discussion on the nature of idiopathic vulvar pain, especially that occurring during sexual activity and vaginal penetration. The 2003 terminology divided vulvar pain into 2 overarching categories: vulvar pain related to a specific disorder and vulvodynia, defined specifically as "vulvar discomfort, most often described as burning pain, occurring in the absence of relevant visible findings or a specific, clinically identifiable neurologic disorder." Therefore, the term vulvodynia was reserved for those cases in which the pain could not be attributed to an identifiable "visible" cause.

Since 2003, the category of identifiable causes of vulvar pain has evolved substantially, as have the potential factors associated with vulvodynia. These developments are based on the results of numerous studies examining a wide range of possible etiologic factors (eg, inflammatory, genetic, musculoskeletal, neurosensory, neuropathic) and treatment avenues (eg, oral medication, pelvic floor physical therapy, surgical intervention, psychologic intervention). These studies have also led to the conclusion that vulvodynia is likely not one disease but a constellation of symptoms of several (sometimes overlapping) disease processes that benefits most from a range of treatments based on individual presentation. These studies have widened the scope of etiologic considerations and have resulted in the need to update the description and nomenclature of persistent vulvar pain. In addition, several important pain characteristics of vulvodynia have been introduced (eg, primary and secondary status; intermittent and constant pain pattern).

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As shown on the left, most women with generalized vulvodynia report spontaneous pain in multiple areas of the vulva. Pain tends to be constant, but may be intermittent in some women. Although symptoms are spontaneous, they tend to worsen with provocation. Periods of unexplained pain relief and/or flares can occur. Erythema may or may not be present. This subtype affects 20% of those reporting chronic vulvar pain symptoms (Harlow 2003).

As shown on the right, women with PVD report provoked pain only within the vulvar vestibule. Erythema may co­occur. This subtype affects 80% of those with vulvar pain (Harlow 2003). http://www.medscape.org/viewarticle/877370_print 31/69 21/4/2017 www.medscape.org/viewarticle/877370_print A subset of women report spontaneous widespread vulvar pain, as well as provoked pain localized to the vestibule. The above subtypes may coexist in some women (Reed 2003, Edwards 2004).

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Women may present with marked introital erythema, as seen in patient #1, or the tissue may appear relatively normal, as seen in patient #3. Although patient #3 presented with minimal erythema, she had severe pain that prevented her from engaging in sexual intercourse or inserting a tampon. Recent studies have also shown that pain severity and subsurface inflammation do not consistently correlate with the severity of erythema observed. The relevance of this criterion is disputed.

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Current guidelines recommend that a cotton swab test be performed (Haefner 2005). The 11 sites shown on this diagram should be tested for allodynia and hypoalgesia or hyperalgesia by applying gentle pressure with a dry cotton swab (just enough to slightly indent the skin). If symptoms are provoked and localized to the vestibule, a more thorough evaluation of the vestibule is warranted and is described in the next slide.

Slide 53.

Sites to be tested within the vulvar vestibule can be visualized using a clock face (1 to 12 o'clock) with one vertical and one perpendicular (black) line through the center of the vaginal opening. The 2 and 5 o'clock positions are equidistant to both lines, as are the 7 and 10 o'clock positions. The anterior vestibular sites (2, 10 and 12) are typically assessed first, followed by the posterior sites (5, 6 and 7). Again, gentle pressure is applied to each of these sites and women are asked to rate the pain severity and describe the character of the pain they experience (Zolnoun 2012).

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Slide 54.

NIH­funded foundational work at the University of North Carolina at Chapel Hill is currently ongoing to refine a vulvovaginal neurosensory examination (described in this slide). Current prospective patient­reported outcomes studies are underway to delineate the exam components that are clinically relevant and predictive of treatment response (PI Zolnoun, NIH Grant 5K23HD053631, description available at: https://projectreporter.nih.gov/project_info_results.cfm?aid=7927135&icde=0).

Slide 55.

The muscle assessment begins with the examiner's right index finger (bent approximately 30 to 60 degrees) palpating the patient's right mid­pubic rami, which is the bony landmark for identifying the mid­segment (belly) of puborectalis muscle. http://www.medscape.org/viewarticle/877370_print 34/69 21/4/2017 www.medscape.org/viewarticle/877370_print After confirming the mid­position placement of the index finger, the examiner palpates the puborectalis muscle, which is immediately adjacent/behind the pubic rami. Then, the examiner rotates the index finger downwards (approximate length of 1 to 1.5 cm) parallel to the length of puborectalis, until the transition point/insertion to the superficial muscles (perineal muscle complex) is palpated. Using the left index finger, the examiner assesses the left puborectalis as described above and seen in this slide. The perineal muscle complex, which is immediately beneath the 6 o'clock mucosal position, is palpated last. These muscle sites are adjacent to the respective lower vestibular mucosal sites (5, 6, and 7). Women are asked to describe the pain character and rate the pain severity they experience (Zolnoun 2012).

Slide 56.

Women with vulvodynia commonly report suffering from comorbid pain disorders, mood/sleep alteration, and sexual impairment. It is vital to assess all of the factors that are contributing to a woman's current pain state to delineate the most appropriate components of an individualized, multidisciplinary treatment regimen.

In a 2008 literature review, Desrochers critically examined studies on the psychosexual aspects of vulvodynia and concluded that, despite the presence of methodologic limitations, some findings were consistently replicated. Overall, women with vulvodynia demonstrated impaired sexual functioning, including lower levels of sexual desire, arousal, and frequency of intercourse. Additionally, questionnaires revealed that anxiety, fear of pain, hypervigilance, and depression were more prevalent among these women. Desrochers concluded that more rigorous studies are needed to establish whether psychosexual variables exacerbate and/or maintain vulvodynia.

A growing body of literature documents the association between vulvodynia and other chronic pain conditions. Warren (2008) proposed that vulvodynia may be a referred pain of interstitial cystitis (IC) in many cases. Several authors have proposed that both IC and vulvodynia are syndromes of the urogenital sinus­derived epithelium (McCormack 1990, Burrows 2008). Peters (2008) speculated that the conditions may be linked by a common pelvic floor muscle dysfunction. Others have proposed that a common pathway may stimulate a single disease process (Kennedy 2007), or that in some women, IC and vulvodynia may be the same disease (Peters 2008).

Recently, researchers have explored the relationship between vulvodynia and orofacial pain, specifically temporomandibular disorders. Zolnoun (2008) speculated that a subset of vulvodynia patients may suffer from a widespread musculoskeletal pain disorder influenced more by genetic makeup and central nervous system dysfunction than by an inflammatory process in the vulva.

Kennedy (2007) proposed that irritable bowel syndrome (IBS) may predispose women to certain vulvar conditions (perhaps by the irritant nature of diarrhea, for example), treatment for vulvar conditions may lead to bowel symptoms, or both http://www.medscape.org/viewarticle/877370_print 35/69 21/4/2017 www.medscape.org/viewarticle/877370_print conditions may represent a "pelvic floor pain disorder."

