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Stress, Cortisol, and Periodontitis in a Population Aged 50 Years and Over
1 Post-graduate Program in Epidemiology, Faculty of Medicine, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2600/414 Porto Alegre, RS 90035-003, Brazil; Correspondence: * corresponding author, juhilger{at}terra.com.br
Periodontitis and its relationship with psycho-neuro-immunological variables, such as psychological stress and cortisol, have been little explored. The objective of this study was to evaluate the extent and severity of chronic periodontitis and its association with the levels of salivary cortisol and the scores obtained with a stress questionnaire in a population aged 50 years and over. We studied 235 individuals in a cross-sectional study. They answered the Lipp’s Inventory of Stress Symptoms for Adults, were instructed to collect three saliva samples for cortisol analysis, and were examined for evaluation for periodontitis. Based on logistic regression, cortisol levels were positively associated with the following outcomes: means of clinical attachment level (CAL) > = 4 mm [OR = 5.1, 95%CI (1.2, 20.7)]; 30% of sites with CAL > = 5 mm [OR = 6.9, 95%CI (1.7, 27.1)]; and 26% of sites with probing depth > = 4 mm [OR = 10.7, 95%CI (1.9, 54.1)] after adjustment for confounding variables. The results suggest that cortisol levels were positively associated with the extent and severity of periodontitis.
Key Words: stress • periodontitis • glucocorticoids
Stress has been defined as either stimulus or response. Stimulus definitions focus on events in the environment. Response definitions, which have been prevalent in biology and medicine, refer to state stress. This definition of stress, however, has some drawbacks, and a more modern definition emphasizes the relationship between the person and the environment, taking into account characteristics of the person and the stressful event (Lazarus and Folkman, 1984). An organism’s functions are regulated by the nervous system and the endocrine system, which are interrelated. It is known that two pathways link the brain and the immune system, one of which is the hypothalamus-pituitary-adrenal axis (Guyton and Hall, 2000). It has been known for several decades that stress—whether inflammatory, traumatic, or psychological—is associated with concurrent activation of the hypothalamus-pituitary-adrenal axis. In the early 1990s, it also became apparent that cytokines and other humoral mediators of inflammation are potent activators of the central stress response (Tsigos et al., 1997). On the one hand, the glucocorticoids released via the activation of the hypothalamus-pituitary-adrenal axis seem to be important, due to their ability to regulate the recruitment of immune cells into inflamed tissues, as well as to skew the Th1/Th2 balance toward a Th2-dominant response (Breivik and Thrane, 2001). Also, a negative feedback, with the activation of the immune system, associated with the increase of circulating cytokines, increases the activity of the corticotropine-releasing hormone, activating the hypothalamus-pituitary-adrenal axis and causing an elevation of the levels of cortisol. When the inflammatory action is sufficiently long and profound, systemic manifestations of the disease may become evident, as could happen with periodontitis (LeResche and Dworkin, 2002). There are several studies that have demonstrated a relationship between psychological stress and inflammatory diseases such as rheumatoid arthritis (Zautra et al., 1997) and periodontitis (da Silva et al., 1995; Breivik et al., 1996; Aurer et al., 1999; Genco et al., 1999). However, why and how these factors are associated with increased periodontal disease susceptibility are poorly understood. The field of brain-neuroendocrine-immune interactions, therefore, is an important field to be explored (Breivik and Thrane, 2001). Even though investigators have studied the impact of the immune response and of psychosocial components on the extent and severity of periodontitis, few studies have evaluated the impact of relationships among psychosocial well-being, status of the immune system, and the health of the periodontium. Our hypothesis was that stress elicits hypothalamus-pituitary-adrenal axis hyperactivation and leads to periodontitis. Thus, the purpose of this study was to evaluate the extent and the severity of chronic periodontitis and its association with the levels of cortisol and the scores of an inventory of stress symptoms in a population aged 50 years or older.
Population and Sample In this cross-sectional study, we evaluated 235 participants selected from caregivers of demented patients and from social activity groups of Porto Alegre, Brazil. Caregivers were included because they represent a model for exploring the impact of chronic stress on the endocrine and immune functions (Bauer et al., 2000). The sampling was by convenience. We included individuals with at least 6 teeth, excluding third molars, and who were 50 years old or older, and living independently. Participants who chronically used corticosteroids and/or immune suppressor drugs, as well as those with immune suppressor diseases, were excluded. The study was approved by the Committee of Ethics in Research of the Hospital de Clínicas de Porto Alegre, and all participants provided written informed consent.
