Reduced concentrations of vaginal metabolites involved in steroid hormone biosynthesis are associated with increased vulvar vestibular pain and vaginal muscle tenderness in provoked vestibulodynia: An exploratory metabolomics study

1. 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), the International Pelvic Pain Society (IPPS). Consensus vulvar pain terminology committee of the international society for the study of vulvovaginal disease tISftSoWsSH and the international pelvic pain S. 2015 ISSVD, ISSWSH and IPPS consensus terminology and classification of persistent vulvar pain and vulvodynia. Obstet Gynecol 2016; 127: 745–751.
Google Scholar | Crossref | Medline | ISI2. Lev-Sagie, A, Witkin, SS. Recent advances in understanding provoked vestibulodynia. F1000Res 2016; 5: 2581.
Google Scholar | Crossref | Medline3. Pukall, CF, Goldstein, AT, Bergeron, S, Foster, D, Stein, A, Kellogg-Spadt, S, Bachmann, G. Vulvodynia: definition, prevalence, impact, and pathophysiological factors. J Sex Med 2016; 13: 291–304.
Google Scholar | Crossref | Medline4. Goldstein, AT, Belkin, ZR, Krapf, JM, Song, WT, Khera, M, Jutrzonka, SL, Kim, NN, Burrows, LJ, Goldstein, I. Polymorphisms of the androgen receptor gene and hormonal contraceptive induced provoked vestibulodynia. J Sex Med 2014; 11: 2764–2771.
Google Scholar | Crossref | Medline5. Bhatt, R, Gupta, A, Rapkin, AJ, Kilpatrick, L, Hamadami, K, Pazmany, E, Van Oudenhove, L, Stains, J, Aerts, L, Enzli, P, Tillisch, K, Mayer, EA, Labus, JS. Altered gray matter volume in sensorimotor and thalamic regions associated with pain in localized provoked vestibulodynia: a voxel-based morphometry study. J Pain 2019; 160: 1529–1540.
Google Scholar | Crossref6. Gupta, A, Rapkin, AJ, Gill, Z, Kilpatrick, L, Fling, C, Stains, J, Masghati, S, Tillisch, K, Mayer, EA, Labus, JS. Disease-related differences in resting-state networks: a comparison between localized provoked vulvodynia, irritable bowel syndrome, and healthy control subjects. Pain 2015; 156: 809–819.
Google Scholar | Crossref | Medline7. Gupta, A, Woodworth, DC, Ellingson, BM, Rapkin, AJ, Naliboff, B, Kilpatrick, LA, Stains, J, Masghati, S, Tillisch, K, Mayer, EA, Labus, JS. Disease-related microstructural differences in the brain in women with provoked vestibulodynia. J Pain 2018; 19: 528.e1–e528.e15.
Google Scholar | Crossref8. Hampson, JP, Reed, BD, Clauw, DJ, Bhavsar, R, Gracely, RH, Haefner, HK, Harris, RE. Augmented central pain processing in vulvodynia. J Pain 2013; 14: 579–589.
Google Scholar | Crossref | Medline9. Pukall, CF, Strigo, IA, Binik, YM, Amsel, R, Khalife, S, Bushnell, MC. Neural correlates of painful genital touch in women with vulvar vestibulitis syndrome. Pain 2005; 115: 118–127.
Google Scholar | Crossref | Medline | ISI10. Schweinhardt, P, Kuchinad, A, Pukall, CF, Bushnell, MC. Increased gray matter density in young women with chronic vulvar pain. Pain 2008; 140: 411–419.
Google Scholar | Crossref | Medline | ISI11. Pazmany, E, Ly, HG, Aerts, L, Kano, M, Bergeron, S, Verhaeghe, J, Peeters, R, Tack, J, Dupont, P, Enzlin, P, Van Oudenhove, L. Brain responses to vestibular pain and its anticipation in women with genito-pelvic pain/penetration disorder. Neuroimage Clin 2017; 16: 477–490.
Google Scholar | Crossref | Medline12. Ciszek, BP, Khan, AA, Dang, H, Slade, GD, Smith, S, Bair, E, Maixner, W, Zolnoun, D, Nackley, AG. MicroRNA expression profiles differentiate chronic pain condition subtypes. Transl Res 2015; 166: 706–720.
Google Scholar | Crossref | Medline13. Aalto, A, Huotari-Orava, R, Luhtala, S, Mäenpää, J, Staff, S. Expression of estrogen-related receptors in localized provoked vulvodynia. Biores Open Access 2020; 9: 13–21.
Google Scholar | Crossref | Medline14. Eva, LJ, MacLean, AB, Reid, WM, Rolfe, KJ, Perrett, CW. Estrogen receptor expression in vulvar vestibulitis syndrome. Am J Obstet Gynecol 2003; 189: 458–461.
