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1.  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
2.  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
3.  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
4.  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
5.  Mitigating HPA Axis Dysregulation Associated With Placement Changes in Foster Care 
Psychoneuroendocrinology  2011;36(4):531-539.
Summary
Maltreated foster children often exhibit alterations in diurnal hypothalamic-pituitary-adrenal (HPA) axis activity that are characterized by lower cortisol levels upon waking and smaller declines in morning-to-evening cortisol levels. Previous research has shown that this dysregulated pattern is associated with high caregiver stress levels over the course of foster care placements. In contrast, therapeutic interventions that emphasize consistent and responsive caregiving have been associated with more regulated cortisol rhythms. In this paper, two related issues were explored: whether placement changes (i.e., moving between foster homes or from a foster home to a permanent placement) were associated with more blunted daily cortisol rhythms and whether a caregiver-based intervention exerted a protective effect in this context. Because the intervention program has components specifically designed to prepare foster children for placement changes and to maintain consistent parenting techniques despite them, a prevention effect on HPA axis dysregulation during placement changes was hypothesized. The results of linear mixed modeling analyses showed that placement changes predicted dysregulation in cortisol rhythms in the regular foster care group but not in the intervention foster care group. These findings are discussed in terms of implications for child welfare policy and practice.
doi:10.1016/j.psyneuen.2010.08.007
PMCID: PMC3610565  PMID: 20888698
diurnal cortisol; dysregulation; foster care; intervention; preschool
6.  Salivary cortisol among American Indians with and without posttraumatic stress disorder (PTSD): Gender and alcohol influences 
Brain, behavior, and immunity  2008;23(5):658-662.
Disruptions in hypothalamic-pituitary-adrenal regulation and immunity have been associated with posttraumatic stress disorder (PTSD). We examined the association of PTSD with diurnal rhythms in salivary cortisol in a convenience sample from a population-based study of male and female American Indians. Subjects with and without PTSD were identified from American Indians living on/near a Northern Plains reservation as part of a larger study. Over two days diurnal saliva samples were collected by staff at the University of Colorado Denver Clinical Research Center at waking, 30 minutes after waking, before lunch, and before dinner. Generalized estimating equations linear regression models investigated the influence of PTSD on cortisol over time. The association of a lifetime diagnosis of PTSD with salivary cortisol level was assessed in subjects with complete data (PTSD: n=27; no PTSD n=32) for age, gender, and alcohol consumption in the past month. Subject mean age was 44 years, and 71% were women. When stratified by gender, women with a lifetime diagnosis of PTSD had significantly higher mean cortisol levels throughout the day than women without PTSD (p = 0.01); but there was no significant association between PTSD and cortisol levels in men (p = 0.36). The cortisol awakening response – the difference in cortisol levels from waking to 30 minutes after waking – was not associated with PTSD in men or women. A lifetime diagnosis of PTSD may influence diurnal cortisol among American Indian women. These effects were independent of influences of current alcohol use/abuse. The unexpected elevation in cortisol in American Indian women with a lifetime diagnosis of PTSD may reflect acute anxiety associated with experiencing a number of novel tests in a strange location (e.g., cardiac imaging, medical and dental exams, etc.), or concurrent depression.
doi:10.1016/j.bbi.2008.12.007
PMCID: PMC2711684  PMID: 19146946
Health disparities; Northern Plains Indians; cortisol awakening response
7.  Is There an Association between Work Stress and Diurnal Cortisol Patterns? Findings from the Whitehall II Study 
PLoS ONE  2013;8(12):e81020.
Objective
The evidence on whether there is work stress related dysregulation of the hypothalamic-pituitary-adrenal axis is equivocal. This study assessed the relation between work stress and diurnal cortisol rhythm in a large-scale occupational cohort, the Whitehall II study.
Methods
Work stress was assessed in two ways, using the job-demand-control (JDC) and the effort-reward-imbalance (ERI) models. Salivary cortisol samples were collected six times over a normal day in 2002–2004. The cortisol awakening response (CAR) and diurnal cortisol decline (slope) were calculated.
Results
In this large occupational cohort (N = 2,126, mean age 57.1), modest differences in cortisol patterns were found for ERI models only, showing lower reward (β = −0.001, P-value = 0.04) and higher ERI (β = 0.002, P-value = 0.05) were related to a flatter slope in cortisol across the day. Meanwhile, moderate gender interactions were observed regarding CAR and JDC model.
