Steroid Dysregulation and Stomatodynia (Burning Mouth Syndrome)

Stomatodynia (burning mouth syndrome) is characterized by a spontaneous, continuous burning pain felt in the oral mucosa typically of anxiodepressive menopausal women. Because there is no obvious organic cause, it is considered a nonspecific pain. This Focus Article proposes a hypothesis based on the following pathophysiological cascade: chronic anxiety or posttraumatic stress leads to a dysregulation of the adrenal production of steroids. One consequence is a decreased or a modified production of some major precursors for the neuroactive steroid synthesis occurring in the skin, mucosa, and nervous system. At menopause, the drastic fall of the other main precursor supply, the gonadal steroids, leads to a brisk alteration of the production of neuroactive steroids. This results in neurodegenerative alterations of small nerve fibers of the oral mucosa and/or some brain areas involved in oral somatic sensations. These neuropathic changes become irreversible and precipitate the burning pain, dysgeusia, and xerostomia associated with stomatodynia, which all involve thin nerve fibers.

adrenal steroid; burning mouth syndrome; functional pain; gonadal steroid; idiopathic orofacial pain; neuroactive steroids; neuropathic pain; stomatodynia

1. Fries E, Hesse J, Hellhammer J, Hellhammer DH. A new view on hypocortisolism. Psychoneuroendocrinology 2005;30:1010–1016.

2. Wessely S, Nimnuan C, Sharpe M. Functional somatic syndromes: One or many? Lancet 1999;354:936–939.

3. Woda A, Tubert-Jeannin S, Bouhassira D, et al. Towards a new taxonomy of idiopathic orofacial pain. Pain 2005;116:396–406.

4. Zakrzewska JM. The burning mouth syndrome remains an enigma. Pain 1995;62:253–257.

5. Woda A, Pionchon P. A unified concept of idopathic orofacial pain: Clinical features. J Orofac Pain 1999;13: 172–184.

6. Scala A, Checchi L, Montevecchi M, Marini I, Giamberardino MA. Update on burning mouth syndrome: Overview and patient management. Crit Rev Oral Biol Med 2003;14:275–291.

7. Granot M, Nagler RM. Association between regional idiopathic neuropathy and salivary involvement as the possi- ble mechanism for oral sensory complaints. J Pain 2005;6:581–587.

8. Maltsman-Tseikhin A, Moricca P, Niv D. Burning mouth syndrome: Will better understanding yield better management? Pain Pract 2007;7:151–162.

9. Lauria G, Majorana A, Borgna M, et al. Trigeminal small-fiber sensory neuropathy causes burning mouth syndrome. Pain 2005;115:332–337.

10. Yilmaz Z, Renton T, Yiangou Y, et al. Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci 2007;14:864–871.

11. Formaker BK, Mott AE, Frank ME. The effects of topical anesthesia on oral burning in burning mouth syndrome. Ann NY Acad Sci 1998;855:776–780.

12. Grémeau-Richard C, Woda A, Navez ML, et al. Topical clonazepam in stomatodynia: A randomised placebo-con- trolled study. Pain 2004;108:51–57.

13. Grushka M, Sessle BJ, Howley TP. Psychophysical assessment of tactile, pain, and thermal sensory functions in burning mouth syndrome. Pain 1987;28:169–184.

14. Svensson P, Bjerring P, Arendt-Nielsen L, Kaaber S. Sensory and pain thresholds to orofacial argon laser stimulation in patients with chronic burning mouth syndrome. Clin J Pain 1993;3:207–215.

15. Forssell H, Jaaskelainen S, Tenovuo O, Hinkka S. Sensory dysfunction in burning mouth syndrome. Pain 2002; 99:41–47.

16. Ito M, Kurita K, Ito T, Arao M. Pain threshold and pain recovery after experimental stimulation in patients with burning mouth syndrome. Psychiatry Clin Neurosci 2002;56:161–168.

17. Grushka M. Clinical features of burning mouth syndrome. Oral Surg Oral Med Oral Pathol 1987;63:30–36.

18. Grushka M, Sessle BJ. Taste dysfunction in burning mouth syndrome. Gerodontics 1988;4:256–258.

19. Formaker BK, Frank ME. Taste function in patients with oral burning. Chem Senses 2000;25:575–581.

20. Akal UK, Kucukyavuz Z, Nalcaci R, Yilmaz T. Evaluation of gustatory function after third molar removal. Int J Oral Maxillofac Surg 2004;6:564–568.

