The role of stress in periodontal disease and wound healing


Our current knowledge of etiopathogenesis of periodontal diseases indicates that periodontitis is a multi-factorial disease in which the host factors and the environmental factors play an important role 1. Though, bacterial plaque is considered as the primary etiology of periodontal diseases, other factors like smoking, alcohol consumption, systemic diseases like diabetes, genetic factors and stress can influence the disease progression to a considerable extent. The associations between stress factors and periodontal disease have been examined in several studies 2-5. Stress influences the host defense system by exerting an immunosuppressive effect thereby leading to increased vulnerability to disease 6-7. In the following discussion we shall study different aspects of stress and its direct and indirect effects on periodontal disease progression.


A stressor is any stimulus, situation or circumstance with the potential to induce stress reactions 8. Some of the well accepted definitions of stress are as follows,

Stress is a state of physiological or psychological strain caused by adverse stimuli, physical, mental, or emotional, internal or external, that tend to disturb the functioning of an organism and which the organism naturally desires to avoid 9.

An inharmonious fit between the person and the environment, one in which the person’s resources are taxed or exceeded, forcing the person to struggle, usually in complex ways to cope 10.

Stress is defined as physiological and metabological perturbations caused by various aggressive agents and the psychophysiological response of an organism facing the perception of a challenge or a threat 11.

The word Stress originates from a latin word: ‘stringere’ which means ‘tight’, ‘strained’.

Evidence for relationship of stress and periodontal diseases progression:

The pioneers who suggested psychological stress might play a role as an aetiological agent of periodontal disease were Dean and Dean (1945) and Schluger (1949). Many investigations have shown that psychological stress can downregulate the cellular immune response 12-15 . Many Cross-sectional studies highlighted a clear-cut correlation between the progressive course of periodontal disease and the psychosocial stress status of patients 16-18. Necrotising ulcerative gingivitis and periodontitis (NUG and NUP) are the most frequently associated and well documented periodontal conditions associated with psychological stress 19.

One study analyzed data from 1400 people of 25 – 75 years age to find out if stress, distress and poor coping behaviors are risk factors of periodontitis. It was concluded that people with financial stress had more severe periodontal disease 20. Another study investigated the possible relationship between stress, as measured by urinary steroid excretion rate, in 478 males being screened in military duty. Results showed that patients with ANUG had increased corticosteroid activity in urine. The view that stress is an etiologic factor in ANUG is further strengthened by adrenocortical activity 21.

A prospective observational study done on students assessing clinical signs of periodontal disease (such as gingival bleeding on probing) and diagnosed gingivitis showed that severe deterioration in gingival health from baseline levels was observed during  period of academic examinations in cases as compared to control group 22.

On the contrary, one study failed to confirm the link between type of periodontal disease and psychological stressors that included depression, anxiety, perceived stress and loneliness, and dental plaque as the major dependent variable 19.

The stress pathway:

Stress can be classified as acute and chronic types depending upon its time duration. Acute stress lasts for a period of minutes to hours, whereas chronic stress persists for several hours, a day, weeks or even months 23. Acute stress is often a challenge such as infection which prepares immune system for immediate response. But chronic stress may influence inflammatory processes leading to development of systemic or local diseases such as rheumatoid arthritis 24, diabetes 25, cardiovascular diseases 26 or periodontal diseases 27.

Let us try to understand the effects of stressful events on central nervous system and immune system,

First of all it is important to understand that all the events that occur under stress are subjected to promote protection of the organism 28. Two major pathway systems are involved in the stress pathway: the hypothalamic-pituitary-adrenal (HPA) axis and the systemic/adrenomedullary sympathetic nervous system (SNS). Under the influence of a stressful event, the hypothalamus-pituitary-adrenal (HPA) axis is stimulated by the anterior hypothalamus leading to secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin that act on the pituitary gland. In turn, adrenocorticotrophic hormone is secreted by pituitary gland which acts on the adrenal cortex and increases production and release of cortisol, a glucocorticoid hormone that affects immune responses 29.

Glucocorticoids produced by adrenal cortex have various effects, like suppressing the inflammatory response, modifying cytokine profiles, elevating blood glucose levels, and altering levels of certain growth factors 30-31. At the molecular level, glucocorticoids profoundly inhibit important functions of inflammatory cells including macrophages, neutrophils, eosinophils, and mast cells in functions such as chemotaxis, secretion, and degranulation.


