Periodontology 2000, Vol. 44, 2007, 195210
Printed in Singapore. All rights reserved
The role of stress in periodontal
disease and wound healing
L A K S H M I B O Y A P A T I & H O M -L A Y W A N G
Psychological stress, particularly if sustained over an
extended period of time, can have deleterious effects
on the body, representing an important example of
the mindbody interaction. The role of stress on
systemic health has been well known for decades
(107, 108). Similarly, the role of psychological factors
in periodontal disease has a significant history (7, 77).
Currently, stress is classified as a risk indicator for
periodontal disease (39, 41). The role of psychological
stress in wound healing has been addressed in a
plethora of studies in the medical field (37, 47, 69, 72,
93). However, the link between stress and periodontal
disease is not so clear, and nor is the role of stress in
periodontal wound healing. It is of considerable
importance that the relationship between oral
health and psychological conditions be examined.
This article reviews the current literature, with
emphasis on the potential role of psychological
stress in periodontal disease progression as well as
on wound healing.
The definition of stress
The term stress is used loosely, in layman terms, to
describe adverse emotions or reactions to unpleas-
ant experiences. It is also used, in a somewhat cir-
cular way, to describe experiences that may provoke
these emotions. However, the term stress has a
precise physiological definition. It is a state of
physiological or psychological strain caused by ad-
verse stimuli, physical, mental, or emotional, inter-
nal or external, that tend to disturb the functioning
of an organism and which the organism naturally
desires to avoid (1). Thus, stress can be viewed as a hypothalamus by the infundibulum, a stalk of tissue
process with both psychological and physiological
components.
 2007 The Authors.
Journal compilation  2007 Blackwell Munksgaard
PERIODONTOLOGY 2000
Psychological definitions
A stressor is any stimulus, situation or circumstance
with the potential to induce stress reactions (122).
Whether or not a subject exhibits a stress response
depends on a myriad of factors, including coping
behaviors, genetic predisposition, concomitant stres-
sors, levels of social support, and other lifestyle factors.
Potential effects of the stress response that may be
observed, or even measured, include anxiety, depres-
sion, impaired cognition, and altered self-esteem.
Definitions of stress differ in the periodontal literature,
as seen by the variety of ways in which stress is eval-
uated (Table 1); for example, subjective measure-
ments of so-called stressful situations, to detailed
questionnaires, to measures of specific markers such
as plasma cortisol. It can be seen that a critical element
in studying the psychological stress response is the
measurement of both the presence (or absence) of
potential stressors and the subjects ability to cope
with them. Future studies may benefit from this more
detailed understanding of the stress response.
Physiological definitions
Stress can result in the deregulation of the immune
system, mediated primarily through the hypotha-
lamicpituitaryadrenal and sympatheticadrenal
medullary axes (130) (Fig. 1).
In response to a variety of stressful stimuli, an
elegant sequence of events is initiated. Activation of
the hypothalamicpituitaryadrenal axis by stress
results in the release of an increased concentration of
corticotropin-releasing hormone from the hypotha-
lamus. The pituitary gland is connected to the
that contains nerve fibers and small blood vessels.
Corticotropin-releasing hormone, in turn, acts on the
195
196
Table 1. Summary of human studies
Study design Disease n Findings Reference
Casecontrol study Acute necrotizing Cases (n 35) Both groups showed similar total leukocyte counts (103)
Boyapati & Wang

ulcerative gingivitis Controls (n 35) and percentage distribution of leukocytes; patients

with acute necrotizing ulcerative gingivitis showed
a reduced polymorphonuclear leukocyte response
to antigenic stimuli, decreased phagocytosis and
chemotaxis, and a strong association of anxiety,
depression and psychopathic deviance Stress was
evaluated using a questionnaire
Case series. Associations among Periodontal status n 33 Increased urinary cortisol levels in lonely patients. (8)
loneliness, stressful life events, not assessed Patients scoring higher on the loneliness scale had
urinary cortisol levels, and reduced natural killer cell activity and reduced T-cell
immunocompetency responsiveness. Stress was evaluated using a
questionnaire and assays to assess cellular function
Case series. Related measurements Health to gingivitis n 50 male Measurements of life events stress was significantly (106)
of life events stress to to varying degrees volunteers correlated with clinical measures of periodontal
measurements of periodontal of CP disease Periodontal disease was more severe and
disease more widespread as stressors increased
Case series. Whether oral health Health to gingivitis n 164 men Significant relationship found between periodontal status (113)
status was related to work stress to varying degrees across four and work-related mental demand, marital quality, and SES
of CP SES groups
Cross-sectional study. Investigated RPP; CP; Healthy RPP n 50 Between-subject multivariate analysis showed that (30)
possible associations between controls CP n 50 combined psychosocial variables were related to
psychosocial factors and RPP Health n 50 periodontal disease; the RPP group had significantly
greater depression and loneliness scores compared
with the CP group
Cross-sectional whether RPP and CP RPP n 40 No difference in plaque scores noted between disease (31)
psychosocial factors could predict CP n 40 types. Subjects with RPP tended to smoke more than
dental plaque levels in patients CP subjects. A marginally significant correlation was
with adult-onset RPP and routine CP found between smoking and depression
Casecontrol study. Investigated Health to gingivitis n 100 dental Periodontitis was associated with negative-impact life (48)
the role of life events in to varying degrees patients matched events, number of negative life events, tobacco
periodontitis of CP for age and sex smoking and being unemployed. After adjusting for
other variables, periodontitis was associated with
marital status
 Table 1. Continued

