There are marked social differences in coronary heart disease

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1 Measures of Social Position and Cortisol Secretion in an Aging Population: Findings From the Whitehall II Study MEENA KUMARI, PHD, ELLENA BADRICK, MSC, TARANI CHANDOLA, PHD, NANCY E. ADLER, PHD, ELLISA EPEL, PHD, TERESA SEEMAN, PHD, CLEMENS KIRSCHBAUM, PHD, AND MICHAEL G. MARMOT, FRCP Objective: To examine whether dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis associated with disadvantaged social position in working populations also occurs in older age groups. Methods: This study examines the association of several indicators of social position with two measures of cortisol secretion, a product of the HPA axis. We examined the cortisol awakening response (CAR), and slope of the decline in cortisol secretion across the day. We examine whether the association is mediated by behavioral, psychosocial, and biological factors in 3992 participants of phase 7 ( ) of the Whitehall II study, who provided six salivary cortisol samples across the day. Results: In this older cohort (mean age 61 years; range years), lowest social position (assessed by current or previous occupational grade and wealth) was associated with a flatter slope in the decline in cortisol secretion. For example, over the course of the day, men in the lowest employment grades had a reduction in their cortisol by (nmol/l/h), which was a shallower slope than those in the high grades ( nmol/l/h). The difference in slopes by employment grade among men, but not women, was statistically significant (p.003). The difference in slopes was explained primarily by poor health and sleep behaviors, although financial insecurity also played a role. No effects were apparent with the CAR or other measures of social position. Conclusions: In men, poorer health and sleep behaviors (primarily smoking and short sleep duration), and financial insecurity mediate the impact of occupational status and wealth on cortisol secretion. Key words: cortisol, occupational status, income, financial insecurity, aging cohort. BMI body mass index; CAR cortisol awakening response; CES-D Center for Epidemiological Studies Depression Scale; HPA hypothalamic-pituitary-adrenal. INTRODUCTION There are marked social differences in coronary heart disease throughout the western world such that there is a higher prevalence of disease associated with social disadvantage defined by occupational position, income, and education (1). The pathways through which disadvantaged social position elevates risk factors and increased prevalence of disease are not well established. Findings from the Whitehall II study indicated that, although lifestyle factors, such as smoking, contribute to the social gradient in disease, they fail to explain the association fully (2). The physiological effects associated with increased stress for socially disadvantaged groups are hypothesized to play a role. However, evidence for an association of social position with activation of the hypothalamic-pituitary-adrenal (HPA) axis, a primary stress-mediating pathway leading to From the International Institute for Society and Health (M.K., T.C., M.M.), University College London, London, UK; Centre for Health Sciences (E.B.), Barts and the London School of Medicine and Dentistry, London, UK; Department of Psychiatry (N.A., E.E.), University of California, San Francisco, San Francisco, California; David Geffen School of Medicine at UCLA (T.S.), Los Angeles, California; and Biological Psychology (C.K.), Technical University of Dresden, Dresden, Germany. Address correspondence and reprint requests to Meena Kumari, International Institute for Society and Health, University College London, 1-19 Torrington Place, London, WC1E 6BT, UK. m.kumari@ucl.ac.uk Received for publication May 11, 2009; revision received September 11, The Whitehall II study has been supported by grants from the Medical Research Council (MRC); Economic and Social Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (Grant HL36310), National Institutes of Health: National Institute on Aging (Grant AG13196); Agency for Health Care Policy Research (Grant HS06516); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. M.G.M. is supported by an MRC Professorship. T.C. and M.K. are supported by the Economic and Social Research Council International Centre for Life Course Studies in Society and Health (Grant RES ) as well as the MRC. DOI: /PSY.0b013e3181c85712 Psychosomatic Medicine 72:27 34 (2010) /10/ Copyright 2010 by the American Psychosomatic Society increased peripheral cortisol levels, is mixed. The discrepancies may be related to the diurnal rhythm in cortisol secretion. The typical pattern of cortisol secretion comprises a sharp morning rise in cortisol upon waking followed by a decline in release throughout the day. These components