Conclusions
We conclude that the associations of work stress with cortisol are modest, with associations apparent for ERI model rather than JDC model.
doi:10.1371/journal.pone.0081020
PMCID: PMC3849138  PMID: 24312516
8.  Elevated cortisol in older adults with Generalized Anxiety Disorder is reduced by treatment: a placebo-controlled evaluation of escitalopram 
Background
Generalized Anxiety Disorder (GAD) is a common disorder in older adults which has been linked to hyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) axis in this age group. We examined whether treatment of GAD in older adults with a selective serotonin reuptake inhibitor (SSRI) corrects this HPA axis hyperactivity.
Methods
We examined adults aged 60 and above with GAD in a 12-week randomized controlled trial comparing the SSRI escitalopram to placebo. We collected salivary cortisol at six daily timepoints for two consecutive days to assess peak and total (area under the curve) cortisol, both at baseline and post-treatment.
Results
Compared with placebo-treated subjects, SSRI-treated subjects had a significantly greater reduction in both peak and total cortisol. This reduction in cortisol was limited to subjects with elevated (above the median) baseline cortisol, in whom SSRI-treated subjects showed substantially greater reduction in cortisol than did placebo-treated subjects. Reductions in cortisol were associated with improvements in anxiety. Additionally, genetic variability at the serotonin transporter promoter predicted cortisol changes.
Conclusions
SSRI treatment of GAD in older adults reduces HPA axis hyperactivity. Further research should determine whether these treatment-attributable changes are sustained and beneficial.
doi:10.1097/JGP.0b013e3181ec806c
PMCID: PMC3424606  PMID: 20808146
anxiety; cortisol; aging; health; stress; antidepressant
9.  Examining Cortisol Rhythmicity and Responsivity to Stress in Children with Tourette Syndromea 
Psychoneuroendocrinology  2008;33(6):810-820.
SUMMARY
Background
Tourette syndrome (TS) is characterized by motor and vocal tics, which are often exacerbated by stress. The hypothalamic-pituitary-adrenocortical (HPA) axis, a major stress response system is thus of interest for understanding TS.
Methods
Diurnal cortisol rhythms were estimated in medication-free children 7-to-13 years with TS (N=20) and healthy age-matched controls (N=16). Salivary samples were collected on three consecutive days from the home. HPA responsivity was assessed by examining cortisol in response to a mock and real MRI scan.
Results
The results of diurnal rhythmicity revealed a trend showing marginally lower evening cortisol for the TS group. By contrast, the TS group had higher cortisol levels in response to the stressor. There were strong, negative correlations between evening cortisol and tic severity as well as diurnal cortisol and anxiety.
Conclusions
The children with TS showed increased cortisol in response to the MRI environment, supporting a model of enhanced HPA responsivity. The lower evening cortisol may be the result of chronic daily stress. Alternatively, the negative associations between cortisol and reported anxiety and tics may reflect biologically-based anxiolytic properties of tic expression. Taken together, the results clearly implicate involvement of the HPA axis in the neuropathology of TS.
doi:10.1016/j.psyneuen.2008.03.014
PMCID: PMC2547137  PMID: 18487023
Tourette syndrome; cortisol; HPA axis; stress; anxiety; diurnal rhythm
10.  Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder☆ 
Psychoneuroendocrinology  2008;33(6):773-781.
Summary
Age-associated alterations in hypothalamic–pituitary–adrenal (HPA) axis functioning may make individuals more susceptible to HPA dysregulation in the context of mood and anxiety disorders. Little to no research has been done to examine HPA axis function in generalized anxiety disorder (GAD), particularly in late-life GAD, the most prevalent anxiety disorder in the elderly. The study sample consisted of 71 GAD subjects and 40 nonanxious comparison subjects over 60 years of age. We examined the hypotheses that elderly individuals with GAD will have elevated salivary cortisol levels compared to nonanxious subjects, and that elevated cortisol levels in GAD will be associated with measures of symptom severity. We report that late-life GAD is characterized by elevated basal salivary cortisol levels, with higher peak cortisol levels and larger areas under the curve, compared to nonanxious subjects. Additionally, severity of GAD as measured by the GAD Severity Scale and the Penn State Worry Questionnaire are positively correlated with cortisol levels. These data demonstrate HPA axis dysfunction in late-life GAD and suggest the need for additional research on the influence of aging on HPA axis function in mood and anxiety disorders.
doi:10.1016/j.psyneuen.2008.03.002
PMCID: PMC2766671  PMID: 18407426
Cortisol; Generalized anxiety disorder; Elderly; Worry; HPA axis; Saliva
11.  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
12.  Diurnal Salivary Cortisol and Urinary Catecholamines Are Associated With Diabetes Mellitus: The Multi-Ethnic Study of Atherosclerosis 
Metabolism  2011;61(7):986-995.