When studying the relationship between fibromyalgia and vulvodynia, Pukall (2005, 2006) proposed that the mechanisms involved in vulvodynia may be genital­specific in some women and possibly centrally mediated in others. Whether the generalized sensitivity or vulvar pain occurs first is unknown. For example, an untreated vulvar irritation could lead to central changes in sensory processing in genetically predisposed women, resulting in altered central pain processing and a widespread increase in sensitivity. On the other hand, women with vulvodynia may be more sensitive to pain in general and develop vulvar pain through a locally occurring event, such as a vulvar injury.

Slide 57.

This proposed diagnostic algorithm for vestibulodynia has been adapted from: King M, Rubin R, Goldstein A. Current Uses of Surgery for the Treatment of Genital Pain. Current Sexual Health Reports. 2014;6:252­258. Shown on this slide are 2 potential causes of pain that affect the entire vestibule. King, et al postulate that if the entire vestibular endoderm (mucosa) is painful, it is likely that there is a pathologic process occurring in this tissue. The next 3 slides show additional causes of vestibulodynia with different underlying pathologic mechanisms. Subtle differences in the history (HX) and physical examination (PE) may help to differentiate between potential causes of vestibulodynia, which may lead to disease­ specific treatments.

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Slide 58.

This proposed diagnostic algorithm for vestibulodynia has been adapted from King M, Rubin R, Goldstein A. Current Uses of Surgery for the Treatment of Genital Pain. Current Sexual Health Reports. 2014;6:252­258.

Slide 59.

This proposed diagnostic algorithm for vestibulodynia has been adapted from King M, Rubin R, Goldstein A. Current Uses of Surgery for the Treatment of Genital Pain. Current Sexual Health Reports. 2014;6:252­258.

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Slide 60.

This proposed diagnostic algorithm for vestibulodynia has been adapted from King M, Rubin R, Goldstein A. Current Uses of Surgery for the Treatment of Genital Pain. Current Sexual Health Reports. 2014;6:252­258. In this slide are the potential causes of pain in the posterior vestibule or pain that extends beyond the vestibule. King, et al postulate that if only part of the vestibular endoderm is painful, it is not likely that there is an intrinsic pathologic process occurring within the vestibular tissue. More likely, pain affecting only part of the vestibule is the result of a pathologic process extrinsic to the vestibule such as overactive pelvic floor muscle dysfunction (also known as vaginismus or levator ani syndrome). Tenderness that extends outside of the vestibule is likely pudendal neuralgia.

Individualized Multidisciplinary Treatment

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Slide 61.

Slide 62.

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Slide 63.

Slide 64.

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Slide 65.

*Patient recommendations for vulvar self­care can be viewed at: http://www.nva.org/tips.

^Detailed dosing and side effect information/charts for oral (and topical) medications used to treat vulvodynia are contained in The Vulvodynia Guideline, which can be viewed/downloaded at: www.nva.org/haefner.

**In the medical literature, only 2 randomized controlled trials (RCTs) have evaluated the efficacy of oral tricyclic antidepressants. Neither randomized controlled trial found positive results (ie, the treatment provided only minimal relief of vulvar pain). These studies, however, included women with localized and generalized vulvodynia, as well as women with provoked and unprovoked vulvodynia, so treatment efficacy for specific subgroups is unknown.

Despite their widespread use, even fewer efficacy data are available on anticonvulsants than on tricyclic antidepressants, with only 3 retrospective case series conducted to date. Even though these studies reported positive findings, there were no control groups. The first RCT evaluating gabapentin for treatment of vulvodynia is ongoing (Brown CS, Foster DC, Bachmann GA. A Controlled Trial of Gabapentin in Vulvodynia: Biological Correlates of Response). See the following website for more information, https://clinicaltrials.gov/show/NCT01301001.

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Slide 66.

*Nifedipine was not better than placebo among women with vulvodynia in a double­blind study (107). Other topicals that are not useful include corticosteroids, progesterone, and antifungals (108).

Slide 67.

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Slide 68.

Slide 69.

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Slide 70.

Slide 71.

Landry, et al provide a thorough review of surgical treatment studies (29).

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Slide 72.

Landry, et al provide a thorough review of surgical treatment studies (29).

Slide 73.

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Slide 75.

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Slide 76.

Slide 77.

^Alternative therapies include the following:

Hypnotherapy: Limited findings for hypnotherapy noted significant decrease in pain associated with intercourse and increase in sexual satisfaction in 9 women with vestibulodynia (129, 130).

Acupuncture: Limited reports of improvement in vulvar pain and dyspareunia, including 1 randomized study comparing patients with vulvodynia to waitlist controls (133, 134). http://www.medscape.org/viewarticle/877370_print 47/69 21/4/2017 www.medscape.org/viewarticle/877370_print

Slide 78.

PainTracker is an evidence­based tool available to individual healthcare providers for use to track key domains and treatment outcomes over time. A quick overview of the program, interface, and questionnaire can be viewed at: http://www.nva.org/tools. Request login information to review the web interface from: https://paintracker.cirg.washington.edu/demo/users/login.

*The Female Sexual Function Index (FSFI) can be viewed/downloaded here: www.nva.org/tools.

^Instruments available through NIH PROMIS can be viewed here: https://www.assessmentcenter.net/documents/InstrumentLibrary.pdf.

^^A recent study found that smartphone tracking systems promoted excellent compliance with weekly tracking (135). Examples include: WebMD Pain Coach, My Pain Diary, Chronic Pain Tracker, and Manage My Pain.

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Slide 85.

Reference List

Historical Perspective

Bornstein J, Goldstein AT, Stockdale CK, Bergeron S, Pukall C, Zolnoun D, Coady D; consensus vulvar pain terminology committee of the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women's Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS). 2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia. J Low Genit Tract Dis. 2016;20:126­130.

Haefner HK. Report of the International Society for the Study of Vulvovaginal Disease terminology and classification of vulvodynia. J Low Genit Tract Dis. 2007;11:48­49.

Kelly HA. Dyspareunia. In: Kelly HA, ed. Gynecology. New York, NY: D. Appleton and Company; 1928: 235­239.

Moyal­Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J Reprod Med. 2004;49:772­777.

McElhiney J, Kelly S, Rosen R, Bachmann G. Satyriasis: the antiquity term for vulvodynia? J Sex Med. 2006;3:161­163.

McKay M. Burning vulva syndrome: report of the ISSVD task force. J Reprod Med. 1984;29:457.

Skene AJC. Diseases of the external organs of generation. In: Skene AJC, ed. Treatise of the Diseases of Women. New York, NY: D. Appleton and Company; 1888:77­99.

Thomas TG. Practical Treatise on the Diseases of Women. Philadelphia, PA: Henry C. Lea's Son & Company; 1880.

Magnitude of the Problem

Arnold LD, Bachmann GA, Rosen R, Rhoads GG. Assessment of vulvodynia symptoms in a sample of US women: a prevalence survey with a nested case control study. Am J Obstet Gynecol. 2007;196:128;e1­e6.