Diagram showing  pathophysiology of stress

Stress pathophysiology

Along with this, stimulation of autonomous nervous system (ANS) by adrenergic receptors causes secretion of catecholamines (adrenalin/noradrenalin) (CAs) and chromogranin A (CgA) by adrenal medulla and sensory nerve fibres. Catecholamines alter the immune response whereas chromogranin A (CgA) has antimicrobial properties. The release of neuropeptides from sensory nerve fibers (neurogenic inflammation) causes modulation of immune system activity and the release of cytokines 32.

Changes in production of cytokines and other chemical mediators:

Changes in cytokine production are observed in stress related conditions. Interferon-γ and IL-2, produced by TH1 helper cells are suppressed by glucocorticoids, whereas IL-4 and IL-10, remain unchanged. It leads to suppression of cell mediated immunity 33. Under the influence of glucocorticoids, production of proinflammatory cytokines (IL-6, IL-1, and TNF-α) by monocytes and macrophages is decreased, whereas anti-inflammatory cytokines remain unaffected or are even stimulated 34. Glucocorticoids inhibit arachidonic acid-derived proinflammatory mediators such as prostaglandins and leukotrienes 35. One more function of glucocorticoids is the stimulation of endogenous anti-inflammatory proteins and lipocortins production, which have the capability of inhibiting phospholipase A2, thereby inhibiting generation of eicosanoids 36.

From the above discussion it is clear that glucocorticoids such as cortisol has major suppressive actions on immune and inflammatory responses.

Cytokine feedback and its effects on HPA axis:

The cytokines produced by the action of various mediators during stress can also activate HPA axis. It has been demonstrated that peripherally generated cytokines activate the HPA axis at all of its levels including hypothalamic CRH neuron, pituitary corticotrophs, as well as the adrenal cortex 37-40. The mediators that can activate HPA axis include lymphocyte-derived gamma Interferon, IL-2, IL-6, macrophage-derived IL-1, and tumor necrosis factor.

So, catecholamines, glucocorticoids and pro-inflammatory cytokines are considered among the principal messengers responsible for the bi-directional communication between the central nervous system and the immune system 41.

Relationship of stress with periodontal disease progression

Stress and periodontal disease progression

Effects on humoral immunity:

IgA and IgG are major antibodies involved in protection against periodontal disease progression.  Glucocorticoids downregulate the synthesis of IgA and IgG and also affect functions of neutrophils, which may be important in protection against infection by periodontal organisms. IgA is secretory antibody which is important during initial colonization of bacteria. IgG antibodies provides protection by opsonizing periodontal organisms for phagocytosis and killing by neutrophils.

Behavioral changes due to mental stress:

Many changes occurring during stress have been proposed to cause periodontal destruction. These include behavioral changes affecting oral health include smoking, poor oral hygiene, and poor compliance with dental care. Another behavioural change is overeating, especially a high-fat diet, which then can lead to immunosuppression through increased cortisol production. All these behavioural changes add up to the other factors explained earlier and cause periodontal disease progression.

Effect of stress on wound healing:

During early stages of wound healing immunoinflammatory functions are important. IL-8 and proinflammatory cytokines, such as IL-1 and TNF-α are important during initial healing as they bring about important changes in area of injury. They protect against infection by enhancing the recruitment and activation of phagocytes in area of injury. Along with this cytokines that are released by recruited cells regulate the ability of fibroblasts and epithelial cells to remodel the damaged tissue. Matrix metalloproteinase (MMP) activity in healing area which plays an important role in the destruction and remodelling of the wound to a large extent is regulated by IL-1. Other functions of IL-1 include regulation of fibroblast chemotaxis and the production of collagen, as well as stimulation the production of other cytokines (IL-2, 1L-6 and IL-8) that are important for wound healing. Under the influence of glucocorticoids the production of these cytokines is downregulated, which has adverse effects on wound healing 42.    

Stress and the Microbiology of Periodontal Disease:

It is believed that microorganisms possess the ability to recognize hormones within the host and utilize them to adapt to their surroundings. Based on this concept it is also possible that the periodontal microflora may change during stress. One investigation was done to determine whether noradrenalin (norepinephrine), and adrenaline (epinephrine), which are released during human stress responses, act as environmental cues to alter the growth of 43 microorganisms found within subgingival microbial complexes. In this study it was found that 20 species within the subgingival biofilm significantly grew from inoculation with noradrenalin, and 27 species significantly grew when adrenaline was introduced. It was also found that there was a difference in the growth response within bacterial species and within and between microbial complexes 43.

Soon, it was found that chronic psychological stress has a marked impact on the localized immune response to P. Gingivalis 44.