Google Scholar | Crossref | Medline | ISI15. Johannesson, U, Sahlin, L, Masironi, B, Hilliges, M, Blomgren, B, Rylander, E, Bohm-Starke, N. Steroid receptor expression and morphology in provoked vestibulodynia. Am J Obstet Gynecol 2008; 198: 311 e311–e316.
Google Scholar | Crossref | Medline16. Bohm-Starke, N, Johannesson, U, Hilliges, M, Rylander, E, Torebjork, E. Decreased mechanical pain threshold in the vestibu'lair mucosa of women using oral contraceptives – a contributing factor in vulvar vestibulitis? J Reprod Med 2004; 49: 888–892.
Google Scholar | Medline | ISI17. 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: 254–261.
Google Scholar | Crossref | Medline | ISI18. Goldstein, A, Burrows, L, Goldstein, I. Can oral contraceptives cause vestibulodynia? J Sex Med 2010; 7: 1585–1587.
Google Scholar | Crossref | Medline19. Harlow, BL, Vitonis, AE, Stewart, EG. Influence of oral contraceptive use on the risk of adult-onset vulvodynia. J Reprod Med 2008; 53: 102–110.
Google Scholar | Medline | ISI20. Griebling, TL, Liao, ZH, Smith, PG. Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women. Menopause 2012; 19: 630–635.
Google Scholar | Crossref | Medline21. Hornung, R, Benton, W, Tongkhuya, S, Uphouse, L, Averitt, D. Protective role of progesterone against allodynia in rats with persistent temporomandibular joint inflammation. J Pain 2017; 18: S5.
Google Scholar | Crossref22. Labrie, F, Martel, C, Pelletier, G. Is vulvovaginal atrophy due to a lack of both estrogens and androgens? Menopause 2017; 24: 452–461.
Google Scholar | Crossref | Medline23. Murina, F, Barbieri, S, Lubrano, C, Cetin, I. Vestibular mucosa thickness measured by ultrasound in patients affected by vestibulodynia: a case-control study. Sex Med 2021; 9: 100320.
Google Scholar | Crossref | Medline24. Coronel, MF, Labombarda, F, De Nicola, AF, González, SL. Progesterone reduces the expression of spinal cyclooxygenase-2 and inducible nitric oxide synthase and prevents allodynia in a rat model of central neuropathic pain. Eur J Pain 2014; 18: 348–359.
Google Scholar | Crossref | Medline | ISI25. Coronel, MF, Labombarda, F, Roig, P, Villar, MJ, De Nicola, AF, González, SL. Progesterone prevents nerve injury-induced allodynia and spinal NMDA receptor upregulation in rats. Pain Med 2011; 12: 1249–1261.
Google Scholar | Crossref | Medline26. Jarahi, M, Sheibani, V, Safakhah, HA, Torkmandi, H, Rashidy-Pour, A. Effects of progesterone on neuropathic pain responses in an experimental animal model for peripheral neuropathy in the rat: a behavioral and electrophysiological study. Neuroscience 2014; 256: 403–411.
Google Scholar | Crossref | Medline27. Traish, AM, Vignozzi, L, Simon, JA, Goldstein, I, Kim, NN. Role of androgens in female genitourinary tissue structure and function: implications in the genitourinary syndrome of menopause. Sex Med Rev 2018; 6: 558–571.
Google Scholar | Crossref | Medline28. Ivanisevic, J, Thomas, A. Metabolomics as a tool to understand pathophysiological processes. Methods Mol Biol 2018; 1730: 3–28.
Google Scholar | Crossref | Medline29. Kaddurah-Daouk, R, Weinshilboum, R, Pharmacometabolomics Research Network. Metabolomic signatures for drug response phenotypes: pharmacometabolomics enables precision medicine. Clin Pharmacol Ther 2015; 98: 71–75.
Google Scholar | Crossref | Medline30. Wishart, DS. Emerging applications of metabolomics in drug discovery and precision medicine. Nat Rev Drug Discov 2016; 15: 473–484.
Google Scholar | Crossref | Medline | ISI31. Wishart, DS. Metabolomics for investigating physiological and pathophysiological processes. Physiol Rev 2019; 99: 1819–1875.
Google Scholar | Crossref | Medline32. Handelman, SK, Romero, R, Tarca, AL, Pacora, P, Ingram, B, Maymon, E, Chaiworapongsa, T, Hassan, SS, Erez, O. The plasma metabolome of women in early pregnancy differs from that of non-pregnant women. Plos One 2019; 14: e0224682.
Google Scholar | Crossref | Medline33. Watson, E, Reid, G. Metabolomics as a clinical testing method for the diagnosis of vaginal dysbiosis. Am J Reprod Immunol 2018; 80: e12979.
