Semin Reprod Med 2015; 33(04): 239-245
DOI: 10.1055/s-0035-1554919
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Vulvodynia: The Role of Inflammation in the Etiology of Localized Provoked Pain of the Vulvar Vestibule (Vestibulodynia)

Alin L. Akopians
1   Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California, Los Angeles, California
,
Andrea J. Rapkin
2   Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California
› Author Affiliations
Further Information

Publication History

Publication Date:
01 July 2015 (online)

Abstract

Vulvar pain affecting the vestibule (vestibulodynia) is an enigmatic pain disorder that greatly affects quality of life and sexual functioning. The most common form of the disorder (localized provoked vulvodynia) is initiated by genital contact but is otherwise asymptomatic. Findings on examination are limited to excessive tenderness of the vestibule with light touch with cotton swab but may also include localized erythema and pelvic floor muscle tightness and tenderness. This review will summarize the literature regarding the role of inflammation in the genesis of the disorder. Some evidence exists for altered histology consisting of increased numbers of mast cells and nerve endings. Immunological abnormalities that have been reported include altered cytokines and neurokines. Abnormal inflammatory response and heightened sensitivity of the vaginal opening has been documented in a murine model of vaginal infection with Candida albicans. In vitro studies of fibroblasts from the vestibule of affected women with vestibulodynia demonstrate a proinflammatory response to C albicans that may be important in the initiation of pain. However, thus far none of the findings have led to adequate treatments.