Presently we have sufficient evidence that stress can act as a significant risk factor in development of periodontal diseases. Evaluation of the patient’s stress level during diagnosis may help us in determining the prognosis of the periodontal condition. Furthermore, it is likely that systemic diseases such as diabetes, cardiovascular disease, preterm delivery, and osteoporosis may share psychosocial stress as a common risk factor in progression of periodontal diseases. Extensive research work is required to fully understand the molecular and cellular basis of the role of stress in periodontal diseases.


  1. Page RC, Offenbacher S, Schroeder HE, Seymour GJ, Kornman KS. Advances in the pathogenesis of periodontitis: summary of developments, clinical implications and future directions. Periodontol 2000. 1997; 14:216–48.
  2. Linden GJ, Mullally BH, Freeman R (1996) Stress and the progression of periodontal disease. Journal of Clinical Periodontology 23(7): 675-680.
  3. Shizukuishi S, Hayashi N, Tamagawa H, Hanioka T, Maruyama S, Takeshita T, Morimoto K (1998) Lifestyle and periodontal health status of Japanese factory workers. Annals of Periodontology 3(1): 303-31.
  4. Wimmer G, Janda M, Wieselmann-Penkner K, Jakse N, Polansky R, Pertl C (2002) Coping with stress: its influence on periodontal disease. Journal of Periodontology 73(11): 1343-1351.
  5. Pistorius A, Krahwinkel T, Willershausen B, Boekstegen C (2002) Relationship between stress factors and periodontal disease. European Journal of Medical Research 7(9): 393-398.
  6. Rogers MP, Dubey D, Reich P. The influenece of the psyche and brain on immunity and disease susceptibility. A critical review. Psychosom Med 1979;41:147-64.
  7. Ishisaka A, Ansai T, Soh I, Inenaga K, Awano S, Yoshida A, et al. Association of cortisol and dehydroepiandrosterone sulphate levels in serum with periodontal status in older Japanese adults. J Clin Periodontol 2008;35:853-61.
  8. Vingerhoets A, Health Psychology. Oxford, UK: Blackwell Publishing, 2004.
  9. Dorland. Dorland's Illustrated Medical Dictionary. Oxford, UK: WB Saunders; 2000.
  10. Richard S. Lazarus. Puzzles in the study of daily hassles. J Behavioral Med. 1984; 7(4): 375-389.
  11. Reners M, Breex M. Stress and periodontal disease. Int J Dent Hygiene 2007; 5: 199–204.
  12. Marcenes WS, Sheiham A. The relationship between work stress and oral health status. Soc Sci Med 1992; 35:1511-1520.
  13. Freeman R, Goss S. Stress measures as predictors of periodontal disease – A preliminary communication. Community Dent Oral Epidemiol 1993;21:176-177.
  14. Monteiro da Silva AM, Newman HN, Oakley DA. Psychosocial factors in inflammatory periodontal diseases. A review. J Clin Periodontol 1995;22:516-526.
  15. Breivik T, Thrane OS, Murison R, Gjermo P. Emotional stress effects on immunity, gingivitis and periodontitis. Eur J Oral Sci 1996;104:327-334.
  16. Deinzer R, Kottmann W, Forsters P, Herforth A, Stiller-Winkler R, Idel H. After-effects of stress on crevicular interleukin-1b. J Clin Periodontol 2000;27:74-77.
  17. Elter JR, White BA, Gaynes BN, Bader OD. Relationship of clinical depression to periodontal treatment outcome. J Periodontol 2002;73:441-449.
  18. Kamma JJ, Giannopoulou C, Vasdekis VGS, Mombelli A. Cytokine profile in gingival crevicular fluid of aggressive periodontitis: Influence of smoking and stress. J Clin Periodontol 2004;31:894-902.
  19. Monteiro da Silva, Newman HN, AM Oakley DA and O’Leary R. Psychosocial factors, dental plaque levels and smoking in periodontitis patients. J Clin Periodontol 1998; 25: 517-523.
  20. Genco RJ. Financial stress linked to periodontal disease. J Am Dent Assoc 1995;126:1346.
  21. Shannon IL, Kilgore WG, O’Leary T. Stress as a predisposing factor in necrotizing ulcerative ulcerative gingivitis. J Periodontol 1969;40: 240-242.
  22. Deinzer R, Ruttermann S, Mobes O, Herforth A. Increase in gingivalinflammation under academic stress. J Clin Periodontol 1998;25: 431-433.
  23. Dhabbar FS. Stress-induced augmentation of immune function-The role of stress hormones, leukocyte trafficking, and cytokines. Brain Behav Immun. 2002;16:785–798.
