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1.  Daytime Trajectories of Cortisol: Demographic and Socioeconomic Differences. Findings from The National Study of Daily Experiences 
Psychoneuroendocrinology  2013;38(11):10.1016/j.psyneuen.2013.06.010.
Summary
Cortisol's daytime rhythm is thought to be altered by aging and by exposure to chronic stress. However, measurement of an individual's usual cortisol rhythm is hampered by the effects of acute stressors, by differences between working days and weekends, by between-day variation in waking time and sleep duration, by variability in cortisol sampling times, and by possible variability in the timing of cortisol peak and nadir. Therefore, to determine differences in the usual daytime cortisol rhythm by age, socioeconomic status, and race/ethnicity, we measured salivary cortisol levels at four time-points, repeated over four days that included both weekdays and weekend days, in 1,693 men and women from a national sample, and used three alternate growth curve specifications for the underlying cortisol rhythm (linear spline, quadratic spline, piece-wise linear-cubic) in order to minimize the impact of sample timing and other methodological issues. Model-predicted mean values of (and demographic and socioeconomic differences in) cortisol peak, nadir, and area under the curve (AUC) were nearly identical across model specifications. Older age and male gender were independently associated with higher cortisol peak, nadir, and AUC. Low education and minority race/ethnicity status were independently associated with lower cortisol peak and higher nadir, but were not associated with AUC. We also found significant cortisol peak and AUC associations with waking time, sleep duration, and workday vs. weekend day status, suggesting the importance of measuring these confounders and of collecting cortisol measurements over multiple days in research studies. We conclude that daytime cortisol levels are higher in older age and in men compared to women, and that the daytime cortisol rhythm is flatter (more blunted) in less privileged segments of society. Flattening of daytime cortisol rhythms may represent one mechanism by which social stressors lead to poor health outcomes.
doi:10.1016/j.psyneuen.2013.06.010
PMCID: PMC3812359  PMID: 23831263
Cortisol diurnal rhythm; socioeconomic status; age; gender; race; spline regression; cortisol peak; cortisol nadir; cortisol area under the curve
2.  Relationship between the cortisol awakening response and other features of the diurnal cortisol rhythm: The Multi-Ethnic Study of Atherosclerosis 
Psychoneuroendocrinology  2013;38(11):10.1016/j.psyneuen.2013.06.032.
Summary
Cumulative cortisol burden is known to influence neuropsychiatric and metabolic disorders. To better understand the relationship between daily cortisol exposure and measures of the diurnal circadian cortisol rhythm, we examined the cross-sectional association of the cortisol awakening response (CAR) with wake-up cortisol, bedtime cortisol, diurnal slope, and total cortisol area under the curve (AUC). Up to 18 salivary cortisol samples were collected over 3 days from 935 White, Hispanic, and Black individuals (mean age 65 ± 9.8 years) in the Multi-Ethnic Study of Atherosclerosis. Outcome measures included awakening cortisol, CAR (awakening to 30 min post-awakening), early decline (30 min to 2 h post-awakening), late decline (2 h post-awakening to bedtime), and the corresponding AUCs. Total cortisol AUC was a summary measure of cumulative cortisol exposure. Higher CAR was associated with significantly lower wake-up cortisol (β = −0.56; 95% CI: −0.59 to −0.53) and a higher early decline AUC (β = 0.38; 95% CI: 0.34–0.42) but was not associated with total cortisol AUC (β = 0.04; 95% CI: −0.01 to 0.09), or other diurnal cortisol curve components following multivariable adjustment. Total cortisol AUC was significantly and positively associated with wake-up cortisol (β = 0.36; 95% CI: 0.32–0.40), bedtime cortisol (β = 0.61; 95% CI: 0.58–0.64), and other AUC measures, following multivariable adjustment. Associations were similar by sex, race/ethnicity, and age categories. We conclude that bedtime cortisol showed the strongest correlation with total cortisol AUC, suggesting it may be a marker of daily cortisol exposure.
doi:10.1016/j.psyneuen.2013.06.032
PMCID: PMC3812410  PMID: 23890985
Cortisol awakening response (CAR); Hypothalamic–pituitary–adrenal (HPA) axis; Diurnal cortisol; Correlation; Population-based study
3.  Cumulative Stress and Cortisol Disruption among Black and Hispanic Pregnant Women in an Urban Cohort 
While adult hypothalamic-pituitary-adrenocortical (HPA) axis functioning is thought to be altered by traumatic experiences, little data exist on the effects of cumulative stress on HPA functioning among pregnant women or among specific racial and ethnic groups. Individuals may be increasingly vulnerable to physiological alterations when experiencing cumulative effects of multiple stressors. These effects may be particularly relevant in urban poor communities where exposure to multiple stressors is more prevalent. The goal of this study was to explore the effects of multiple social stressors on HPA axis functioning in a sample of urban Black (n = 68) and Hispanic (n = 132) pregnant women enrolled in the Asthma Coalition on Community, Environment, and Social Stress (ACCESS). Pregnant women were administered the Revised Conflict Tactics Scale (R-CTS) survey to assess interpersonal violence, the Experiences of Discrimination (EOD) survey, the Crisis in Family Systems-Revised (CRISYS-R) negative life events survey, and the My Exposure to Violence (ETV) survey, which ascertains exposure to community violence. A cumulative stress measure was derived from these instruments. Salivary cortisol samples were collected five times per day over three days to assess area under the curve (AUC), morning change, and basal awakening response in order to characterize diurnal salivary cortisol patterns. Repeated measures mixed models, stratified by race/ethnicity, were performed adjusting for education level, age, smoking status, body mass index and weeks pregnant at time of cortisol sampling. The majority of Hispanic participants (57%) had low cumulative stress exposure, while the majority of Black participants had intermediate (35%) or high (41%) cumulative stress exposure. Results showed that among Black but not Hispanic women, cumulative stress was associated with lower morning cortisol levels, including a flatter waking to bedtime rhythm. These analyses suggest that the combined effects of cumulative stressful experiences are associated with disrupted HPA functioning among pregnant women. While the etiology of racial/ethnic differences in stress-induced HPA alterations is not clear, this warrants further research.
doi:10.1037/a0018953
PMCID: PMC3057193  PMID: 21423846
4.  Hair cortisol levels as a retrospective marker of hypothalamic-pituitary axis activity throughout pregnancy: Comparison to salivary cortisol 
Physiology & behavior  2011;104(2):348-353.