Study design Disease n Findings Reference

Casecontrol study to investigate One group that Responding well Subjects in the nonresponding group displayed indications of (107)
whether a stress system disorder responded well to n 11 increased psychological strain and a more passive-dependent
plays a role in the pathogenesis periodontal therapy. Responding poorly personality
of therapy-resistant periodontitis A second group that n 11
responded poorly
Split-mouth study using punch Periodontal health n 11 The average healing time for standardized wounds (104)
biopsy wounds in medical was 3 days longer during stressful exam periods.
students during stressful exams The production of interleukin-1 was reduced by
and during vacation 68% during exams
Cross-sectional study to examine Health to gingivitis n 1,426 Only financial strain was significantly associated with (24)
a possible association between to varying degrees attachment and alveolar bone loss. Subjects with
stress, distress, and coping of CP inadequate coping mechanisms had a higher risk of
behaviors, and periodontal greater attachment loss. Increased risk was not
disease evident in subjects with good coping strategies
Casecontrol study. Relationship of Group 1: PD < 3 mm Group1 n 22 Frequency of moderate CAL (46 mm) and moderate (112)
stress and anxiety to periodontal Group 2: PD 4 mm Group2 n 27 PPD (46 mm) were significantly associated with
clinical parameters but <6 mm Group3 n 30 higher trait anxiety scores. Stress was evaluated
Group 3: PD 6 mm through the use of a questionnaire
Cross-sectional study. Prevalence of Health to gingivitis n 298 Swedish Risk factors for severe periodontal disease included (114)
negative life events and their to varying degrees adults age, oral hygiene status, smoking, loss of a spouse,
relationship to periodontal disease of CP and the personality trait of exercising extreme
external control
Retrospective casecontrol study. Varying degrees of CP n 89 When stratified according to disease severity, (109)
Investigated various forms of stress CP Healthy controls patients with defensive coping styles displayed
behavior and their relationship with n 63 significantly greater attachment loss
CP
Prospective study. Influence of CP n 80 Patients with suppressive coping styles showed (108)
different coping behaviors on both more cases of advanced disease and a
nonsurgical periodontal therapy poorer response to nonsurgical therapy
and the course of periodontal
disease during 2 years of supportive
periodontal therapy

CAL, clinical attachment level; CP, chronic periodontitis; PD, pocket depth; PPD, probing pocket depth; RPP, rapidly progressing periodontitis; SES, socioeconomic status.
Stress in periodontal disease and wound healing

197
Boyapati & Wang
Fig. 1. Pathophysiology of the stress responses.
anterior pituitary, resulting in the release of adreno-
corticotropic hormone (corticotropin). The adreno-
corticotropic hormone then acts on the adrenal
cortex and causes the production and release of
glucocorticoid hormones (predominantly cortisol)
into the circulation. The glucocorticoids then pro-
duce a myriad of effects throughout the body, such as
suppressing the inflammatory response, modifying
cytokine profiles, elevating blood glucose levels, and
altering levels of certain growth factors (87, 118).
198
Importantly, it has been established that pro-
inflammatory cytokines, such as interleukin-1, can
also activate the hypothalamicpituitaryadrenal
axis, leading to a feedback loop (33). Immune
function plays a critical role early in the wound
healing cascade. Pro-inflammatory cytokines, such
as interleukin-1 and tumor necrosis factor, are just
two of the essential cytokines in this regard. It has
been speculated that success in the later stages of
healing is critically dependent on these early events
 Stress in periodontal disease and wound healing

(46, 63, 127). After experimentally created blister

wounds were inflicted in human subjects, it was
found that women who reported higher stress levels
produced lower cytokine levels than women
reporting lower levels of stress. In addition, the
individuals exhibiting greater stress had higher sal-
ivary cortisol levels (46).
The second major pathway to be activated is the
sympathetic nervous system. A well-known example
of this is the so-called flight or fight response to
potentially harmful stimuli. Stress activates the nerve
fibers of the autonomic nervous system, which
innervate the tissues of the immune system. The
adrenal medulla is actually a modified sympathetic
ganglion. Its nerve bodies, instead of possessing
axons, secrete their products directly into the
bloodstream. The release of catecholamines results in
the hormonal secretion of norepinephrine and epi-
nephrine from the adrenal medulla, which results in
a range of effects that may act to modulate immune
responses. Catecholamines, released during stress,
contribute to the development of hyperglycemia by
directly stimulating glucose production and interfer-
ing with the tissue disposal of glucose (87). In addi-
tion, the sympathetic nervous system has a role in
regulating immune cell activities (2).
From the above discussion it is apparent that the
response of the human body to stressful stimuli is at
once helpful and potentially therapeutic, even
though a potentially harmful imbalance occurs when
the stressful stimuli, or perceived stimuli, are pro-
longed. Examples include chronic anxiety states and
depression (6, 14, 40, 44, 45).
Stress and wound healing
The impact of stress on periodontal wound healing
may be influenced by factors that can be classified
into the following two broad categories (Table 2):
health-impairing behaviors (126), such as poor oral
hygiene; and factors that have pathophysiological
effects, such as altered cytokine profiles.
Health-impairing behaviors include neglecting oral
hygiene practices (74, 86, 90), increased consumption
of cigarettes (89) and alcohol, and disturbed sleeping
patterns. Other behaviors potentially harmful to the
periodontium are bruxing, anxiety-induced forget-
fulness, and difficulty concentrating (79).
Depression has consistently been associated with
smoking (3, 55, 57, 96). Although depression is not
synonymous with stress, it has been used in various
studies as an indicator of the level of stress that a
subject may be under. Usually this takes the form of
questions on standardized questionnaires, regarding
feelings of sadness, hopelessness, and depression.
This provides a strong link between depression and
periodontal disease, as smoking is a well-established
risk factor for periodontal disease (9, 53, 81, 98, 119).
In addition, smoking has been shown to impair
collagen synthesis and increase matrix metallopro-
teinase-8 levels in blister wounds, compared with
nonsmoking controls (73). Smoking and diabetes,
both known risk factors, act as physical stressors
capable of activating the stress-immune system.
Stress management has even been shown to be a
novel means of improving glycemic control in type 2