of cortisol secretion may have different correlates. For example, greater cortisol responses to awakening have been related to greater perceived stress (3) and depressive symptoms (4). Greater average daily cortisol levels are associated with weak social networks (5) and loss of sleep (6). Flatter, or less steep, slopes in cortisol secretion are associated with fatigue in clinical populations and with mortality in patients with breast cancer (7,8). With regard to social position, a study of over 750 adults aged between 35 years and 65 years showed positive associations between morning cortisol, a measure reflecting both diurnal regulation and HPA activation in response to waking, sampled at 7 AM to 8 AM, and social position defined by education or occupation (9). In a sample of older patients, increased morning cortisol secretion was associated with lower subjective social position (10). In the 1958 British birth cohort, disadvantaged social class was associated with increased area under the curve in early morning cortisol secretion (collected 45 minutes and 3.5 hours after waking) (11) independently of waking time and body mass index (BMI). Findings from a subset of 227 healthy participants of the Whitehall II study aged between 45 years and 58 years showed no association of civil service employment grade and morning cortisol secretion but an increased release of cortisol throughout the day from men and decreased release in women working in lower employment grades compared with those working in higher employment grades (12). Most recently, Vreeberg et al. reported no association of educational attainment with a number of measures of cortisol secretion (13). The Coronary Artery Risk Development In young Adults (CARDIA) study also reported no association of morning cortisol secretion with social position, assessed by years of education and income, but cortisol was increased in the after- 27

2 M. KUMARI et al. noon and evening and slope of cortisol secretion was flatter or more shallow in those with less education or income (14). In CARDIA, elevated evening levels of cortisol among those with lower social position were mostly explained by differences in health behaviors, primarily smoking, although psychosocial factors also played a role. In the Whitehall II study, we previously described the role of a number of psychosocial factors including future financial insecurity in social differences in health (15). However, the association of financial insecurity and cortisol secretion has not been examined. Here we examine the patterns of cortisol release in 3992 participants of the Whitehall II study. Participants were aged between 55 years and 72 years and 42% of men and 49% of women described themselves as retired. In older cohorts, education, occupational status, and income may not be the optimal measures of current social position given that participants may be retired or have completed their education decades previously (16). Other measures, such as accumulation of wealth, may be more applicable to the current situation in older age groups. We therefore compare cortisol secretion by a number of measures of social position; educational attainment, last known or current civil service employment grade, current income, wealth, and a subjective measure of social position the MacArthur subjective social position scale. The distribution of social position is very different in men and women, and so the associations are examined separately. Cortisol secretion is assessed in two ways: 1) cortisol awakening response; and 2) slope of cortisol secretion. We examine the cortisol awakening response as our measure of morning cortisol. Our review of the association of morning cortisol and measures of social position is equivocal in its conclusions as three of six studies reported no association. Analyses here are descriptive in a large community-based study. Two of three previous studies that have examined daytime or slope in cortisol secretion lead us to hypothesize that higher social position will be associated with a steeper slope in diurnal cortisol secretion. We examine a role for health behaviors and psychosocial factors in these associations. MATERIALS AND METHODS Participants Data reported here are from phase 7 ( ) of the Whitehall II study. The Whitehall II cohort was initially recruited between 1985 and 1988 (phase 1) from 20 London-based civil service departments; 10,308 people participated; details of the clinical cohort have been reported elsewhere (17). There were 6941 participants at phase 7. Saliva sample collection was initiated part way through phase 7, and of those participants who were asked to collect saliva samples, 90.1% (n 4609) returned samples. In analyses reported here, fewer participants were in the lowest employment grades compared with phase 1 of the study; however, this difference was