  24. Culshaw S, Mcinnes IB, Liew FY. What can the periodontal community learn from the pathophysiology of rheumatoid arthritis? J Clin Periodontol. 2011;38:106–113.
  25. Chida Y, Hamer M. An association of adverse psychosocial factors with diabetes mellitus: a meta-analytic review of longitudinal cohort studies. Diabetologia. 2008;51:2168-2178.
  26. Backe´ EM, Seidler A, Latza U, Rossnagel K, Schumann B. The role of psychosocial stress at work for the development of cardiovascular diseases: a systematic review. Int Arch Occup Environ Health. 2012;85:67–79.
  27. Stabholz A, Soskolne WA, Shapira L. Genetic and environmental risk factors for chronic periodontitis and aggressive periodontitis. Periodontol 2000. 2010;53:138–153.
  28. Stanford TW, Rees TD. Acquired immune suppression and other risk factors/indicators for periodontal disease progression. Periodontol 2000. 2003;32:118–135.
  29. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002; 53:865–871.
  30. Miller DB, O’Callaghan JP. Neuroendocrine aspects of the response to stress. Metabolism 2002: 51: 5–10.
  31. Takada T, Yoshinari N, Sugiishi S, Kawase H, Yamane T, Noguchi T. Effect of restraint stress on the progression of experimental periodontitis in rats. J Periodontol 2004: 75: 306–315.
  32. Bartold PM, Kylstra A, Lawson R. Substance-P: An immunohistochemical and biochemical study in human gingival tissue. A role for neurogenic inflammation? J Periodontol 1994;65:1113-1121.
  33. Agarwal SK, Marshall GDJr. Glucocorticoid-induced type1/type2 cytokine alterations in humans: a model for stress-related immune dysfunction. J Interferon Cytokine Res 1998; 18: 1059–68.
  34. Franchimont D, Martens H, Hagelstein MT, Louis E, Dewe W, Chrousos GP, Belaiche J, Geenen V. Tumor necrosis factor-α decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor. J Clin Endocrinol Metab 1999; 84: 2834–9.
  35. Williams TJ, Yarwood H. Effect of glucocorticosteroids on microvascular permeability. Am Rev Respir Dis 1990;141:S39-S43.
  36. Schleimer RP, Freeland HS, Peters SP, Brown KE, Derse CP. An assessment of the effects of glucocorticoids on degranulation, Chemotaxis, binding to vascular endothelium, and formation of leukotriene- B4 by purified human neutrophils. J Pharmacol Exp Ther 1989;250:598-605.
  37. Woloski BM, Smith EM, Meyer WJ III, Fuller GM, Bialock JE. Corticotropin-releasing activity of monokines. Science 1985;230:1035-1037.
  38. Bernton EW, Beach JE, Holaday JW, Smallridge RC, Fein HG. Release of multiple hormones by direct action of interleukin-1 on pituitary cells. Science 1987;238:519-521.
  39. Bernardini R, Luger A, Gold PW, Chiarenza A, Legakis J, Chrousos GP. Cytokines stimulate pituitary adrenal function via activation of the CHR neuron. In: F. Petraglia, ed. New Trends in Brain and Female Reproductive Function. Rome: CIG Edizioni Internazionali; 1988.
  40. Sternberg EM. Monokines, lymphokines, and the brain. In: Cruse JM, Lewis RE Jr, eds. The Year in Immunology, vol. 5. Basel, Switzerland: Karger; 1988:205-217.
  41. Maes M; Song C; Lin A; Jongh R D; Gastel A V; Kenis G; Bosmans E; Meester I D; Benoy I; Neels H; Demedts P; Janca A; Scharpé S; Smith R S (1998) the effects of Psychosocial stress on humans: increased production of proinflammatory Cytokines and a th1-like response in stress induced Anxiety. Cytokine 10: 313-318.
  42. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R. Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci U S A 2003: 100: 9090–9095.
  43. Roberts A, Matthews JB, Socransky SS, et al. Stress and periodontal diseases: effects of catecholamines on the growth of periodontal bacteria in vitro. Oral Microbiol Immunol. Oct 2002;17(5):296-303.
  44. Houri-Haddad Y, Itzchaki O, Ben-Nathan D, et al. The effect of chronic emotional stress on the humoral immune response to Porphyromonas gingivalis in mice. J Periodontol Res. Apr 2003;38(2):204-9.

One Response

  1. Steve says:

    i think there are many other effects of stress on humoral immunity. recent research has shown effects of stress on immunoglobulin synthesis as well as other aspects of humoral immunity.

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