Measures
Psychological Evaluation
Clinical Examinations We conducted a "pre-study" reliability test by performing duplicate dental examinations in six participants selected at the geriatric dental clinic of the Federal University of Rio Grande do Sul. The re-examinations to evaluate reproducibility "during the study" were performed 2 hrs after the end of the initial examination (Van der Weijden et al., 1994), in 6.5% (16 participants) of 247 participants who had dental examinations.
Severe periodontitis was defined as a mean CAL
Cortisol Analysis All samples were stored in a freezer at –20°C. After being defrosted, samples were centrifuged for 5 min at 1500 g. Salivary cortisol in the samples was measured by means of radioimmunoassay (Coat-A-Coat kit, DPC, Los Angeles, CA, USA) for the quantitative in vitro determination of cortisol in saliva. Analyses were performed in duplicate in serial sets. Inter- and intra-assay coefficients of variation varied from 5.1 to 7.9%. For our investigation, the three measurements were summarized by the area under the curve (AUC). All individuals whose cortisol AUC was at least 34.94 nmol/L/hr (90th percentile for AUC) were classified as hypercortisolemics.
Statistical Analysis AUC values for the cortisol radioimmunoassay were obtained by use of the trapezoidal rule with the Software GraphPad Prism 4.00 (GraphPad Software, San Diego, CA, USA). The intra- and inter-examiner reproducibilities of the categorical measurements obtained before and during the study (VPI, GBI, and BOP) were summarized by Cohen’s Kappa coefficient (Fleiss and Chilton, 1983). Reproducibility of continuous variables (PD and CAL) was examined by the method described by Bland and Altman (1998) and also summarized by the intraclass correlation coefficient (Bland and Altman, 1998). Lipp’s Stress Inventory reliability was tested by means of the Cronbach’s Alpha Coefficient (Lipp, 2000). We calculated Spearman correlations to check for association between Lipp’s Stress Inventory and salivary cortisol. Multivariate logistic regression allowed adjustment of the association between hypercortisolemia and periodontitis for possible confounders, such as demographic and socio-economic variables, as well as for diabetes, smoking, oral hygiene habits, time since the last visit to the dentist, previous periodontal treatment, VPI, GBI, BOP, Lipp’s Stress Inventory (stress phases and scores), and caregiving status. Demographic and socioeconomic variables, diabetes, smoking, and oral hygiene habits were self-reported. Analysis was performed by means of SPSS (SPSS Inc., Chicago, IL, USA). All independent variables that showed association with p < 0.25, as well as those with clinical-epidemiological relevance, according to literature reports, were included in the multivariable model (Hosmer and Lemeshow, 1989). Any variable that was not significantly associated with the outcome, with p > 0.25, was eliminated, and a new model was calculated. The new model was always compared with the previous one by the likelihood ratio test. Adjusted Odds Ratios (OR) are shown with the 95% confidence intervals (95%CI). More details regarding drop-outs, psychological evaluation, clinical reproducibility analysis and data, salivary cortisol analyses, and assessment of confounders in the study are presented in the APPENDIX.
Characteristics of the studied sample are shown in Table 1  . There was a higher percentage of female individuals. Age ranged from 50 to 86 yrs, and the average monthly income was higher than US$ 750.00. There was a significantly higher number of non-caregivers with hypercortisolemia (30% vs. 54%, p = 0.04) (Table 1).
The kappa coefficients for intra- and inter-examiner reproducibilities of VPI before and during the study ranged from 0.7 to 0.84. For GBI and BOP, Kappa was about 0.50. Intra- and inter-examiners’ mean absolute differences between measured variables (i.e., PD and CAL) were between 0.22 and 0.35 mm. The intraclass correlation coefficients for intra- and inter-examiner reproducibilities of PD and CAL before and during the study ranged from 0.72 to 0.94. Cronbach’s Alpha value for Lipp’s Stress Inventory reliability evaluation was 0.89. Values of Spearman’s correlations (rS) between the different Lipp’s Stress Inventory phases and scores and the AUC of salivary cortisol measures are included in the supplemental material. Analysis of the data showed no statistically significant associations between or among any of the evaluated items (–0.1 < rS < 0.1, p > 0.18).