small. Ethical approval for the Whitehall II study was obtained from the University College London Medical School committee on the ethics of human research. Informed consent for involvement in the study was obtained from every participant. Cortisol Collection and Analysis Saliva sample collection was initiated part way through phase 7 of the Whitehall II study (18). In a face-to-face interview, participants were requested to provide six saliva samples in salivettes over the course of a normal weekday at waking, 30 minutes, 2.5 hours, 8 hours, 12 hours, and bedtime. Participants were instructed to not brush teeth, eat, or drink anything for 15 minutes before sample collection. An instruction booklet was used to record information on the day of sampling including date of collection, wake time, time each sample was taken, and stressful events. The salivettes and booklet were returned via post. Salivettes were centrifuged at 3000 rpm for 5 minutes, resulting in a clear supernatant of low viscosity. Salivary cortisol levels were measured, using a commercial immunoassay with chemiluminescence detection (CLIA, IBLHamburg, Hamburg, Germany). The lower concentration limit of this assay was 0.44 nmol/l; intra- and interassay coefficients of variance were 8%. Any sample 50 nmol/l was repeated. Measures of Social Position Educational attainment was assessed by highest educational qualification achieved. Participants of phase 5 ( ) chose one of 11 categories, which were collapsed to four groups (higher university denoting higher degree, university denoting degree; high secondary and low secondary denoting low secondary or no formal education). Social position at phase 7 was determined by employment grade if still in the civil service, or based on last employment grade if they had left the service. As for previous analyses (18,19), 12 nonindustrial civil service grades were collapsed into three or six categories. Income was assessed by questionnaire and precoded categories were collapsed into three equal groups; low income was defined as earning 15,000 a year. Wealth was assessed by the question: If you sold all your assets your household owns, for example, [list of assets], and cashed in savings and investments and paid off all your debts (including your mortgage), how much money do you think you would have? Six precoded categories were split into three groups: low wealth ( 0 199,000); medium ( 200, ,000); and high ( 400,000).Wealth and income were categorized into approximate tertiles as previously described for earlier phases of data collection (20). A measure of subjective social position, the MacArthur subjective social position scale, was attained at phase 7 by asking the participants to rate their social position vis à vis others in society on a visual analogue scale represented by a ladder containing ten rungs. These were categorized into three groups for presentation (21). Retirement status at phase 7 was assessed by asking the participants whether they were still working and if not, the reasons for not working. Assessment of Covariates at Phase 7 ( ) Demographic and Sample Collection Variables Age and sex were assessed by questionnaire. Waking up time was assessed by participants records on the day of the collection of saliva. Time difference between waking and taking the first sample was categorized into 5-minute intervals. Weekend (collection on Saturday or Sunday) and weekday collections were noted from date of sample collection. Health Behavior Variables Smoking status (18) was defined as current smokers versus the noncurrent smokers. Participants were also asked to record the time of falling asleep the night before and sleep duration the night before sample collection was calculated from these responses. Diet was assessed by questions on types of bread consumed and fruit and vegetable consumption. Vigorous physical activity was measured as previously described (22,23). Psychological/Psychosocial Variables The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms, using a cut point of 16 (24). Stress on the day of cortisol sampling was measured by questions as to whether the participant had experienced a stressful event, and if yes, how stressful this was. Responses were grouped into binary categories: no/not at all and somewhat/very stressful. Social support was assessed by questions assessing the number of close persons and confidants, negative and practical support available (25). This scale was summed for analyses and tertiles created for presentational purposes. Financial insecurity was assessed by the question, Thinking of the next 10 years, how financially secure do you feel? (15). 28 Psychosomatic Medicine 72:27 34 (2010)

