Journal of

Oral Rehabilitation

Journal of Oral Rehabilitation 2013 40; 60--68

Review Article

Periodontal diseases and stress: a brief review

A. AKCALI*, O. HUCK, H. TENENBAUM, J. L. DAVIDEAU & N. BUDUNELI*
*Department of Periodontology, School of Dentistry, Ege University, Izmir, Turkey and Department of Periodontology, Dental Faculty,
University of Strasbourg, Strasbourg, France

SUMMARY Periodontal diseases are common chronic

inflammatory diseases caused by pathogenic
microorganisms colonising the subgingival area
and inducing local and systemic elevations of
pro-inflammatory cytokines resulting in tissue
destruction. Apparition and evolution of periodontal diseases are influenced by many local or
systemic risk factors. Psychological stress has been
suggested as one of them and may negatively
influence the outcome of periodontal treatment.
However, mechanisms explaining the possible
relationship between stress and increased susceptibility to periodontal disease remain poorly

Introduction
Periodontal diseases
Periodontal diseases are defined as inflammatory diseases caused by pathogenic microflora organised in
biofilms surrounding the teeth and divided into two
main forms. Gingivitis is a superficial and reversible
affection of gingiva without destruction of alveolar
bone and periodontitis corresponding to profound disease associated with destruction of teeth-supporting
tissues that can lead to tooth loss (1). Aetiology of
periodontal diseases is highly related to periodontal
bacteria such as Porphyromonas gingivalis (P. gingivalis),
Prevotella intermedia or Aggregatibacter actinomycetemcomitans (2). These bacteria induce the destruction of
periodontal tissues with their numerous virulence factors such as lipopolysaccharide, fimbriae or gingipans
(3). Many physiopathological processes are involved
in periodontal destruction in terms of the inflammatory and immune host response, especially pro 2012 Blackwell Publishing Ltd

understood. Several stress markers are found in

blood and saliva of patients with periodontal
diseases and influence the development of periodontal diseases by several mechanisms including
modifications of the inflammatory response and
changes in the composition of the dental biofilm.
The aim of this review is to provide an insight into
the relationship between psychological stress and
periodontal diseases.
KEYWORDS: cortisol, periodontal diseases, psychological stress, saliva
Accepted for publication 30 June 2012

inflammatory cytokines or matrix metalloproteinases

(MMPs) (46). Studies showed the essential role of
bacteria in periodontitis but bacteria alone seem to be
insufficient to explain occurrence or progression of
the disease (7). Age, tobacco use, systemic diseases
and psychological stress have been identified as
important risk factors for periodontitis (8, 9). Psychological stress is related to periodontitis by several studies. Psychological stress can directly affect periodontal
health by various biological mechanisms, and also, it
can have indirect effects through the changes in lifestyle such as ignoring oral-hygiene measures, smoking
more heavily and consuming more fat and sugar in
diet (10). In an early study, adult subjects under
financial strain and exhibiting poor coping behaviours
were reported to be at increased risk for severe periodontitis (11). Periodontitis patients with inadequate
stress behaviours strategies (defensive coping) were
suggested to be at higher risk for severe periodontal
diseases (12). In a clinical study, academic stress
appears to affect periodontal health, shown by more
doi: 10.1111/j.1365-2842.2012.02341.x

PERIODONTAL DISEASES AND STRESS

plaque accumulation, gingival inflammation during
the examination period of students (13, 14). Furthermore, increased production of interleukin-6 was
reported in response to psychological stress (6).
Despite numerous clinical and epidemiological studies
that confirmed an association between psychological
stress and periodontitis, biological mechanisms
involved are not fully understood (1517). The aim of
this review is to provide an insight into psychological
stress pathways and potential effects of stress markers
in blood and saliva on host response and on oral biofilms in an attempt to provide an overview of the
mechanisms involved in the interactions between psychological stress and periodontal diseases.

Materials and methods

Search strategy
A literature search of the last 15 years was performed
using the ISI and PubMed database from 1995 to 10
April 2012, with the following search strategy: (periodontitis OR periodontal disease) AND (psychological stress OR mental stress OR emotional stress OR
stress markers) AND (saliva OR gingival crevicular
fluid OR serum OR plasma). The search was limited to the English language. In vitro studies on cell
cultures, experimental studies on animal models and
human studies particularly investigating possible role
of psychological stress on periodontal diseases were
included. The literature search was particularly
focused on studies evaluating psychological stress
pathways markers together with clinical periodontal
findings.