Maternal stress during pregnancy is associated with negative maternal/child outcomes. One potential biomarker of the maternal stress response is cortisol, a product of activity of the hypothalamic-pituitary-adrenal axis. This study evaluated cortisol levels in hair throughout pregnancy as a marker of total cortisol release. Cortisol levels in hair have been shown to be easily quantifiable and may be representative of total cortisol release more than single saliva or serum measures. Hair cortisol provides a simple way to monitor total cortisol release over an extended period of time. Hair cortisol levels were determined from each trimester (15, 26 and 36 wks gestation) and 3 months postpartum. Hair cortisol levels were compared to diurnal salivary cortisol collected over 3 days (3 times/day) at 14, 18, 23, 29, and 34 wks gestational age and 6 wks postpartum from 21 pregnant women. Both salivary and hair cortisol levels rose during pregnancy as expected. Hair cortisol and diurnal salivary cortisol area under the curve with respect to ground (AUCg) were also correlated throughout pregnancy. Levels of cortisol in hair are a valid and useful tool to measure long-term cortisol activity. Hair cortisol avoids methodological problems associated with collection other cortisol measures such as plasma, urine, or saliva and is a reliable metric of HPA activity throughout pregnancy reflecting total cortisol release over an extended period.
doi:10.1016/j.physbeh.2011.02.041
PMCID: PMC3118940  PMID: 21397617
hypothalamic pituitary adrenal axis; stress biomarkers; thrifty phenotype; early programming
5.  The Relationship Between Fluticasone Furoate Systemic Exposure and Cortisol Suppression 
Clinical Pharmacokinetics  2013;52(10):885-896.
Introduction
The inhaled corticosteroid (ICS) fluticasone furoate is in development, in combination with the long-acting beta2-agonist vilanterol for the once-daily treatment of asthma and chronic obstructive pulmonary disease and as a monotherapy treatment for asthma. Corticosteroids, including ICSs, have the potential to induce dose-dependent systemic effects on the hypothalamic–pituitary–adrenal (HPA) axis. Cortisol suppression has been observed in asthma patients with normal HPA axis function at baseline on receiving high doses of ICSs, and is associated with adverse effects on a number of physiological processes. The measurement of 24-h serum cortisol and 24-h urinary cortisol excretion are sensitive methods for assessing adrenocortical activity, and can evaluate cortisol suppression in a dose-dependent manner.
Objective
The purpose of the meta-analysis presented here was to characterize the population pharmacokinetic/pharmacodynamic relationship between fluticasone furoate systemic exposure [as measured by area under the concentration–time curve over 24 h postdose (AUC24)] and both 24-h weighted mean serum cortisol (WM24) and 24-h urine cortisol excretion in healthy subjects and subjects with asthma.
Methods
The serum cortisol meta-analysis integrated eight studies; five Phase I studies in healthy subjects, two Phase IIa studies, and one Phase III study in subjects with asthma. Each study included serial blood sampling for estimation of WM24. The urine cortisol meta-analysis integrated three studies: one Phase I study in healthy subjects, and one Phase IIb and one Phase III study in subjects with asthma. Each study included complete 0–24 h urine collection for estimation of urine cortisol excretion. All studies included blood sampling for estimation of fluticasone furoate AUC24. A sigmoid maximum effect (Emax) model was fitted to fluticasone furoate AUC24 and serum cortisol and urine cortisol data using nonlinear mixed-effect modeling with the computer program NONMEM®.
Results
Over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range, the relationship between fluticasone furoate AUC24 and WM24 and 24-h urine cortisol excretion was well described by an Emax model. The average estimate of AUC producing 50 % of maximum effect (AUC50) was similar for the serum cortisol and urine cortisol models with values of 1,556 and 1,686 pg·h/mL, respectively. Although formulation/inhaler was shown to be a significant covariate on the estimates of both WM24 at zero concentration (C0) and AUC50 in the serum cortisol model, the differences were small and believed to be due to study variability. Age was shown to be a significant covariate on the estimates of both C0 and AUC50 in the urine cortisol model, and was considered to be a reflection of lower urine cortisol excretion in adolescents.
Conclusion
A pharmacokinetic/pharmacodynamic model has been established over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range to both WM24 and 24-h urine cortisol excretion. The values of AUC50 of 1,556 and 1,686 pg·h/mL, respectively, are several times higher than average fluticasone furoate AUC24 values observed at clinical doses of fluticasone furoate (≤200 μg). The models predict a fluticasone furoate AUC24 of 1,000 pg·h/mL would be required to reduce 24-h serum cortisol or 24-h urine cortisol excretion by 20 and 17 %, respectively.
doi:10.1007/s40262-013-0078-1
PMCID: PMC3779313  PMID: 23719680
6.  Associations of salivary cortisol levels with inflammatory markers: the Multi-Ethnic Study of Atherosclerosis 
Psychoneuroendocrinology  2011;37(7):1009-1018.