3 SOCIAL DIFFERENCES IN CORTISOL SECRETION Participants who responded that they felt fairly insecure and insecure were categorized as financially insecure. Biological Variables Blood pressure, height, and weight to assess BMI and waist circumference were assessed, using previously described methods at phase 7 (22,23). Hypertension was classified as 140/90 mm Hg and high waist was defined as 102 cm in men and 88 cm in women. Statistics Cortisol data were skewed and were therefore logged for analysis. Conventionally, analyses are restricted to samples that are collected within 10 minutes of waking (sample 1 taken 10 minutes n 615) due to a reduced cortisol awakening response (CAR) (26). However, we did not see a difference in lateness by any measure of social position, so all participants were retained and adjustments were made by including time delay dummies in the models. Data were analyzed for interactions with both retirement status and weekday/workday collection and were not significant and were combined for analysis. Data were analyzed, using multilevel modeling which showed a cortisol secretion and measures of social position interaction with time of day, and so the CAR and slope of cortisol secretion were analyzed separately. Data were examined for interactions between sex and diurnal cortisol secretion and were found to be significant for slope in cortisol secretion only; therefore, combined data are shown for CAR but data for slope in cortisol secretion are shown separately for men and women. The CAR was calculated by subtracting cortisol at time 1 from cortisol at time 2. The slope of the decline in cortisol levels over the day was calculated by regressing cortisol values on time after waking samples were taken for samples 1, 3, 4, 5, and 6. As it is suggested that the CAR and slope in cortisol secretion are under different neurobiological control systems (27), sample 2 was not included to ensure that the CAR does not obscure the slope calculation. The diurnal slope in cortisol secretion across the day was derived from a hierarchical linear model to predict log cortisol in which measurement occasion was used as a level 1 identifier and person as a level 2 identifier with sample time as the independent variable and random intercepts and random slopes. The slope was estimated for each person as the overall slope (which was negative) plus the level two slope residual; lower (more negative) slopes indicate more rapid the decline in cortisol levels, whereas slope values closer to zero reflect flatter diurnal rhythms. Data were analyzed for linear and nonlinear interactions with time of day and only linear interactions were found to be significant. Social position markers were examined for an interaction with time over the day; if significant, this indicates a different rate of cortisol secretion over the day by group. To describe participant s characteristics, linear regression is used for continuous variables and chi squared for categorical variables. To examine the role of confounders and mediators of the association of social position and cortisol secretion, we ran models with initial adjustment age, wake time, time between waking and taking sample 1, time since waking. Then we ran models with additional adjustments for other potential mediators entered individually and then entered together. Final analyses were limited to data from the participants with complete data only. Analyses were performed, using SAS v9.1 and MLWin. V2.10 beta6. Psychosomatic Medicine 72:27 34 (2010) RESULTS Missing Data From the samples returned, 168 individual samples were not taken by participants, which equates to 0.6% of the total number of samples expected. During analysis, a total of 1002 individual samples were not assayed for technical reasons. Participants who reported taking any steroid medications were removed from the analysis (n 236). Final numbers available for analyses were Participants who were included in the study had a higher prevalence of current smoking than those who attended phase 7 (9.7% and 6.2%, respectively), lower prevalence of depressive symptoms (12.3% and 12.9%, respectively) but a similar BMI (mean [standard deviation] of 26.7 [4.4] and 26.8 [4.4], respectively). Table 1 shows the characteristics of participants included in the study by sex. We see that, compared with men, women are found in the lowest employment grades and income groups, have the least wealth, and report more financial insecurity. In analyses adjusted for age, waking time and time since waking only, the CAR is greater in women than men as is the decline in cortisol secretion across the day. The CAR was not associated with any measure of social position (Table 2). These data were apparent whether analyses TABLE 1. Participant Characteristics for Men and Women With Data Available for Measures of Social Position and Cortisol Secretion at Phase 7 of the Whitehall II Study ( ) Men SD Women SD Number with valid data Social position (%) Lowest employment grade Lowest income 15, Lowest wealth 100, Lowest