 
  • References

  • 1 Moyal-Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J Reprod Med 2004; 49 (10) 772-777
  • 2 McKay M. Vulvodynia. A multifactorial clinical problem. Arch Dermatol 1989; 125 (2) 256-262
  • 3 Friedrich Jr EG. Vulvar vestibulitis syndrome. J Reprod Med 1987; 32 (2) 110-114
  • 4 Young AW. Burning vulva syndrome: report of the ISSVD task force. J Reprod Med 1984; 29: 457
  • 5 Friedrich Jr EG. The vulvar vestibule. J Reprod Med 1983; 28 (11) 773-777
  • 6 Woodruff JD, Friedrich Jr EG. The vestibule. Clin Obstet Gynecol 1985; 28 (1) 134-141
  • 7 Slone S, Reynolds L, Gall S , et al. Localization of chromogranin, synaptophysin, serotonin, and CXCR2 in neuroendocrine cells of the minor vestibular glands: an immunohistochemical study. Int J Gynecol Pathol 1999; 18 (4) 360-365
  • 8 Lundqvist EN, Hofer PA, Olofsson JI, Sjöberg I. Is vulvar vestibulitis an inflammatory condition? A comparison of histological findings in affected and healthy women. Acta Derm Venereol 1997; 77 (4) 319-322
  • 9 Bohm-Starke N, Hilliges M, Brodda-Jansen G, Rylander E, Torebjörk E. Psychophysical evidence of nociceptor sensitization in vulvar vestibulitis syndrome. Pain 2001; 94 (2) 177-183
  • 10 Leclair CM, Goetsch MF, Korcheva VB, Anderson R, Peters D, Morgan TK. Differences in primary compared with secondary vestibulodynia by immunohistochemistry. Obstet Gynecol 2011; 117 (6) 1307-1313
  • 11 Edwards L. New concepts in vulvodynia. Am J Obstet Gynecol 2003; 189 (3, Suppl): S24-S30
  • 12 Reed BD, Cantor LE. Vulvodynia in preadolescent girls. J Low Genit Tract Dis 2008; 12 (4) 257-261
  • 13 Clare CA, Yeh J. Vulvodynia in adolescence: childhood vulvar pain syndromes. J Pediatr Adolesc Gynecol 2011; 24 (3) 110-115
  • 14 Goetsch MF. Vulvar vestibulitis: prevalence and historic features in a general gynecologic practice population. Am J Obstet Gynecol 1991; 164 (6, Pt 1) 1609-1614 , discussion 1614–1616
  • 15 Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia?. J Am Med Womens Assoc 2003; 58 (2) 82-88
  • 16 Reed BD, Harlow SD, Sen A , et al. Prevalence and demographic characteristics of vulvodynia in a population-based sample. Am J Obstet Gynecol 2012; 206 (2) 170.e1-9
  • 17 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 (4) 601-608
  • 18 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 (1) 62-67
  • 19 Bachmann GA, Rosen R, Pinn VW , et al. Vulvodynia: a state-of-the-art consensus on definitions, diagnosis and management. J Reprod Med 2006; 51 (6) 447-456
  • 20 Nguyen RH, Ecklund AM, Maclehose RF, Veasley C, Harlow BL. Co-morbid pain conditions and feelings of invalidation and isolation among women with vulvodynia. Psychol Health Med 2012; 17 (5) 589-598
  • 21 Nguyen RH, Veasley C, Smolenski D. Latent class analysis of comorbidity patterns among women with generalized and localized vulvodynia: preliminary findings. J Pain Res 2013; 6: 303-309
  • 22 Sarton J. Assessment of the pelvic floor muscles in women with sexual pain. J Sex Med 2010; 7 (11) 3526-3529
  • 23 Wesselmann U, Bonham A, Foster D. Vulvodynia: Current state of the biological science. Pain 2014; 155 (9) 1696-1701
  • 24 Feldhaus-Dahir M. The causes and prevalence of vestibulodynia: a vulvar pain disorder. Urol Nurs 2011; 31 (1) 51-54
  • 25 Nyirjesy P. Vulvar vestibulitis syndrome: a post-infectious entity?. Curr Infect Dis Rep 2000; 2 (6) 531-535
  • 26 Turner ML, Marinoff SC. Association of human papillomavirus with vulvodynia and the vulvar vestibulitis syndrome. J Reprod Med 1988; 33 (6) 533-537
  • 27 Pathak D, Agrawal S, Dhali TK. Prevalences of and risk factors for vulvar diseases in Nepal: a hospital-based study. Int J Dermatol 2011; 50 (2) 161-167
  • 28 Nguyen RH, Swanson D, Harlow BL. Urogenital infections in relation to the occurrence of vulvodynia. J Reprod Med 2009; 54 (6) 385-392
  • 29 Ramirez DE, Knott HM, McCormick TS , et al. Cutaneous hypersensitivity to Candida albicans in idiopathic vulvodynia. Contact Dermatitis 2005; 53 (4) 214-218
  • 30 Edgardh K, Abdelnoor M. Vulvar vestibulitis and risk factors: a population-based case-control study in Oslo. Acta Derm Venereol 2007; 87 (4) 350-354
  • 31 Jayaram A, Witkin SS, Zhou X , et al. The bacterial microbiome in paired vaginal and vestibular samples from women with vulvar vestibulitis syndrome. Pathog Dis 2014; 72 (3) 161-166
  • 32 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 (101) 101ra91
  • 33 Ventolini G, Gygax SE, Adelson ME, Cool DR. Vulvodynia and fungal association: a preliminary report. Med Hypotheses 2013; 81 (2) 228-230
  • 34 Foster DC, Falsetta ML, Woeller CF , et al. Site-specific mesenchymal control of inflammatory pain to yeast challenge in vulvodynia-afflicted and pain-free women. Pain 2015; 156 (3) 386-396
  • 35 Foster DC, Hasday JD. Elevated tissue levels of interleukin-1 beta and tumor necrosis factor-alpha in vulvar vestibulitis. Obstet Gynecol 1997; 89 (2) 291-296
  • 36 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 (4) 696-700
  • 37 Chadha S, Gianotten WL, Drogendijk AC, Weijmar Schultz WC, Blindeman LA, van der Meijden WI. Histopathologic features of vulvar vestibulitis. Int J Gynecol Pathol 1998; 17 (1) 7-11
  • 38 Foster DC, Piekarz KH, Murant TI , et al. Enhanced synthesis of proinflammatory cytokines by vulvar vestibular fibroblasts: implications for vulvar vestibulitis. Am J Obstet Gynecol 2007; 196 (4) 346.e1-8
  • 39 Cunha FQ, Poole S, Lorenzetti BB, Ferreira SH. The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia. Br J Pharmacol 1992; 107 (3) 660-664
  • 40 Eliav E, Benoliel R, Herzberg U, Kalladka M, Tal M. The role of IL-6 and IL-1beta in painful perineural inflammatory neuritis. Brain Behav Immun 2009; 23 (4) 474-484