21. Boucher Y, Berteretche MV, Farahang F, Arvy MP, Azerad J, Faurion A. Taste deficit related to dental deafferentation: An electrogustometric study in humans. Eur J Oral Sci 2006;114:456–464.

22. Boucher Y, Simons CT, Faurion A, Azérad J, Carstens E. Trigeminal modulation of gustatory neurons in the nucleus of the solitary tract. Brain Res 2003;2:265–274.

23. Yanagisawa K, Bartoshuk LM, Catalanotto FA, Karrer TA, Kveton JF. Anesthesia of the chorda tympani nerve and taste phantoms. Physiol Behav 1998;63:329–335.

24. Jääskeläinen S, Forssell H, Tenovuo O. Abnormalities of the blink reflex in burning mouth syndrome. Pain 1997; 73:455–460.

25. Gao S, Wang Y, Wang Z. Assessment of trigeminal somatosensory evoked potentials in burning mouth syndrome. Chin J Dent Res 2000;3:40–46.

26. Heckmann SM, Heckmann JG, HiIz MJ, et al. Oral mucosal blood flow in patients with burning mouth syndrome. Pain 2001;90:281–286.

27. Nagler RN, Hershkovich O. Sialochemical and gustatory analysis in patients with oral sensory complaints. J Pain 2004;5:56–63.

28. Orstavik K, Weidner C, Schmidt R, et al. Pathological C- fibres in patients with a chronic painful condition. Brain 2003;126:567–578.

29. Hagelberg N, Forssell H, Aalto S, et al. Striatal D1 and D2 receptors in burning mouth syndrome. Pain 2003;101:149–154.

30. Jääskeläinen SK, Rinne JO, Forssell H, et al. Role of the dopaminergic system in chronic pain-a fluorodopa-PET study. Pain 2001;90:257–260.

31. Albuquerque RJ, de Leeuw R, Carlson CR, Okeson JP, Miller CS, Andersen AH. Cerebral activation during thermal stimulation of patients who have burning mouth disorder: An fMRI study. Pain 2006;122:223–234.

32. Grémeau-Richard C, Dubray C, Aublet-Cuvelier B, Ughetto S, Woda A. Effect of lingual nerve block on stomatodynia (burning mouth syndrome). A randomized crossover trial. Pain (in press).

33. Lamey PJ, Freeman R, Eddie SA, Pankhurst C, Rees T. Vulnerability and presenting symptoms in burning mouth syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:48–54.

34. Woda A, Pionchon P. A unified concept of idiopathic orofacial pain: Pathophysiologic features. J Orofac Pain 2000;14:196–212.

35. Ferguson M, Carter J, Boyle P, Hart D, Lindsay R. Oral complaints related to climacteric symptoms in oöphorectomized women. J R Soc Med 1981;74:492–498.

36. Bergdahl M, Bergdahl J. Burning mouth syndrome: Prevalence and associated factors. J Oral Pathol Med 1999;28:350–354.

37. Feinmann C, Harris M, Cawley R. Psychogenic facial pain: Presentation and treatment. Br Med J 1984;288: 436–438.

38. Bogetto F, Maina G, Ferro G, Carbone M, Gandolfo S. Psychiatric comorbidity in patients with burning mouth syndrome. Psychosom Med 1998;60:378–385.

39. Eli I, Kleinhauz M, Baht R, Littner M. Antecedents of burning mouth syndrome (glossodynia). Recent life events vs. psychopathologic aspects. J Dent Res 1994;73: 567–572.

40. Grushka M, Sessle BJ. Burning mouth syndrome. Dent Clin North Am 1991;35:171–184.

41. Pokupec-Gruden JS, Cekic-Arambasin A, Gruden V. Psychogenic factors in the aetiology of stomatopyrosis. Coll Antropol 2000;24:119–126.

42. Rojo L, Silvestre FJ, Bagan JV, De Vicente T. Prevalence of psychopathology in burning mouth syndrome. A comparative study among patients with and without psychiatric disorders and controls. Oral Surg Oral Med Oral Pathol 1994;78:312–316.