Stress pathways and reflection of stress in

blood and saliva as stress markers
Stress pathways
Despite the vast number of studies on stress and
stress-related diseases, there is still no real consensus
on the definition of stress. Stress is regarded as a cognitive perception of uncontrollability and/or unpredictability that is expressed in a physiological and
behavioural response (18). Stress is often classified as
acute and chronic types. Acute stress lasts for a period
of minutes to hours, whereas chronic stress persists
for several hours, a day, weeks or even months (19).
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In case of acute stress, stress response may prepare

the immune system for challenges such as infection
that may be imposed by the stressor (19). When stress
becomes chronic, it may influence inflammatory processes leading to development of systemic or local diseases such as rheumatoid arthritis (20), diabetes (21),
cardiovascular diseases (22) or periodontal diseases
(23).
In response to stressful events, the hypothalamus
pituitaryadrenal (HPA) axis is stimulated by the
anterior hypothalamus leading to secretion of corticotropin-releasing hormone and arginine vasopressin
that act on the pituitary gland. This gland releases
adrenocorticotrophic hormone that acts on the adrenal cortex and increases production and release of
cortisol, a glucocorticoid hormone that stimulates
immune responses (24). The autonomous nervous
system (ANS) is stimulated by adrenergic receptors
leading to secretion of catecholamines (adrenalin/noradrenalin) (CAs) and chromogranin A (CgA) by adrenal medulla and sensory nerve fibres. Catecholamines
regulate the immune response by stimulation of
immune cell proliferation and activity (25, 26), while
CgA or its derivate peptides have antimicrobial effects
(27). Autonomous nervous system can also moderate
the HPA axis by stimulating central nervous system
(CNS) and sensory nerve fibers leading to secretion of
neuropeptides such as substance P (SP) (28). Autonomous nervous system plays a powerful role on salivary glands through adrenergic mechanisms in stress
by secreting enzymes such as salivary alpha-amylase
(sAA) (29). Salivary alpha-amylase acts as the first
line of defence by neutralising and preventing pathogens entering the body via mucosal surfaces (30) and
is considered the best indicator of mucosal immunity
in the oral cavity by inhibiting the adherence and
growth of bacteria (29, 31). Furthermore, SP regulates
pro-inflammatory cytokines and influences a variety
of other immunological processes that support inflammation (32).
All of these pathways are activated by stressful
events to promote protection of the organism (33).
Several stress markers are found in blood and saliva
in patients with periodontal diseases (16, 34, 35), and
they may influence the development of periodontal
diseases by different mechanisms including modifications of the inflammatory response and changes in
the composition of the microbial dental biofilms (36,
37) (Fig. 1).

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was suggested to offer advantages over serum cortisol
(42). Many reports have shown that psychological
stress activates the HPA axis by changing the cortisol
level in saliva (43, 44). Cortisol acts as an anti-inflammatory and immunosuppressive hormone by inhibiting the formation of T lymphocytes and suppressing
the function of natural killer cells (NK) or macrophages (43, 45). In addition to these effects, it induces an
increase in blood sugar concentration and influences
fat metabolism (30).
Catecholamines

Fig. 1. Stress pathways and potential effects on periodontal diseases. Stress-related mediators could influence inflammatory
response involved in periodontal diseases development and may
promote changes in the composition of subgingival biofilms and
especially pathogenic bacterial species.

Stress markers: reflection of stress in

blood and saliva
Blood and saliva can be used to monitor the systemic as well as the oral health status (35). Furthermore, stress is also a factor that can be followed by
analysis of saliva, especially by determining the levels of stress-related markers (38). These markers
have biological properties that influence genesis and
development of periodontal diseases. There are
numerous stress-related molecules involved in different aspects of stress response. This review is focused
on major salivary and blood stress markers that have
been studied so far more intensively with regard to
psychological stress and periodontal disease interactions.
Cortisol
Cortisol is a well-known stress-related hormone that
can be detected in blood, saliva and gingival crevicular
fluid (GCF) (14, 39). Cortisol circulates in the blood
predominantly as bound to the plasma protein corticosteroid-binding globulin, transcortin or albumin and is
also present in the free bioactive form (40). Salivary
level of cortisol reliably reflects HPA axis activity and
is used in human psychological studies as a biological
marker of stress (41). Recently, salivary-free cortisol