Objective
To examine the cross-sectional association of diurnal salivary cortisol curve components and urinary catecholamines with diabetes status.
Methods
Up to 18 salivary cortisol samples over 3 days and overnight urinary catecholamines were collected from 1,002 participants in the Multi-Ethnic Study of Atherosclerosis. Diabetes was defined as a fasting blood glucose ≥126 mg/dL or medication use. Cortisol curve measures included awakening cortisol, cortisol awakening response (CAR), early decline, late decline, and cortisol area under the curve (AUC). Urinary catecholamines included epinephrine, norepinephrine, and dopamine.
Results
Participants with diabetes had significantly lower CAR (β=−0.19; 95% CI: −0.34 to −0.04) than those without diabetes in multivariable models. While men with diabetes had a non-significant trend toward lower total AUC (β=−1.56; 95% CI: −3.93 to 0.80), women with diabetes had significantly higher total AUC (β=2.62; 95% CI: 0.72 to 4.51) (p=0.02 for interaction) compared to those without diabetes. Men but not women with diabetes had significantly lower urinary catecholamines, compared to those without diabetes (p<0.05).
Conclusions
Diabetes is associated with neuroendocrine dysregulation, which may differ by sex. Further studies are needed to determine the role of the neuroendocrine system in the pathophysiology of diabetes.
doi:10.1016/j.metabol.2011.11.006
PMCID: PMC3319636  PMID: 22209664
diabetes; hypothalamic-pituitary-adrenal (HPA) axis; salivary cortisol; catecholamines; epidemiology
13.  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
14.  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
15.  Diurnal rhythm of cortisol during late pregnancy: Associations with maternal psychological well-being and fetal growth 
Psychoneuroendocrinology  2008;33(9):1225-1235.
Maternal psychological functioning during pregnancy affects both maternal and fetal well-being. The hypothalamic-pituitary-adrenal (HPA) axis provides one mechanism through which maternal psychosocial factors may be transduced to the fetus. However, few studies have examined maternal psychological factors or birth outcomes in relation to the diurnal pattern of cortisol across the day. The current study examined maternal psychological well-being, parity status, and birth weight in relation to the maternal cortisol diurnal rhythm in a group of 98 low-risk pregnant women (51 primiparae). At 36 weeks gestation, participants completed both pregnancy-specific and general self-report measures of psychological functioning and provided saliva samples at 800, 1200, and 1600h on 2 consecutive working days for the assay of cortisol. The expected diurnal decline in salivary cortisol was observed. Higher trait anxiety was associated with a flatter afternoon decline for all mothers. For primiparae, steeper morning cortisol declines were associated with lower infant birth weight. The findings suggest that regulation of the HPA axis may differ by parity status with downstream implications for fetal growth and development.
doi:10.1016/j.psyneuen.2008.06.008
PMCID: PMC2806090  PMID: 18692319
cortisol diurnal rhythm; pregnancy; parity; fetus; anxiety; birth weight
16.  Association of the Period3 clock gene length polymorphism with salivary cortisol secretion among police officers 
Neuro endocrinology letters  2013;34(1):27-37.
OBJECTIVE
This study evaluated whether measures of waking or diurnal cortisol secretion, or self-reported psychological disturbances differed among police officers with a Period3 (PER3) clock gene length polymorphism.
METHODS
The cortisol awakening response was characterized via the area under the salivary cortisol curve with respect to the increase (AUCI) or total waking cortisol (AUCG). Diurnal cortisol measures included the slope of diurnal cortisol and the diurnal AUCG. Psychological disturbances were characterized using the Center for Epidemiologic Studies Depression Scale, Impact of Events Scale, and Life Events Scale.
RESULTS
Officers with a 4/5 or 5/5 genotype had higher awakening AUCG and greater diurnal cortisol AUCG levels compared to officers with the 4/4 genotype. Among those working more afternoon or night shifts, waking AUCI and AUCG were greater among officers with a 4/5 or 5/5 genotype compared to the 4/4 referents.
CONCLUSION
Cortisol secretion was modified among police officers with different PER3 VNTR clock gene variants.