Table 2. Mechanisms by which stress may affect periodontal wound healing

Health-impairing behaviors
Poor oral hygiene
Increased consumption of cigarettes
Increased alcohol consumption
Forgetfulness and difficulty
concentrating
Disturbed sleeping patterns
Poor nutritional intake
Pathophysiological effects
Higher glucocorticoid levels (cortisol) and higher catecholamine levels
(epinephrine and norepinephrine), which may lead to any or all of the
following:
Hyperglycemia, which may impair neutrophil function and impair the
initial phase of wound healing
Reduced levels of growth hormone, which may down-regulate the
tissue repair response
Altered cytokine profiles, which may affect recruitment of cells important
to wound remodeling, such as macrophages and fibroblasts
Reduced tissue matrix metalloproteinase levels, leading to impaired tissue
turnover and reduced wound remodeling
Decreased natural killer cell levels, reducing the host ability to mount an
appropriate immune response to periodontal pathogens
Altered Th1/Th2 ratio, leading to an increased susceptibility to
periodontal disease

Th1, T helper 1 cell; Th2, T helper 2 cell.

199
Boyapati & Wang
diabetes (15, 117). Negishi and colleagues examined
the effect of lifestyle on periodontal disease status in
57 diabetic Japanese subjects (94). Data were collec-
ted, including clinical measures of periodontal status,
diabetic status, lifestyle habits, and behavioral fac-
tors. Factors that were found to correlate with poorer
periodontal status were glycosylated haemoglobin
(>9%), drinking habit, and irascible behavior. It was
concluded that lifestyle and psychosocial stress may
affect the periodontal status of diabetic patients.
Various studies have established a link between
stressful life events and poor oral hygiene (19, 32, 74,
105). In a series of studies on a population of medical
students undergoing academic stress, Deinzer and
co-workers reported increased dental plaque accu-
mulation and gingival inflammation compared with
control students not taking examinations (23, 26).
Gingival crevice fluid levels of interleukin-1, inter-
leukin-6, and cortisol may also increase in stressed
subjects (25, 66). However, in another study,
conducted to determine whether psychological dis-
turbances could lead to neglected oral hygiene and
increased plaque levels, no correlation was found.
Because the patient pool consisted entirely of sec-
ondary referrals, it is possible that a relationship may
have emerged in a less specialized population, such
as that found at a general dental office (89).
Disturbed sleep patterns, as a result of stress,
could result in a reduction of growth hormone,
which may act to down-regulate the tissue repair
response (101). This, in addition to poor nutritional
intake because of unhealthy eating habits, and
excessive alcohol and cigarette consumption, could
further impair tissue wound healing. Therefore, it is
possible that correlations between stress and an
impaired healing response could be secondary to
stress-induced changes in health behaviors, which
themselves act to down-regulate an individuals
immune response (29).
Stressful stimuli can induce a set of reactions that
have effects on virtually all body systems. The ef-
fects are primarily mediated through the hypotha-
lamicpituitary axis and the sympathetic nervous
system (103). The increased levels of cortisol and
epinephrine can disrupt homeostasis and increase
susceptibility to disease through a wide range of
mechanisms.
Cortisol, produced by the adrenal cortex, can exert
potent anti-inflammatory and immunosuppressive
effects. The administration of large amounts of cort-
isol profoundly reduces the inflammatory response
to injury or infection. It has been demonstrated that
the application of topical glucocorticoids slows the
200
healing process in dermal wounds (50). Moss and
co-workers conducted a casecontrol study and
obtained self-reported information, regarding
depression and daily strain, relating to financial,
social, and role-related aspects of the subjects life. A
strong correlation between serum immunoglobulin G
levels to a putative periodontal pathogen (Tannerella
forsythia) and periodontal disease status was found
among patients with high depression scores. No such
association was found in subjects with low depres-
sion scores (92). The authors speculated on a possible
psychneuroimmune link between the production of
antibodies to this pathogen and periodontitis.
In a study utilizing a bacterial vaccine which did
not induce T-cell immunity, immunoglobulin G lev-
els were measured in caregivers, former caregivers,
and controls. Caregivers were elderly spouses caring
for a spouse with progressive dementia and thus were
undoubtedly under a great deal of chronic stress. The
results demonstrated that current caregivers had
lower antibody titres, 6 months post-vaccination,
than former caregivers or controls (48). Two pro-
posed reasons for the difference are that chronic
stress may either inhibit the stability of the immu-
noglobulin G antibody response to a bacterial vaccine
or have an impact on the number of immunoglobulin
G-producing lymphocytes (44, 45). These findings
have particular significance, with respect to perio-
dontal therapy, as regular periodontal maintenance
has been referred to as a form of immunization and
has been shown to elicit an antibody response (27,
28, 80).
Ebrecht et al. (29) inflicted standardized 4 mm
punch biopsy wounds in 24 nonsmoking males.
Psychological status was assessed (using question-
naires) on perceived stress, health behaviors, and
personality factors. Saliva was collected to determine
cortisol levels, and wound healing was assessed using
high-resolution ultrasound scanning at 7, 14, and
21 days post-biopsy. The results indicated that
wound healing was negatively correlated with per-
ceived stress and positively correlated with perceived
optimism. Another finding was that the cortisol re-
sponse on the morning of the biopsy was negatively
correlated with the speed of wound healing (29).
Similarly, animal models challenged with low corti-
costeroid levels are more resistant to developing
periodontal disease than those with high cortico-
steroid levels (10, 11).
Studies evaluating the effect of high levels of
glucocorticoids on pro-inflammatory cytokines, such
as interleukin-1 and tumor necrosis factor-a, are
conflicting. Using a mouse model, isolation and cold