educational attainment (low secondary) Lowest score on Macarthur subjective social position scale (0 4) Demographic and sample collection variables Mean age, years Mean wake up time (hr) Health behavior variables Current smokers (%) Sleep duration on night before sampling (hr) once a week eat fresh fruit/veg (%) Vigorous exercise ( METS) at least once per week (%) Psychological/psychosocial characteristics Depressive symptoms (%) Stress on day of sampling (%) Mean social support score (possible range 15 60) High financial insecurity (%) Biological characteristics Mean BP, mm Hg Systolic Diastolic Mean BMI, kg/m Mean waist circumference (cm) Mean cortisol awakening response (nmol/l) Mean slope in cortisol secretion (nmol/l/hr) SD standard deviation; METS metabolic equivalent of task score; BP blood pressure; BMI body mass index. 29

4 M. KUMARI et al. TABLE 2. Measures of Social Position and Cortisol Awakening Response at Phase 7 of the Whitehall II Study ( ), Age, Sex, Time of Waking and Time Since Waking Are Used as Covariates n CAR Confidence intervals Educational attainment High university , 8.0 University , 7.7 High secondary , 8.0 Low secondary , Employment grade High , 7.9 Middle , 7.7 Low , Wealth High , 7.6 Middle , 8.0 Low , Income High , 7.8 Middle , 7.8 Low , Subjective social position (tertiles) High , 7.8 Middle , 8.2 Low , The p values are from linear regression, using measures of social position entered as continuous variables. were conducted with those who collected their first sample within 10 minutes of waking (data available from authors) or whether the analyses were conducted in the whole group, adjusting for waking time and time since waking. No association was apparent with educational attainment and slope of cortisol secretion (Table 3). Those in the lowest employment grades had the least steep or flattest curves. For example, over the course of the day, men in the lowest employment grades had a reduction in their cortisol by nmol/l/h, which was a shallower slope than those in the highest grades ( nmol/l/h). This difference in slopes by employment grade among men was statistically significant (p.003). Similar data were apparent for wealth (p.0007) but were not significant for income. Table 4 describes mean cortisol secretion at each time point and shows that men working in the lowest employment grades have low cortisol levels on waking and a linear decline throughout the day, whereas those working in higher grades have higher waking cortisol values, but the decline in cortisol secretion across the day seems rapid and sustained. In women, cortisol values in the day were increased in those working in the lower grades compared with those working in the higher employment grades. Similar data are apparent for wealth and cortisol secretion. A flat slope in cortisol secretion was associated with early wake time, short sleep duration, current smoking, a poor diet, report of a very stressful event on the day of sampling, low social support, and high financial insecurity in men. Similar trends were apparent in women. These data are shown in p Table 5. Further examination of the association of cortisol section with obesity suggested a nonlinear association of BMI and waist circumference with slope in cortisol secretion (p.001 for quadratic term). When both BMI and waist circumference were included in the same model, only waist circumference remained significant. Thus, only waist circumference is included in the final models. The role of health behaviors, psychosocial/psychological factors, and biological factors in the association of employment grade, wealth, and slope in cortisol secretion were examined. For employment grade, when health and sleep behaviors were entered individually, smoking status statistically explained 34% of the association in men, whereas sleep duration explained 22.9%, together explaining 52% of the association (p.11 post adjustment). Further adjustment with the additional health and sleep behaviors examined provided little further influence on the association. Of the psychological and psychosocial factors examined, financial insecurity explained 21.6%, with other factors individually explaining 10% of the association. Further adjustment with the additional factors failed to provide substantially greater explanatory power. Biological characteristics played a small role. Simultaneous adjustment with smoking, financial insecurity, and waist circumference explained 73% of the association between employment grade and cortisol secretion in men (p.45 post adjustment). Results are TABLE 3. Measures of Social Position and Slope of Diurnal Cortisol Secretion at Phase 7 of the Whitehall II Study ( ), Age and Waking Time and Time Since Waking Are Used as Covariates Men Women Educational attainment High university University High secondary Low secondary p Employment grade High Middle Low p Wealth High Middle Low p Income High Middle Low p Subjective social position (tertiles) High Middle Low p The p values are from linear regression in which measures of social position were entered as continuous variables. 30 Psychosomatic Medicine 72:27 34 (2010)