PMCID: PMC3655703  PMID: 23524621
PER3 VNTR; circadian; cortisol; shiftwork; police
17.  Childhood sexual abuse is associated with cortisol awakening response over pregnancy: Preliminary findings 
Psychoneuroendocrinology  2012;37(9):1425-1430.
Introduction
Childhood sexual abuse (CSA) has been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in non-pregnant samples. However, it is not yet known whether CSA is associated with HPA dysregulation over pregnancy. In the present study we assessed whether maternal cortisol levels across pregnancy differed in women with CSA histories compared to women with histories of non-sexual child abuse (CA) and no abuse (NA).
Methods
135 pregnant mothers (CSA=30, CA=58, NA=47) provided salivary cortisol samples at wakeup, wake +30 minutes, and bedtime for 3 consecutive days at 1–3 time points over second and third trimester. Cortisol awakening responses and slopes were computed.
Results
Women with CSA histories displayed increasing cortisol awakening response over pregnancy compared to women with CA and NA histories. Group differences were not observed for slope.
Conclusions
This is the first study to show that cortisol awakening responses increase over pregnancy in women with CSA histories compared to women with CA and NA histories.
doi:10.1016/j.psyneuen.2012.01.009
PMCID: PMC3368071  PMID: 22341730
child abuse; cortisol; cortisol awakening response; cortisol slope; pregnancy
18.  Racial and Ethnic Differences in Diurnal Cortisol Rhythms in Preadolescents: The Role of Parental Psychosocial Risk and Monitoring 
Hormones and behavior  2012;61(5):661-668.
Racial/ethnic minorities experience persistent health disparities due in part to their exposure to chronic SES and psychosocial risk. The hypothalamic-pituitary-adrenal axis and its hormonal end product, cortisol, are believed to mediate the associations between chronic stress and poor health. In this study, racial/ethnic differences in diurnal salivary cortisol rhythms in 179 preadolescent youths and the contributing roles of SES risk, psychosocial risk, perceived discrimination, harsh parenting, and parental monitoring were examined. The analyses revealed racial/ethnic differences in diurnal cortisol rhythms, with African Americans having significantly flatter morning-to-evening cortisol slopes than Caucasians and with Latinos having significantly lower evening cortisol levels than Caucasians. Greater psychosocial risk and less parental monitoring were associated with flatter cortisol slopes. Racial/ethnic differences on the cortisol measures persisted when controlling for SES, psychosocial risk, and parenting quality. The need to assess chronic risk across the lifespan and disentangle possible genetic from environmental contributors is discussed.
doi:10.1016/j.yhbeh.2012.02.025
PMCID: PMC3419379  PMID: 22414445
cortisol; race/ethnicity; preadolescent youths; psychosocial risk; parental monitoring
19.  Testosterone Suppression of CRH-stimulated Cortisol in Men 
Despite observations of age-dependent sexual dimorphisms in hypothalamic-pituitary-adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in ten men (ages 18–45) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (p < .05, .005, and .01, respectively) during testosterone replacement compared with the induced hypogonadal condition (leuprolide plus placebo); cortisol area under the curve was lower at a trend level (p < .1). Paradoxically, CRH-stimulated ACTH was increased significantly during testosterone replacement (p < .05). The cortisol:ACTH ratio, a measure of adrenal sensitivity, was lower during testosterone replacement (p < .1). A mixed effects regression model showed that testosterone but not estradiol or CBG significantly contributed to the variance of cortisol. These data demonstrate that testosterone regulates CRH-stimulated HPA axis activity in men, with the divergent effects on ACTH and cortisol suggesting a peripheral (adrenal) locus for the suppressive effects on cortisol. Our results further demonstrate that the enhanced stimulated HPA axis activity previously described in young men compared with young women cannot be ascribed to an activational upregulation of the axis by testosterone.
doi:10.1038/sj.npp.1300742
PMCID: PMC1470424  PMID: 15841103
testosterone; cortisol; HPA axis; ACTH; CRH; men
20.  Loneliness and Cortisol: Momentary, Day-to-day, and Trait Associations 
Psychoneuroendocrinology  2009;35(3):430-441.