Socioeconomic and psychosocial factors have been found to be associated with systemic inflammation. Although stress is often proposed as a contributor to these associations, no population studies have investigated the links between inflammation and biomarkers of stress. The current study examines associations between daily cortisol profiles and inflammatory markers interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor (TNF-a) in a population-based sample of 869 adults with repeat measures of cortisol over multiple days. Persons with higher levels of IL-6 had a less pronounced cortisol awakening response, a less steep daily decline, and higher cortisol area under the curve for the day with associations persisting after controls for risk factors and other cytokines. Persons with higher levels of TNF-a had lower cortisol levels upon waking, and flatter daily decline, although associations with decline were attenuated when controlling for inflammatory risk factors. Higher levels of IL-10 were associated with marginally flatter daily cortisol decline (p < .10). This study is the first to identify associations of basal cortisol activity and inflammatory markers in a population-based sample. Findings are consistent with the possibility that HPA axis activity may mediate associations between psychosocial stressors and inflammatory processes. Additional prospective data are necessary to clarify the directionality of associations between cortisol and inflammatory markers.
doi:10.1016/j.psyneuen.2011.11.009
PMCID: PMC3358540  PMID: 22178583
HPA Axis; cortisol; inflammation; cytokines
7.  Allostasis model facilitates understanding race differences in the diurnal cortisol rhythm 
Development and psychopathology  2011;23(4):1167-1186.
The concept of allostasis suggests that greater cumulative stress burden can influence stress-responsive physiology. Dysregulation of allostatic mediators, including the hypothalamic-pituitary-adrenal (HPA) axis, is thought to precede many other signs of age-related pathology as the persistent burden of stressors accumulates over the individual's lifespan. We predicted that even in young adulthood, HPA regulation would differ between Blacks and Whites reflecting, in part, higher rates of stressor exposure and greater potential for stressors to “get under the skin”. We examined whether stressor exposure, including experiences with racism and discrimination, explained race differences in waking cortisol and the diurnal rhythm. We also examined whether HPA functioning was associated with mental health outcomes previously linked to cortisol. Salivary cortisol was assayed in 275 young adults (127 Blacks, 148 Whites, 19 to 22 years old), four times a day across 3 days. Hierarchical linear models revealed flatter slopes for Blacks, reflecting significantly lower waking and higher bedtime cortisol levels compared to Whites. Associations of HPA functioning with stressors were typically more robust for Whites such that more stress exposure created an HPA profile that resembled that of Black young adults. For Blacks, greater stressor exposure did not further impact HPA functioning, or, when significant, was often associated with higher cortisol levels. Across both races, flatter slopes generally indicated greater HPA dysregulation and were associated with poor mental health outcomes. These differential effects were more robust for Whites. These findings support an allostatic model in which social contextual factors influence normal biorhythms, even as early as young adulthood.
doi:10.1017/S095457941100054X
PMCID: PMC3583352  PMID: 22018088
allostasis; cortisol; race differences; HPA axis
8.  Genetic and environmental influences on individual differences in cortisol level and circadian rhythm in middle childhood 
Hormones and Behavior  2012;62(1):36-42.
Individuals differ widely in cortisol output over the day, but the etiology of these individual differences remains poorly understood. Twin studies are useful for quantifying genetic and environmental influences on variation in cortisol output, lending insight into underlying influences on the components of Hypothalamic-Pituitary-Adrenal (HPA) axis functioning.
Salivary cortisol was assayed on 446 twin pairs (157 monozygotic, 289 dizygotic; ages 7–8). Parents helped youth collect saliva 30 min after waking, mid-afternoon, and 30 minutes prior to bedtime across 3 consecutive days. We used hierarchical linear modeling to extract predicted cortisol levels and to distinguish cortisol’s diurnal rhythm using a slopes-as-outcome piecewise growth curve model; two slopes captured the morning-to-afternoon and afternoon-to-evening rhythm, respectively. Separate genetic models were then fit to cortisol level at waking, mid-afternoon, and evening as well as the diurnal rhythm across morning-to-afternoon and afternoon-to-evening hours.
Three results from these analyses are striking. First, morning-to-afternoon cortisol level showed the highest additive genetic variance (heritability), consistent with prior research. Second, cortisol’s diurnal rhythm had an additive genetic component, particularly across the morning-to-afternoon hours. In contrast, additive genetic variation did not significantly contribute to variation in afternoon-to-evening slope. Third, the majority of variance in cortisol concentration was associated with shared family environments. In summary, both genetic and environmental factors influence cortisol’s circadian rhythm, and they do so differentially across the day.
doi:10.1016/j.yhbeh.2012.04.014
PMCID: PMC3377812  PMID: 22583671
HPA axis; cortisol; diurnal rhythm; twins; behavior genetics
9.  Blunted Diurnal Decline of Cortisol among Older Adults with Low Socioeconomic Status 
Low socioeconomic status (SES) is associated with increased risk for adverse health outcomes; those with low SES are thought to experience more environmental disadvantage and exposure to chronic stress over the life course. The effects of chronic stress on health have been measured by cortisol levels and variations in their diurnal pattern. However, the patterns of association between SES and cortisol have been equivocal in older adults. This paper examined in 98 older adults participating in the Brain Health Substudy of the Baltimore Experience Corps Trial baseline patterns of diurnal variation in salivary cortisol associated with lower versus higher SES using total income and perceived SES relative to others. For each measure, participants stratified into lower vs. higher SES showed a more blunted rate of decline in diurnal salivary cortisol over the day in adjusted models (P values ≤ 0.05). There were no SES-related differences in awakening cortisol, cortisol awakening response, or area under the curve. These findings confirm prior evidence of a biologic pathway through which socioeconomic disadvantage is linked to biologic vulnerability, and through which the impact of volunteer service in Experience Corps may be measured.
doi:10.1111/j.1749-6632.2011.06151.x
PMCID: PMC3369216  PMID: 21884161
socioeconomic status; salivary cortisol; stress; diurnal pattern; HPA axis; resilience
10.  Diurnal Salivary Cortisol is Associated With Body Mass Index and Waist Circumference: The Multi-Ethnic Study of Atherosclerosis 
Obesity (Silver Spring, Md.)  2013;21(1):E56-E63.