Donaldson RL, Meana M. Early dyspareunia experience in young women: confusion, consequences, and help­seeking barriers. J Sex Med. 2011;8:814­823. http://www.medscape.org/viewarticle/877370_print 52/69 21/4/2017 www.medscape.org/viewarticle/877370_print Harlow BL, Kunitz CG, Nguyen RH, Rydell SA, Turner RM, MacLehose RF. Prevalence of symptoms consistent with a diagnosis of vulvodynia: population­based estimates from 2 geographic regions. Am J Obstet Gynecol. 2014;210:40.e1­8.

Harlow BL, Stewart EG. A population­based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc. 2003;58:82­88.

Johnson NS, Harwood EM, Nguyen RH. "You have to go through it and have your children": reproductive experiences among women with vulvodynia. BMC Pregnancy Childbirth. 2015:114.

Landry T, Bergeron S. How young does vulvo­vaginal pain begin? Prevalence and characteristics of dyspareunia in adolescents. J Sex Med. 2009;6:927­935.

Nguyen RH, Ecklund AM, MacLehose RF, Veasley C, Harlow BL. Co­morbid pain conditions and feelings of invalidation and isolation among women with vulvodynia. Psychol Health Med. 2012;17;589­598.

Nguyen RH, MacLehose RF, Veasley C, Turner RM, Harlow BL, Horvath KJ. Comfort in discussing vulvar pain in social relationships among women with vulvodynia. J Reprod Med. 2012;57:109­114.

Nguyen RH, Mathur C, Wynings EM, Williams DA, Harlow BL. Remission of vulvar pain among women with primary vulvodynia. J Low Genit Tract Dis. 2015;19:62­67.

Piper CK, Legocki LJ, Moravek MB, Lavin K, Haefner HK, Wade K, Reed BD. Experience of symptoms, sexual function, and attitudes toward counseling of women newly diagnosed with vulvodynia. J Low Genit Tract Dis. 2012;16:447­453.

Reed BD, Cantor LE. Vulvodynia in preadolescent girls. J Low Genit Tract Dis. 2008;12:257­261.

Reed BD, Crawford S, Couper M, Cave C, Haefner HK. Pain at the vulvar vestibule: a web­based survey. J Low Genit Tract Dis. 2004;8:48­57.

Reed BD, Haefner HK, Harlow SD, Gorenflo DW, Sen A. Reliability and validity of self­reported symptoms for predicting vulvodynia. Obstet Gynecol. 2006;108:906­913.

Reed BD, Haefner HK, Sen A, Gorenflo DW. Vulvodynia incidence and remission rates among adult women: a 2­year follow­up study. Obstet Gynecol. 2008;112(2 Pt 1):231­237.

Reed BD, Harlow SD, Sen A, Legocki LJ, Edwards RM, Arato N, Haefner HK. Prevalence and demographic characteristics of vulvodynia in a population­based sample. Am J Obstet Gynecol. 2012;206:170.e1­9.

Reed BD, Legocki LJ, Plegue MA, Sen A, Haefner HK, Harlow SD. Factors associated with vulvodynia incidence. Obstet Gynecol. 2014;123:225­231.

Xie Y, Shi L, Xiong X, Wu E, Veasley C, Dade C. Economic burden and quality of life of vulvodynia in the United States. Curr Med Res Opin. 2012;28:601­608.

Anatomy and Neurobiology of the Urogenital Tract

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Herschorn S. Female pelvic floor anatomy: the pelvic floor, supporting structures, and pelvic organs. Rev Urol. 2004;6(5):S2­S10.

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Terminology and Classification

Bornstein J, Goldstein AT, Stockdale CK, et al.; consensus vulvar pain terminology committee of the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women's Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS). 2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia. J Low Genit Tract Dis. 2016;20:126­130.

Pathophysiology

Bornstein J, Goldshmid N, Sabo E. Hyperinnervation and mast cell activation may be used as histopathologic diagnostic criteria for vulvar vestibulitis. Obstet Gynecol Invest. 2004;58:171­178.

Bornstein J, Goldstein AT, Stockdale CK, et al.; consensus vulvar pain terminology committee of the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women's Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS). 2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia. J Low Genit Tract Dis. 2016;20:126­130.

Bornstein J, Zarfati D, Goldshmid N, Stolar Z, Lahat N, Abramovici H. Vestibulodynia ­ a subset of vulvar vestibulitis or a novel syndrome. Am J Obstet Gynecol. 1997;177:1439­1443.

Bornstein J, Zarfati D, Sela S, Cohen Y, Ophir E. Involvement of heparanase in the pathogenesis of localized vulvodynia. Int J Gynecol Pathol. 2008;27:136­141.

