Stress and Glucocorticoid Action in the Brain and Ear: Implications for Tinnitus

  • E. R. de Kloet
  • Agnieszka J. SzczepekEmail author


This contribution highlights the role of stress and cortisol in tinnitus. Firstly, stressors such as loud noise, infection, and injury can cause hearing loss and tinnitus pathology. Secondly, stress-induced cortisol levels are decreased in individuals with tinnitus with consequences for functioning of the inner ear, the central auditory system, and its targets in the limbic brain circuit relevant for processing of stressful acoustic information. Thirdly, the phantom sound experienced by the tinnitus patient eventually may precipitate signs of a stress-related disorder. The chapter concludes with options to exploit cortisol action for tinnitus management.


Tinnitus Stress Brain Corticosteroids Mineralocorticoid receptors Glucocorticoid receptors 



The support to ER de Kloet by the Royal Netherlands Academy of Arts and Sciences, COST Action ADMIRE BM1301 and STW Take-off 14095 is gratefully acknowledged.

AJ Szczepek thankfully acknowledges the research support of Dürr Foundation and the German Tinnitus Foundation.

Declaration of Interest

E R. de Kloet is on the scientific advisory Board of Dynacorts Therapeutics and Pharmaseed Ltd. and owns stock of Corcept Therapeutics. The current paper bears no relationship to these interests.


  1. Akiyama K, Miyashita T, Matsubara A, Inamoto R, Mori T, Nishiyama A, Mori N (2010) Expression and localization of 11beta-hydroxysteroid dehydrogenase (11betaHSD) in the rat endolymphatic sac. Acta Otolaryngol 130:228–232PubMedCrossRefGoogle Scholar
  2. Araujo MF, Oliveira CA, Bahmad FM Jr (2005) Intratympanic dexamethasone injections as a treatment for severe, disabling tinnitus: does it work? Arch Otolaryngol Head Neck Surg 131(2):113–117. doi: 10.1001/archotol.131.2.113 PubMedCrossRefGoogle Scholar
  3. Barreto MA, Silva IB, de Oliveira CA, Bahmad F Jr (2012) Intratympanic corticotherapy and tinnitus control after sudden hearing loss. Int Tinnitus J 17:186–193PubMedCrossRefGoogle Scholar
  4. Barrett CE, Arambula SE, Young LJ (2015) The oxytocin system promotes resilience to the effects of neonatal isolation on adult social attachment in female prairie voles. Transl Psychiatry 5:e606PubMedPubMedCentralCrossRefGoogle Scholar
  5. Basappa J, Graham CE, Turcan S, Vetter DE (2012) The cochlea as an independent neuroendocrine organ: expression and possible roles of a local hypothalamic-pituitary-adrenal axis-equivalent signaling system. Hear Res 288:3–18PubMedPubMedCentralCrossRefGoogle Scholar
  6. van den Berg DT, de Kloet ER, van Dijken HH, de Jong W (1990) Differential central effects of mineralocorticoid and glucocorticoid agonists and antagonists on blood pressure. Endocrinology 126:118–124PubMedCrossRefGoogle Scholar
  7. Betancur C, Borrell J, Guaza C (1995) Cytokine regulation of corticosteroid receptors in the rat hippocampus: effects of interleukin-1, interleukin-6, tumor necrosis factor and lipopolysaccharide. Neuroendocrinology 62:47–54PubMedCrossRefGoogle Scholar
  8. Bogdan R, Perlis RH, Fagerness J, Pizzagalli DA (2010) The impact of mineralocorticoid receptor iso/val genotype (rs5522) and stress on reward learning. Genes Brain Behav 9:658–667PubMedPubMedCentralGoogle Scholar
  9. Bogdan R, Williamson DE, Hariri AR (2012) Mineralocorticoid receptor iso/val (rs5522) genotype moderates the association between previous childhood emotional neglect and amygdala reactivity. Am J Psychiatry 169:515–522PubMedPubMedCentralCrossRefGoogle Scholar
  10. Cabib S, Puglisi-Allegra S (2012) The mesoaccumbens dopamine in coping with stress. Neurosci Biobehav Rev 36:79–89PubMedCrossRefGoogle Scholar
  11. Cannon WB (1939) The wisdom of the body, Rev. and enlarged edn. Norton, New YorkGoogle Scholar