43. Van der Ploeg HM, Van der Wal N, Eijkman MAJ, Van der Waal I. Psychological aspects of patients with burning mouth syndrome. Oral Surg Oral Med Oral Pathol 1987;63:664–668.

44. Zilli C, Brooke RI, Lau CL. Screening for psychiatric illness in patients with oral dysesthesia by means of the general health questionnaire-twenty-eight item version (GHQ-28) and the irritability, depression, and anxiety scale (IDA). Oral Surg Oral Med Oral Pathol 1989;67: 384–389.

45. Hammaren M, Hugoson A. Clinical psychiatric assessment of patients with burning mouth syndrome resisting oral treatment. Swed Dent J 1989;13:77–88.

46. Essex MJ, Klein MH, Cho E, Kalin NH. Maternal stress beginning in infancy may sensitize children to later stress exposure: Effects on cortisol and behavior. Biol Psychiatry 2002;52:776–784.

47. Biondi M, Picardi A. Psychological stress and neuroendocrine function in humans: The last two decades of research. Psychother Psychosom 1999;68:114–150.

48. Jogems-Kosterman BJ, de Knijff DW, Kusters R, van Hoof JJ. Basal cortisol and DHEA levels in women with borderline personality disorder. J Psychiatr Res 2007;41: 1019–1026.

49. Rinne T, de Kloet ER, Wouters L, Goekoop JG, de Rijk RH, van den Brink W. Hyperresponsiveness of hypothalamic-Pituitary-adrenal axis to combined dexamethasone/ corticotropin-releasing hormone challenge in female borderline personality disorders subjects with a history of sustained childhood abuse. Biol Psychiatry 2002;52: 1102–1112.

50. Rinne T, de Kloet ER, Wouters L, Goekoop JG, de Rijk RH, van den Brink W. Fluvoxamine reduces responsiveness of HPA axis in adult female BPD patients with a history of sustained childhood abuse. Neuropsycho- pharmacology 2003;28:126–132.

51. Yehuda R. Biology of posttraumatic stress disorder. J Clin Psychiatry 2001;62(suppl 17):41–46.

52. Amenábar JM, Pawlowski J, Hilgert JB, et al. Anxiety and salivary cortisol levels in patients with burning mouth syndrome: Case-control study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:460–465.

53. Heuser I, Lammers CH. Stress and the brain. Neurobiol Aging 2003;24(suppl 1):S69–S76.

54. Ritsner M, Maayan R, Gibel A, Strous RD, Modai I, Weizman A. Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients. Eur Neuropsychopharmacol 2004;14:267–273.

55. Tafet GE, Bernardini R. Psychoneuroendocrinological links between chronic stress and depression. Prog Neuropsychopharmacol Bio Psychiatry 2003;27:893–903.

56. Belanoff JK, Rothschild AJ, Cassidy F, et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry 2002;52:381–385.

57. Heuser I, Bissette G, Dettling M, et al. Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: Response to amitriptyline treatment. Depress Anxiety 1998;8:71–79.

58. Kahl KG, Bens S, Ziegler K, et al. Cortisol, the cortisoldehydroepiandrosterone ratio, and pro-inflammatory cytokines in patients with current major depressive disorder comorbid with borderline personality disorder. Biol Psychiatry 2006;59:667–671.

59. Parker KJ, Schatzberg AF, Lyons DM. Neuroendocrine aspects of hypercortisolism in major depression. Horm Behav 2003;43:60–66.

60. Tse WS, Bond AJ. Relationship between baseline cortisol, social functioning, and depression: A mediation analysis. Psychiatry Res 2004;126:197–201.

61. Hoelsboer F. Neuroendocrinology of mood disorders. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, 1995:957–970.

62. Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 2005;4:141–194.

63. Gervasoni N, Bertschy G, Osiek C, et al. Cortisol responses to combined dexamethasone/CRH test in outpatients with a major depressive episode. J Psychiatr Res 2004;38: 553–557.

