Trigonitis) Can Be Challenging and Frustrating for Both the Triad of ﬁndings: 1) Severe Pain with Vestibular Touch Or Patient and Clinician

9-2 Painful Conditions of the Urogenital Sinus

Nathan Guerette and G.Willy Davila

Diagnosis and treatment of lower urogenital pain condi- Friedrich3 characterized vulvar vestibulitis as a persist- tions (vulvar vestibulitis, urethral pain syndrome, and ent syndrome lasting more than 6 months consisting of a trigonitis) can be challenging and frustrating for both the triad of findings: 1) severe pain with vestibular touch or patient and clinician. However, a methodical approach to attempted vaginal penetration, 2) tenderness in response evaluation and management can lead to remarkable to pressure within the vulvar vestibule, and 3) physical improvements. findings of erythema confined to the vestibule of varying degrees. Embryology Clinical Presentation In early female gestation, the cloaca separates into anterior and posterior divisions. The anterior division develops into Typically, patients will present with a history of vaginal the urogenital sinus. This endodermal structure then pain or burning and dyspareunia. Upon further question- morphs into the bladder, urethra, and vaginal bulb. The ing, the pain is localized to the introitus and usually bulb forms a portion of the superior vagina and inferiorly described as a burning or cutting that initiates with entry. fuses with the genital ectoderm. This fusion point forms Often tampon insertion or other activities increasing pres- the vulvar vestibule. sure in the vestibule will elicit similar symptoms. Many The common embryologic origin of the vestibule, patients will present with “recurrent cystitis,” caused by urethra, and bladder has suggested an etiologic association episodic burning with urination. Upon detailed question- among chronic painful conditions involving these tissues. ing, it is determined that the burning is external, typically This may help explain the similarity in physical and histo- after voiding and frequently with negative urine cultures, logic findings, prevalence rates, and treatment strategies and it resolves whether or not antibiotics are taken. for vulvar vestibulitis, trigonitis, urethritis, and interstitial Other vulvar dysesthesias can be difficult to distinguish cystitis.1,2 Interstitial cystitis is considered in a separate from vestibulitis. The key difference is that vulvar vestibu- chapter. litis has provoked symptoms, with pain initiated by direct physical contact. Women with vestibulitis will often have great apprehension about sexual intercourse and largely Vulvar Vestibulitis cease activity secondary to the degree of pain. Distinctions have been made between women with Anatomy and Definition primary vestibulitis, dyspareunia at the initiation of their sexual experience, and secondary vestibulitis (dyspareunia The vulvar vestibule is the most inferior portion of the after a time of asymptomatic intercourse) because patients urogenital sinus. It is a ringed structure delineated superi- with primary vestibulitis do not tend to respond as well to orly by the hymen, inferiorly by the more pigmented skin treatment.4 at the base of the labium minus (Hart’s line), anteriorly by the clitoris, and posteriorly by the fourchette and fossa navicularis. It is composed of thinly keratinized stratified Epidemiology and Demographics squamous epithelium. The urethra, Bartholin’s glands, Skene’s glands, and numerous minor mucous glands drain No large studies have been performed to accurately esti- into the vestibule. mate the prevalence of vestibulitis in the population. In 251 252 Pain and Irritative Syndromes Therapy