stress increased nitric oxide production, but reduced
tumor necrosis factor-a production, in response to
the subcutaneous introduction of Porphyromonas
gingivalis (110, 111). Increased levels of interleukin-1
in gingival crevice fluid, and decreased levels of
salivary immunoglobulin A, have been found in
students during periods of stressful examinations (24,
25). In addition, stress was shown to enhance the
production of periodontal disease-induced produc-
tion of interleukin-1b (22, 42, 123). In contrast, Kie-
colt-Glaser and co-workers used a group of women
who were caregivers for a spouse suffering from
dementia. Wounds consisted of a 3.5 mm punch
biopsy on the forearm of all women, after which
interleukin-1b messenger ribonucleic acid levels were
measured in peripheral blood leukocytes after sti-
mulation with lipopolysaccharide. The rate of wound
healing was measured using photography. Wound
healing took 9 days longer (24% longer) in caregivers
compared with controls. In addition, interleukin-1b
mRNA levels were also down-regulated compared
with those of the controls. The authors concluded
that alteration in interleukin-1b levels may impair
wound healing, particularly in the early stages (70).
Reductions in interleukin-1 and interleukin-8 have
also been found in fluid from blister wounds in pa-
tients exhibiting higher stress scores, compared with
controls. Interestingly, these patients also exhibited
higher salivary cortisol levels (46).
Recently, Broadbent and co-workers investigated
the relationship between psychological stress and
wound repair in patients following routine surgery
(10). Forty-seven adults were given standardized
questionnaires to assess levels of perceived stress
before and after undergoing open incision repair of
an inguinal hernia. Wound healing was measured
using wound fluid levels of interleukin-1, interleukin-
6, and matrix metalloproteinase-9. Other outcome
measures included patient self-reports of recovery
and the cytokine response to lipopolysaccharide sti-
mulation of peripheral blood leukocytes. As predic-
ted, higher levels of reported stress prior to surgery
predicted impaired cellular processes during early
wound-healing phases. Reduced interleukin-1 and
matrix metalloproteinase-9 levels at the wound were
significant findings (13). A fourfold increase in
interleukin-6 levels has been demonstrated in a
group of caregivers compared with controls when
longitudinally monitored over a 6-year period (71).
The authors speculated that this may be a key
mechanism by which chronic stressors may have
compelling consequences for the health of older
adults, possibly accelerating the risk of age-related
Stress in periodontal disease and wound healing
diseases. Several studies (75, 85) have failed to sup-
port the above findings. Differences in the patho-
physiology of the diseases under investigation,
variable sample size, and variation in the hypotha-
lamicpituitaryadrenal and sympatheticadrenal
medullary axes to stress may, at least in part, account
for these differences. Taken together, the above
studies lend weight to the body of evidence demon-
strating a negative impact on wound healing by
chronic stress. Longer duration of wound healing,
altered cytokine profiles, and increased circulating
cortisol levels are all consistent findings.
As catecholamines are known to alter blood flow
and trafficking of inflammatory cells, stress-induced
activation of the sympathetic nervous system may
also play a regulatory role in wound healing. Stress-
induced activation of the sympathetic nervous sys-
tem results in the release of highly active hormones,
such as catecholamines, which can alter blood flow.
Peripheral vasoconstriction may affect important
oxygen-dependent healing mechanisms, such as an-
giogenesis, collagen synthesis, and epithelization
(125). A recent study, demonstrating that hyperbaric
oxygen therapy may correct stress-impaired dermal
wound healing in a murine model, supports the
above contention (34).
Increased sympathetic stimulation can also act to
decrease salivary secretions, typically experienced as
anxiety-induced dry mouth. In a situation of reduced
salivary flow, the composition may become critical.
Higher salivary cortisol levels have been demonstra-
ted in patients presenting with severe periodontal
disease compared with healthy controls (41). Cortisol
is also detectable in gingival crevice fluid (4) and may
be more significant to periodontal wound healing in
this location. Periodontal organisms demonstrate
differing growth responses to epinephrine and nor-
epinephrine (99, 100). In a more recent study, the
same group investigated the possible mechanisms
underlying growth effects of catecholamines. Forty-
three microbial organisms, normally found within the
subgingival environment, were grown in vitro with
iron-, norepinephrine- or Escherichia coli autoin-
ducer-supplemented media. Growth responses for all
cultures were determined by subtracting the values of
the noninoculated controls and taking the mean
responses. The results demonstrated large, significant
increases in growth in cultures supplemented with
iron, E. coli autoinducer and norepinephrine, com-
pared with nonsupplemented controls (100). The