Results of logistic regression analysis are shown in terms of crude and adjusted OR’s and corresponding 95%CI (Tables 2
The variables hypercortisolemia (yes/no), BOP on at least 26% of the sites (yes/no), male gender and last dental visit more than a year ago (yes/no) showed to be independently associated with severity of periodontitis (mean CAL > = 4 mm vs. < 4 mm) (Table 2  ). Hypercortisolemia (yes/no), age (> 60 yrs vs.  60, with a positive and significant trend between age and outcome), gender, BOP in 25% of the sites vs. 25%, and oral hygiene (brushing vs. brushing and flossing) were independently associated with the extent of periodontitis, as defined by CAL (at least 30% of the sites having at least 5 mm attachment loss vs. less than 30%). The variables hypercortisolemia (yes/no), age (> 70 vs. 60), BOP (in  26% vs. < 26% of the sites), and GBI (in 40% vs. < 40% of the sites were independently associated with extensive periodontitis, as defined by PD ( 26% vs. < 26% of the sites with PD 4 mm) (Table 3). Further results are presented in the APPENDIX.
The results of this cross-sectional study suggest that, in a population aged at least 50 yrs, elevated levels of cortisol were associated with the extent and severity of periodontitis, even after adjustment for several important variables, such as age, sex, oral hygiene, BOP, smoking, Lipp’s Stress Inventory phases, and scores in a population aged 50 or older. The reproducibility values of both CAL and PD measures were considered good (López et al., 2003). The reproducibility of the intra-examiner VPI measures’ values was considered excellent, while the inter-examiner VPI values and intra- and inter-examiners’ GBI were good (Fleiss and Chilton, 1983). The Alpha coefficient value was = 0.89 for Lipp’s Stress Inventory, which means good reliability for the instrument. The age group chosen for evaluation in this study was adults aged at least 50 yrs, because epidemiologic studies have indicated that both the severity (Norderyd and Hugoson, 1998; Wimmer et al., 2002) and the prevalence (Heitz-Mayfield et al., 2003) of chronic periodontitis are higher in individuals of this age group. In this study, cortisol level was not associated with the psychosocial stress phases index. This lack of association is compatible with the results of Mengel (Mengel et al., 2002) and Vedhara (Vedhara et al., 2003), who did not find any association between cortisol and psychological stress. This result may be related to how individuals deal with stress, and it would be in agreement with evidence indicating that different strategies of coping can produce different stress responses in the hypothalamus-pituitary-adrenal axis (cortisol). According to Bohnen (Bohnen et al., 1991), there is a negative correlation between stress coping and the individual response of cortisol to stress. Cortisol was associated with the three outcomes studied, even after adjustment for several variables. Analysis of these data suggests that the activation of the hypothalamus-pituitary-adrenal axis may be associated with the observed periodontal destruction. Animal studies have shown that rats with extreme genetic differences in their hypothalamus-pituitary-adrenal axis structure, and in reactivity to stressful stimuli, show significant differences in their susceptibility to periodontal disease (Breivik et al., 2001). The behavioral and neuroendocrine genetic differences between individuals with high- and low-responding hypothalamus-pituitary-adrenal axes, however, can be modulated by environmental factors (Breivik and Thrane, 2001). Two human studies examined the association between cortisol and periodontal disease. The first verified that, in a subsample of individuals with and without periodontitis (Genco et al., 1998), the mean of cortisol was higher in the group of patients with the disease. In the other study, cortisol was measured in patients with periodontitis to examine interactions with psychosocial stress. The study did not find statistically significant correlations among the immunological mediators (IL-1β, IL-6), cortisol, and stress (Mengel et al., 2002); however, sample sizes were small. Susceptibility to periodontal disease seems to be partly due to the inhibition of T-cell immune responses mediated by glucocorticoids. This leads to a change toward the antibody-mediated immunity (Th2-mediated response) that can, subsequently, lead to a growth of pathogenic micro-organisms that activates a cellular response (Elenkov et al., 1996). The price to be paid to support the activation of this response is the local tissue destruction observed during active periodontal disease (Breivik and Thrane, 2001). This is one of the first human studies to evaluate the important role of the hyperactivation of the hypothalamus-pituitary-adrenal axis, assessed by salivary levels of cortisol, on the extent and severity of chronic periodontitis. However, other, mainly longitudinal, studies are necessary to confirm this hypothesis. It is also important that new studies in the periodontal epidemiology area evaluate the role of social support and stress-coping strategies, together with psychosocial/physiological stress, on the establishment and progression of periodontitis. Our results suggest that, in a population aged 50 years or older, cortisol and chronic periodontitis are associated.
This investigation was supported by CNPq and Casa do Psicólogo.
A supplemental appendix to this article is published electronically only at http://www.dentalresearch.org. Received for publication June 2, 2004. Revision received October 23, 2005. Accepted for publication November 7, 2005.
Journal of Dental Research, Vol. 85, No. 4,
324-328 (2006)
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ABSTRACT
INTRODUCTION