  12. Carroll BJ, Curtis GC, Mendels J (1976) Neuroendocrine regulation in depression. II. Discrimination of depressed from nondepressed patients. Arch Gen Psychiatry 33:1051–1058PubMedCrossRefGoogle Scholar
  13. Chapman K, Holmes M, Seckl J (2013) 11beta-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev 93:1139–1206PubMedPubMedCentralCrossRefGoogle Scholar
  14. Choi SJ, Lee JB, Lim HJ, In SM, Kim JY, Bae KH, Choung YH (2013) Intratympanic dexamethasone injection for refractory tinnitus: prospective placebo-controlled study. Laryngoscope 123(11):2817–2822. doi: 10.1002/lary.24126 PubMedCrossRefGoogle Scholar
  15. Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267:1244–1252PubMedCrossRefGoogle Scholar
  16. Dallman MF (2010) Stress-induced obesity and the emotional nervous system. Trends Endocrinol Metab 21:159–165PubMedCrossRefGoogle Scholar
  17. Dallman MF, Hellhammer DH (2011) Regulation of the hypothalamo-pituitary-adrenal axis, chronic stress, and energy: the role of brain networks. Springer, New YorkGoogle Scholar
  18. Datson NA, van den Oever JM, Korobko OB, Magarinos AM, de Kloet ER, McEwen BS (2013) Previous history of chronic stress changes the transcriptional response to glucocorticoid challenge in the dentate gyrus region of the male rat hippocampus. Endocrinology 154:3261–3272PubMedPubMedCentralCrossRefGoogle Scholar
  19. Day TA (2005) Defining stress as a prelude to mapping its neurocircuitry: no help from allostasis. Prog Neuro-Psychoph 29:1195–1200CrossRefGoogle Scholar
  20. De Maria R, Landolina M, Gasparini M, Schmitz B, Campolo J, Parolini M, Sanzo A, Galimberti P, Bianchi M, Brand SM, Parodi O, Lunati M (2012) Genetic variants of the renin-angiotensin-aldosterone system and reverse remodeling after cardiac resynchronization therapy. J Card Fail 18:762–768PubMedCrossRefGoogle Scholar
  21. Dehmel S, Cui YL, Shore SE (2008) Cross-modal interactions of auditory and somatic inputs in the brainstem and midbrain and their imbalance in tinnitus and deafness. Am J Audiol 17:S193–S209PubMedPubMedCentralCrossRefGoogle Scholar
  22. DeRijk RH, Wust S, Meijer OC, Zennaro MC, Federenko IS, Hellhammer DH, Giacchetti G, Vreugdenhil E, Zitman FG, de Kloet ER (2006) A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness. J Clin Endocrinol Metab 91:5083–5089PubMedCrossRefGoogle Scholar
  23. Di S, Malcher-Lopes R, Halmos KC, Tasker JG (2003) Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23:4850–4857PubMedGoogle Scholar
  24. Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, Costa RM, Sousa N (2009) Chronic stress causes frontostriatal reorganization and affects decision-making. Science 325:621–625PubMedCrossRefGoogle Scholar
  25. Dodson KM, Sismanis A (2004) Intratympanic perfusion for the treatment of tinnitus. Otolaryngol Clin N Am 37:991–1000CrossRefGoogle Scholar
  26. Dogan R, Meric A, Gedik O, Tugrul S, Eren SB, Ozturan O (2015) Does systemic steroid deficiency affect inner ear functions? Am J Otolaryngol 36:568–574PubMedCrossRefGoogle Scholar
  27. Edwards CR, Stewart PM, Burt D, Brett L, McIntyre MA, Sutanto WS, de Kloet ER, Monder C (1988) Localisation of 11 beta-hydroxysteroid dehydrogenase—tissue specific protector of the mineralocorticoid receptor. Lancet 2:986–989PubMedCrossRefGoogle Scholar
  28. Evans RM, Arriza JL (1989) A molecular framework for the actions of glucocorticoid hormones in the nervous system. Neuron 2:1105–1112PubMedCrossRefGoogle Scholar
  29. Fagelson MA (2007) The association between tinnitus and posttraumatic stress disorder. Am J Audiol 16:107–117PubMedCrossRefGoogle Scholar
  30. Ferguson D, Sapolsky R (2007) Mineralocorticoid receptor overexpression differentially modulates specific phases of spatial and nonspatial memory. J Neurosci 27:8046–8052PubMedCrossRefGoogle Scholar
  31. Funder JW (2015) Primary aldosteronism: seismic shifts. J Clin Endocrinol Metab 100:2853–2855PubMedCrossRefGoogle Scholar