Vulvodynia Pathophysiology

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Impact of genetic variation in interleukin­1 receptor antagonist and melanocortin­1 receptor genes on vulvar vestibulitis syndrome. J Reprod Med. 2004;49:503­509. 31. Lev­Sagie A, Linhares IM, Ledger WJ, Witkin SS. A manganese superoxide dismutase gene polymorphism and development of vulvar vestibulitis syndrome following physical vaginal trauma. Int J Gynaecol Obstet. 2010;22:59­ 64. 32. Pukall CF, Baron M, Amsel R, Khalifé S, Binik YM. Tender point examination in women with vulvar vestibulitis syndrome. Clin J Pain. 2006;22:601­609. 33. Pukall CF, Strigo IA, Binik YM, Amsel R, Khalifé S, Bushnell MC. Neural correlates of painful genital touch in women with vulvar vestibulitis syndrome. Pain. 2005;115:118­127. 34. Foster DC, Dworkin RH, Wood RW. Effects of intradermal foot and forearm capsaicin injections in normal and vulvodynia­afflicted women. Pain. 2005;117:128­136. 35. Johannesson U, de Boussard CN, Brodda Jansen G, Bohm­Starke N. Evidence of diffuse noxious inhibitory controls (DNIC) elicited by cold noxious stimulation in patients with provoked vestibulodynia. Pain. 2007;130:31­39. 36. Schweinhardt P, Kuchinad A, Pukall CF, Bushnell MC. Increased gray matter density in young women with chronic vulvar pain. Pain. 2008;140:411­419. 37. Jantos M, Burns NR. Vulvodynia. Development of a psychosexual profile. J Reprod Med. 2007;52:63­71. 38. Witkin SS, Gerber S, Ledger WJ. Differential characterization of women with vulvar vestibulitis syndrome. Am J Obstet Gynecol. 2002;187:589­594. 39. Bornstein J, Maman M, Abramovici H. "Primary" versus "secondary" vulvar vestibulitis: one disease, two variants. Am J Obstet Gynecol. 2001;184:28­31. http://www.medscape.org/viewarticle/877370_print 55/69 21/4/2017 www.medscape.org/viewarticle/877370_print 40. Goetsch MF. Vulvar vestibulitis: prevalence and historic features in a general gynecologic practice population. Am J Obstet Gynecol. 1991;164(6 Pt 1):1609­1614. 41. Greenstein A, Sarig J, Chen J, Matzkin H, Lessing JB, Abramov L. Childhood nocturnal enuresis in vulvar vestibulitis syndrome. J Reprod Med. 2005;50:49­52. 42. Granot M, Friedman M, Yarnitsky D, Tamir A, Zimmer EZ. Primary and secondary vulvar vestibulitis syndrome: systemic pain perception and psychophysical characteristics. Am J Obstet Gynecol. 2004;191:138­142. 43. Sutton KS, Pukall CF, Chamberlain S. Pain, psychosocial, sexual, and psychophysical characteristics of women with primary vs. secondary provoked vestibulodynia. J Sex Med. 2009;6:205­214. 44. Burrows LJ, Klingman D, Pukall CF, Goldstein AT. Umbilical hypersensitivity in women with primary vestibulodynia. J Reprod Med. 2008;53:413­416. 45. Zolnoun D, Park EM, Moore CG, Liebert CA, Tu FF, As­Sanie S. Somatization and psychological distress among women with vulvar vestibulitis syndrome. Int J Gynaecol Obstet. 2008;103:38­43. 46. Bornstein J, Goldik Z, Stolar Z, Zarfati D, Abramovici H. Predicting the outcome of surgical treatment of vulvar vestibulitis. Obstet Gynecol. 1997;89(5 Pt 1):695­698. 47. Bohm­Starke N, Rylander E. Surgery for localized, provoked vestibulodynia: a long­term follow­up study. J Reprod Med. 2008;53:83­89. 48. Harris D, Coady D, Robinson­Papp J. Autonomic testing for small fiber neuropathies in vulvodynia patients. Abstract presented at ISSVD XXI World Congress. J Low Genit Tract Dis. 2011;15(5). 49. Murina F, Bianco V, Radici G, Felice R, Signaroldi M. Electrodiagnostic functional sensory evaluation of patients with generalized vulvodynia: a pilot study. J Low Genit Tract Dis. 2010;14:221­224. 50. Zhang Z, Zolnoun DA, Francisco EM, Holden JK, Dennis RG, Tommerdahl M. Altered central sensitization in subgroups of women with vulvodynia. Clin J Pain. 2011;27:755­763.

Differential Diagnosis

Risk Factors

Arnold LD, Bachmann GA, Rosen R, Kelly S, Rhoads GG. Vulvodynia: characteristics and associations with comorbidities and quality of life. Obstet Gynecol. 2006;107:617­624.

Babula O, Danielsson I, Sjoberg I, Ledger WJ, Witkin SS. Altered distribution of mannose­binding lectin alleles at exon I codon 54 in women with vulvar vestibulitis syndrome. Am J Obstet Gynecol. 2004;191:762­766.

Babula O, Linhares IM, Bongiovanni AM, Ledger WJ, Witkin SS. Association between primary vulvar vestibulitis syndrome, defective induction of tumor necrosis factor­alpha, and carriage of the mannose­binding lectin codon 54 gene polymorphism. Am J Obstet Gynecol. 2008;198:101.e1­4.

Battaglia C, Battaglia B, Mancini F, Busacchi P, Paganotto MC, Morotti E, Venturoli S. Sexual behavior and oral contraceptives: a pilot study. J Sex Med. 2012;9:550­557.

Bazin S, Bouchard C, Brisson J, Morin C, Meisels A, Fortier M. Vulvar vestibulitis syndrome: an exploratory case­control study. Obstet Gynecol. 1994;83:47­50.

Berglund AL, Nigaard L, Rylander E. Vulvar pain, sexual behavior and genital infections in a young population: a pilot study. Acta Obstet Gynecol Scand. 2002;81:738­742.

Bohm­Starke N. Medical and physical predictors of localized provoked vulvodynia. Acta Obstet Gynecol Scand. 2010;89:1504­1510.

Bohm­Starke N, Johannesson U, Hilliges M, Rylander E, Torebjörk E. Decreased mechanical pain threshold in the vestibular mucosa of women using oral contraceptives: a contributing factor in vulvar vestibulitis? J Reprod Med. 2004;49:888­892.

Bornstein J, Cohen Y, Zarfati D, Sela S, Ophir E. Involvement of heparanase in the pathogenesis of localized vulvodynia. Int J Gynecol Pathol. 2008;27:136­141.

Bornstein J, Goldschmid N, Sabo E. Hyperinnervation and mast cell activation may be used as histopathologic diagnostic criteria for vulvar vestibulitis. Gynecol Obstet Invest. 2004;58:171­178.

http://www.medscape.org/viewarticle/877370_print 56/69 21/4/2017 www.medscape.org/viewarticle/877370_print Bouchard C, Brisson J, Fortier M, Morin C, Blanchette C. Use of oral contraceptive pills and vulvar vestibulitis: a case­ control study. Am J Epidemiol. 2002;156:254­261.

Breshears LM, Peterson ML, Harlow BL. Gene expression analysis reveals altered immuno­inflammatory response in patients with Provoked Vestibulodynia. Abstract presented at ISSVD XXI World Congress. J Low Genit Tract Dis. 2011;15.

Coombs A, Edwards L. Erosive Vulvovaginal Lichen Planus and Vulvodynia: an association? Abstract presented at the ISSVD XXI World Congress. J Low Genit Tract Dis. 2011;15.

Dalton VK, Haefner HK, Reed BD, Senapati S, Cook A. Victimization in patients with vulvar dysesthesia/vestibulodynia. Is there an increased prevalence? J Reprod Med. 2002;47:829­834.

Driul L, Bertozzi S, Londero AP, et al. Risk factors for chronic pelvic pain in a cohort of primipara and secondipara at one year after delivery: association of chronic pelvic pain with autoimmune pathologies. Minerva Ginecol. 2011;63:181­187.

Edgardh K, Abdelnoor M. Vulvar vestibulitis and risk factors: a population­based case­control study in Oslo. Acta Derm Venereol. 2007;87:350­354.

Edwards L, Mason M, Phillips M, Norton J, Boyle M. Childhood sexual and physical abuse. Incidence in patients with vulvodynia. J Reprod Med. 1997;42:135­139.

Falik­Zaccai TC, Kalfon L, Azran A, Farajun Y, Tubin E, Hemo O, et al. A novel genetic association for primary severe Localized Provoked Vestibulodynia. Abstract presented at ISSVD XXI World Congress. J Low Genit Tract Dis. 2011;15.

Farmer MA, Taylor AM, Bailey AL, et al. Repeated vulvovaginal fungal infections cause persistent pain in a mouse model of vulvodynia. Sci Transl Med. 2011;3:101ra91.

Ferris DG, Dekle C, Litaker MS. Women's use of over­the­counter antifungal medications for gynecologic symptoms. J Fam Pract. 1996;42:595­600.