Neuroendocrine abnormalities, such as activation of the hypothalamic-pituitary-adrenal (HPA) axis, are associated with obesity; however, few large-scale population-based studies have examined HPA axis and markers of obesity. We examined the cross-sectional association of the cortisol awakening response (CAR) and diurnal salivary cortisol curve with obesity. The Multi-Ethnic Study of Atherosclerosis (MESA) Stress Study includes 1,002 White, Hispanic, and Black men and women (mean age 65±9.8 years) who collected up to 18 salivary cortisol samples over 3 days. Cortisol profiles were modeled using regression spline models that incorporated random parameters for subject-specific effects. Cortisol curve measures included awakening cortisol, CAR (awakening to 30 minutes post-awakening), early decline (30 minutes to 2 hours post-awakening), late decline (2 hours post-awakening to bedtime), and the corresponding areas under the curve (AUC). Body-mass-index (BMI) and waist circumference (WC) were used to estimate adiposity. For the entire cohort, both BMI and WC were negatively correlated with awakening cortisol (p<0.05), AUC during awakening rise and early decline and positively correlated to the early decline slope (p<0.05) after adjustments for age, race/ethnicity, gender, diabetes status, socioeconomic status, beta blockers, steroids, hormone replacement therapy and smoking status. No heterogeneities of effects were observed by gender, age, and race/ethnicity. Higher BMI and WC are associated with neuroendocrine dysregulation, which is present in a large population sample, and only partially explained by other covariates.
doi:10.1002/oby.20047
PMCID: PMC3602310  PMID: 23404865
adiposity; hypothalamic-pituitary-adrenal (HPA) axis; salivary cortisol; diurnal cortisol; cortisol awakening response; epidemiology; obesity; body mass index; waist circumference; epidemiology
11.  Dysregulated diurnal cortisol pattern is associated with glucocorticoid resistance in women with major depressive disorder 
Biological psychology  2013;93(1):150-158.
Dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis is believed to play a role in the pathophysiology of depression. To investigate mechanisms that may underlie this effect, we examined several indices of HPA axis function – specifically, diurnal cortisol slope, cortisol awakening response, and suppression of cortisol release following dexamethasone administration – in 26 pre-menopausal depressed women and 23 never depressed women who were matched for age and body mass index. Salivary cortisol samples were collected at waking, 30 min after waking, and at bedtime over three consecutive days. On the third day, immediately after the bedtime sample, participants ingested a 0.5 mg dexamethasone tablet; they then collected cortisol samples at waking and 30 min after waking the following morning. As predicted, depressed women exhibited flatter diurnal cortisol rhythms and more impaired suppression of cortisol following dexamethasone administration than non-depressed women over the three sampling days. In addition, flatter diurnal cortisol slopes were associated with reduced cortisol response to dexamethasone treatment, both for all women and for depressed women when considered separately. Finally, greater self-reported depression severity was associated with flatter diurnal cortisol slopes and with less dexamethasone-related cortisol suppression for depressed women. Depression in women thus appears to be characterized by altered HPA axis functioning, as indexed by flatter diurnal cortisol slopes and an associated impaired sensitivity of cortisol to dexamethasone. Given that altered HPA axis functioning has been implicated in several somatic conditions, the present findings may be relevant for understanding the pathophysiology of both depression and depression-related physical disease.
doi:10.1016/j.biopsycho.2013.01.018
PMCID: PMC3687535  PMID: 23410758
Stress; Depression; Diurnal cortisol slope; Cortisol awakening response; Dexamethasone suppression test; Inflammation; Health; Disease
12.  A day-centered approach to modeling cortisol: Diurnal cortisol profiles and their associations among U.S. adults 
Psychoneuroendocrinology  2013;38(10):2354-2365.
Summary
Diurnal cortisol is a marker of HPA-axis activity that may be one of the biological mechanisms linking stressors to age-related health declines. The current study identified day-centered profiles of diurnal cortisol among 1,101 adults living in the United States. Participants took part in up to four consecutive days of salivary cortisol collection, assessed at waking, 30 minutes post-waking, before lunch, and before bedtime. Growth Mixture Modeling with latent time basis was used to estimate common within-day trajectories of diurnal cortisol among 2,894 cortisol days. The 3-class solution provided the best model fit, showing that the majority of study days (73%) were characterized by a Normative cortisol pattern, with a robust cortisol awakening response (CAR), a steep negative diurnal slope, coupled with low awakening and bedtime levels. Relative to this profile, diurnal cortisol on the remainder of days appeared either Elevated throughout the day (20% of days) or Flattened (7% of days). Relative to the Normative trajectory, the Elevated trajectory was distinguished by a higher morning cortisol level, whereas the Flattened trajectory was characterized by a high bedtime level, with weaker CAR and diurnal slope parameters. Relative to the Normative profile, Elevated profile membership was associated with older age and cigarette smoking. Greater likelihood of the Flattened cortisol pattern was observed among participants who were older, male, smoked cigarettes, used medications that are known to affect cortisol output, and reported poorer health. The current study demonstrates the value of a day-centered Growth Mixture Modeling approach to the study of diurnal cortisol, showing that deviations from the classic robust rhythm of diurnal cortisol are associated with older age, male sex, use of medications previously shown to affect cortisol levels, poorer health behaviors, and poorer self-reported health.
doi:10.1016/j.psyneuen.2013.05.003
PMCID: PMC3776005  PMID: 23770247
Aging; Daily Diary; Diurnal Rhythm; HPA Axis; Latent Growth Curve Modeling; Mixture Modeling; Salivary Cortisol; Stress
13.  The effect of oral contraceptives on cortisol metabolism 
The administration of oral contraceptives which contain oestrogen increases non-protein-bound plasma cortisol levels at 9 am as well as protein-bound and total cortisol levels. These increases are dependent on the dose of oestrogen; they are not usually seen with progestogen-only or `low-dose' oestrogen (0·05 mg mestranol or less) preparations. `Standard' oral contraceptives (0·1 mg mestranol or equivalent) produce some elevation of unbound cortisol levels at 9 am (from a normal mean of 0·66 μg/100 ml to 1·02 on the `pill') but this elevation is less than that associated with high-dose oestrogen treatment of, for example, prostate cancer (mean 1·8 μg/100 ml). Since unbound cortisol levels in plasma are controlled by a hypothalamic feedback mechanism, it appears that oral contraceptives have some effect on this mechanism. Possible long-term effects of oral contraceptives on hypothalamopituitary function require examination.