5 SOCIAL DIFFERENCES IN CORTISOL SECRETION TABLE 4. Mean Cortisol Secretion at Each Time Point Examined by Current or Last Known Employment Grade and Wealth in Men and Women Men Women Low Medium High p Low Medium High p Employment Grade Waking Waking 2.5 hrs Waking 8 hrs Waking 12 hrs Bedtime Wealth Waking Waking 2.5 hrs Waking 8 hrs Waking 12 hrs Bedtime The p values are from linear regression, using current or last known employment grade or wealth as continuous variables with six categories. presented in Table 6 where similar results were apparent for wealth. DISCUSSION We find that social disadvantage, measured by the lowest civil service employment grades or lesser wealth accumulation, was associated with a flatter slope of cortisol secretion across the day in men. The associations with income were not significant, although in a similar direction. In women, many but not all of the trends were in similar direction but not significant. Our findings suggest that health and sleep behaviors explain the relationships, although day-to-day experiences and psychosocial factors also play a role in mediating differences in cortisol secretion. No associations were seen for the CAR. We confirm the findings of the CARDIA study, examining the association of social position and cortisol secretion (14), and we extend these findings to an older cohort, in which 42% of men and 49% of women are no longer working. We see no association between measures of social position and the CAR as seen in a previous study of a healthy subset of Whitehall II men, when the participants were aged between 45 years and 58 years (12). The failure to confirm a previous study describing an association of subjective social position with CAR (5) may be because we examined a community-dwelling population rather than an older patient population. It is unclear how our findings relate to those from the 1958 British Birth Cohort, where disadvantaged adult social class was associated with an increase in morning area under the curve and with abnormal secretion patterns, due to methodological differences, specifically different timing of samples. Trends in the association between measures of social position and slope of cortisol secretion were similar in men and women. Previously, in a healthy subset of working women in the Whitehall II study, higher levels of cortisol were observed in women working in higher employment grades than in lower employment grades (12), and effects were attributed to differing work-related characteristics, such as job control and demands (28). This Psychosomatic Medicine 72:27 34 (2010) difference in our findings may be because 49% of our women described themselves as retired at phase 7. Our findings suggest that the effect of occupation remains associated with cortisol secretion in men, but not in women. Although we confirm that higher social position is associated with a steeper decline in cortisol secretion as found in the CARDIA study, the actual measures of social position to be significantly associated differed. Thus, in CARDIA, associations were observed with income and educational attainment, whereas in the Whitehall II cohort, no associations were observed for educational attainment and income was not significantly related to cortisol secretion. This may reflect the differences in educational attainment in the two cohorts or may reflect a period effect. It is unclear why income was not related to cortisol secretion in Whitehall II. The average age of this cohort was 61 years, and the mandatory age of retirement in the civil service at the time of data collection ranged from 60 years to 65 years. This means that the majority of participants was approaching or had just reached retirement when sampled. This may complicate the assessment of income for the participants, as it may be that they are experiencing new or changing financial arrangements (for example, maturity of pension schemes). Educational attainment may not be the most appropriate measure of social position in an older cohort, who may have completed education decades previously. We confirm findings from our work and other studies that smoking (18), sleep behavior, and social supports (5,6,29) are associated with dysregulation of cortisol secretion. Our finding of no association of cortisol secretion with depressive symptoms is contrary to expectation (30,31) but may be related to the assessment of depressive symptoms, rather than major depression. We find a nonlinear association of adiposity with cortisol secretion with a more important role for waist circumference than BMI, supporting previous data suggesting a role for the HPA axis in central obesity (32,33). Interestingly, we see that financial insecurity is associated with flatter slopes in cortisol secretion in men. Trends were similar in women but not 31