Ferris DG, Nyirjesy P, Sobel JD, Soper D, Pavletic A, Litaker MS. Over­the­counter antifungal drug misuse associated with patient­diagnosed vulvovaginal candidiasis. Obstet Gynecol. 2002;99:419­425.

Foster DC, Piekarz KH, Murant TI, LaPoint R, Haidaris CG, Phipps RP. Enhanced synthesis of proinflammatory cytokines by vulvar vestibular fibroblasts: implications for vulvar vestibulitis. Am J Obstet Gynecol. 2007;196:346.e1­8.

Foster DC, Hasday JD. Elevated tissue levels of interleukin­1 beta and tumor necrosis factor­alpha in vulvar vestibulitis. Obstet Gynecol. 1997;89:291­296.

Foster DC, Sazenski TM, Stodgell CJ. Impact of genetic variation in interleukin­1 receptor antagonist and melanocortin­1 receptor genes on vulvar vestibulitis syndrome. J Reprod Med. 2004;49:503­509.

Gerber S, Bongiovanni AM, Ledger WJ, Witkin SS. Interleukin­1beta gene polymorphism in women with vulvar vestibulitis syndrome. Eur J Obstet Gynecol Reprod Biol. 2003;107:74­77.

Gerber S, Bongiovanni AM, Ledger WJ, Witkin SS. Defective regulation of the proinflammatory immune response in women with vulvar vestibulitis syndrome. Am J Obstet Gynecol. 2002;186:696­700.

Granot M, Friedman M, Yarnitsky D, Tamir A, Zimmer EZ. Primary and secondary vulvar vestibulitis syndrome: systemic pain perception and psychophysical characteristics. Am J Obstet Gynecol. 2004;191:138­142.

Greenstein A, Ben­Aroya Z, Fass O, Militscher I, Roslik Y, Chen J, et al. Vulvar vestibulitis syndrome and estrogen dose of oral contraceptive pills. J Sex Med. 2007;4:1679­1683.

Greenstein A, Sarig J, Chen J, Matzkin H, Lessing JB, Abramov L. Childhood nocturnal enuresis in vulvar vestibulitis syndrome. J Reprod Med. 2005;50:49­52.

Harlow BL, He W, Nguyen RH. Allergic reactions and risk of vulvodynia. Ann Epidemiol. 2009;19:771­777.

Harlow BL, Stewart EG. Adult­onset vulvodynia in relation to childhood violence victimization. Am J Epidemiol. 2005;161:871­880. http://www.medscape.org/viewarticle/877370_print 57/69 21/4/2017 www.medscape.org/viewarticle/877370_print Harlow BL, Stewart EG. A population­based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc. 2003;58:82­88.

Harlow BL, Vitonis AF, Stewart EG. Influence of oral contraceptive use on the risk of adult­onset vulvodynia. J Reprod Med. 2008;53:102­110.

Harlow BL, Wise LA, Stewart EG. Prevalence and predictors of chronic lower genital tract discomfort. Am J Obstet Gynecol. 2001;185:545­550.

Heddini U, Bohm­Starke N, Grönbldh A, Nyberg F, Nilsson KW, Johannesson U. GCH1­polymorphism and pain sensitivity among women with provoked vestibulodynia. Mol Pain. 2012;8:68.

Jeremias J, Ledger WJ, Witkin SS. Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis. Am J Obstet Gynecol. 2000;182:283­285.

Khandker M, Brady SS, Vitonis AF, Maclehose RF, Stewart EG, Harlow BL. The influence of depression and anxiety on risk of adult onset vulvodynia. J Womens Health. 2011;20:1445­1451.

Landry T, Bergeron S. How young does vulvo­vaginal pain begin? Prevalence and characteristics of dyspareunia in adolescents. J Sex Med. 2009;6:927­935.

Ledger WJ, Monif GR. A growing concern: inability to diagnose vulvovaginal infections correctly. Obstet Gynecol. 2004;103:782­784.

Legocki L, Edwards RM, Harlow SD, Sen A, Haefner HK, Reed BD. Childhood urogenital hypersensitivity among adult women with and without vulvodynia. Abstract presented at ISSVD XXI World Congress. J Low Genit Tract Dis. 2011;15.

Lev­Sagie A, Prus D, Linhares IM, Lavy Y, Ledger WJ, Witkin SS. Polymorphism in a gene coding for the inflammasome component NALP3 and recurrent vulvovaginal candidiasis in women with vulvar vestibulitis syndrome. Am J Obstet Gynecol. 2009;200:303.e1­6.

Nguyen RH, Swanson D, Harlow BL. Urogenital infections in relation to the occurrence of vulvodynia. J Reprod Med. 2009;54:385­392.

Plante AF, Kamm MA. Life events in patients with vulvodynia. BJOG. 2008;115:509­14.

Ramirez De Knott HM, McCormick TS, Do SO, et al. Cutaneous hypersensitivity to Candida albicans in idiopathic vulvodynia. Contact Dermatitis. 2005;53:214­218.

Reed BD, Haefner HK, Punch MR, Roth RS, Gorenflo DW, Gillespie BW. Psychosocial and sexual functioning in women with vulvodynia and chronic pelvic pain. A comparative evaluation. J Reprod Med. 2000;45:624­632.

Reed BD, Payne CM, Harlow SD, Legocki LJ, Haefner HK, Sen A. Urogenital symptoms and pain history as precursors of vulvodynia: a longitudinal study. J Womens Health. 2012;21:1139­1143.

Schwiertz A, Taras D, Rusch K, Rusch V. Throwing the dice for the diagnosis of vaginal complaints? Ann Clin Microbiol Antimicrob. 2006;5:4.

Sjöberg I, Nylander Lundqvist EN. Vulvar vestibulitis in the north of Sweden. An epidemiologic case­control study. J Reprod Med. 1997;42:166­168.

Rule­Out Diagnoses

Abed H, Rahn DD, Lowenstein L, Balk EM, Clemons JL, Rogers RG, et al. Incidence and management of graft erosion, wound granulation, and dyspareunia following vaginal prolapse repair with graft materials: a systematic review. Int Urogynecol J. 2011;22:789­798.

Alkatout I, Schubert M, Garbrecht N, Weigel MT, Jonat W, Mundhenke C, et al. Vulvar cancer: epidemiology, clinical presentation, and management options. Int J Womens Health. 2015;7:305­313.

http://www.medscape.org/viewarticle/877370_print 58/69 21/4/2017 www.medscape.org/viewarticle/877370_print Baumgart J, Nilsson K, Evers AS, Kallak TK, Poromaa IS. Sexual dysfunction in women on adjuvant endocrine therapy after breast cancer. Menopause. 2013;20:162­168.

Bekker MD, Hogewoning CR, Wallner C, Elzevier HW, DeRuiter MC. The somatic and autonomic innervations of the clitoris: preliminary evidence of sexual dysfunction after minimally invasive slings. J Sex Med. 2012;9:1566­1578.