data suggested that the autoinducer mechanism
affects oral microorganisms, thus providing a further
link between stress and periodontal disease.
201
Boyapati & Wang
Alteration of the T helper 1 cell/T
helper 2 cell ratio
It has been well established that periodontal disease
is a result of an inappropriate host response to
infecting microorganisms. The host response may be
divided into innate and adaptive immunity. Innate
immune mechanisms operate without any previous
exposure to the pathogenic organism. Innate immu-
nity includes physical barriers, various cell popula-
tions (such as neutrophils, monocytes and natural
killer cells), complement, and a large number of
antimicrobial peptides. Adaptive immunity is a highly
specific response that is amplified on exposure to
specific pathogens. It consists of humoral and cell-
mediated immunity.
The nature of the adaptive immune response, in
particular the nature of lymphocytes involved in
immunity, may partly explain the differences in host
response between individuals. Breivik and co-workers
have proposed a model in which the extent of
inflammatory periodontal disease may be predicted by
reactivity of the hypothalamicpituitaryadrenal axis
and its effects on T-lymphocyte numbers (12). Helper
T lymphocytes can be divided into two subpopulations
T helper 1 cells and T helper 2 cells based on their
cytokine production (91). T helper 1 cells stimulate
cellular immunity through the production of inter-
feron-c and interleukin-2. T helper 2 cells promote B-
cell differentiation and humoral immunity through the
release of interleukin-4, interleukin-5, interleukin-6
and interleukin-10. Numerous in vitro and animal
studies support the contention that increased levels of
plasma glucocorticoid may provoke an inappropriate
T helper 2 cell response (12, 21, 65). Marshall and co-
workers demonstrated a cytokine profile, consistent
with a T helper 2 cell response, in medical students
during stressful examination periods (83).
It has been hypothesized that a dominant T helper
2 cell response increases susceptibility to infectious
diseases (11). In fact T helper 1 cell responses may
actually be protective against periodontitis, whereas a
T helper 2 cell response may increase periodontal
breakdown (109). In order to test this hypothesis, two
genetically distinct types of rat, which differed in
response to stress, were compared (11). One group of
rats were high cortisone-responding rats; the other
were low cortisone-responding rats. Ligature-in-
duced periodontitis was produced in the maxillary
right second molars of all rats and was measured
using digital radiographic and histological examina-
tion. Previous work has demonstrated that in com-
202
parison to low cortisone-responding rats, the high
cortisone-responding group generates a stronger T
helper 2 cell response to infectious agents (68). The
high cortisone-responding rats exhibited greater
alveolar bone loss and more loss of connective tissue
fibers. These data lend weight to the contention that
a shift to the T helper 2 cell immune response may be
more destructive. These findings have more recently
been refuted (61). Using a mouse model, P. gingivalis
was implanted subcutaneously, and the immune re-
sponse was monitored in two groups undergoing
restrain or isolation stress and in a control stress-
free group. Chamber exudates and serum was col-
lected and analyzed for antibodies to P. gingivalis.
The results showed a lower immunoglobulin G1/
immunoglobulin G2 ratio, which indicated an eleva-
ted T helper 1 cell response during the stressful
conditions. The above studies confirm the contention
that an altered T helper 1 cell/T helper 2 cell lym-
phocyte profile, resulting from chronic stress, can
exacerbate periodontal disease in animal models.
This remains to be confirmed in human subjects.
Animal studies
There are obvious limitations of studying the effects of
stress on wound healing in humans. These include
ethical issues regarding inflicting standardized
wounds, variability in response to stress, and control-
ling potentially confounding variables. Hence, animal
models may be beneficial in understanding the mech-
anisms behind this possible association (Table 1).
Animal models allow a reproducible stress to be applied
to the same animal and between animals of differing
treatment or disease status groups. Studies have con-
firmed a negative effect of stress on the rate of wound
healing in animals (34, 36, 56, 95). Animal studies have
used a variety of stress-inducing stimuli, such as noise,
isolation, increased population density, handling by
animal keepers, exposure to extremes of temperature,
and maternal separation (38, 49, 95, 112, 113).
Padgett and co-workers examined the stress-
induced delay in wound healing in female mice fol-
lowing inflicting a 3.5 mm punch wound. Test mice
were subjected to restraint stress for 3 days prior to,
and for 5 days following, the wounding. The results
demonstrated that stressed mice took an average of
3 days longer to heal (95). In general, results from
animal studies suggest that prolonged stress on per-
iodontal tissues has adverse effects, such as reduced
alveolar crest bone height, increased probing depths,
reduced clinical attachment levels, and delayed