6 M. KUMARI et al. TABLE 5. Slope of Cortisol Secretion and Association With Potential Confounding and Mediating Factors, Adjusted for Age and Waking Time at Phase 7 ( ) of the Whitehall II Study n Men n Women Demographic and collection variables Wake up time (hr) a 6 AM After 6 AM p.001 p.001 Health behavior variables Smokers Current Ex/never p.001 p.008 Sleep duration (hr) 5 hrs hrs p.001 p.001 Diet once a week eat fresh fruit/vegetables once a week eat fresh fruit/vegetables p.028 p.193 Exercise No vigorous exercise At least one occasion of vigorous exercise p.455 p.706 Psychological/psychosocial characteristics Depressive symptoms score 16 (CES-D) (CES-D) p.08 p.15 Stress on day of sampling Very stressful event on day of sampling No stressful event on day of sampling p.0003 p.497 Social support Lowest tertile of support All others p.005 p.02 Financial insecurity Financially insecure Financially secure p.002 p.76 Biological characteristics Hypertensive Normotensive p.20 p.55 Obese Overweight 25 to Normal weight p.36 p.10 Waist circumference Raised waist b Normal waist p.35 p.06 a These analyses are adjusted for age, waking time on day of sampling, and time of sample collection since waking. b More than 102 cm in men and 88 cm in women. The p value is from tests for heterogeneity for smoking, diet, depressive symptoms, and stress variables. Other p values are derived from linear analyses of continuous variables. The p values for blood pressure are derived from analysis of systolic blood pressure. Associations of anthropometry and slope in cortisol secretion were nonlinear (for example, quadratic term for body mass index in men, p.001 and women, p.0001). CES-D Center for Epidemiological Studies Depression Scale. 32 Psychosomatic Medicine 72:27 34 (2010)

7 SOCIAL DIFFERENCES IN CORTISOL SECRETION TABLE 6. Role of Confounders and Mediators and the Association of Measures of Social Position With Slope of Cortisol Secretion in Men. Analyses Limited to Those With Complete Data at Phase 7 (2002 to 2004) of the Whitehall II Study n Age, Wake Time, Time Between Waking and Taking Sample 1, Time Since Waking (Model 1) Model 1 Smoking and Sleep Duration Model 1 Financial Insecurity Model 1 Waist 2 Model 1 All Mediators Last known employment grade High Middle Low p Wealth High Middle Low p The p values represent tests for trend from linear regression. significant. Proximity to retirement may play a role here and it will be interesting to see whether this relationship remains when participants are further into retirement. In accordance with CARDIA (14), we find that social difference in cortisol secretion could be explained by health and sleep behaviors. Of the psychosocial factors examined, we found that financial insecurity, which is a measure of the perception of future financial difficulties, played a role in mediating social differences in cortisol secretion. It is unclear whether a flatter slope in cortisol is due to stress-related elevations, resulting from a stressful day, or long-term changes in circadian regulation as a result of chronic stress. Either way, a flattened slope in cortisol secretion is a risk factor. It has been related to earlier mortality in cancer patients (8). The prognostic properties of cortisol secretion for disease and mortality and the role of cortisol in mediating social differences in these and other outcomes remain to be determined in our cohort. The strengths and limitations of our study need to be considered. This is a large study of participants in early old age with an excellent response rate in which a number of measures of social position were examined. Indicators suggest that the participants understood the instructions and took samples correctly. A large number of possible confounders and mediators are examined. However, these are cross-sectional analyses that make it difficult to assess the direction of the association, which may be important in a study in which a number of participants have recently retired where there may be a differential change in health behavior by social position (23). Potential weaknesses are that the Whitehall II study is an occupational cohort and, therefore, not representative of the population, which may reduce the generalizability of the results (34). Cortisol secretion was assessed on a single day only, which may have obscured the CAR to situational rather than chronic correlates (35,36). In summary, we find that social disadvantage, assessed by wealth and current or previous occupational status, is associated with a flatter cortisol profile in older men. 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