  32. Funder JW, Pearce PT, Smith R, Smith AI (1988) Mineralocorticoid action—target tissue-specificity is enzyme, not receptor, mediated. Science 242:583–585PubMedCrossRefGoogle Scholar
  33. Geerling JC, Loewy AD (2009) Aldosterone in the brain. Am J Physiol Renal Physiol 297:F559–F576PubMedPubMedCentralCrossRefGoogle Scholar
  34. Georgiewa P, Szczepek AJ, Rose M, Klapp BF, Mazurek B (2016) Cerebral processing of emotionally loaded acoustic signals by tinnitus patients. Audiol Neurootol 21:80–87PubMedCrossRefGoogle Scholar
  35. Groch S, Wilhelm I, Lange T, Born J (2013) Differential contribution of mineralocorticoid and glucocorticoid receptors to memory formation during sleep. Psychoneuroendocrinology 38:2962–2972PubMedCrossRefGoogle Scholar
  36. Hamstra DA, de Kloet ER, van Hemert AM, de Rijk RH, Van der Does AJ (2015) Mineralocorticoid receptor haplotype, oral contraceptives and emotional information processing. Neuroscience 286:412–422PubMedCrossRefGoogle Scholar
  37. Harris AP, Holmes MC, de Kloet ER, Chapman KE, Seckl JR (2013) Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour. Psychoneuroendocrinology 38:648–658PubMedCrossRefGoogle Scholar
  38. Hasegawa J, Hidaka H, Kuriyama S, Obara T, Hashimoto K, Tateda Y, Okumura Y, Kobayashi T, Katori Y (2015) Change in and long-term investigation of neuro-otologic disorders in disaster-stricken Fukushima prefecture: retrospective cohort study before and after the great East Japan earthquake. PLoS One 10:e0122631PubMedPubMedCentralCrossRefGoogle Scholar
  39. Hebert S, Lupien SJ (2007) The sound of stress: blunted cortisol reactivity to psychosocial stress in tinnitus sufferers. Neurosci Lett 411:138–142PubMedCrossRefGoogle Scholar
  40. Hebert S, Canlon B, Hasson D (2012) Emotional exhaustion as a predictor of tinnitus. Psychother Psychosom 81:324–326PubMedCrossRefGoogle Scholar
  41. Henkin RI, Daly RL (1968) Auditory detection and perception in normal man and in patients with adrenal cortical insufficiency: effect of adrenal cortical steroids. J Clin Invest 47:1269–1280PubMedPubMedCentralCrossRefGoogle Scholar
  42. Herman JP (2013) Neural control of chronic stress adaptation. Front Behav Neurosci 7:61PubMedPubMedCentralCrossRefGoogle Scholar
  43. Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol 24:151–180PubMedCrossRefGoogle Scholar
  44. Hermans EJ, Henckens MJ, Joels M, Fernandez G (2014) Dynamic adaptation of large-scale brain networks in response to acute stressors. Trends Neurosci 37:304–314PubMedCrossRefGoogle Scholar
  45. Heuser I, Yassouridis A, Holsboer F (1994) The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J Psychiatr Res 28:341–356PubMedCrossRefGoogle Scholar
  46. Hinton DE, Chhean D, Pich V, Hofmann SG, Barlow DH (2006) Tinnitus among cambodian refugees: relationship to PTSD severity. J Trauma Stress 19:541–546PubMedCrossRefGoogle Scholar
  47. Hobson CE, Alexander TH, Harris JP (2016) Primary treatment of idiopathic sudden sensorineural hearing loss with intratympanic dexamethasone. Curr Opin Otolaryngol Head Neck Surg 24(5):407–412PubMedCrossRefGoogle Scholar
  48. Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23:477–501PubMedCrossRefGoogle Scholar
  49. ter Horst JP, van der Mark MH, Arp M, Berger S, de Kloet ER, Oitzl MS (2012) Stress or no stress: mineralocorticoid receptors in the forebrain regulate behavioral adaptation. Neurobiol Learn Mem 98:33–40PubMedCrossRefGoogle Scholar
  50. Jaisser F, Farman N (2016) Emerging roles of the mineralocorticoid receptor in pathology: toward new paradigms in clinical pharmacology. Pharmacol Rev 68:49–75PubMedCrossRefGoogle Scholar
  51. Joels M, Baram TZ (2009) The neuro-symphony of stress. Nat Rev Neurosci 10:459–466PubMedPubMedCentralGoogle Scholar
  52. Joels M, de Kloet ER (1989) Effects of glucocorticoids and norepinephrine on the excitability in the hippocampus. Science 245:1502–1505PubMedCrossRefGoogle Scholar