Catecholamines are the most important molecules to

relay information from the CNS to the immune system (46). Catecholamines modulate a wide range of
immune functions, including cell proliferation, inhibition of pro-inflammatory cytokines such as interferon
gamma (IFN-c), interleukin-2 (IL-2), interleukin-6
(IL-6) as well as interleukin-12 (IL-12) and tumour
necrosis factor-alpha (TNF-a) (47), suppression of
lymphocyte proliferation, NK activity (48), antibody
production and cytolytic activity (49). In the ANS system, CAs are derived from spillover of synaptic noradrenaline from the sympathetic nervous system, and
its level appears to be a useful index of overall sympathetic activity in the periphery (50). Catecholamines
are elevated by psychological stress factors, as they
come from the bloodstream. Salivary CAs may be a
useful index of sympathetic adrenomedullary system
activity (SAM) (51).
Chromogranin A
Chromogranin A is an acidic phosphorylated secretory
glycoprotein that is stored and released by exocytosis
with CAs from the adrenal medulla and sympathetic
nerve endings as well as by serous and ductal cells of
human submandibular gland. Thus, it is considered to
be a sensitive and important index of SAM and a
novel stress marker in the saliva (52, 53). Chromogranin A has the potential to act as a useful index of psychological stress (26).
Salivary alpha-amylase
Salivary alpha-amylase is one of the major salivary
enzymes in humans and is secreted in response to
sympathetic stimuli (54). Salivary alpha-amylase
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PERIODONTAL DISEASES AND STRESS

displays its inhibitory activity against microorganisms
(55) and is defined as an indirect indicator of ANS
activity (31).
Neuropeptides
Neuropeptides are generated primarily in the CNS
and play important roles in neurogenic inflammation,
including vasodilatation, plasma extravasation and
recruitment of immune cells (32, 56). Substance P is
important in initiating and sustaining inflammation,
increasing pro-inflammatory cytokine production and
by limiting the production of transforming growth
factor-b (TGF-b) and interferon gamma (IFN-c)-activated macrophages (57).
It is quite clear that blood and salivary stress markers have a major role in reflecting the inflammatory
status and mediating the host response in stressful
conditions. These markers generally act as hormonal
mediators and play a role in the ability of stress to promote diseases by influencing the host response (58).

Manifestations of stress and influence on

host response
Communications between HPA axis, ANS, CNS and
the immune system regulate the immune and inflammatory responses (14). Periodontal diseases are
inflammatory diseases associated with local and systemic elevations of pro-inflammatory cytokines such
as TNF-a, IL-6 and prostaglandins and result in tissue
destruction by the contribution of MMPs (59, 60).
Stress impairs the balance between pro-inflammatory
and anti-inflammatory responses. The relationship
between stress and periodontal diseases might be
mediated by alterations in GCF IL-1, IL-6 levels and
reduction in polymorphonuclear leucocyte chemotaxis
and phagocytosis and reduced proliferation of lymphocytes (61). Subsequently, this process could
increase vulnerability of periodontal tissues to pathogenic microorganisms by activation of cellular
responses leading to local tissue destruction (62).
Susceptibility to periodontal diseases seems to be
partly explained by the inhibition of T-cell immune
responses mediated by glucocorticoids. They can regulate the recruitment of immune cells into inflamed
tissues, as well as changing Th1/Th2 balance towards
a Th2-dominant response, and by this mechanism,
inflammatory processes are able to shut down to
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prevent host destruction by the prolonged immune

