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1.  Cancer Survivors’ Responses to Daily Stressors: Implications for Quality of Life 
Health Psychology  2012;31(3):360-370.
Objective
This study examined cancer survivors’ experience of and responses to challenges and stressors associated with every-day living. The impact of daily stressors on quality of life concerns and cortisol patterns was also investigated.
Design
Participants were 111 cancer survivors who participated in a national telephone diary study of daily experiences (NSDE). Their responses were compared with those of 111 sociodemographically-matched participants with no cancer history using a multilevel modeling approach.
Main Outcome Measures
Over an 8-day period, participants completed a daily inventory of the occurrence and impact of stressful events, affect, and physical symptoms. Salivary cortisol was sampled 4 times per day, and indices of awakening response (CAR), diurnal slope, and overall output (AUC) were examined.
Results
Cancer survivors experienced similar numbers and types of stressful events as the comparison group. While appraisals were largely comparable, cancer survivors showed a modest tendency to perceive stressors as more severe and disruptive, particularly those involving interpersonal tensions. The occurrence of stressors was associated with increased negative affect, decreased positive affect, and increased physical symptoms, but little change in cortisol. Relative to the comparison group, cancer survivors showed less pronounced changes in positive affect and cortisol output when stressors occurred, but a greater increase in negative affect in response to interpersonal conflicts.
Conclusions
Findings indicate that cancer survivors show a resilient ability to respond to day-to-day stressors and challenges. However, daily stressors can have a significant impact on survivors’ mood and physical symptoms and therefore may be an important intervention target.
doi:10.1037/a0027018
PMCID: PMC3348391  PMID: 22268712
cancer; stress; affect; cortisol; quality of life
2.  Association of Cortisol with Neuropsychological Assessment in Older Adults with Generalized Anxiety Disorder 
Aging & mental health  2013;17(4):432-440.
Objectives
Older adults with Generalized Anxiety Disorder (GAD) have elevated diurnal cortisol patterns and show an increased cortisol stress response, which may increase risk for cognitive dysfunction. The current secondary data analysis examined how neuropsychological assessment as a possible laboratory stressor affects cortisol levels in late-life GAD and, in turn, how cortisol levels affect cognitive performance.
Methods
The current sample consisted of 69 individuals with late-life GAD and 39 psychiatrically-healthy group-matched comparison participants. Cognitive performance was measured with a neuropsychological battery and salivary cortisol was collected at several time points. Hierarchical regressions were performed to assess the moderating role of cortisol in the relationship between GAD status and cognitive performance.
Results
The results revealed that older adults with GAD showed significantly lower cortisol levels during neuropsychological assessment, compared to their baseline levels. Further, there was a significant interaction between post-neuropsychological assessment cortisol levels and GAD status on several measures of cognitive performance. The interaction indicated that there is a significant negative relationship between cortisol level and cognitive performance in the GAD participants and no such relationship in the comparison participants.
Conclusions
Our results revealed that participating in a neuropsychological assessment was associated with reduced cortisol in GAD participants, suggesting that refocusing attention such as engaging in cognitive tasks had a cortisol-lowering effect. Further, a higher cortisol level appears to have a detrimental effect on cognitive performance for individuals with GAD but not psychiatrically-healthy comparison participants. The methodological and treatment implications of these findings are discussed.
doi:10.1080/13607863.2012.761673
PMCID: PMC3625449  PMID: 23336532
Generalized anxiety disorder (GAD); HPA axis; neuropsychological assessment; cortisol; stress
3.  Associations among Daily Stressors and Salivary Cortisol: Findings from the National Study of Daily Experiences 
Psychoneuroendocrinology  2013;38(11):2654-2665.