  53. Joels M, de Kloet ER (1990) Mineralocorticoid receptor-mediated changes in membrane properties of rat CA1 pyramidal neurons in vitro. Proc Natl Acad Sci USA 87:4495–4498PubMedPubMedCentralCrossRefGoogle Scholar
  54. Joels M, de Kloet ER (1992) Control of neuronal excitability by corticosteroid hormones. Trends Neurosci 15:25–30PubMedCrossRefGoogle Scholar
  55. Joels M, de Kloet ER (2012) Nothing is written in stone. Biol Psychiatry 72:432–433PubMedCrossRefGoogle Scholar
  56. Joels M, Karst H, DeRijk R, de Kloet ER (2008) The coming out of the brain mineralocorticoid receptor. Trends Neurosci 31:1–7PubMedCrossRefGoogle Scholar
  57. Joels M, Sarabdjitsingh RA, Karst H (2012) Unraveling the time domains of corticosteroid hormone influences on brain activity: rapid, slow, and chronic modes. Pharmacol Rev 64:901–938PubMedCrossRefGoogle Scholar
  58. Kanatsou S, Fearey BC, Kuil LE, Lucassen PJ, Harris AP, Seckl JR, Krugers H, Joels M (2015) Overexpression of mineralocorticoid receptors partially prevents chronic stress-induced reductions in hippocampal memory and structural plasticity. PLoS One 10:e0142012PubMedPubMedCentralCrossRefGoogle Scholar
  59. Karssen AM, Meijer OC, van der Sandt IC, Lucassen PJ, de Lange EC, de Boer AG, de Kloet ER (2001) Multidrug resistance p-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. Endocrinology 142:2686–2694PubMedCrossRefGoogle Scholar
  60. Karssen AM, Meijer OC, van der Sandt IC, De Boer AG, De Lange EC, de Kloet ER (2002) The role of the efflux transporter p-glycoprotein in brain penetration of prednisolone. J Endocrinol 175:251–260PubMedCrossRefGoogle Scholar
  61. Karssen AM, Meijer OC, Berry A, Sanjuan Pinol R, de Kloet ER (2005) Low doses of dexamethasone can produce a hypocorticosteroid state in the brain. Endocrinology 146:5587–5595PubMedCrossRefGoogle Scholar
  62. Karst H, Berger S, Turiault M, Tronche F, Schutz G, Joels M (2005) Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci USA 102:19204–19207PubMedPubMedCentralCrossRefGoogle Scholar
  63. Karst H, Berger S, Erdmann G, Schutz G, Joels M (2010) Metaplasticity of amygdalar responses to the stress hormone corticosterone. Proc Natl Acad Sci USA 107:14449–14454PubMedPubMedCentralCrossRefGoogle Scholar
  64. Kil SH, Kalinec F (2013) Expression and dexamethasone-induced nuclear translocation of glucocorticoid and mineralocorticoid receptors in guinea pig cochlear cells. Hear Res 299:63–78PubMedPubMedCentralCrossRefGoogle Scholar
  65. Kirby SE, Yardley L (2008) Understanding psychological distress in meniere’s disease: a systematic review. Psychol Health Med 13:257–273PubMedCrossRefGoogle Scholar
  66. de Kloet ER (1991) Brain corticosteroid receptor balance and homeostatic control. Front Neuroendocrinol 12:95–164Google Scholar
  67. de Kloet ER (1997) Why dexamethasone poorly penetrates in brain. Stress 2:13–20PubMedCrossRefGoogle Scholar
  68. de Kloet ER (2014) From receptor balance to rational glucocorticoid therapy. Endocrinology 155:2754–2769PubMedCrossRefGoogle Scholar
  69. de Kloet ER, Reul JM (1987) Feedback action and tonic influence of corticosteroids on brain function: a concept arising from the heterogeneity of brain receptor systems. Psychoneuroendocrinology 12:83–105PubMedCrossRefGoogle Scholar
  70. de Kloet ER, Joels M (2016) Stress research: past, present, and future. In: Pfaff DW (ed) Neuroscience in the 21st century from basic to clinical. Springer, New York, pp 1979–2007Google Scholar
  71. de Kloet ER, Molendijk ML (2016) Coping with the forced swim stressor: towards understanding an adaptive mechanism. Neural Plast 2016:6503162PubMedPubMedCentralCrossRefGoogle Scholar
  72. de Kloet ER, van der Vies J, de Wied D (1974) The site of the suppressive action of dexamethasone on pituitary-adrenal activity. Endocrinology 94:61–73PubMedCrossRefGoogle Scholar