64. Rubin RT, Phillips JJ. Adrenal gland enlargement in major depression. Arch Gen Psychiatry 1993;50:833–835.

65. Gameiro GH, da Silva Andrade A, Nouer DF, Ferraz de Arruda Veiga MC. How may stressful experiences contribute to the development of temporomandibular disorders. Clin Oral Investig 2006;10:261–268.

66. Kanter ED, Wilkinson CW, Radant AD, et al. Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder. Biol Psychiatry 2001;50:238–245.

67. Mason JW, Wang S, Yehuda R, Riney S, Charney DS, Southwick SM. Psychogenic lowering of urinary cortisol levels linked to increased emotional numbing and a shame-depressive syndrome in combat-related posttraumatic stress disorder. Psychosom Med 2001;63:387–401.

68. Kellner M, Yehuda R, Arlt J, Wiedemann K. Longitudinal course of salivary cortisol in post-traumatic stress disorder. Acta Psychiatr Scand 2002;105:153–156.

69. Hakeberg M, Hallberg LRM, Berggren U. Burning mouth syndrome: Experiences from the perspective of female patients. Eur J Oral Sci 2003;111:305–311.

70. de Leeuw R, Bertoli E, Schmidt JE Carlson CR. Prevalence of post-traumatic stress disorder symptoms in orofacial pain patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:558–568.

71. Labrie F, Luu-The V, Labrie C, et al. Endocrine and intracrine sources of androgens in women: Inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev 2003;24: 152–182.

72. Gago N, El-Etr M, Sananes N, et al. 3a,5a-Tetra- hydroprogesterone (allopregnanolone) and -y-aminobutyric acid: Autocrine/paracrine interactions in the control of neonatal PSA-NCAM+ progenitor proliferation. J Neurosci Res 2004;78:770–783.

73. Mameli M, Carta M, Partridge LD, Valenzuela CF. Neurosteroid-induced plasticity of immature synapses via retrograde modulation of presynaptic NMDA receptors. J Neurosci 2005;25:2285–2294.

74. Rune GM, Frotscher M. Neurosteroid synthesis in the hippocampus: Role in synaptic plasticity. Neuroscience 2005;136:833–842.

75. Belelli D, Herd MB, Mitchell EA, et al. Neuroactive steroids and inhibitory neurotransmission: Mechanisms of action and physiological relevance. Neuroscience 2006;138:821–829.

76. Baulieu EE. Neurosteroids: A novel function of the brain. Psychoneuroendocrinology 1998;23:963–987.

77. Dubrovsky BO. Steroids, neuroactives steroids, and neurosteroids in psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:169–192.

78. Mellon SH, Griffin LD. Neurosteroids: Biochemistry and clinical significance. Trends Endocrinol Metab 2002;13:35–43.

79. Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992;6:2311–2322.

80. Rupprecht R. Neuroactive steroids: Mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology 2003;28:139–168.

81. Rupprecht R, Holsboer F. Neuroactive steroids: Mechanisms of action and neuropsychopharmacological perspectives. Trend Neurosci 1999;22:410–416.

82. Baulieu EE. Steroid hormones in the brain: Several mechanisms. In: Fuxe K, Gustafson JA, Wetterberg L (eds). Steroid Hormones Regulation of the Brain. Elmsford, NY: Pergamon, 1981:3–14.

83. Corpechot C, Synguelakis M, Talha S, et al. Pregnenolone and its sulfate ester in the rat brain. Brain Res 1983;270: 119–125.

84. Papadopoulos V. Peripheral-type benzodiazepine/ diazepam binding inhibitor receptor: Biological role in steroidogenic cell function. Endoc Rev 1993;14:222–240.

85. Melcangi RC, Cavarretta IT, Ballabio M, et al. Peripheral nerves: A target for the action of neuroactive steroids. Brain Res Rev 2005;48:328–338.

86. Belelli D, Lambert JJ. Neurosteroids: Endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci 2005; 6:565–575.

87. Azcoitia I, Leonelli E, Magnaghi V, Veiga S, Garcia- Segura LM, Melcangi RC. Progesterone and its derivatives dihydroprogesterone and tetrahydroprogesterone reduce myelin fiber morphological abnormalities and myelin fiber loss in the sciatic nerve of aged rats. Neurobiol Aging 2003;24:853–860.