wound healing. In a study on two genetically distinct
rat lines with significant differences in both behavi-
oral and neuro-endocrine responses to stress, signi-
ficant differences in susceptibility to periodontal
disease were found (11). This implies that individuals
under greater stress are more prone to periodontal
disease and/or poorer wound healing following
periodontal therapy.
Until recently, however, a lack of adequate animal
models has impaired investigation into the relation-
ship between stress and periodontal wound healing
(59). Takada and co-workers have, of late, presented a
useful murine model to study stress (118). Ligature-
induced periodontitis was created around the max-
illary second molars in 100 male Wistar strain rats,
which were randomly assigned to either restraint
stress groups or control groups. Restraint stress was
created by enclosing each animal in flexible wire
mesh for 12-h periods. The animals were not allowed
food or water in either experimental group. Blood
samples were taken and stress was measured using
blood glucose levels, corticosteroid levels, and epi-
nephrine levels. Atrophy of the thymus and spleen
were also measured by histologic examination.
Periodontal status was assessed by measuring
alveolar bone changes utilizing digital subtraction
radiography. Using this novel model, the authors
found that the restraint stress appeared to increase
the levels of periodontal bone loss. The model was
deemed suitable for investigating the association
between stress and periodontal disease (118).
The regulation of pro-inflammatory cytokines
during wound healing in normal and glucocorticoid
treated mice has also been studied. After inflicting
full-thickness wounds on the dorsal surface of mice,
the induction of interleukin-1b and tumor necrosis
factor-a was significantly reduced during wound
healing in glucocorticoid-treated mice compared
with untreated controls (63). Similarly to human
studies, animal studies have demonstrated conflict-
ing results. Benatti and co-workers examined the ef-
fects of stress, in association with nicotine adminis-
tration, on periodontal breakdown (8). Twenty adult
male Wistar strain rats had ligature-induced perio-
dontitis created around their mandibular molars. The
rats were divided into groups receiving immobiliza-
tion stress and those not receiving stress. In each
group, the mandibular molars were randomly as-
signed to receive either an intraperitoneal nicotine
injection or a control saline injection. The results
demonstrated that although stress alone did not af-
fect periodontitis, it significantly enhanced the effect
of nicotine on the periodontal tissues (8).
Stress in periodontal disease and wound healing
Although animal studies have several notable
advantages in terms of studying the physiological
stress response, they are limited with respect to
studying the psychological aspects of the stress re-
sponse. For example, whether a mouse confined to a
small cage can be compared with a human under-
going examination stress, seems doubtful. Future
research should focus on the mechanisms of the
stress response that may enable a more complete
understanding of the effects of stress on periodontal
wound healing.
Human studies
The most well-documented association between
stress and periodontal disease is acute forms of
necrotizing gingivitis and periodontitis (17, 31, 90).
Risk factors for these conditions include smoking,
poor oral hygiene, stress, and immunosuppressive
states (67, 102). An increased incidence of this
condition has been well documented in military
personnel during stressful activities (54, 97) and in
students during examination periods (43). Increased
levels of cortisol found during episodes of disease are
normalized after recovery (17). Alterations in cellular
immunity have also been reported, including reduced
chemotaxis and phagocytosis by polymorphonuclear
leukocytes, and reduced proliferative capacity of
lymphocytes (16).
Marucha and co-workers conducted a series of
studies to delineate the oral effects of academic stress
(84). In one study, medical students had punch
biopsy wounds inflicted on the hard palatal mucosa.
Wounds in the test group were made during stressful
examination periods, whereas control groups had the
wound created whilst on vacation. Wounds placed on
the hard palate, 3 days before a major examination,
healed, on average, 40% more slowly than those in
the same persons during the vacation period (84). In
another study, using the academic stress model,
Kiecolt-Glaser and co-workers found a lower level of
natural killer cell activity in students who scored
higher in stressful life events and loneliness scales
(69). In addition, these students had higher urinary
cortisol levels when compared with students who
were subjectively less stressed (69). Also, reduction of
blood natural killer cells has been reported during
stressful military training (51).
Human studies have proposed a correlation be-
tween chronic periodontal disease and negative life
events (19, 32, 52). Axtellius and co-workers con-
ducted a prospective study on the impact of
203
Boyapati & Wang
psychological conditions in response to periodontal
therapy (5). The authors reported that response to
therapy was lower in subjects with greater psycho-
social strain and a more passive-dependent person-
ality (5). A recent study, examining the effect of stress
on nonsurgical periodontal therapy, confirmed the
above results (129). In 80 patients with chronic per-
iodontitis who were treated nonsurgically and
maintained for 2 years, patients with defensive cop-
ing styles had a significantly impaired healing re-
sponse, as indicated by poorer attachment values
(129).
In a more recent study, patients with inadequate
stress behavior strategies (defensive coping) were at
greater risk for severe periodontal disease (128). It is
well known that different individuals experience and
cope with similar stresses in a variety of ways. It may
be that the variability of response to stressful stimuli
occurs as a result of genetic variability (115). Differ-
ent strains of rat may be bred to exhibit differences in
their hypothalamicpituitaryadrenal axis respon-
siveness to a range of stressful stimuli. Rats with
higher levels of stress (as measured by serum cortisol
levels) exhibit greater periodontal breakdown com-
pared with controls (11, 116).
Vettore and colleagues examined 79 patients and
assigned them into three groups according to perio-
dontal disease severity (121). Patients undertook
stress and anxiety evaluations and had social and