1995, Baggish and Miklos5 performed a meta-analysis of 15 natural killer cell activity increases after application of studies with 450 patients in an attempt to more accurately interferon.17 characterize women with vulvar vestibulitis. The typical vulvar vestibulitis patient is white, nulliparous, well- educated, and young. The women have frequently seen Etiology multiple clinicians, and have sought treatment for 2 to 3 years before the diagnosis is made. Many are diagnosed Numerous theories have been investigated to identify the with recurrent urinary tract infections,candidal infections, etiology of vulvar vestibulitis. Chronic bacterial and viral human papillomavirus (HPV), and allergies. An increased infections have been the strongest focus of study. Candida, rate of prior sexual abuse in these patients has been chlamydia, gonorrhea, mycoplasma, contact dermatitis and reported, but is controversial.6,7 other allergic responses, hormonal reaction, and psycho- Psychological testing on women with vulvar vestibulitis somatic causes have also been considered. Despite these has found higher rates of introversion, somatization, and extensive investigations, the etiology remains unclear and interference with sexual function. Overall levels of psycho- may be multifactorial. logical distress, negative feelings toward sex, self-esteem, Human papillomavirus has been the most thoroughly and marital satisfaction are conflicted in the literature with studied virus as an etiology. Numerous studies have tried some studies showing no difference from matched controls to correlate the presence of HPV with vulvar vestibulitis and others finding opposite results. Furthermore, the order symptoms, but the results have been highly variable, of causation remains unclear, with many authors suggest- reporting 0% to 85% rates of identifiable HPV in vestibu- ing a circular relationship of the physical condition and litis patients.18–22 In addition, no difference has been noted psychological changes.8–10 in HPV-positive and -negative women in response to treatment.23 Human papillomavirus does not seem to be causative or, if present, affect treatment outcomes. Histopathology During the initiation of urination, urine separates the labia minora and thus wets the entire vestibule, thus, Historic terms for vulvar vestibulitis (vulvar adenitis, ery- contact with urinary irritants, particularly oxalates, has thematous vulvitis, burning vulva syndrome) all implicate been researched as a possible etiology. Oxalates are organic inflammatory changes, but it was not until the late 1970s acids excreted in the urine that can cause pruritus and and 1980s that the histologic changes associated with burning. Many studies have shown higher rates of hyper- vestibulitis were better characterized. oxaluria in women with vestibulitis. These findings, A 1988 study analyzed 41 surgical specimens from however, have been inconsistent.24–26 patients diagnosed with vulvar vestibulitis. Chronic interstitial inflammation was seen in all cases and the glands were not involved. The etiology of this inflammation was Evaluation undetermined.7 More recently, controlled studies have produced more mixed results with similar patterns of A careful evaluation is necessary to design an effective inflammation but often no differences from control treatment regimen. We obtain a thorough history, includ- specimens.6,11,12 ing previous treatments and any contributing psychologi- When investigating hypotheses that vascular injury, cal factors, including sexual abuse, when timing is immunologic alterations, or changes in nociception may be appropriate.A broad differential should be used to rule out contributing factors, additional histologic findings have other vulvar or vaginal conditions such as candidal vagini- been noted. Inflammatory cytokines interleukin-1 and tis,lichen planus,or a chronic abscess of Bartholin’s glands. tumor necrosis factor were elevated in vestibulitis speci- Any potential allergens or irritants should be identified. mens compared with perineoplasty specimens from Particular attention should be given to patterns of exacer- asymptomatic women.13 Increased levels of perivascular bation of vestibulitis symptoms in conjunction with immunoglobulin M,complement,and fibrinogen,as well as ingestion of foods with high oxalate concentrations. For heightened angiogenesis have been noted in vestibulitis example, we have found a strong relationship between specimens compared with controls.14 Studies have noted consumption of various types of berries and worsening increased neural hyperplasia in vestibulitis subjects and symptoms. found the degree of vestibular nerve formation When vestibulitis is suspected, a detailed vulvar and significantly correlated with the degree of inflamma- vaginal examination must be performed. Any cutaneous tion.15,16 Whether these changes are causative or secondary or mucosal abnormalities as well as atrophic changes in remains unclear. the vaginal mucosa should be noted. The vestibule must Immune dysfunction has also been postulated as an be inspected for erythema and other signs of chronic underlying factor in vulvar vestibulitis with decreased inflammation. Pain mapping with a cotton-tipped swab natural killer cell activity in the vestibular tissues of should be done, before any vaginal instrumentation, symptomatic women. It has also been observed that to delineate the area of sensitivity (Figure 9-2.1). This Painful Conditions of the Urogenital Sinus 253

Upper genital tract pain, elicited on bimanual examination, may be suggestive of pelvic inﬂammatory disease, endometriosis, or a pelvic mass. A gentle, methodical approach to the vulvovaginal examination in patients with a history suggestive of urogenital sinus pain is imperative.

Treatment Education

Women diagnosed with vulvar vestibulitis, particularly at specialty centers, have usually seen multiple clinicians, received numerous courses of medications for infections, and have often been told the problem is psychological. Giving patients a ﬁrm diagnosis, reassuring them the problem is real and not “in their head,” and using the examination to educate them on their genital anatomy can assuage many of their anxieties and increase compliance with recommended therapy.