However, the plasma unbound cortisol to which the tissues are exposed at 9 am does not measure the overall exposure of tissues to cortisol throughout the 24 hours. Neither does measurement of cortisol production rate or urinary metabolite excretion accurately reflect the exposure of tissues to cortisol during oestrogen treatment, because of the complex effects of oestrogen on hepatic metabolism of steroids, steroid-protein binding, and the increased size of the extracellular cortisol pool.
The overall exposure of tissues to unbound cortisol is measured better by urinary free cortisol excretion. Urinary free cortisol excretion is a measure of the integrated area under the diurnal curve of plasma unbound cortisol, ie, of the 24-hour exposure of tissues to unbound cortisol. Urinary free cortisol excretion is normal in women taking low-dose oestrogen or progestogen-only contraceptives, and is only trivially increased by the standard `pill'. Thus increased exposure of tissues to unbound cortisol is likely to be only a minor factor in the metabolic responses to oral contraceptives. In contrast, urinary free cortisol excretion (mean normal 38 μg/24 hours) is increased by high-dose oestrogen administration for prostatic cancer (mean 110 μg/24 hours); this is because the diurnal rhythm of unbound cortisol is impaired.
It is thus unwise to ascribe effects of oral contraceptives to increased exposure of tissues to cortisol, except in the liver where it is possible that the increased concentration of protein-bound cortisol they cause may exert metabolic effects. The preparations which cause least change in cortisol metabolism are the low-dose oestrogen or progestogen-only contraceptives.
PMCID: PMC1436049
14.  Association of Salivary Cortisol Circadian Pattern with Cynical Hostility: The Multi-Ethnic Study of Atherosclerosis 
Psychosomatic medicine  2009;71(7):748-755.
Objective
To determine if cynical hostility is associated with alterations in diurnal profiles of cortisol. Hostility has been linked to cardiovascular disease but the biological mechanisms mediating this association remain unknown.
Methods
Up to 18 measures of salivary cortisol taken over three days were obtained from each of 936 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Cynical hostility was measured using an 8-item subscale of the Cook-Medley Hostility scale. Cortisol profiles were modeled using regression spline models incorporating random parameters for subject-specific effects. Models were adjusted for race, sex, age, socioeconomic position, and lifestyle factors. The association of cynical hostility with key features of the cortisol diurnal profile, both in the full sample and important subsamples, was examined.
Results
Waking cortisol levels as well as the extent of the morning surge in cortisol levels did not differ significantly across tertiles of cynical hostility. However respondents in the lowest tertile of cynical hostility experienced a 22% sharper decline in salivary cortisol (age-and sex-adjusted slope of −.49 μg/dl per hour) than respondents in the highest tertile (−.40 μg/dl per hour, p for difference=.0004). Intertertile differences in these parameters remained unaltered after further adjustment for potential confounders. This pattern of differences in cortisol diurnal profile tended to be related in a dose-response way to level of cynical hostility, and persisted in stratified analyses.
Conclusions
Cynical hostility is associated with the declining phase of the awakening cortisol response. The implications of this for cardiovascular and other health outcomes remain to be determined.
doi:10.1097/PSY.0b013e3181ad23e7
PMCID: PMC3040517  PMID: 19592518
Cortisol rhythms; cynical hostility; regression splines; random effects; cortisol awakening response
15.  Relationships between lead biomarkers and diurnal salivary cortisol indices in pregnant women from Mexico City: a cross-sectional study 
Environmental Health  2014;13:50.
Background
Lead (Pb) exposure during pregnancy may increase the risk of adverse maternal, infant, or childhood health outcomes by interfering with hypothalamic-pituitary-adrenal-axis function. We examined relationships between maternal blood or bone Pb concentrations and features of diurnal cortisol profiles in 936 pregnant women from Mexico City.
Methods
From 2007–11 we recruited women from hospitals/clinics affiliated with the Mexican Social Security System. Pb was measured in blood (BPb) during the second trimester and in mothers’ tibia and patella 1-month postpartum. We characterized maternal HPA-axis function using 10 timed salivary cortisol measurements collected over 2-days (mean: 19.7, range: 14–35 weeks gestation). We used linear mixed models to examine the relationship between Pb biomarkers and cortisol area under the curve (AUC), awakening response (CAR), and diurnal slope.
Results
After adjustment for confounders, women in the highest quintile of BPb concentrations had a reduced CAR (Ratio: −13%; Confidence Interval [CI]: −24, 1, p-value for trend < 0.05) compared to women in the lowest quintile. Tibia/patella Pb concentrations were not associated with CAR, but diurnal cortisol slopes were suggestively flatter among women in the highest patella Pb quantile compared to women in the lowest quantile (Ratio: 14%; CI: −2, 33). BPb and bone Pb concentrations were not associated with cortisol AUC.
Conclusions
Concurrent blood Pb levels were associated with cortisol awakening response in these pregnant women and this might explain adverse health outcomes associated with Pb. Further research is needed to confirm these results and determine if other environmental chemicals disrupt hypothalamic-pituitary-adrenal-axis function during pregnancy.
doi:10.1186/1476-069X-13-50
PMCID: PMC4068833  PMID: 24916609
Lead; Cortisol; Epidemiology; Pregnancy
16.  Examining the association between salivary cortisol levels and subclinical measures of atherosclerosis: the Multi-Ethnic Study of Atherosclerosis 
Psychoneuroendocrinology  2012;38(7):1036-1046.