  73. de Kloet R, Wallach G, McEwen BS (1975) Differences in corticosterone and dexamethasone binding to rat brain and pituitary. Endocrinology 96:598–609PubMedCrossRefGoogle Scholar
  74. de Kloet ER, Joels M, Oitzl M, Sutanto W (1991) Implication of brain corticosteroid receptor diversity for the adaptation syndrome concept. Methods Achiev Exp Pathol 14:104–132PubMedGoogle Scholar
  75. de Kloet ER, Oitzl MS, Schobitz B (1994) Cytokines and the brain corticosteroid receptor balance: relevance to pathophysiology of neuroendocrine-immune communication. Psychoneuroendocrinology 19:121–134PubMedCrossRefGoogle Scholar
  76. de Kloet ER, Vreugdenhil E, Oitzl MS, Joels M (1998) Brain corticosteroid receptor balance in health and disease. Endocr Rev 19:269–301PubMedGoogle Scholar
  77. de Kloet ER, Van Acker SA, Sibug RM, Oitzl MS, Meijer OC, Rahmouni K, de Jong W (2000) Brain mineralocorticoid receptors and centrally regulated functions. Kidney Int 57:1329–1336PubMedCrossRefGoogle Scholar
  78. de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475PubMedCrossRefGoogle Scholar
  79. de Kloet ER, Otte C, Kumsta R, Kok L, Hillegers MH, Hasselmann H, Kliegel D, Joels M (2016) Stress and depression: a crucial role of the mineralocorticoid receptor. J Neuroendocrinol. doi: 10.1111/jne.12379
  80. Klok MD, Giltay EJ, Van der Does AJ, Geleijnse JM, Antypa N, Penninx BW, de Geus EJ, Willemsen G, Boomsma DI, van Leeuwen N, Zitman FG, de Kloet ER, DeRijk RH (2011) A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females. Transl Psychiatry 1:e62PubMedPubMedCentralCrossRefGoogle Scholar
  81. Knipper M, Van Dijk P, Nunes I, Ruttiger L, Zimmermann U (2013) Advances in the neurobiology of hearing disorders: recent developments regarding the basis of tinnitus and hyperacusis. Prog Neurobiol 111:17–33PubMedCrossRefGoogle Scholar
  82. Koolhaas JM, Bartolomucci A, Buwalda B, de Boer SF, Flugge G, Korte SM, Meerlo P, Murison R, Olivier B, Palanza P, Richter-Levin G, Sgoifo A, Steimer T, Stiedl O, van Dijk G, Wohr M, Fuchs E (2011) Stress revisited: a critical evaluation of the stress concept. Neurosci Biobehav Rev 35:1291–1301PubMedCrossRefGoogle Scholar
  83. Korte SM, Buwalda B, Meijer O, De Kloet ER, Bohus B (1995) Socially defeated male rats display a blunted adrenocortical response to a low dose of 8-OH-DPAT. Eur J Pharmacol 272:45–50PubMedCrossRefGoogle Scholar
  84. Kraus KS, Canlon B (2012) Neuronal connectivity and interactions between the auditory and limbic systems. Effects of noise and tinnitus. Hear Res 288:34–46PubMedCrossRefGoogle Scholar
  85. Kruk MR, Haller J, Meelis W, de Kloet ER (2013) Mineralocorticoid receptor blockade during a rat’s first violent encounter inhibits its subsequent propensity for violence. Behav Neurosci 127:505–514PubMedCrossRefGoogle Scholar
  86. Lavigne P, Lavigne F, Saliba I (2016) Intratympanic corticosteroids injections: a systematic review of literature. Europ Arc Otorhinolaryngol 273(9):2271–2278CrossRefGoogle Scholar
  87. Lazarus RS (2006) Emotions and interpersonal relationships: toward a person-centered conceptualization of emotions and coping. J Pers 74:9–46PubMedCrossRefGoogle Scholar
  88. van Leeuwen N, Caprio M, Blaya C, Fumeron F, Sartorato P, Ronconi V, Giacchetti G, Mantero F, Fernandes-Rosa FL, Simian C, Peyrard S, Zitman FG, Penninx BW, de Kloet ER, Azizi M, Jeunemaitre X, Derijk RH, Zennaro MC (2010) The functional c.-2g>c variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels. Hypertension 56:995–1002Google Scholar
  89. van Leeuwen N, Bellingrath S, de Kloet ER, Zitman FG, DeRijk RH, Kudielka BM, Wust S (2011) Human mineralocorticoid receptor (MR) gene haplotypes modulate MR expression and transactivation: implication for the stress response. Psychoneuroendocrinology 36:699–709PubMedCrossRefGoogle Scholar