While much research has focused on linking stressful experiences to emotional and biological reactions in laboratory settings, there is an emerging interest in extending these examinations to field studies of daily life. The current study examined day-to-day associations among naturally-occurring daily stressors and salivary cortisol in a national sample of adults from the second wave of the National Study of Daily Experiences (NSDE). A sample of 1,694 adults (Age=57, Range=33–84; 44% male) completed telephone interviews detailing their stressors and emotions on eight consecutive evenings. Participants also provided saliva samples upon waking, 30 minutes post-waking, before lunch and before bed, on four consecutive interview days resulting in 5,995 days of interview/cortisol data. Analyses revealed three main findings. First, cortisol AUC was significantly higher on stressor days compared to stressor-free days, particularly for arguments and overloads at home, suggesting that daily stressors are associated with increased cortisol output, but that not all daily stressors have such an influence. Second, individuals reporting a greater frequency of stressor days also exhibited a steeper diurnal cortisol slope. Finally, daily stressor-cortisol associations were unaltered after adjustment for daily negative affect and physical symptoms. Our discussion focuses on the influence of naturally-occurring daily stressors on daily cortisol and the role of daily diary approaches for studying healthy cortisol responses to psychosocial stressors outside of traditional laboratory settings.
doi:10.1016/j.psyneuen.2013.06.023
PMCID: PMC3914662  PMID: 23856186
Daily Stress; Salivary Cortisol; Daily Diary; Negative Affect; Physical Symptoms; Cortisol Awakening Response; Diurnal Cortisol Slope; HPA Axis
4.  Short- and long-term effects of tactile massage on salivary cortisol concentrations in Parkinson’s disease: a randomised controlled pilot study 
Background
Parkinson’s disease (PD) is a chronic neurodegenerative disorder with limited knowledge about the normal function and effects of non-pharmacological therapies on the hypothalamic-pituitary-adrenal (HPA) axis. The aim of the study was to analyse the basal diurnal and total secretion of salivary cortisol in short- and long-term aspects of tactile massage (TM).
Methods
Design: Prospective, Controlled and Randomised Multicentre Trial.
Setting and interventions: Forty-five women and men, aged 50–79 years, were recruited. Twenty-nine of them were blindly randomised to tactile massage (TM) and 16 of them to the control group, rest to music (RTM). Ten interventions were given during 8 weeks followed by a 26 weeks of follow up. Salivary cortisol was collected at 8 am, 1 pm, 8 pm, and 8 am the next day, on five occasions. With the first and eighth interventions, it was collected immediately before and after intervention.
Main outcome measures: The primary aim was to assess and compare cortisol concentrations before and immediately after intervention and also during the follow-up period. The secondary aim was to assess the impact of age, gender, body mass index (BMI), duration and severity of PD, effects of interventional time-point of the day, and levodopa doses on cortisol concentration.
Results
The median cortisol concentrations for all participants were 16.0, 5.8, 2.8, and 14.0 nmol/L at baseline, later reproduced four times without significant differences. Cortisol concentrations decreased significantly after TM intervention but no change in diurnal salivary cortisol pattern was found. The findings of reduced salivary cortisol concentrations immediately after the interventions are in agreement with previous studies. However, there was no significant difference between the TM and control groups. There were no significant correlations between cortisol concentrations and age, gender, BMI, time-point for intervention, time interval between anti-parkinson pharmacy intake and sampling, levodopa doses, duration, or severity of PD.
Conclusions
Diurnal salivary cortisol rhythm was normal. Salivary cortisol concentrations were significantly reduced after the TM intervention and after RTM, but there were no significant differences between the groups and no sustained long-term effect. No associations were seen between salivary cortisol concentration and clinical and/or pharmacological characteristics.
Trial registration
ClinicalTrial.gov, NCT01734876 and FoU Sweden 108881.
doi:10.1186/1472-6882-13-357
PMCID: PMC3878723  PMID: 24330473
Circadian rhythm; Complementary therapies; Cortisol; Massage; Parkinson disease; Stress
5.  Cortisol Diurnal Rhythm and Stress Reactivity in Male Adolescents with Early-Onset or Adolescence-Onset Conduct Disorder 
Biological Psychiatry  2008;64(7):599-606.
Background
Previous studies have reported lower basal cortisol levels and reduced cortisol responses to stress in children and adolescents with conduct disorder (CD). It is not known whether these findings are specific to early-onset CD. This study investigated basal and stress-induced cortisol secretion in male participants with early-onset and adolescence-onset forms of CD.