Bornstein J, Goldstein AT, Stockdale CK, et al.; consensus vulvar pain terminology committee of the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women's Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS). 2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia. J Low Genit Tract Dis. 2016;20:126­130.

Burrows LJ, Shaw HA, Goldstein AT. The vulvar dermatoses. J Sex Med. 2008;5:276­283.

Chi CC, Kirtschig G, Baldo M, Lewis F, Wang SH, Wojnarowska F. Systematic review and meta­analysis of randomized controlled trials on topical interventions for genital lichen sclerosus. J Am Acad Dermatol. 2012;67:305­312.

Finch A, Metcalfe KA, Chiang JK, Elit L, McLaughlin J, Springate C, et al. The impact of prophylactic salpingo­ oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation. Gynecol Oncol. 2011;121:163­168.

Haefner HK. Report of the International Society for the Study of Vulvovaginal Disease terminology and classification of vulvodynia. J Low Genit Tract Dis. 2007;11:48­49.

Hiers RH, Long D, North RB, Oaklander AL. Hiding in plain sight: a case of Tarlov perineural cysts. J Pain. 2010;11:833­ 837.

Insola A, Granata G, Padua L. Alcock canal syndrome due to obturator internus muscle fibrosis. Muscle Nerve. 2010;42:431­432.

Kimberlin DW, Rouse DJ. Clinical practice. Genital herpes. N Engl J Med. 2004;350:1970­1977.

Labat JJ, Delavierre D, Sibert L, Rigaud J. Symptomatic approach to chronic pudendal pain. Prog Urol. 2010;20:922­929.

Ledger WJ, Witkin SS. Vulvovaginal Infections. London, UK: Manson Publishing; 2007.

Lewis FM, Bogliatto F. Erosive vulval lichen planus­­a diagnosis not to be missed: a clinical review. Eur J Obstet Gynecol Reprod Biol. 2013;171:214­219.

Loprinzi CL, Wolf SL, Barton DL, Laack NN. Symptom management in premenopausal patients with breast cancer. Lancet Oncol. 2008;9:993­1001.

Margesson LJ. Contact dermatitis of the vulva. Dermatol Ther. 2004;17:20­27.

Masata J, Hubka P, Martan A. Pudendal neuralgia following transobturator inside­out tape procedure (TVT­O) – case report and anatomical study. Int Urogynecol J. 2012;23:505­557.

Moyal­Barracco M, Wendling J. Vulvar dermatosis. Best Pract Res Clin Obstet Gynaecol. 2014;28:946­958.

Nyirjesy P. Vulvovaginal candidiasis and bacterial vaginosis. Infect Dis Clin North Am. 2008;22:637­652.

Oaklander AL, Rissmiller JG. Postherpetic neuralgia after shingles: an under­recognized cause of chronic vulvar pain. Obstet Gynecol. 2002;99:625­628.

Paulson JD, Baker J. De novo pudendal neuropathy after TOT­O surgery for stress urinary incontinence. JSLS. 2011;15:326­330.

Parnell BA, Johnson EA, Zolnoun DA. Genitofemoral and perineal neuralgia after transobturator midurethral sling. Obstet Gynecol. 2012;119:428­431.

Peng PWH, Antolak Jr SJ, Gordon AS. Pudendal Neuralgia. In: Goldstein AT, Pukall CF, Goldstein I, eds. Female Sexual Pain Disorders. Oxford, UK: Wiley­Blackwell; 2009:112­118. http://www.medscape.org/viewarticle/877370_print 59/69 21/4/2017 www.medscape.org/viewarticle/877370_print Schwebke JR, Burgess D. Trichomoniasis. Clin Microbiol Rev. 2004;17:794­803.

Soper D. Trichomoniasis: under control or undercontrolled? Am J Obstet Gynecol. 2004;190:281­290.

Stavraka C, Ford A, Ghaem­Maghami S, Crook T, Agarwal R, Gabra H, Blagden S. A study of symptoms described by ovarian cancer survivors. Gynecol Oncol. 2012;125:59­64.

Kollberg KS, Waldenström AC, Bergmark K, Dunberger G, Rossander A, Wilderäng U, et al. Reduced vaginal elasticity, reduced lubrication, and deep and superficial dyspareunia in irradiated gynecological cancer survivors. Acta Oncol. 2015;54:772­779.

Tan IL, Polydefkis MJ, Ebenezer GJ, Hauer P, McArthur JC. Peripheral nerve toxic effects of nitrofurantoin. Arch Neurol. 2012;69:265­268.

Turmo M, Echevarria M, Rubio P, Almeida C. Development of chronic pain after episiotomy. Rev Esp Anestesiol Reanim. 2015;62:436­442.

United Nations Children's Fund. Female Genital Mutilation/Cutting: What might the future hold? New York, NY: UNICEF; 2014.

Van de Kelft E, Van Vyve M. Chronic perineal pain related to sacral meningeal cysts. Neurosurgery. 1991;29:223­226.

Vulvodynia Assessment

Bergeron S, Binik YM, Khalifé S, Pagidas K, Glazer HI. Vulvar vestibulitis syndrome: reliability of diagnosis and evaluation of current diagnostic criteria. Obstet Gynecol. 2001;98:45­51.

Bornstein J, Goldstein AT, Stockdale CK, et al.; consensus vulvar pain terminology committee of the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women's Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS). 2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia. J Low Genit Tract Dis. 2016;20:126­130.

Burrows LJ, Klingman D, Pukall CF, Goldstein AT. Umbilical hypersensitivity in women with primary vestibulodynia. J Reprod Med. 2008;53:413­416.

Desrochers G, Bergeron S, Landry T, Jodoin M. Do psychosexual factors play a role in the etiology of provoked vestibulodynia? A critical review. J Sex Marital Ther. 2008;34:198­226.

Edwards L. Subsets of vulvodynia: overlapping characteristics. J Reprod Med. 2004;49:883­887.

Farage MA, Singh M, Ledger WJ. Investigation of the sensitivity of a cross­polarized light visualization system to detect subclinical erythema and dryness in women with vulvovaginitis. Am J Obstet Gynecol. 2009;201:20.e1­6.

Haefner HK. Report of the International Society for the Study of Vulvovaginal Disease terminology and classification of vulvodynia. J Low Genit Tract Dis. 2007;11:48­49.

Haefner HK, Collins ME, Davis GD, Edwards L, Foster DC, Hartmann ED, Kaufman RH, Lynch PJ, Margesson LJ, Moyal­ Barracco M, Piper CK, Reed BD, Stewart EG, Wilkinson EJ. The vulvodynia guideline. J Low Genit Tract Dis. 2005;9:40­ 51.

Harlow BL, Stewart EG. A population­based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc. 2003;58:82­88.

Harlow BL, Vazquez G, MacLehose RF, Erickson DJ, Oakes JM, Duval SJ. Self­reported vulvar pain characteristics and their association with clinically confirmed vestibulodynia. J Womens Health. 2009;18:1333­1340.

