Catechol-O-methyltransferase gene polymorphism and vulvar pain in women with vulvodynia

Published:October 22, 2016DOI:


      The underlying causes of vulvar pain in women with vulvodynia remain poorly understood. Catechol-O-methyltransferase, an enzyme that metabolizes catecholamines, is a neuromodulator that is involved with perception and sensitivity to pain. The catechol-O-methyltransferase gene is polymorphic, and a single nucleotide polymorphism is associated with low activity and heightened pain sensitivity. The variant allele that encodes this polymorphism commonly is called the “L allele” because of its low enzyme activity as opposed to the normal H (high activity) allele.


      The methionine-containing catechol-O-methyltransferase protein coded by the L allele results in elevated catecholamine levels, reduced inactivation of the dopaminergic and adrenergic systems, and increased sensitivity to pain. This polymorphism not only may decrease the pain threshold in response to acute pain but also may facilitate the development of chronic pain. Therefore, the objective of our study was to assess whether a variation in the catechol-O-methyltransferase genotype is involved in increased pain sensitivity in women with vulvodynia.

      Study Design

      We conducted a prospective cohort study.


      Buccal swabs were collected from 167 white women with vulvodynia and 107 control subjects; the DNA was tested for a single nucleotide polymorphism at position 158 (rs4680) in the catechol-O-methyltransferase gene.


      Women with vulvodynia had a marginally increased, yet not significant, prevalence of the catechol-O-methyltransferase genotype that is associated with high activity of the coded protein: 32.9% in the women with vulvodynia, as opposed to 21.5% in the control subjects (odds ratio, 1.80; 95% confidence interval, 1.02–3.15). Subgrouping the cases based on pain frequency revealed that the elevated occurrence of this catechol-O-methyltransferase genotype was present in 40.6% of the subset of women who experienced pain only with sexual intercourse vs only 21.5% of control subjects (odds ratio, 2.50; 95% confidence interval, 1.27–4.93). Also, women with primary vulvodynia had a significantly higher prevalence of the H allele than did the control subjects (62.9% vs 48.1%; odds ratio, 1.82; 95% confidence interval, 1.05–3.17).