demographic data recorded. Scores of trait anxiety
were statistically associated with moderate clinical
attachment level frequencies and moderate probing
pocket depth frequencies, after adjusting for socioe-
conomic status. This casecontrol study lends weight
to the argument that individuals with high levels of
trait anxiety are more prone to periodontal disease
(121). Other casecontrol studies have found similar
results (40, 82, 90, 128).
Hugoson and co-workers examined the relation-
ship between psychological reactions to negative life
events and periodontal health using a longitudinal
study design (64). Using previous data obtained in a
cross-sectional study in 1993 in Sweden, a subset of
298 dentate individuals was re-examined. Clinical
and radiographic data were available. In addition, a
questionnaire assessing socioeconomic status, life
events, and psychological and stress-related factors,
was used. The variables gender, loneliness, subjective
wellbeing, and marital status did not significantly
contribute to explaining the status of severe perio-
dontal disease. Factors that were associated with in-
creased risk of severe periodontal disease were age,
plaque index, and internal vs. external locus of con-
204
trol. Subjects who believed that they did not have
control over their disease (external locus) had a worse
disease status than those subjects who maintained a
positive attitude about their ability to influence the
progression of disease (internal locus). Hence, it was
concluded that the individuals ability to cope with
stress played an important role in the progression
of periodontal disease. The retrospective, cross-
sectional nature of the study design would seem to
preclude such strong conclusions.
The above data were supported by a cross-sec-
tional study performed on 1,426 subjects (40). After
adjusting for age, gender, smoking, and financial
strain, it was found that an inadequate coping strat-
egy was associated with an increased severity of
periodontal disease. Subjects with better coping be-
haviors (high levels of problem-focused coping) had
less periodontal tissue destruction, even though they
reported high levels of financial strain. In another
casecontrol study, the number and impact of neg-
ative life events, including unemployment, all corre-
lated significantly with severity of periodontitis (19).
The diagnosis of any disease, or seeking treatment,
may be seen as a potential stressor. It was unclear, in
this study, whether the life events were the conse-
quence or the cause of the disease.
Certain personality traits are over-represented in
establishing a link between stress and periodontal
disease, notably depression and poor coping strat-
egies. Subjects who are less able to cope tend to be
less responsive to therapy, indicating a poorer heal-
ing capacity (5). Thus, it may be that a patients
ability to cope with stressful situations is more
important than the stressful stimuli itself (30).
In general, human studies lack both a standardized
method to define stress and to quantify it (Table 3).
Defining stress ranges from subjective assessments of
stressful situations, such as during examinations or
military service, to physiological measurements, such
as plasma cortisol levels, cytokine profiles, and heart
rate. A major limitation is that these parameters all
show divergent reaction patterns, both within an
individual at different time points and between dif-
ferent individuals (122). In addition, the type of
studies that predominate in this area of investigation,
within the dental field, are case series and cross-
sectional studies. These study designs, by their very
nature, preclude a cause-and-effect relationship to be
concluded. Prospective clinical trials are required at
this time. Another potential confounding factor is
that subjects under high levels of stress may be more
likely to report symptoms. It is unclear whether it is
stress that is causing the reported signs and
 Table 3. Summary of animal studies
Animal model
Male albino rats. Vascular permeability
in gingival and alveolar mucosa after
ligature placement
Female mice. Cytokine expression
after cutaneous wound healing
Herpes simplex virus-1 antibody-negative
male mice infected with herpes simplex
virus-1 and time allowed establishment
of latency
Male SpragueDawley rats. Wound healing
in an immunocompromised host
Male Wistar rats. Effects of stress associated
with nicotine administration on periodontal
breakdown resulting from ligature-induced
periodontitis
Female Sabra mice. Impact of emotional
stress on the humoral immune response
to Porphyromonas gingivalis
Male Wistar rats. Effects of ligation, restraint
stress and their combination on
ligature-induced periodontitis
IgG1, immunoglobulin G1; IgG2a, immunoglobulin G2a.
205
Stress model
Capsaicin treatment
Mice were either treated with
subcutaneous injections of
dexamethasone or
phosphate-buffered saline
control
Stressors included disruption
of social hierarchy and
restraint stress
Rats had varying degrees of
immunosuppression induced,
indicated by circulating
neutrophil and lymphocyte
counts
Immobilization stress, with
and without intraperitoneal
nicotine injections
Emotional stress induced by
a combination of isolation
and limited living space.
Controls did not have
restraint stress imposed
Restraint stress inflicted
using a flexible wire mesh
adapted to the animals body
Findings Reference
No elevation of vascular permeability of gingivomucosal tissue was noted (130)
around ligated teeth in rats pretreated with capsaicin
Induction of interleukin-1 and tumor necrosis factor were significantly (19)
reduced during wound repair in glucocorticoid-treated mice.
Disruption of social hierarchy increased aggression, activated the (87)
hypothalamicpituitaryadrenal axis, and caused reactivation of
latent herpes simplex virus-1 in >40% of latently infected mice.
Activation of the hypothalamic-pituitary-adrenal axis using restraint
stress did not activate latent virus
Hydrocortisone treatment impaired wound healing. Decreased cell (88)
proliferation and significant reductions in tensile strength and
hydroxyproline content
Immobilization stress alone did not affect ligature-induced periodontitis. (95)
Presence of stress significantly enhanced the effects of nicotine on
alveolar bone loss
Lower antibody titres to Porphyromonas gingivalis in stressed animals (86)
7 days post-challenge were not statistically significant. A lower
IgG1/IgG2a ratio observed in stressed animals may suggest an elevated
T helper 1 cell response