  90. Leung MA, Flaherty A, Zhang JA, Hara J, Barber W, Burgess L (2016) Sudden sensorineural hearing loss: primary care update. Hawaii J Med Public Health 75:172–174PubMedPubMedCentralGoogle Scholar
  91. Levine S (2005) Developmental determinants of sensitivity and resistance to stress. Psychoneuroendocrinology 30:939–946PubMedCrossRefGoogle Scholar
  92. Lightman SL, Conway-Campbell BL (2010) The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat Rev Neurosci 11:710–718PubMedCrossRefGoogle Scholar
  93. Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445PubMedCrossRefGoogle Scholar
  94. Mazurek B, Olze H, Haupt H, Szczepek AJ (2010) The more the worse: the grade of noise-induced hearing loss associates with the severity of tinnitus. Int J Environ Res Public Health 7:3071–3079PubMedPubMedCentralCrossRefGoogle Scholar
  95. Mazurek B, Haupt H, Olze H, Szczepek AJ (2012) Stress and tinnitus-from bedside to bench and back. Front Syst Neurosci 6:47PubMedPubMedCentralCrossRefGoogle Scholar
  96. Mazurek B, Szczepek AJ, Hebert S (2015) Stress and tinnitus. HNO 63:258–265PubMedCrossRefGoogle Scholar
  97. McCormick ZL, Walega DR (2015) Cervical epidural steroid injection for refractory somatic tinnitus. Pain Pract 15:e28–e33PubMedCrossRefGoogle Scholar
  98. McEwen BS (2007) Stress, definitions and concepts of. In: Fink G (ed) Encyclopedia of stress, vol 3, 2nd edn. Academic Press, San Diego, CA, pp 653–654CrossRefGoogle Scholar
  99. McEwen BS (2016) Stress-induced remodeling of hippocampal CA3 pyramidal neurons. Brain Res 1645:50–54PubMedCrossRefGoogle Scholar
  100. McEwen BS, Wingfield JC (2010) What is in a name? Integrating homeostasis, allostasis and stress. Horm Behav 57:105–111PubMedCrossRefGoogle Scholar
  101. McEwen BS, Gianaros PJ (2011) Stress- and allostasis-induced brain plasticity. Annu Rev Med 62:431–445PubMedPubMedCentralCrossRefGoogle Scholar
  102. McEwen BS, Weiss JM, Schwartz LS (1968) Selective retention of corticosterone by limbic structures in rat brain. Nature 220:911–912PubMedCrossRefGoogle Scholar
  103. McEwen BS, Gray JD, Nasca C (2015) 60 years of neuroendocrinology: redefining neuroendocrinology: stress, sex and cognitive and emotional regulation. J Endocrinol 226:T67–T83PubMedPubMedCentralCrossRefGoogle Scholar
  104. McIntosh AR, Gonzalez-Lima F (1998) Large-scale functional connectivity in associative learning: interrelations of the rat auditory, visual, and limbic systems. J Neurophysiol 80:3148–3162PubMedGoogle Scholar
  105. Meijer OC, de Lange EC, Breimer DD, de Boer AG, Workel JO, de Kloet ER (1998) Penetration of dexamethasone into brain glucocorticoid targets is enhanced in MDR1a p-glycoprotein knockout mice. Endocrinology 139:1789–1793PubMedCrossRefGoogle Scholar
  106. Meltser I, Canlon B (2011) Protecting the auditory system with glucocorticoids. Hear Res 281:47–55PubMedCrossRefGoogle Scholar
  107. Middleton JW, Tzounopoulos T (2012) Imaging the neural correlates of tinnitus: a comparison between animal models and human studies. Front Syst Neurosci 6:35PubMedPubMedCentralCrossRefGoogle Scholar
  108. Munck A, Guyre PM, Holbrook NJ (1984) Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 5:25–44PubMedCrossRefGoogle Scholar
  109. Nasca C, Zelli D, Bigio B, Piccinin S, Scaccianoce S, Nistico R, McEwen BS (2015) Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity. Proc Natl Acad Sci USA 112:14960–14965PubMedPubMedCentralCrossRefGoogle Scholar
  110. Oitzl MS, de Kloet ER (1992) Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning. Behav Neurosci 106:62–71PubMedCrossRefGoogle Scholar
  111. Oitzl MS, Champagne DL, van der Veen R, de Kloet ER (2010) Brain development under stress: hypotheses of glucocorticoid actions revisited. Neurosci Biobehav Rev 34:853–866PubMedCrossRefGoogle Scholar
  112. Olijslagers JE, de Kloet ER, Elgersma Y, van Woerden GM, Joels M, Karst H (2008) Rapid changes in hippocampal CA1 pyramidal cell function via pre- as well as postsynaptic membrane mineralocorticoid receptors. Eur J Neurosci 27:2542–2550PubMedCrossRefGoogle Scholar