88. Raval AP, Bramlett H, Perez-Pinzon MH. Estrogen pre- conditioning protects the hippocampal CA1 against ischemia. Neuroscience 2006;141:1721–1730.

89. Sayeed I, Guo Q, Hoffman SW, Stein DG. Allopregnanolone, a progesterone metabolite, is more effective than progesterone in reducing cortical infarct volume after transient middle cerebral artery occlusion. Ann Emerg Med 2006;47:381–389.

90. Schumacher M, Weill-Engerer S, Liere P, et al. Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog Neurobiol 2003;71: 3–29.

91. di Michele F, Lekieffre D, Pasini A, Bernardi G, Benavides J, Romeo E. Increased neurosteroids synthesis after brain and spinal cord injury in rats. Neurosci Lett 2000;284: 65–68.

92. Labombarda F, Gonzalez S, Gonzalez Deniselle MC, et al. Progesterone increases the expression of myelin basic protein and the number of cells showing NG2 immunostain- ing in the lesioned spinal cord. J Neurotrauma 2006;23:181–192.

93. Melcangi RC, Azcoitia I, Ballabio M, et al. Neuroactive steroids influence peripheral myelination: A promising opportunity for preventing or treating age-dependent dysfunctions of peripheral nerves. Prog Neurobiol 2003;371:57–66.

94. Lapchak PA, Araujo DM. Preclinical development of neurosteroids as neuroprotective agents for the treatment of neurodegenerative diseases. Int Rev Neurobiol 2001;46:379–397.

95. Seckl JR, Olsson T. Glucocorticoid hypersecretion and the age-impaired hippocampus: Cause or effect? J Endocrinol 1995;145:201–211.

96. Marklund N, Peltonen M, Nilsson TK, Olsson T. Low and high circulating cortisol levels predict mortality and cognitive dysfunction early after stroke. J Intern Med 2004;256:15–21.

97. Akama KT, McEwen BS. Gene therapy to bet on: Protecting neurons from stress hormones. Trends Pharmacol Sci 2005;4:169–172.

98. Kaufer D, Ogle WO, Pincus ZS, et al. Restructuring the neuronal stress response with anti-glucocorticoid gene delivery. Nat Neurosci 2004;9:947–953.

99. McEwen BS. Glucocorticoids, depression, and mood disorders: Structural remodeling in the brain. Metabolism 2005;57(5 suppl):20–23.

100. Sapolsky RM, McEwen BS. Stress, glucocorticoids, and their role in degenerative changes in the aging hippocampus. In: Crook T, Bartens RT, Ferris S, Gershon S (eds). Treatment Development Strategies for Alzheimer’s Disease. New Canaan, CT: Marc Powley, 1986:151–171.

101. Bartoshuk LM, Snyder DJ, Grushka M, Berger AM, Duffy V, Kveton JF. Taste damage: Previously unsuspected consequences. Chem Senses 2005;30(suppl 1):218–219.

102. Pajot J, Ressot C, Ngom I, Woda A. Gonadectomy induces site-specific differences in nociception in rats. Pain 2003;104:367–373.

103. Seko K, Kagami H, Senga K, Ozeki K, Mizutani H, Ueda

M. Effects of ovariectomy and estrogen replacement on rat oral mucosa. Maturitas 2005;50:44–51.

104. Treister NS, Richards SM, Rowley P, Jensen RV, Sullivan DA. Influence of testosterone on gene expression in the ovariectomized mouse submandibular gland. Eur J Oral Sci 2006;114:328–336.

105. Pisanty S, Rafaely B, Polishuk WZ. The effect of steroid hormones on buccal mucosa of menopausal women. Oral Med 1975;40:346–353.

106. Basker RM, Sturdee DW, Davenport JC. Patients with burning mouths: A clinical investigation of causative factors, including the climacteric and diabetes. Br Dent J 1978;145:9–16.

107. Wardrop RW, Hailes J, Burger H, Reade PC. Oral discomfort at menopause. Oral Surg Oral Med Oral Pathol 1989;67:535–540.

108. Forabosco A, Criscuolo M, Coukos G. Efficacy of hormone replacement therapy in postmenopausal women with oral discomfort. Oral Surg Oral Med Oral Pathol 1992;73:570–574.