      Increased pain sensitivity in women with vulvodynia is not due to a genetically determined low catechol-O-methyltransferase enzyme activity. Other mechanisms may account for alterations in catechol-O-methyltransferase activity in women with pain that is limited to intercourse or primary vulvodynia that contributes to pain sensitivity.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Reed B.D.
        • Harlow S.D.
        • Sen A.
        • et al.
        Prevalence and demographic characteristics of vulvodynia in a population-based sample.
        Am J Obstet Gynecol. 2012; 206: 170.e1-170.e9
        • Harlow B.L.
        • Stewart E.G.
        A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia?.
        J Am Med Womens Assoc. 2003; 58: 82-88
        • Lamvu G.
        • Nguyen R.H.
        • Burrows L.J.
        • et al.
        The evidence-based vulvodynia assessment project. a national registry for the study of vulvodynia.
        J Reprod Med. 2015; 60: 223-235
        • Wesselmann U.
        • Bonham A.
        • Foster D.
        Vulvodynia: current state of the biological science.
        Pain. 2014; 155: 1696-1701
        • Ledger W.J.
        • Witkin S.S.
        Vulvovaginal infections.
        2nd Ed. CRC Press, Boca Raton (FL)2016
        • Cheung C.K.
        • Wu J.C.
        Genetic polymorphism in pathogenesis of irritable bowel syndrome.
        World J Gastroenterol. 2014; 20: 17693-17698
        • Matsuda J.B.
        • Barbosa F.R.
        • Morel L.J.
        • et al.
        Serotonin receptor (5-HT 2A) and catechol-O-methyltransferase (COMT) gene polymorphisms: triggers of fibromyalgia?.
        Rev Bras Rheumatol. 2010; 50: 141-149
        • Inanir A.
        • Karakus N.
        • Ates O.
        • et al.
        Clinical symptoms in fibromyalgia are associated to catechol-O-methyltransferase (COMT) gene Val158Met polymorphism.
        Xenobiotica. 2014; 44: 952-956
        • Smith S.B.
        • Maixner D.W.
        • Greenspan J.D.
        • et al.
        Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study.
        J Pain. 2011; 12: T92-T101
        • Babula O.
        • Danielsson I.
        • Sjoberg I.
        • Ledger W.J.
        • Witkin S.S.
        Altered distribution of mannose-binding lectin alleles at exon I codon 54 in women with vulvar vestibulitis syndrome.
        Am J Obstet Gynecol. 2004; 191: 762-766
        • Gerber S.
        • Bongiovanni A.M.
        • Ledger W.J.
        • Witkin S.S.
        Interleukin-1beta gene polymorphism in women with vulvar vestibulitis syndrome.
        Eur J Obstet Gynecol Reprod Biol. 2003; 107: 74-77
        • Gerber S.
        • Bongiovanni A.M.
        • Ledger W.J.
        • Witkin S.S.
        A deficiency in interferon-alpha production in women with vulvar vestibulitis.
        Am J Obstet Gynecol. 2002; 186: 361-364
        • Foster D.C.
        • Sazenski T.M.
        • Stodgell C.J.
        Impact of genetic variation in interleukin-1 receptor antagonist and melanocortin-1 receptor genes on vulvar vestibulitis syndrome.
        J Reprod Med. 2004; 49: 503-509
        • Goldstein A.T.
        • Belkin Z.R.
        • Krapf J.M.
        • et al.
        Polymorphisms of the androgen receptor gene and hormonal contraceptive induced provoked vestibulodynia.
        J Sex Med. 2014; 11: 2764-2771
        • Heddini U.
        • Bohm-Starke N.
        • Gronbladh A.
        • Nyberg F.
        • Nilsson K.W.
        • Johannesson U.
        Serotonin receptor gene (5HT-2A) polymorphism is associated with provoked vestibulodynia and comorbid symptoms of pain.
        J Sex Med. 2014; 11: 3064-3071
        • Lev-Sagie A.
        • Prus D.
        • Linhares I.M.
        • Lavy Y.
        • Ledger W.J.
        • Witkin S.S.
        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.e1-303.e6
        • Andersen S.
        • Skorpen F.
        Variation in the COMT gene: implications for pain perception and pain treatment.
        Pharmacogenomics. 2009; 10: 669-684
        • Zubieta J.K.
        • Heitzeg M.M.
        • Smith Y.R.
        • et al.
        COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor.
        Science. 2003; 299: 1240-1243
        • Lotta T.
        • Vidgren J.
        • Tilgmann C.
        • et al.
        Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme.
        Biochemistry. 1995; 34: 4202-4210
        • Fernandez-de-las-Penas C.
        • Ambite-Quesada S.
        • Rivas-Martinez I.
        • et al.
        Genetic contribution of catechol-O-methyltransferase polymorphism (Val158Met) in children with chronic tension-type headache.
        Pediatr Res. 2011; 70: 395-399
        • Hamajima N.
        • Matsuo K.
        • Tajima K.
        • et al.
        Limited association between a catechol-O-methyltransferase (COMT) polymorphism and breast cancer risk in Japan.
        Int J Clin Oncol. 2001; 6: 13-18
        • Axelrod J.
        • Inscoe J.K.
        • Senoh S.
        • Witkop B.
        O-methylation, the principal pathway for the metabolism of epinephrine and norepinephrine in the rat.
        Biochim Biophys Acta. 1958; 27: 210-211
        • Nackley A.G.
        • Shabalina S.A.
        • Lambert J.E.
        • et al.
        Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs.
        PloS One. 2009; 4: e5237
        • Nackley A.G.
        • Shabalina S.A.
        • Tchivileva I.E.
        • et al.
        Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure.
        Science. 2006; 314: 1930-1933
        • Belfer I.
        • Segall S.K.
        • Lariviere W.R.
        • et al.
        Pain modality- and sex-specific effects of COMT genetic functional variants.
        Pain. 2013; 154: 1368-1376
        • Tchivileva I.E.
        • Nackley A.G.
        • Qian L.
        • Wentworth S.
        • Conrad M.
        • Diatchenko L.B.
        Characterization of NF-kB-mediated inhibition of catechol-O-methyltransferase.
        Mol Pain. 2009; 5: 13
        • Yan Y.
        • Jiang W.
        • Liu L.
        • et al.
        Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome.
        Cell. 2015; 160: 62-73
        • Gerber S.
        • Bongiovanni A.M.
        • Ledger W.J.
        • Witkin S.S.
        Defective regulation of the proinflammatory immune response in women with vulvar vestibulitis syndrome.
        Am J Obstet Gynecol. 2002; 186: 696-700
        • Foster D.C.
        • Hasday J.D.
        Elevated tissue levels of interleukin-1 beta and tumor necrosis factor-alpha in vulvar vestibulitis.
        Obstet Gynecol. 1997; 89: 291-296
        • Ghosh S.
        • Dass J.F.
        Study of pathway cross-talk interactions with NF-kappaB leading to its activation via ubiquitination or phosphorylation: a brief review.
        Gene. 2016; 584: 97-109
        • Falsetta M.L.
        • Foster D.C.
        • Woeller C.F.
        • et al.
        Identification of novel mechanisms involved in generating localized vulvodynia pain.
        Am J Obstet Gynecol. 2015; 213: 38.e1-38.e12
        • Babula O.
        • Linhares I.M.
        • Bongiovanni A.M.
        • Ledger W.J.
        • Witkin S.S.
        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: 101.e1-101.e4
        • Bornstein J.
        • Maman M.
        • Abramovici H.
        “Primary” versus “secondary” vulvar vestibulitis: one disease, two variants.
        Am J Obstet Gynecol. 2001; 184: 28-31
        • Granot M.
        • Friedman M.
        • Yarnitsky D.
        • Tamir A.
        • Zimmer E.Z.
        Primary and secondary vulvar vestibulitis syndrome: systemic pain perception and psychophysical characteristics.
        Am J Obstet Gynecol. 2004; 191: 138-142
        • Hagen K.
        • Pettersen E.
        • Stovner L.J.
        • Skorpen F.
        • Zwart J.A.
        The association between headache and Val158Met polymorphism in the catechol-O-methyltransferase gene: the HUNT Study.
        J Headache Pain. 2006; 7: 70-74
        • Cargnin S.
        • Magnani F.
        • Viana M.
        • et al.
        An opposite-direction modulation of the COMT Val158Met polymorphism on the clinical response to intrathecal morphine and triptans.
        J Pain. 2013; 14: 1097-1106