  113. Pattyn T, Van Den Eede F, Vanneste S, Cassiers L, Veltman DJ, Van De Heyning P, Sabbe BC (2016) Tinnitus and anxiety disorders: a review. Hear Res 333:255–265PubMedCrossRefGoogle Scholar
  114. Pfaff DW, Martin EM, Ribeiro AC (2007) Relations between mechanisms of CNS arousal and mechanisms of stress. Stress 10:316–325PubMedCrossRefGoogle Scholar
  115. Polman JA, Hunter RG, Speksnijder N, van den Oever JM, Korobko OB, McEwen BS, de Kloet ER, Datson NA (2012) Glucocorticoids modulate the mTOR pathway in the hippocampus: differential effects depending on stress history. Endocrinology 153:4317–4327PubMedCrossRefGoogle Scholar
  116. Polman JA, de Kloet ER, Datson NA (2013) Two populations of glucocorticoid receptor-binding sites in the male rat hippocampal genome. Endocrinology 154:1832–1844PubMedCrossRefGoogle Scholar
  117. Portas CM, Krakow K, Allen P, Josephs O, Armony JL, Frith CD (2000) Auditory processing across the sleep-wake cycle: simultaneous EEG and FMRI monitoring in humans. Neuron 28:991–999PubMedCrossRefGoogle Scholar
  118. Quax RA, Manenschijn L, Koper JW, Hazes JM, Lamberts SW, van Rossum EF, Feelders RA (2013) Glucocorticoid sensitivity in health and disease. Nat Rev Endocrinol 9:670–686PubMedCrossRefGoogle Scholar
  119. Raff H (2005) Teaching glucocorticoid negative feedback and adrenocortical regulation using a classic paper by Dr. Dwight Ingle. Adv Physiol Educ 29:141–143PubMedCrossRefGoogle Scholar
  120. Ratka A, Sutanto W, Bloemers M, de Kloet ER (1989) On the role of brain mineralocorticoid (type I) and glucocorticoid (type II) receptors in neuroendocrine regulation. Neuroendocrinology 50:117–123PubMedCrossRefGoogle Scholar
  121. Rauschecker JP, Leaver AM, Muhlau M (2010) Tuning out the noise: limbic-auditory interactions in tinnitus. Neuron 66:819–826PubMedPubMedCentralCrossRefGoogle Scholar
  122. Reul JM, de Kloet ER (1985) Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117:2505–2511PubMedCrossRefGoogle Scholar
  123. Roozendaal B, McGaugh JL (2011) Memory modulation. Behav Neurosci 125:797–824PubMedPubMedCentralCrossRefGoogle Scholar
  124. Sapolsky RM, Romero LM, Munck AU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21:55–89PubMedGoogle Scholar
  125. Sarabdjitsingh RA, Conway-Campbell BL, Leggett JD, Waite EJ, Meijer OC, de Kloet ER, Lightman SL (2010a) Stress responsiveness varies over the ultradian glucocorticoid cycle in a brain-region-specific manner. Endocrinology 151:5369–5379PubMedCrossRefGoogle Scholar
  126. Sarabdjitsingh RA, Isenia S, Polman A, Mijalkovic J, Lachize S, Datson N, de Kloet ER, Meijer OC (2010b) Disrupted corticosterone pulsatile patterns attenuate responsiveness to glucocorticoid signaling in rat brain. Endocrinology 151:1177–1186PubMedCrossRefGoogle Scholar
  127. Schwabe L, Schachinger H, de Kloet ER, Oitzl MS (2010a) Corticosteroids operate as a switch between memory systems. J Cogn Neurosci 22:1362–1372PubMedCrossRefGoogle Scholar
  128. Schwabe L, Schachinger H, de Kloet ER, Oitzl MS (2010b) Stress impairs spatial but not early stimulus-response learning. Behav Brain Res 213:50–55PubMedCrossRefGoogle Scholar
  129. Schwabe L, Tegenthoff M, Hoffken O, Wolf OT (2013) Mineralocorticoid receptor blockade prevents stress-induced modulation of multiple memory systems in the human brain. Biol Psychiatry 74:801–808PubMedCrossRefGoogle Scholar
  130. Selye H (1936) A syndrome produced by diverse nocuous agents. Nature 138:32CrossRefGoogle Scholar
  131. Selye H (1952) The story of the adaptation syndrome. Acta Inc., Medical Publishers, Montreal, CanadaGoogle Scholar
  132. She W, Dai Y, Du X, Yu C, Chen F, Wang J, Qin X (2010) Hearing evaluation of intratympanic methylprednisolone perfusion for refractory sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 142(2):266–271. doi: 10.1016/j.otohns.2009.10.046 PubMedCrossRefGoogle Scholar