Objective
To investigate the association between salivary cortisol and two markers of subclinical cardiovascular disease (CVD), coronary calcification (CAC), and ankle-brachial index (ABI).
Methods
Data from an ancillary study to the Multi-Ethnic Study of Atherosclerosis (MESA), the MESA Stress Study, were used to analyze associations of salivary cortisol data collected six times per day over three days with CAC and ABI. The authors used mixed models with repeat cortisol measures nested within persons to determine if specific features of the cortisol profile were associated with CAC and ABI.
Results
total of 464 participants were included in the CAC analysis and 610 in the ABI analysis. The mean age of participants was 65.6 years. A 1-unit increase in log coronary calcium was associated with a 1.77% flatter early decline in cortisol (95% CI: 0.23, 3.34) among men and women combined. Among women low ABI was associated with a steeper early decline (−13.95% CI:−25.58, −3.39) and a marginally statistically significant flatter late decline (1.39% CI: −0.009, 2.81). The cortisol area under the curve and wake to bedtime slope were not associated with subclinical CVD.
Conclusions
This study provides weak support for the link between cortisol and measures of subclinical atherosclerosis. We found an association between some features of the diurnal cortisol profile and coronary calcification and ABI but associations were not consistent across subclinical measures. There are methodological challenges in detecting associations of cortisol measures at a point in time with health outcomes that develop over a lifetime. Studies of short-term mechanisms linking stress to physiological processes related to the development of early atherosclerosis may be more informative.
doi:10.1016/j.psyneuen.2012.10.007
PMCID: PMC4020284  PMID: 23146655
salivary cortisol; ankle brachial index; coronary calcification; atherosclerosis; stress; cortisol awakening response; cortisol diurnal pattern; Multi-Ethnic Study of Atherosclerosis
17.  Alterations in Stress Reactivity After Long-Term Treatment with Paroxetine in Women with Posttraumatic Stress Disorder 
Posttraumatic stress disorder (PTSD) is typically accompanied by both acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but studies have also used a challenge model to assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. The purpose of this article was to assess the effect of long-term treatment with the selective reuptake inhibitor (SSRI), paroxetine, on stress reactivity in patients with PTSD. We assessed diurnal salivary cortisol and urinary cortisol as well as cortisol, heart rate, and behavioral responses to a standardized cognitive stress challenge, in 13 female patients with chronic PTSD before and after 12 months of paroxetine treatment. Treatment resulted in a significant decrease in PTSD symptoms. Twenty-four-hour urinary cortisol was lower compared to base line after successful treatment. Treatment resulted in a decrease of salivary cortisol levels on all time points on a diurnal curve. Despite similar stress perception, cortisol response to the cognitive stress challenge resulted in a 26.5% relative decrease in stress-induced salivary cortisol with treatment. These results suggest that successful treatment with SSRI in chronic PTSD is associated with a trend for a decrease in baseline diurnal cortisol and with reduced cortisol reactivity to stress.
doi:10.1196/annals.1364.014
PMCID: PMC3230329  PMID: 16891570
cortisol; PTSD; stress; paroxetine; SSRI; challenge; HPA axis
18.  Shiftwork Duration and the Awakening Cortisol Response Among Police Officers 
Chronobiology international  2011;28(5):446-457.
Police officers are required to work irregular hours, which induces stress, fatigue, and sleep disruption, and they have higher rates of chronic disease and mortality. Cortisol is a well-known “stress hormone” produced via activation of the hypothalamic-pituitary-adrenal axis. An abnormal secretion pattern has been associated with immune system dysregulation and may serve as an early indicator of disease risk. This study examined the effects of long- and short-term shiftwork on the cortisol awakening response among officers (n = 68) in the Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) pilot study (2001–2003). The time each officer spent on day (start time: 04:00–11:59 h), afternoon (12:00–19:59 h), or night (20:00–03:59 h) shifts was summarized from 1994 to examination date to characterize long-term (mean: 14 ± 9 yrs) and short-term (3, 5, 7, or 14 days prior to participation) shiftwork exposures. The cortisol awakening response was characterized by summarizing the area under the curve (AUC) for samples collected on first awakening, and at 15-, 30-, and 45-min intervals after waking. Data were collected on a scheduled training or off day. The cortisol AUC with respect to ground (AUCG) summarized total cortisol output after waking, and the cortisol AUC with respect to increase (AUCI) characterized the waking cortisol response. Officers also completed the Center for Epidemiologic Studies Depression scale. Waking cortisol AUC values were lower among officers working short-term night or afternoon shifts than day shifts, with maximal differences occurring after 5 days of shiftwork. The duration of long-term shiftwork was not associated with the cortisol awakening response, although values were attenuated among officers with more career shift changes.
doi:10.3109/07420528.2011.573112
PMCID: PMC3655701  PMID: 21721860
Cortisol awakening response; Police; Shiftwork; Stress
19.  Cortisol Patterns Are Associated with T Cell Activation in HIV 
PLoS ONE  2013;8(7):e63429.
Objective
The level of T cell activation in untreated HIV disease is strongly and independently associated with risk of immunologic and clinical progression. The factors that influence the level of activation, however, are not fully defined. Since endogenous glucocorticoids are important in regulating inflammation, we sought to determine whether less optimal diurnal cortisol patterns are associated with greater T cell activation.
Methods
We studied 128 HIV-infected adults who were not on treatment and had a CD4+ T cell count above 250 cells/µl. We assessed T cell activation by CD38 expression using flow cytometry, and diurnal cortisol was assessed with salivary measurements.