Google Scholar | Crossref | Medline34. Borgogna, JC, Shardell, MD, Santori, EK, Nelson, TM, Rath, JM, Glover, ED, Ravel, J, Gravitt, PE, Yeoman, CJ, Brotman, RM. The vaginal metabolome and microbiota of cervical HPV-positive and HPV-negative women: a cross-sectional analysis. BJOG 2020; 127: 182–192. 2019/11/22. DOI: 10.1111/1471-0528.15981.
Google Scholar | Crossref | Medline35. Romero, R, Mazaki-Tovi, S, Vaisbuch, E, Kusanovic, JP, Chaiworapongsa, T, Gomez, R, Nien, JK, Yoon, BH, Mazor, M, Luo, J, Banks, D, Ryals, J, Beecher, C. Metabolomics in premature labor: a novel approach to identify patients at risk for preterm delivery. J Matern-Fetal Neonatal Med 2010; 23: 1344–1359.
Google Scholar | Crossref | Medline | ISI36. Polat, IH, Marin, S, Rios, J, Larroya, M, Sanchez-Garcia, AB, Murillo, C, Rueda, C, Cascante, M, Gratacos, E, Cobo, T. Exploratory and confirmatory analysis to investigate the presence of vaginal metabolome expression of microbial invasion of the amniotic cavity in women with preterm labor using high-performance liquid chromatography. Am J Obstet Gynecol 2021; 224: 90.e1–90.e9.
Google Scholar | Crossref37. Miller, JS, Rodriguez-Saona, L, Hackshaw, KV. Metabolomics in central sensitivity syndromes. Metabolites 2020; 10: 164.
Google Scholar | Crossref38. Teckchandani, S, Nagana Gowda, GA, Raftery, D, Curatolo, M. Metabolomics in chronic pain research. Eur J Pain 2021; 25: 313–326.
Google Scholar | Crossref | Medline39. Tokarz, J, Haid, M, Cecil, A, Prehn, C, Artati, A, Moller, G, Adamski, J. Endocrinology meets metabolomics: achievements, pitfalls, and challenges. Trends Endocrinol Metab 2017; 28: 705–721.
Google Scholar | Crossref | Medline40. Alappattu, M, Robinson, M, Lamvu, G. Vulvodynia is not created equally: pain-related distress subgroups in vulvodynia. J Pain 2016; 17: S21.
Google Scholar | Crossref41. Rosen R, Brown C, Heiman I, Leiblum, Meston C, Shabsigh R, Ferguson D, D'Agostin Jr, R. The Femail Function Index (FSFI): a multidimensional self-report intrument for the assessment of female sexual funtion. J Sex Marital Therapy 2000; 26: 191–208.
Google Scholar42. Destrieux C, Fischl B, Dale A, Halgren E. Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature. Neuroimage 2010; 53: 1–15.
Google Scholar43. Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT, Albert MS, Killiany RJ. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 2006; 31: 968–980.
Google Scholar44. Hancock GR, Klockars AJ. The quest for alpha: developments in multiple comparison procedures in The Quarter century since games (1971). Rev Educ Res 1996; 66: 269–306.
Google Scholar45. Rosenthal R, Rosnow RL, Rubin DB. Contrasts and effect sizes in behavioral research: a correlational approach. Cambridge, UK: Cambridge University Press, 2000. p. 212.
Google Scholar46. Stockstill K, Doyle TM, Yan X, Chen Z, Janes K, Little JW, Braden K, Lauro F, Giancotti LA, Harada CM, Yadav R, Xiao WH, Lionberger JM, Neumann WL, Bennett GJ, Weng HR, Spiegel S, Salvemini D. Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain. J Exp Med 2018; 215: 1301–1313.
Google Scholar47. Wang MD, Rahman M, Zhu D, Johansson IM, Backstrom T. 3Beta-hydroxysteroids and pregnenolone sulfate inhibit recombinant rat GABA(A) receptor through different channel property. Eur J Pharmacol 2007; 557: 124–131.
Google Scholar48. Traish A , Bolanos J, Nair S, Saad F, Morgentaler A. Do androgens modulate the pathophysiological pathways of inflammation? Appraising the contemporary evidence. JCM 2018; 7: 549.
Google Scholar49. Hertel J, Konig J, Homuth G, Van der Auwera S, Wittfeld K, Pietzner M, Kacprowski T, Pfeiffer L, Kretschmer A, Waldenberger M, Kastenmller G, Artati A, Suhre K, Adamski J, Langner S, Volker U, Volzke H, Nauck M, Friedrich N, Grabe HJ. Evidence for stress-like alterations in the HPA-Axis in women taking oral contraceptives. Sci Rep-Uk 2017; 7: 14111.
Google Scholar

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