  133. Shim HJ, Song SJ, Choi AY, Hyung Lee R, Yoon SW (2011) Comparison of various treatment modalities for acute tinnitus. Laryngoscope 121(12):2619–2625. doi: 10.1002/lary.22350 PubMedCrossRefGoogle Scholar
  134. Shorter E, Fink M (2010) Endocrine psychiatry. Solving the riddle of melancholia. Oxford University Press, OxfordGoogle Scholar
  135. Simoens VL, Hebert S (2012) Cortisol suppression and hearing thresholds in tinnitus after low-dose dexamethasone challenge. BMC Ear Nose Throat Disord 12:4PubMedPubMedCentralCrossRefGoogle Scholar
  136. Sterling P (2012) Allostasis: a model of predictive regulation. Physiol Behav 106:5–15PubMedCrossRefGoogle Scholar
  137. Sterling P, Eyer J (1988) Allostasis: a new paradigm to explain arousal pathology. In: Fisher S, Reason J (eds) Handbook of life stress, cognition, and health. Wiley, Chicester, NYGoogle Scholar
  138. Szczepek AJ, Haupt H, Klapp BF, Olze H, Mazurek B (2014) Biological correlates of tinnitus-related distress: an exploratory study. Hear Res 318:23–30PubMedCrossRefGoogle Scholar
  139. Terakado M, Kumagami H, Takahashi H (2011) Distribution of glucocorticoid receptors and 11 beta-hydroxysteroid dehydrogenase isoforms in the rat inner ear. Hear Res 280:148–156PubMedCrossRefGoogle Scholar
  140. Topak M, Topak A, Sahin Yilmaz T, Ozdoganoglu HB, Yilmaz M, Ozbay M (2009) Intratympanic methylprednisolone injections for subjective tinnitus. J Laryngol Otol 123(11):1221–1225PubMedCrossRefGoogle Scholar
  141. Trune DR, Canlon B (2012) Corticosteroid therapy for hearing and balance disorders. Anat Rec 295:1928–1943CrossRefGoogle Scholar
  142. Van den Berg DT, de Jong W, de Kloet ER (1994) Mineralocorticoid antagonist inhibits stress-induced blood pressure response after repeated daily warming. Am J Phys 267:E921–E926Google Scholar
  143. Veenema AH, Meijer OC, de Kloet ER, Koolhaas JM (2003) Genetic selection for coping style predicts stressor susceptibility. J Neuroendocrinol 15:256–267PubMedCrossRefGoogle Scholar
  144. Vinkers CH, Joels M, Milaneschi Y, Gerritsen L, Kahn RS, Penninx BW, Boks MP (2015) Mineralocorticoid receptor haplotypes sex-dependently moderate depression susceptibility following childhood maltreatment. Psychoneuroendocrinology 54:90–102PubMedCrossRefGoogle Scholar
  145. Vogel S, Klumpers F, Krugers HJ, Fang Z, Oplaat KT, Oitzl MS, Joels M, Fernandez G (2015) Blocking the mineralocorticoid receptor in humans prevents the stress-induced enhancement of centromedial amygdala connectivity with the dorsal striatum. Neuropsychopharmacology 40:947–956PubMedCrossRefGoogle Scholar
  146. Vogel S, Fernandez G, Joels M, Schwabe L (2016) Cognitive adaptation under stress: a case for the mineralocorticoid receptor. Trends Cogn Sci 20:192–203PubMedCrossRefGoogle Scholar
  147. Young LJ (2015) Oxytocin, social cognition and psychiatry. Neuropsychopharmacology 40:243–244PubMedCrossRefGoogle Scholar
  148. Zalachoras I, Verhoeve SL, Toonen LJ, van Weert LT, van Vlodrop AM, Mol IM, Meelis W, de Kloet ER, Meijer OC (2016) Isoform switching of steroid receptor co-activator-1 attenuates glucocorticoid-induced anxiogenic amygdala CRH expression. Mol Psychiatry 21(12):1733–1739PubMedCrossRefGoogle Scholar
  149. Zirke N, Seydel C, Arsoy D, Klapp BF, Haupt H, Szczepek AJ, Olze H, Goebel G, Mazurek B (2013) Analysis of mental disorders in tinnitus patients performed with composite international diagnostic interview. Qual Life Res 22:2095–2104PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Division of Endocrinology, Department of Internal MedicineLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Department of Otorhinolaryngology, Head and Neck SurgeryCharité University HospitalBerlinGermany

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