Stressed animals exhibited a higher blood glucose level, plasma (16)
adrenocorticotropic hormone, corticosterone and adrenaline levels.
Stressed animals also exhibited marked alveolar bone resorption
compared with the control group
Stress in periodontal disease and wound healing
Boyapati & Wang
symptoms, or whether the signs and symptoms ari-
sing from a disease process cause the subject to feel
stressed. Future studies will benefit from a pros-
pective study design incorporating both physiological
and psychological measurements of stress.
Drawbacks of current models of
stress
Two major models to study the effect of stress on
systemic health have been proposed (89). The first
focuses on the role of major life events (60). The
second focuses on smaller, day-to-day, stresses (88).
There are two major problems with this relatively
simplistic classification. First, it is obvious that not all
factors inducing stress fall neatly into one or another
of these categories. For example, the death of a
spouse or loss of employment may be considered a
major life event, but the subsequent changes in life-
style may be seen as day-to-day stresses. Second, it is
difficult to determine whether it is the stressful events
that caused the altered disease pattern, or whether
the stress response is a consequence of having a
disease. Further studies in this area may benefit from
more sophisticated questionnaires and interview
methods to assess stress.
Another problem in this area of investigation,
within the dental field, is the lack of a uniform defi-
nition of stress. As alluded to previously, stress has
both a physiological and a psychological definition.
In addition, stress studies differ regarding whether
acute or chronic stress is the target of investigation.
Studies should be viewed with these points in mind
as the type of stress examined varies greatly between
published studies. Acute and chronic stress are
somewhat arbitrary terms. How can acute stress be
differentiated from chronic stress in a meaningful
way? This concept is one that is central to under-
standing the literature and how stress can affect
biological processes, such as wound healing. Take,
for example, an animal model where a session of
shock therapy may be considered an acute stressor,
whereas shocks on multiple occasions may be con-
sidered a chronic stressor. However, it could be ar-
gued that the initial contact could be referred to as
the acute phase and all time periods after this as the
chronic stage. This concept becomes important be-
cause it is generally agreed that the initial response to
acute stress is beneficial. It helps to ward off the
stressful event and maintain homeostasis (114).
However, when a stress becomes prolonged, these
mechanisms may become pathologic.
206
One of the major drawbacks of all of the current
studies stems from the lack of a uniform method of
quantifying stress (59). Methods to measure/quantify
stress, and the ability of a subject to cope with the
stress, usually consist of a number of questionnaires.
Questionnaires quantify psychological states, such as
anxiety, depression, loneliness, self-worth, and cop-
ing behaviors (13, 20, 29, 104). For example, when
using a stress scale, with only six items, to evaluate
anxiety, Genco et al. (40) found no differences among
groups with respect to any of the measured perio-
dontal parameters. An association may have been
found if participants had been given a more com-
prehensive questionnaire. In a sample of older sub-
jects, individuals scoring high on the Hospital Anxiety
and Depression Scale exhibited significantly im-
paired healing of chronic wounds (18).
In addition, the effects of stress may be altered by
gender, personality type, age, lifestyle, psychological
disorders, and varying coping styles (35, 40, 76).
Studies vary in the ethnic and gender distributions.
Some studies report higher rates of female patients
(89), which may be consistent with the gender dis-
tribution of depressive illness. Weinberger et al. (124)
suggested considering factors such as a subjects so-
cial, cultural, and economic background, in relation
to their ability to cope with stressful situations.
Various measures of wound healing have been
used, from reduction in the diameter of a wound and
amount of peroxide foaming (70), to measures of
alveolar bone height using digital subtraction radi-
ography (8). Histological and molecular markers of
wound healing are currently the gold standard for
measuring wound healing in vivo. Measures of peri-
odontal wound healing include wound strength (58),
gingival crevice fluid markers (such as osteocalcin)
(78), and various clinical and radiographic parame-
ters (62, 106, 120). A standard of quantifying stress
may enable future studies to be compared more
effectively.
Clinical implications
Traditional methods of treating periodontal disease
and optimizing wound healing after periodontal
surgery include thorough debridement of root surfa-
ces, optimizing oral hygiene, utilization of antimi-
crobial substances, and (more recently) adjunct use
of growth factors in various delivery vehicles. The
above literature, however, demonstrates that stress-
reduction protocols may have some value in the
management of periodontal disease. Assessment of a

patients stress levels (and perhaps more importantly,
their ability to cope with stress) and stress-reduction
protocols might be of value when instituted as part of
routine periodontal treatment.
Conclusion
The role of stress in human periodontal disease has
a plausible pathophysiological basis. Evidence has
suggested that stress is associated with more severe
periodontal disease, as well as poorer healing re-
sponses to traditional periodontal therapy. This is
because stress can cause behavior modification (e.g.
smoking, alcohol abuse, etc.) and immunosuppres-
sive effects (e.g. decreased polymorphonuclear leu-
kocyte function, altered T helper 1 cell/T helper 2 cell
ratio, etc.), which may result in greater severity of
periodontal disease as well as delayed wound healing.
This suggests that stress management may be a
valuable component for current periodontal practice.
However, at present, the majority of the literature
consists of case series and retrospective studies.
There are even fewer studies dealing with the role of
stress and periodontal wound healing. Thus, the ex-
act role of psychological factors in periodontal
wound healing remains to be elucidated, and further
well controlled, prospective clinical trials are war-
ranted.
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