Summary
In attempts to understand the social determinants of health, strong associations have been found between measures of loneliness, physiological stress processes, and physical and mental health outcomes. Feelings of loneliness are hypothesized to have implications for physiological stress processes, including activity of the hypothalamic-pituitary-adrenal (HPA) axis. In a community sample of young adults, multilevel modeling was used to examine whether trait and state feelings of loneliness were related to changes in levels of the stress-sensitive hormone cortisol, and whether the associations between loneliness and cortisol were mediated or moderated by the presence of concurrent depression or high levels of chronic life stress. Results indicated that trait loneliness was associated with a flattening of the diurnal cortisol rhythm. In addition, both daily and momentary state variations in loneliness were related to cortisol. Prior-day feelings of loneliness were associated with an increased cortisol awakening response the next morning and momentary experiences of loneliness during the day were associated with momentary increases in cortisol among youth who also had high chronic interpersonal stress. Results were significant after covarying current depression, both chronic and momentary reports of stress, and medical and lifestyle covariates. This study expanded on prior work by investigating and revealing three different time-courses of association between loneliness and HPA axis activity in young adults: trait, daily and momentary.
doi:10.1016/j.psyneuen.2009.08.005
PMCID: PMC2841363  PMID: 19744794
loneliness; cortisol diurnal rhythms; HPA axis; young adults; momentary emotion; CAR
21.  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
22.  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
23.  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
24.  The Role of Daily Activities in Youths’ Stress Physiology 
Purpose
This study examined links between diurnal patterns of the stress hormone, cortisol, and adolescents’ time in nine common daily activities.
Method
During eight consecutive nightly telephone interviews, 28 youths (n = 12 girls), 10-18 years of age, reported their day’s activities. On four days, four saliva samples also were collected and assayed for cortisol. Multilevel models assessed within- and between-person associations between time in each activity and cortisol Area Under the Curve (AUC), cortisol awakening response (CAR), morning peak (30 minutes after wake up) and daily decline (morning peak to bedtime).
Results
Links with AUC were found for most activities; significant associations with cortisol rhythms suggested that most effects were due to anticipation of the day’s activities. Specifically, on days when youths spent more time than usual on videogames and TV they had lower AUCs, with lower morning peaks. Youths who spent more time reading (within-person) and in computer activities (between-person) had higher AUCs, with stronger CARs (within-person). Youths who slept more had lower AUCs, with lower morning peaks on both the between- and within-person levels. Amounts of time spent in clubs, and for older adolescents, sports, were also linked to lower AUCs. Finally, youths who spent more time in school/schoolwork had lower AUCs, but on days when youths spent more time than usual in school, they had higher AUCs, stronger CARs, and steeper daily declines.
Conclusion
Beyond their known implications for psychological adjustment, youths’ everyday activities are linked to stress physiology.
doi:10.1016/j.jadohealth.2012.03.016
PMCID: PMC3532943  PMID: 23174474
stress; salivary cortisol; daily activities; time use
25.  Reliability of hypothalamic–pituitary–adrenal axis assessment methods for use in population-based studies 
European journal of epidemiology  2011;26(7):511-525.
Population-based studies have been hampered in exploring hypothalamic–pituitary–adrenal axis (HPA) activity as a potential explanatory link between stress-related and metabolic disorders due to their lack of incorporation of reliable measures of chronic cortisol exposure. The purpose of this review is to summarize current literature on the reliability of HPA axis measures and to discuss the feasibility of performing them in population-based studies. We identified articles through PubMed using search terms related to cortisol, HPA axis, adrenal imaging, and reliability. The diurnal salivary cortisol curve (generated from multiple salivary samples from awakening to midnight) and 11 p.m. salivary cortisol had the highest between-visit reliabilities (r = 0.63–0.84 and 0.78, respectively). The cortisol awakening response and dexamethasone-suppressed cortisol had the next highest between-visit reliabilities (r = 0.33–0.67 and 0.42–0.66, respectively). Based on our own data, the inter-reader reliability (rs) of adrenal gland volume from non-contrast CT was 0.67–0.71 for the left and 0.47–0.70 for the right adrenal glands. While a single 8 a.m. salivary cortisol is one of the easiest measures to perform, it had the lowest between-visit reliability (R = 0.18–0.47). Based on the current literature, use of sampling multiple salivary cortisol measures across the diurnal curve (with awakening cortisol), dexamethasone-suppressed cortisol, and adrenal gland volume are measures of HPA axis tone with similar between-visit reliabilities which likely reflect chronic cortisol burden and are feasible to perform in population-based studies.
doi:10.1007/s10654-011-9585-2
PMCID: PMC3697932  PMID: 21533585
Adrenal gland volume; Cortisol awakening response; Cortisol diurnal curve; Dexamethasone suppression test; Reliability; Salivary cortisol

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