Kennedy CM, Nygaard IE, Bradley CS, Galask RP. Bladder and bowel symptoms among women with vulvar disease: are they universal? J Reprod Med. 2007;52:1073­1078.

McCormack WM. Two urogenital sinus syndromes. Interstitial cystitis and focal vulvitis. J Reprod Med. 1990;35:873­876.

http://www.medscape.org/viewarticle/877370_print 60/69 21/4/2017 www.medscape.org/viewarticle/877370_print Peters K, Girdler B, Carrico D, Ibrahim I, Diokno A. Painful bladder syndrome/interstitial cystitis and vulvodynia: a clinical correlation. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19:665­669.

Pukall CF, Baron M, Amsel R, Khalifé S, Binik YM. Tender point examination in women with vulvar vestibulitis syndrome. Clin J Pain. 2006;22:601­609.

Pukall CF, Strigo IA, Binik YM, Amsel R, Khalifé S, Bushnell MC. Neural correlates of painful genital touch in women with vulvar vestibulitis syndrome. Pain. 2005;115:118­127.

Reed BD, Gorenflo DW, Haefner HK. Generalized vulvar dysesthesia vs. vestibulodynia. Are they distinct diagnoses? J Reprod Med. 2003;48:858­864.

Warren JW, Langenberg P, Greenberg P, Diggs C, Jacobs S, Wesselmann U. Sites of pain from interstitial cystitis/painful bladder syndrome. J Urol. 2008;180:1373­1377.

Zolnoun D, Bair E, Essick G, Gracely R, Goyal V, Maixner W. Reliability and reproducibility of novel methodology for assessment of pressure pain sensitivity in pelvis. J Pain. 2012;13:910­920.

Zolnoun DA, Rohl J, Moore CG, Perinetti­Liebert C, Lamvu GM, Maixner W. Overlap between orofacial pain and vulvar vestibulitis syndrome. Clin J Pain. 2008;24:187­191.

Vestibulodynia: A Diagnostic Algorithm

King M, Rubin R, Goldstein A. Current Uses of Surgery for the Treatment of Genital Pain. Current Sexual Health Reports. 2014;6:252­258.

Comorbidity References

Chronic Headache

Nappi RE, Terreno E, Tassorelli C, Sances G, Allena M, Guaschino E, Anonaci F, Albani F, Polatti F. Sexual function and distress in women treated for primary headaches in a tertiary university center. J Sex Med. 2012;9:761­769.

Xie Y, Shi L, Xiong X, Wu E, Veasley C, Dade C. Economic burden and quality of life of vulvodynia in the United States. Curr Med Res Opin. 2012;28:601­608.

Endometriosis

Gardella B, Porru D, Nappi RE, Daccò MD, Chiesa A, Spinillo A. Interstitial cystitis is associated with vulvodynia and sexual dysfunction – a case­control study. J Sex Med. 2011;8:1726­1734.

Nguyen RH, Ecklund AM, Maclehose RF, Veasley C, Harlow BL. Co­morbid pain conditions and feelings of invalidation and isolation among women with vulvodynia. Psychol Health Med. 2012;17:589­598.

Xie Y, Shi L, Xiong X, Wu E, Veasley C, Dade C. Economic burden and quality of life of vulvodynia in the United States. Curr Med Res Opin. 2012;28:601­608.

Fibromyalgia & Chronic Fatigue Syndrome

Arnold LD, Bachmann GA, Rosen R, Rhoads GG. Assessment of vulvodynia symptoms in a sample of US women: a prevalence survey with a nested case control study. Am J Obstet Gynecol. 2007;196:128.e1­6.

Nguyen RH, Ecklund AM, Maclehose RF, Veasley C, Harlow BL. Co­morbid pain conditions and feelings of invalidation and isolation among women with vulvodynia. Psychol Health Med. 2012;17:589­598.

Pukall CF, Baron M, Amsel R, Khalifé S, Binik YM. Tender point examination in women with vulvar vestibulitis syndrome. Clin J Pain. 2006;22:601­609.

Pukall CF, Strigo IA, Binik YM, Amsel R, Khalifé S, Bushnell MC. Neural correlates of painful genital touch in women with vulvar vestibulitis syndrome. Pain. 2005;115:118­127.

http://www.medscape.org/viewarticle/877370_print 61/69 21/4/2017 www.medscape.org/viewarticle/877370_print Reed BD, Harlow SD, Sen A, Rayna E, Chen D, Haefner HK. Relationship between vulvodynia and chronic comorbid pain conditions. Obstet Gynecol. 2012;120:145­151.

Xie Y, Shi L, Xiong X, Wu E, Veasley C, Dade C. Economic burden and quality of life of vulvodynia in the United States. Curr Med Res Opin. 2012;28:601­608.

Interstitial Cystitis/Painful Bladder Syndrome

Alagiri M, Chottiner S, Ratner V, Slade D, Hanno PM. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology. 1997;49(5A Suppl):52­57.

Bohm­Starke N, Hilliges M, Falconer C, Rylander E. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest. 1998;46:256­260.

Bornstein J, Goldschmid N, Sabo E. Hyperinnervation and mast cell activation may be used as histopathologic diagnostic criteria for vulvar vestibulitis. Gynecol Obstet Invest. 2004;58:171­178.

Burrows LJ, Klingman D, Pukall CF, Goldstein AT. Umbilical hypersensitivity in women with primary vestibulodynia. J Reprod Med. 2008;53:413­416.

Carrico DJ, Sherer KL, Peters KM. The relationship of interstitial cystitis/painful bladder syndrome to vulvodynia. Urol Nurs. 2009;29:233­238.

Foster DC, Hasday JD. Elevated tissue levels of interleukin­1 beta and tumor necrosis factor­alpha in vulvar vestibulitis. Obstet Gynecol. 1997;89:291­296.

Gardella B, Porru D, Nappi RE, Daccò MD, Chiesa A, Spinillo A. Interstitial cystitis is associated with vulvodynia and sexual dysfunction – a case­control study. J Sex Med. 2011;8:1726­1734.

Gerber S, Bongiovanni AM, Ledger WJ, Witkin SS. Interleukin­1beta gene polymorphism in women with vulvar vestibulitis syndrome. Eur J Obstet Gynecol Reprod Biol. 2003;107:74­77.

Gunter J. Is there an association between vulvodynia and interstitial cystitis? Obstet Gynecol. 2000; 95:S4.

Hohenfellner M, Nunes L, Schmidt RA, Lampel A, Thüroff JW, Tanagho EA. Interstitial cystitis: increased sympathetic innervation and related neuropeptide synthesis. J Urol. 1992;147:587­591.

Jeremias J, Ledger WJ, Witkin SS. Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis. Am J Obstet Gynecol. 2000;182:283­285.

Kahn BS, Tatro C, Parsons CL, Willems JJ. Prevalence of interstitial cystitis in vulvodynia patients detected by bladder potassium sensitivity. J Sex Med. 2010;7(2 Pt 2):996­1002.