activity (15). Pro-inflammatory cytokines, such as IL1 and IL-6, are also potent activators of the HPA axis
demonstrating an important link between cytokines
and glucocorticoids (63). It is negatively controlled by
glucocorticoids and positively controlled by CAs (64)
leading to regulation of immune responses, acute
phase protein synthesis and hematopoiesis (63).
Numerous studies have reported correlation
between psychosocial stress such as academic stress,
job-related stress and clinical periodontal parameters
such as plaque accumulation and gingival inflammation (14, 34, 6567). Patients suffering from periodontitis who are under stressful conditions have increased
levels of IL-6 and IL-1b in GCF (66, 68, 69), and similarly, patients with aggressive forms of periodontitis
have elevated levels of IL-6 and IL-1b in serum. On
the contrary, another study failed to find any correlation between IL-6 and IL-1b and cortisol levels in
peripheral blood of aggressive forms of patients with
periodontitis (70).
Periodontal status was investigated in relation to
inflammatory markers and cortisol in the GCF and
saliva (66). Results showed that women on long-term
sick leave for depression have more severe periodontitis and higher concentrations of IL-6 in GCF than
healthy controls. Serum cortisol concentration was
reported to be associated with clinical periodontal
parameters such as pocket depth, clinical attachment
level and bleeding on probing (34). Associations
between clinical parameters of periodontal diseases,
psychological factors and salivary markers of stress
including CgA, cortisol, sAA, and b-endorphin, psychoneuroimmunologic variables and health behaviours are still under investigation mainly concerning
mechanisms involved notably immunologic and
behavioural changes related to psychological stress. A
number of studies have investigated the effects of circadian rhythm on the stress-related markers such as
cortisol. Cortisol has increased concentrations towards
the early hours of the morning peaking shortly after
awakening and decreasing concentrations over the
day and lowest at night (71). Taking samples soon
after post-awakening could overcome this effect.
Experimental studies using different animal models
indicated a relation between psychological stress and
inflammatory response (7274). In an experimental
rat model, the effects of superior cervical ganglionectomy and oral challenge with P. gingivalis on alveolar

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bone loss were investigated to find a link between
sympathetic nervous system and cytokine synthesis
(75). Results showed an increased expression of the
cytokines IL-1a, TNF-a and IL-6 in the superiorcervical
ganglionectomy group. Furthermore, oral challenge
with P. gingivalis accelerated alveolar bone loss and
osteoclastic activity when compared with the control
group. Variable moderate chronic stress model was
used to investigate the effects of stress on experimental
ligature-induced periodontal disease in rats (76). In
this model, the mechanism between psychological
stress and oxygen metabolism was evaluated. Results
indicated a correlation between periodontitis severity
and psychological stress that may worsen periodontal
tissue hypoxia (76). Another similar experimental
study in rats has investigated the effects of two different chronic stress models as physical and variable
stress on ligature-induced periodontitis. Higher attachment and bone losses were reported in the physical
stress group compared to the other study groups (77).
Cell culture studies were performed to investigate
the possible role of stress on progression of periodontal diseases. Macrophages were isolated from experimentally stressed and non-stressed mice and
stimulated by P. gingivalis lipopolysaccharide. Results
demonstrated that stress modulates the response of
macrophages by upregulating nitric oxide secretion
(78). Findings of another cell culture study indicated
higher hydrocortisone concentrations that significantly upregulated the expression of MMP-1, MMP-2,
MMP-7 and MMP-11 and tissue inhibitor of MMP
(TIMP)-1 in human gingival fibroblasts (16).
It can be concluded that the results of various clinical,
experimental, in vivo and in vitro studies highly suggest
a correlation between psychological stress and salivary
and blood stress markers, and these markers are related
with inflammatory response and periodontal disease
progression. As yet, there is no proven cause-and-effect
relationship between stress and periodontal disease. In
medical field, stress has been documented to have
strong association as a risk factor for various diseases of
which cardiovascular diseases are the leading one, and
even for cardiovascular diseases, stress is accepted as a
risk factor rather than a cause (79).

Interactions with oral microbiota

Periodontitis is mainly related to changes in the composition of oral biofilms especially colonising species

such as P. gingivalis, P. intermedia or A. actinomycetemcomitans (80). Stress induced by psychosocial factors

could influence periodontal ecology but mechanisms
involved remain unclear. In 1993, the concept of
microbial endocrinology has been proposed (81). This
theory argues that several bacteria could use hormones produced by host to promote bacterial growth
and infectious diseases (81). Considering periodontal
diseases, studies mainly investigate effects of CAs such
as noradrenaline on periodontal pathogens (82). It
has been demonstrated that this hormone has different effects on bacterial growth depending on the bacterial species (82). Noradrenalin reduces growth of
P. gingivalis and A. actinomycetemcomitans but increases
growth of other species such as Eikenella corrodens (82,
83). Interestingly, the same hormone increases
expression of virulence factors like gingipans but at
the same time reduces expression of auto-inducer
(83), molecule that is involved in quorum-sensing
process of this bacteria (84). These observations indicate that stress-induced hormones may have specific
effects depending on species of bacteria. Periodontal
destruction is the result of an imbalance between bacterial aggression and host response. Stress-related hormones are likely to favour the infection by increasing
bacterial growth, thereby inducing a breakdown in
oral biofilms. Specific mechanisms underlying these
effects on periodontal microbiota remain unknown,
and further studies are required to evaluate possible
effects of these hormones, especially on triggering of
virulence factors or quorum-sensing development
(85).