Elimination of Potential Irritants

Removing all possible irritants is a critical component of Figure 9-2.1. Vulvar vestibule and pain map. (Reprinted with the permission of The Cleve- successful treatment. Women with vulvar vestibulitis land Clinic Foundation.) should discontinue use of all hygiene products,creams,and lubricants. Minimizing the irritative effect of urine on the vulvar vestibule is also important.Women are instructed to should be recorded in the medical record for future spread their labia before initiation of voiding to reduce reference. contact with urine. We place all patients on a low oxalate Pain along the posterior vestibule and inner aspect of the diet (Table 9-2.1), and recommend taking calcium citrate labia minora is typical. If the painful area is difficult to (Citracal) as a binding agent with each meal to reduce discern, diluted acetic acid on the swab helps define the urinary excretion of oxalates. The currently available diet area with acetowhite changes, but may be quite uncom- is by no means comprehensive, and oxalates may not be fortable for the patient and is rarely necessary. the only irritating dietary factor in the urine. Patients The urethra and trigone should be palpated transvagi- are informed to be diet conscious and look for temporal nally to identify other potential areas of tenderness. Puru- relationships between certain foods and worsening of lent urethral discharge indicates the need for urethral their symptoms. cultures and possibly antibiotic therapy before further work-up. Isolated trigonal sensitivity should be further evaluated with cystourethroscopy to look for evidence of Medications chronic infection. If localized trigonal pain is identified, we will frequently initiate empiric tetracycline therapy for 3 to Topical corticosteroids and interferon have been used in 4 weeks. an attempt to reduce the chronic inflammatory changes, The vaginal speculum examination is then performed, but significant response rates are disappointing. Topical and is important in order to identify inflammatory or estrogen cream has been shown to be beneficial. Women infectious vaginitis.Vaginal lichen planus characteristically are instructed to use the cream at a dose of 1g intravagi- presents as well-delineated marked mucosal erythema and nally two times a week and to digitally apply a small desquamation with a mucopurulent discharge. Microscopy amount daily to the vestibule. The cream is soothing should be used to rule out bacterial vaginosis or yeast and over time thickens the vestibular epithelium, which infections. may distance the nociceptors from the surface of the The vaginal mucosa of a woman with atrophic vaginitis skin. Alone, local estrogen has produced, generally, usually will be pale, thin, and have loss of rugations, but disappointing results. There may also be a direct effect of milder degrees of atrophy may have a more subtle presen- estrogen on vestibular nerve fibers. We routinely use estro- tation. A maturation index or pH may be helpful in quan- gen warn in one multi-modality treatment of vulvar tifying the degree of atrophy and therapeutic response. vestibulitis. 254 Pain and Irritative Syndromes Therapy

Table 9-2.1. Oxalate content of common foods dose to the usual therapeutic dose. We typically add Elavil Low Oxalate Medium Oxalate High Oxalate (10mg at bedtime) if a low oxalate, local Xylocaine, and Cola Coffee Cocoa estrogen cream do not result in significant relief. Apple juice Fruit juices Most berry juices Milk Grape Blackberries Surgery Butter Orange Blueberries Yogurt Tomato Raspberries Because the etiology of vulvar vestibulitis remains unclear, Cheese Apples Strawberries surgery to remove the affected tissue has been controver- Mayonnaise Pineapples Whole wheat bread sial.However,it remains the single most effective treatment Red wine White bread Peanuts option for vestibulitis, with most studies reporting success Grapes Pasta Soy products rates of 70% to 80%. A randomized prospective trial Lemons Asparagus Celery comparing treatment with surgery, cognitive therapy, and Melons Broccoli Collards biofeedback noted significantly greater improvement in the 23 Raisins Carrots Green peppers surgery group. Rice Corn Popcorn The key to effectively treating with surgery is proper patient selection. Nonsurgical options, as noted above, Coconut Cucumber Spinach should have been attempted and failed. We also suggest a Bacon Garlic Tomato sauce course of psychological counseling to help identify and Beef Lettuce Yams address any potentially unfounded factors such as previous Chicken Mushrooms sexual abuse. The patient must have pain specifically local- Eggs Onions ized to the vestibule. This requires careful pain mapping. Fish Peppers Women with more generalized vaginal, vulvar, or pelvic Squash Potato and potato chips pain are not candidates for surgery. Zucchini Tomato Numerous procedures have been described to treat Peas vulvar vestibulitis including laser,highly localized excision, and undercutting for denervation. Most of these have had Source: Adapted from Rowan’s Resources. More dietary selections and additional variable success. At our center, because the inflammatory information available at www.vulvarpainfoundation.org. process involves the entire vestibule, we believe a vestibulectomy with vaginal advancement should be performed. This will connect thick vaginal mucosa directly to Biofeedback vulvar skin. The vestibulectomy incision should be made in a horse- Pelvic floor muscle hypertonicity is not infrequently a con- shoe manner and include the hymen, periurethral mucosa, tributing factor to the dyspareunia associated with vestibu- and posterior fourchette to the perineal skin pigmented litis. Biofeedback with therapists experienced in managing border (Figures 9-2.2–9-2.4). The vaginal mucosa is the pelvic floor can notably reduce the degree of spasm in then undermined and advanced to close the defect these muscles, providing a useful adjunct to treatment. without tension. Our success rates with this technique have exceeded 80% in allowing reinitiation of sexual intercourse. Alteration of Pain Sensation