Kennedy CM, Nygaard IE, Bradley CS, Galask RP. Bladder and bowel symptoms among women with vulvar disease: are they universal? J Reprod Med. 2007;52:1073­1078.

McCormack WM. Two urogenital sinus syndromes. Interstitial cystitis and focal vulvitis. J Reprod Med. 1990;35:873­876.

Nguyen RH, Ecklund AM, Maclehose RF, Veasley C, Harlow BL. Co­morbid pain conditions and feelings of invalidation and isolation among women with vulvodynia. Psychol Health Med. 2012;17:589­598.

Peters K, Girdler B, Carrico D, Ibrahim I, Diokno A. Painful bladder syndrome/interstitial cystitis and vulvodynia: a clinical correlation. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19:665­669.

Reed BD, Harlow SD, Sen A, Rayna E, Chen D, Haefner HK. Relationship between vulvodynia and chronic comorbid pain conditions. Obst and Gyn. 2012;120:145­151.

Rodríguez MA, Afari N, Buchwald DS; National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Urological Chronic Pelvic Pain. Evidence for overlap between urological and nonurological unexplained clinical conditions. J Urol. 2013;189(1 Suppl):S66­S74.

http://www.medscape.org/viewarticle/877370_print 62/69 21/4/2017 www.medscape.org/viewarticle/877370_print Stewart EG, Berger BM. Parallel pathologies? Vulvar vestibulitis and interstitial cystitis. J Reprod Med. 1997;42:131­134.

Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology. 2001;57(6 Suppl 1):47­55.

Warren JW, Howard FM, Cross RK, Good JL, Weissman MM, Wesselmann U, Langenberg P, Greenberg P, Clauw DJ. Antecedent nonbladder syndromes in case­control study of interstitial cystitis/painful bladder syndrome. Urology. 2009;73:52­57.

Warren JW, Langenberg P, Greenberg P, Diggs C, Jacobs S, Wesselmann U. Sites of pain from interstitial cystitis/painful bladder syndrome. J Urol. 2008;180:1373­1377.

Wesselmann U. Interstitial cystitis: a chronic visceral pain syndrome. Urology. 2001;57(6 Suppl 1):32­39.

Weström LV, Willén R. Vestibular nerve fiber proliferation in vulvar vestibulitis syndrome. Obstet Gynecol. 1998;91:572­576.

Wu EQ, Birnbaum H, Mareva M, et al. Interstitial Cystitis: Cost, treatment and co­morbidities in an employed population. Pharmacoeconomics. 2006;24:55­65.

Xie Y, Shi L, Xiong X, Wu E, Veasley C, Dade C. Economic burden and quality of life of vulvodynia in the United States. Curr Med Res Opin. 2012;28:601­608.

Irritable Bowel Syndrome

Arnold LD, Bachmann GA, Rosen R, Rhoads GG. Assessment of vulvodynia symptoms in a sample of US women: a prevalence survey with a nested case control study. Am J Obstet Gynecol. 2007;196:128.e1­6.

Kennedy CM, Nygaard IE, Bradley CS, Galask RP. Bladder and bowel symptoms among women with vulvar disease: are they universal? J Reprod Med. 2007;52:1073­10078.

Nguyen RH, Ecklund AM, Maclehose RF, Veasley C, Harlow BL. Co­morbid pain conditions and feelings of invalidation and isolation among women with vulvodynia. Psychol Health Med. 2012;17:589­598.

Reed BD, Harlow SD, Sen A, Rayna E, Chen D, Haefner HK. Relationship between vulvodynia and chronic comorbid pain conditions. Obst and Gyn. 2012;120:145­151.

Xie Y, Shi L, Xiong X, Wu E, Veasley C, Dade C. Economic burden and quality of life of vulvodynia in the United States. Curr Med Res Opin. 2012;28:601­608.

Orofacial Pain

Xie Y, Shi L, Xiong X, Wu E, Veasley C, Dade C. Economic burden and quality of life of vulvodynia in the United States. Curr Med Res Opin. 2012;28:601­608.

Zolnoun DA, Rohl J, Moore CG, Perinetti­Liebert C, Lamvu GM, Maixner W. Overlap between orofacial pain and vulvar vestibulitis syndrome. Clin J Pain. 2008;24:187­191.

Psychosocial and Sexual Impairment

Bergeron S, Rosen NO, Morin M. Genital pain in women: Beyond interference with intercourse. Pain. 2011;152:1223­1225.

Desrochers G, Bergeron S, Landry T, Jodoin M. Do psychosexual factors play a role in the etiology of provoked vestibulodynia? A critical review. J Sex Marital Ther. 2008;34:198­226.

Treatment Options

General Principles

Andrews JC. Vulvodynia interventions – systematic review and evidence grading. Obstet Gynecol Surv. 2011;66:299­315.

http://www.medscape.org/viewarticle/877370_print 63/69 21/4/2017 www.medscape.org/viewarticle/877370_print Brotto LA, Yong P, Smith KB, Sadownik LA. Impact of a multidisciplinary vulvodynia program on sexual functioning and dyspareunia. J Sex Med. 2015;12:238­247.

Davis SN, Bergeron S, Binik YM, Lambert B. Women with provoked vestibulodynia experience clinically significant reductions in pain regardless of treatment: results from a 2­year follow­up study. J Sex Med. 2013;12:3080­3087.

Heddini U, Bohm­Starke N, Nilsson KW, Johannesson U. Provoked vestibulodynia – medical factors and comorbidity associated with treatment outcome. J Sex Med. 2012;9:1400­1406.

Jodoin M, Bergeron S, Khalife S, Dupuis MJ, Desrochers G, Leclerc B. Attributions about pain as predictors of psychological symptomatology, sexual function, and dyadic adjustment in women with vestibulodynia. Arch Sex Behav. 2011;40:87­97.

Labat JJ, Bensignor M, Boutet M, Delavierre D, Sibert L, Rigaud J. The doctor­patient relationship in chronic pelvic and perineal pain. Prog Urol. 2010;20:911­916.

Nguyen RHN, Mathur C, Wynings EM, Williams DA, Harlow BL. Remission of vulvar pain among women with primary vulvodynia. J Low Genit Tract Dis. 2015;19:62­67.

Sadownik, LA, Seal BN, Brotto LA. Provoked vestibulodynia­women's experience of participating in a multidisciplinary vulvodynia program. J Sex Med. 2012;9:1086­1093.

Spoelstra SK, Dijkstra JR, van Driel MF, Weijmar Schultz WC. Long­term results of an individualized, multifaceted, and multidisciplinary therapeutic approach to provoked vestibulodynia. J Sex Med. 2011;8:489­496.

Stockdale CK, Lawson HW. 2013 Vulvodynia Guideline Update. J Low Genit Tract Dis. 2014;18:93­100.

Ventolini G, Barhan S, Duke J. Vulvodynia, a step­wise therapeutic prospective cohort study. J Obstet Gynaecol. 2009;29:648­650.

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