Results
Lower waking cortisol levels correlated with greater T cell immune activation, measured by CD38 mean fluorescent intensity, on CD4+ T cells (r = −0.26, p = 0.006). Participants with lower waking cortisol also showed a trend toward greater activation on CD8+ T cells (r = −0.17, p = 0.08). A greater diurnal decline in cortisol, usually considered a healthy pattern, correlated with less CD4+ (r = 0.24, p = 0.018) and CD8+ (r = 0.24, p = 0.017) activation.
Conclusions
These data suggest that the hypothalamic-pituitary-adrenal (HPA) axis contributes to the regulation of T cell activation in HIV. This may represent an important pathway through which psychological states and the HPA axis influence progression of HIV.
doi:10.1371/journal.pone.0063429
PMCID: PMC3724863  PMID: 23922644
20.  Is body size at birth related to circadian salivary cortisol levels in adulthood? Results from a longitudinal cohort study 
BMC Public Health  2010;10:346.
Background
The hypothesis of fetal origins of adult disease has during the last decades received interest as an explanation of chronic, e.g. cardiovascular, disease in adulthood stemming from fetal environmental conditions. Early programming and enduring dysregulations of the hypothalamic-pituitary-adrenal (HPA axis), with cortisol as its end product, has been proposed as a possible mechanism by which birth weight influence later health status. However, the fetal origin of the adult cortisol regulation has been insufficiently studied. The present study aims to examine if body size at birth is related to circadian cortisol levels at 43 years.
Methods
Participants were drawn from a prospective cohort study (n = 752, 74.5%). Salivary cortisol samples were collected at four times during one day at 43 years, and information on birth size was collected retrospectively from delivery records. Information on body mass during adolescence and adulthood and on health behavior, medication and medical conditions at 43 years was collected prospectively by questionnaire and examined as potential confounders. Participants born preterm or < 2500 g were excluded from the main analyses.
Results
Across the normal spectrum, size at birth (birth weight and ponderal index) was positively related to total (area under the curve, AUC) and bedtime cortisol levels in the total sample. Results were more consistent in men than in women. Descriptively, participants born preterm or < 2500 g also seemed to display elevated evening and total cortisol levels. No associations were found for birth length or for the cortisol awakening response (CAR).
Conclusions
These results are contradictory to previously reported negative associations between birth weight and adult cortisol levels, and thus tentatively question the assumption that only low birth weight predicts future physiological dysregulations.
doi:10.1186/1471-2458-10-346
PMCID: PMC2908578  PMID: 20553630
21.  Diurnal Cortisol and Functional Outcomes in Post-Acute Rehabilitation Patients 
Background.
Cortisol is a stress-related hormone with a robust circadian rhythm where levels typically peak in the morning hours and decline across the day. Although acute cortisol increases resulting from stressors are adaptive, chronic elevated cortisol levels are associated with poor functioning. Studies have shown age-related changes in cortisol levels. The present study investigated the relationship between salivary diurnal cortisol and functional outcomes among older adults undergoing inpatient post-acute rehabilitation.
Methods.
Thirty-two older adults (mean age 78 years; 84% men) in a Veterans Administration inpatient post-acute rehabilitation unit were studied. Functional outcomes were assessed with the motor component of the Functional Independence Measure (mFIM; where mFIM change = discharge − admission score). Saliva samples were collected on 1 day at wake time, 45 minutes later, 11:30 AM, 2 PM, 4:30 PM, and bedtime. We analyzed the relationship between cortisol measures and functional outcomes, demographics, and health measures.
Results.
The analyses consistently showed that greater functional improvement (mFIM change) from admission to discharge was associated with lower comorbidity scores and higher cortisol levels at 2 PM, 4:30 PM, and bedtime. A morning cortisol rise was also associated with greater mFIM change.
Conclusions.
Measurement of cortisol in saliva may be a useful biological marker for identification of patients who are “at risk” of lower benefits from inpatient rehabilitation services and who may require additional assistance or intervention during their post-acute care stay.
doi:10.1093/gerona/glr230
PMCID: PMC3348493  PMID: 22219521
Cortisol; Older adults; Rehabilitation; Inpatient; Functional Status
22.  Stress Sensitivity in Metastatic Breast Cancer: Analysis of Hypothalamic-Pituitary-Adrenal Axis Function 
Psychoneuroendocrinology  2006;31(10):1231-1244.
The normal diurnal cortisol cycle has a peak in the morning, decreasing rapidly over the day, with low levels during the night, then rising rapidly again to the morning peak. A pattern of flatter daytime slopes has been associated with more rapid cancer progression in both animals and humans. We studied the relationship between the daytime slopes and other daytime cortisol responses to both pharmacological and psychosocial challenges of hypothalamic-pituitary-adrenal (HPA) axis function as well as DHEA in a sample of 99 women with metastatic breast cancer, in hopes of elucidating the dysregulatory process.
We found that the different components of HPA regulation: the daytime cortisol slope, the rise in cortisol from waking to 30 minutes later, and cortisol response to various challenges, including dexamethasone (DEX) suppression, corticotrophin releasing factor (CRF) activation, and the Trier Social Stress Task, were at best modestly associated. Escape from suppression stimulated by 1 mg of dexamethasone administered the night before was moderately but significantly associated with flatter daytime cortisol slopes (r=0..28 to .30 at different times of the post dexamethasone administration day, all p<.01) . Daytime cortisol slopes were also moderately but significant associated with the rise in cortisol from waking to 30 minutes after awakening (r=.29, p=.004, N=96), but not with waking cortisol level (r=−0.13, p=.19). However, we could not detect any association between daytime cortisol slope and activation of cortisol secretion by either CRF infusion or the Trier Social Stress Task. The CRF activation test (following 1.5 mg of dexamethasone to assure that the effect was due to exogenous CRF) produced ACTH levels that were correlated (r=0.66 p<.0001, N = 74) with serum cortisol levels, indicating adrenal responsiveness to ACTH stimulation. Daytime cortisol slopes were significantly correlated with the slope of DHEA (r=.21, p=.04, N=95). Our general findings suggest that flatter daytime cortisol slopes among metastatic breast cancer patients may be related to disrupted feedback inhibition rather than hypersensitivity in response to stimulation.
doi:10.1016/j.psyneuen.2006.09.004
PMCID: PMC1790857  PMID: 17081700
Cortisol; HPA; stress; dexamethasone; CRF; metastatic breast cancer
23.  Familial Longevity Is Marked by Lower Diurnal Salivary Cortisol Levels: The Leiden Longevity Study 
PLoS ONE  2012;7(2):e31166.