Conclusions in relation to clinical

applications
Stress is a part of the human being that is present
universally with varying degrees and has different
effects on individuals health (86).
Questionnaires such as Modified and Perceived
Stress Scale have been developed to better identify
and classify stress (87). These questionnaires lack
standard psychological scales for quantification and
definition of stress. More comprehensive questionnaires including lifestyle and other strong effects such
as gender, age and character would better clarify the
persons psychological stress as well as its impact on
lifestyle. Because of the diversity of questionnaires
used as psychometric instrument and the lack of a
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PERIODONTAL DISEASES AND STRESS

standardised psychological analysis for the quantification and definition of stress, biological markers could
be more objective to monitor the psychosocial status.
In questionnaires, people may give false responses
with or without intention. Furthermore, the particular persons character, that is, being an optimistic or
pessimistic person strongly affects his attitudes, and
this issue can neither be verified nor controlled. This
fact may eventually lead unreliable questionnaire data
and false diagnosis of stress.
Saliva has been used as a diagnostic biofluid to
measure host responses to a variety of triggering factors in systemic and oral diseases (88). Saliva analyses have advantages of quick and easy sample
collection not requiring specialised equipment or personnel. Moreover, its sampling is painless and noninvasive, and therefore, saliva sampling does not
cause stress in the patients. It is one of the most
promising mediums for its diagnostic potential for
various diseases including stress-related diseases, and
it is readily available any time and for repeated
samplings. Saliva analysis provides objective and
numerical data rather than the subjective and nonparametric data obtained by questionnaires. However,
there are also limitations of saliva as the biologic
sample. First of all, a large amount of saliva is
needed to evaluate multiple parameters at a single
sampling. Secondly, each biologic parameter may
need a different technique to be measured accurately. Thirdly, saliva content may be affected by systemic as well as local factors. Last but not the least,
the type of saliva sample, that is, whole or special
saliva and the particular saliva sampling technique,
stimulated or unstimulated may directly affect the
findings (89). Thus, there is a need to develop better
and more standardised methods to detect multiple
markers using a small amount of saliva. Individual
variation is another difficulty, which is very hard to
overcome (90). No normal range has been established for any mediator in saliva, and therefore, it is
yet not possible to judge on the exact meaning of
salivary data. Future studies on stress-related salivary
markers may clarify not only the presence but also
the severity of stress and its possible effects on periodontal health. If the relationship between stress and
periodontal disease can be verified in saliva samples,
diagnosing stress by means of saliva analysis can be
helpful for differential diagnosis from the evidencebased point of view in various medical fields. Thus,
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Fig. 2. Major risk factors for periodontitis.

pioneering periodontal research may open up new

pathways for medical research. However, it is quite
clear that development of reliable chair-side tests is
not an easy task.
Particularly, cortisol, CAs and alpha-amylase may
open up new perspectives in the field of periodontology to categorise a patient according to the risk factors
that may enable prompt medical intervention. Identifying reliable stress-related biomarkers in saliva may
eventually end up in development of chair-side tests
with potential multidisciplinary applications. Determining patients under chronic stress could develop specific multidisciplinary treatment strategies for ultimate
outcome of coping with stress factors. There is no doubt
stress has important clinical implications in periodontal
disease development and also influences treatment
outcomes. We know psychological factors influence
susceptibility to periodontitis by affecting the lifestyle
such as poor oral hygiene, poor compliance, high-fat
diet and smoking and environmental changes in terms
of oral microbiota and finally host response modulation
that is also correlated with genetics and epigenetics
(91) (Fig. 2). These effects suggest a need for the development of preventive treatment strategies and maintenance care for patients under stress. We would like to
know the normal ranges for stress-related biochemical
parameters. Investigations into stress markers in saliva,
blood and GCF may become a routine for screening the
response to treatment in the near future but could also
be used to quantify patients stress.

Conflicts of interest
The authors declare no conflicts of interest.

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