  • 41 Firestein GS, Alvaro-Gracia JM, Maki R. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol 1990; 144 (9) 3347-3353
  • 42 Daymond TJ, Rowell FJ. Reduction of prostaglandin E2 concentrations in synovial fluid of patients suffering from rheumatoid arthritis following tiaprofenic acid or indomethacin treatment. Drugs 1988; 35 (Suppl. 01) 4-8
  • 43 Zanjani TM, Sabetkasaei M, Mosaffa N, Manaheji H, Labibi F, Farokhi B. Suppression of interleukin-6 by minocycline in a rat model of neuropathic pain. Eur J Pharmacol 2006; 538 (1-3) 66-72
  • 44 Falsetta ML, Foster DC, Woeller CF , et al. Identification of novel mechanisms involved in generating localized vulvodynia pain. Am J Obstet Gynecol 2015; ; Epub ahead of print
  • 45 Gerber S, Bongiovanni AM, Ledger WJ, Witkin SS. Interleukin-1beta gene polymorphism in women with vulvar vestibulitis syndrome. Eur J Obstet Gynecol Reprod Biol 2003; 107 (1) 74-77
  • 46 Jeremias J, Ledger WJ, Witkin SS. Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis. Am J Obstet Gynecol 2000; 182 (2) 283-285
  • 47 Babula O, Danielsson I, Sjoberg I, Ledger WJ, Witkin SS. Altered distribution of mannose-binding lectin alleles at exon I codon 54 in women with vulvar vestibulitis syndrome. Am J Obstet Gynecol 2004; 191 (3) 762-766
  • 48 Babula O, Linhares IM, Bongiovanni AM , et al. Association between primary vulvar vestibulitis syndrome, defective induction of tumor necrosis factor-alpha, and carriage of the mannose-binding lectin codon 54 gene polymorphism. Am J Obstet Gynecol 2008; 198 (1) 101.e1-4
  • 49 Foster DC, Sazenski TM, Stodgell CJ. Impact of genetic variation in interleukin-1 receptor antagonist and melanocortin-1 receptor genes on vulvar vestibulitis syndrome. J Reprod Med 2004; 49 (7) 503-509
  • 50 Gerber S, Witkin SS, Stucki D. Immunological and genetic characterization of women with vulvodynia. J Med Life 2008; 1 (4) 432-438
  • 51 Witkin SS, Gerber S, Ledger WJ. Differential characterization of women with vulvar vestibulitis syndrome. Am J Obstet Gynecol 2002; 187 (3) 589-594
  • 52 Summerfield JA, Sumiya M, Levin M, Turner MW. Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series. BMJ 1997; 314 (7089) 1229-1232
  • 53 Garred P, Madsen HO, Halberg P , et al. Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. Arthritis Rheum 1999; 42 (10) 2145-2152
  • 54 Tympanidis P, Terenghi G, Dowd P. Increased innervation of the vulval vestibule in patients with vulvodynia. Br J Dermatol 2003; 148 (5) 1021-1027
  • 55 Tympanidis P, Casula MA, Yiangou Y, Terenghi G, Dowd P, Anand P. Increased vanilloid receptor VR1 innervation in vulvodynia. Eur J Pain 2004; 8 (2) 129-133
  • 56 Donders G, Bellen G. Characteristics of the pain observed in the focal vulvodynia syndrome (VVS). Med Hypotheses 2012; 78 (1) 11-14
  • 57 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 (1) 45-51
  • 58 Bohm-Starke N, Falconer C, Rylander E, Hilliges M. The expression of cyclooxygenase 2 and inducible nitric oxide synthase indicates no active inflammation in vulvar vestibulitis. Acta Obstet Gynecol Scand 2001; 80 (7) 638-644
  • 59 Pukall CF, Binik YM, Khalifé S, Amsel R, Abbott FV. Vestibular tactile and pain thresholds in women with vulvar vestibulitis syndrome. Pain 2002; 96 (1-2) 163-175
  • 60 Sonni L, Cattaneo A, De Marco A, De Magnis A, Carli P, Marabini S. Idiopathic vulvodynia. Clinical evaluation of the pain threshold with acetic acid solutions. J Reprod Med 1995; 40 (5) 337-341
  • 61 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 (9) 910-920
  • 62 Turner ML, Marinoff SC. Pudendal neuralgia. Am J Obstet Gynecol 1991; 165 (4, Pt 2) 1233-1236
  • 63 Foster DC, Dworkin RH, Wood RW. Effects of intradermal foot and forearm capsaicin injections in normal and vulvodynia-afflicted women. Pain 2005; 117 (1-2) 128-136
  • 64 Ledger WJ, Kessler A, Leonard GH, Witkin SS. Vulvar vestibulitis-a complex clinical entity. Infect Dis Obstet Gynecol 1996; 4 (5) 269-275
  • 65 Babula O, Bongiovanni AM, Ledger WJ, Witkin SS. Immunoglobulin E antibodies to seminal fluid in women with vulvar vestibulitis syndrome: relation to onset and timing of symptoms. Am J Obstet Gynecol 2004; 190 (3) 663-667
  • 66 Harlow BL, Vitonis AF, Stewart EG. Influence of oral contraceptive use on the risk of adult-onset vulvodynia. J Reprod Med 2008; 53 (2) 102-110
  • 67 Bohm-Starke 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 (11) 888-892
  • 68 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 (3) 254-261
  • 69 Johannesson U, Blomgren B, Hilliges M, Rylander E, Bohm-Starke N. The vulval vestibular mucosa-morphological effects of oral contraceptives and menstrual cycle. Br J Dermatol 2007; 157 (3) 487-493
  • 70 Eva LJ, MacLean AB, Reid WM, Rolfe KJ, Perrett CW. Estrogen receptor expression in vulvar vestibulitis syndrome. Am J Obstet Gynecol 2003; 189 (2) 458-461
  • 71 Johannesson U, Sahlin L, Masironi B , et al. Steroid receptor expression and morphology in provoked vestibulodynia. Am J Obstet Gynecol 2008; 198 (3) 311.e1-6
  • 72 Griebling TL, Liao Z, Smith PG. Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women. Menopause 2012; 19 (6) 630-635
  • 73 Bergeron S, Likes WM, Steben M. Psychosexual aspects of vulvovaginal pain. Best Pract Res Clin Obstet Gynaecol 2014; 28 (7) 991-999
  • 74 Khandker M, Brady SS, Stewart EG, Harlow BL. Is chronic stress during childhood associated with adult-onset vulvodynia?. J Womens Health (Larchmt) 2014; 23 (8) 649-656
  • 75 Seckin-Alac E, Akhant SE, Bastu E, Tuzlalik S, Yavuz E. Elevated tissue levels of tumor necrosis factor-α in vulvar vestibulitis syndrome. Clin Exp Obstet Gynecol 2014; 41 (6) 691-693