Background
Reported findings are inconsistent whether hypothalamic-pituitary-adrenal (HPA) signaling becomes hyperactive with increasing age, resulting in increasing levels of cortisol. Our previous research strongly suggests that offspring from long-lived families are biologically younger. In this study we assessed whether these offspring have a lower HPA axis activity, as measured by lower levels of cortisol and higher cortisol feedback sensitivity.
Methods
Salivary cortisol levels were measured at four time points within the first hour upon awakening and at two time points in the evening in a cohort comprising 149 offspring and 154 partners from the Leiden Longevity Study. A dexamethasone suppression test was performed as a measure of cortisol feedback sensitivity. Age, gender and body mass index, smoking and disease history (type 2 diabetes and hypertension) were considered as possible confounding factors.
Results
Salivary cortisol secretion was lower in offspring compared to partners in the morning (Area Under the Curve = 15.6 versus 17.1 nmol/L, respectively; p = 0.048) and in the evening (Area Under the Curve = 3.32 versus 3.82 nmol/L, respectively; p = 0.024). Salivary cortisol levels were not different after dexamethasone (0.5 mg) suppression between offspring and partners (4.82 versus 5.26 nmol/L, respectively; p = 0.28).
Conclusion
Offspring of nonagenarian siblings are marked by a lower HPA axis activity (reflected by lower diurnal salivary cortisol levels), but not by a difference in cortisol feedback sensitivity. Further in-depth studies aimed at characterizing the HPA axis in offspring and partners are needed.
doi:10.1371/journal.pone.0031166
PMCID: PMC3278433  PMID: 22348049
24.  Disentangling psychobiological mechanisms underlying internalizing and externalizing behaviors in youth: Longitudinal and concurrent associations with cortisol 
Hormones and behavior  2010;59(1):123-132.
Research examining cortisol dysregulation is seemingly contradictory with studies showing that both internalizing and externalizing behaviors are related to high and low cortisol. One extant theory to explain divergent findings in the stress literature is that both hypo- and hyper-arousal of the hypothalamic-pituitary-adrenal (HPA) axis may be present depending on time since onset of the stressor. This theory may extend to the onset of internalizing and externalizing behaviors. Data from 96 youth participating in a longitudinal project were used to examine this possibility. Composite measures of internalizing and externalizing behaviors at both childhood and early adolescence were formed using mother and teacher reports. Multiple salivary cortisol samples were also collected over two consecutive days during early adolescence. Problematic behaviors were associated with cortisol and the direction of the association was dependent on amount of time passed since onset of the behaviors. When examined concurrently in adolescence, youth with more internalizing behaviors had higher morning cortisol; however, when examined longitudinally, youth with more internalizing behaviors in childhood had lower morning cortisol levels as adolescents. Youth with more externalizing behaviors in childhood had flattened diurnal cortisol rhythms as adolescents, and this finding persisted when examined in adolescence. Cortisol dysregulation was greatest in children with the most severe behavior problems. Findings support the theoretical model of blunting of the HPA axis over time. While the HPA axis may show hyper-arousal when youth first display behaviors, long-term exposure may lead to a hypo-arousal of the HPA axis which culminates in a dysregulated diurnal rhythm.
doi:10.1016/j.yhbeh.2010.10.015
PMCID: PMC3066166  PMID: 21056565
diurnal cortisol; internalizing behavior; externalizing behavior; blunted; hierarchical linear modeling
25.  Cross-Sectional and 35-Year Longitudinal Assessment of Salivary Cortisol and Cognitive Functioning: The Vietnam Era Twin Study of Aging 
Psychoneuroendocrinology  2011;36(7):1040-1052.
High levels of cortisol, a sign of potential hypothalamic-pituitary-adrenal (HPA) axis dysregulation, have been associated with poor cognitive outcomes in older adults. Most cortisol research has focused on hippocampal-related abilities such as episodic memory; however, the presence of glucocorticoid receptors in the human prefrontal cortex suggests that cortisol regulation is likely to be associated with prefrontally-mediated executive function abilities. We hypothesized that elevated cortisol levels would be associated with poorer frontal-executive function in addition to episodic memory. We assessed cortisol from 15 saliva samples paralleling individual diurnal rhythms across three non-consecutive days in a group of 778 middle-aged twin men ages 51 to 60. Cognitive domains created from 24 standard measures included: general cognitive ability, verbal and visual-spatial ability, verbal and visual-spatial memory, short-term/immediate memory, working memory, executive function, verbal fluency, abstract reasoning, and psychomotor processing speed. Adjusting for general cognitive ability at age 20, age, race, and multiple health and lifestyle indicators, higher levels of average area-under-the-curve cortisol output across three days were significantly associated with poorer performance in three domains: executive (primarily set-shifting) measures, processing speed, and visual-spatial memory. In a 35-year longitudinal component of the study, we also found that general cognitive ability at age 20 was a significant predictor of midlife cortisol levels. These results possibly support the notion that glucocorticoid exposure is associated with cognitive functions that are mediated by frontal-striatal systems, and is not specific to hippocampal-dependent memory. The results also suggest that the direction of effect is complex.
doi:10.1016/j.psyneuen.2011.01.002
PMCID: PMC3130089  PMID: 21295410
Cortisol; HPA Axis; aging; cognition; cognitive aging; VETSA

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