Decreasing the sensitivity of the vestibular nociceptors is Urethral Pain Syndrome another valuable step in successful treatment. Locally, a brief course of 2% Xylocaine gel applied regularly (two to Urethral pain syndrome, previously known as chronic ure- three times per day) may provide relief while additional thritis or urethral syndrome is a rare sensory disorder of treatment avenues are initiated. Patients should be warned, the urethra recently deﬁned by the International Conti- however, that the Xylocaine may burn with initial nence Society as persistent or recurrent urethral pain, with application. frequency and nocturia, lasting at least 6 months, in the Centrally, pain sensation can be altered with tricyclic absence of proven infection or other obvious pathology.27 antidepressants. These agents are widely used for manage- Similar to vestibulitis, the etiology of this disorder ment of chronic pain and are useful in the improvement remains unknown.Evaluation must be thorough to rule out of vulvar vestibulitis symptoms. Amitriptyline (Elavil), infection, anatomic abnormalities (urethral diverticulum), imipramine (Tofranil), nortriptyline (Pamelor, Aventyl), atrophy, and other more generalized conditions of the and desipramine (Norpramin) can all have signiﬁcant side bladder and/or vagina. Cultures, voiding diaries, urody- effects (dry mouth, dry eyes, constipation, sedation, palpi- namics, and cystoscopy should all be included in the tations, etc.) and should be slowly increased from a low work-up. Painful Conditions of the Urogenital Sinus 255

Figure 9-2.2. Vestibulectomy technique: A horseshoe area of vestibule from hymen to vulva is excised.

Figure 9-2.4. Vestibulectomy technique: The defect is closed in a running manner.

Treatment is focused on symptomatic relief. Urethral massage can be therapeutic and aids in making the diagnosis. Removing local and dietary irritants in the same manner as with vestibulitis is necessary. Biofeedback, including functional electrical stimulation, and physical therapy may be helpful. Pain sensation can be reduced with local anesthetics, analgesics, and tricyclics. A bladder- training regimen may decrease associated frequency. On occasion, multichannel urodynamics may demonstrate urethral instability, which may typically respond to functional electrical stimulation. Urethral dilation is no longer recommended as a treatment option, but has historically yielded good results.

Trigonitis

Trigonitis is inflammation localized to the bladder trigone. Symptoms manifest as bladder and urethral pain, as well as frequency and nocturia. Digital palpation will reveal pain localized to the trigone. Acute trigonitis is usually obvious on cystoscopy and may be treated with a routine course of antibiotics. Chronic trigonitis is typically more subtle with mild inflammatory Figure 9-2.3. Vestibulectomy technique: The vaginal mucosa is dissected free. surface changes.Abundant squamous metaplasia, common 256 Pain and Irritative Syndromes Therapy to this tissue, is often mistaken for inflammation by the minor vestibular glands: an immunohistochemical study. Int J inexperienced cystoscopist. Gynecol Pathol 1999;18:360–365. Chronic trigonitis is often preceded by recurrent, docu- 13. Foster DC, Hasday JD. Elevated tissue levels of interleukin-1B and tumor necrosis. Obstet Gynecol 1997;89:291–296. mented urinary tract infections and is thought to represent 14. Stewart EG, Berger BM. 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