Methods
Forty-two participants with early-onset CD, 28 with adolescence-onset CD, and 95 control subjects participated in the study. They collected saliva across the day to assess their cortisol awakening response and diurnal rhythm. Subsequently, salivary cortisol was measured before, during, and after a psychosocial stress procedure designed to elicit frustration. Cardiovascular activity and subjective mood states were also assessed during stress exposure.
Results
There were no group differences in morning cortisol levels or the size of the cortisol awakening response. Basal cortisol levels in the evening and at 11 am during the laboratory visit were higher in both CD subgroups relative to control subjects. In contrast, cortisol and cardiovascular responses to psychosocial stress were reduced in both CD subgroups compared with control subjects. All groups reported similar increases in negative mood states during stress.
Conclusions
Our findings suggest that group differences in cortisol secretion are most pronounced during stress exposure, when participants with CD show cortisol hyporeactivity compared with control subjects. There was no evidence for reduced basal cortisol secretion in participants with CD, but rather increased secretion at specific time points. The results do not support developmentally sensitive differences in cortisol secretion between CD subtypes.
doi:10.1016/j.biopsych.2008.05.022
PMCID: PMC2568813  PMID: 18620338
Antisocial behavior; conduct disorder; cortisol; cortisol awakening response; HPA axis; stress reactivity
6.  Dysregulation of Diurnal Cortisol Secretion Affects Abstinence Induction during a lead-in period of a Clinical Trial for Depressed Cocaine-Dependent Patients 
Background and Objective
Hypothesizing that stress dysregulation may worsen cocaine dependence, we investigated the effect of diurnal cortisol secretion profile, suppression of cortisol secretion, and total cortisol secretion on retention, abstinence-based voucher earnings, days of cravings, and mood status of participants at the end of a 2-week medication-free lead-in prior to randomization in a clinical trial of mirtazapine (60 mg vs. placebo) for depressed cocaine-dependent patients.
Methods
We measured saliva cortisol levels at 9am, 2pm, and 5pm on the first two consecutive days of a 2-week medication-free lead-in period. Results from saliva samples were used to estimate the total daily level of cortisol, the diurnal profile of secretion (typical vs. atypical), and response to dexamethasone suppression (0.1 mg). Seventy-seven patients collected saliva samples at baseline, and 65 (85%) were suitable for profile analysis.
Results
Patients with typical profiles (52%) collected significantly more abstinence-based voucher earnings during the lead-in (U = 299.50, p = .025). Diurnal secretion profile did not significantly affect mood status, days of craving, or retention. There were no significant effects of suppression of cortisol secretion or of total cortisol levels on any outcome measures.
Conclusion
In a subgroup of cocaine-dependent patients, deviation of cortisol secretion away from the homeostatic diurnal pattern was associated with reduced success at achieving early abstinence, an important determinant of treatment success.
doi:10.1111/j.1521-0391.2013.12060.x
PMCID: PMC4049414  PMID: 24313234
stress; cocaine; addiction; cortisol; clinical trial; drug treatment
7.  Blunted Nocturnal Cortisol Rise is Associated With Higher Carotid Artery Intima-Media Thickness (CIMT) in Overweight African American and Latino Youth 
Psychoneuroendocrinology  2013;38(9):1658-1667.
Background
Blunted diurnal cortisol variation has been associated with overt cardiovascular disease in adults. The relationship between the diurnal cortisol variation and subclinical atherosclerosis in youth has yet to be investigated. The objectives of this study were to: 1) determine the relationship between overnight cortisol measures and CIMT in overweight and obese, African-American and Latino children; 2) assess ethnic differences in these relationships and 3) explore whether overnight cortisol and CIMT relationships were independent of inflammatory markers, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α).
Methods
One hundred and fifty-six overweight and obese African-American and Latino children (ages 8–17, 86M/70F, 55 African-American /101 Latino) underwent measures of CIMT by B-mode ultrasound, nocturnal cortisol rise (NCR=salivary cortisol rise from 2200hrs to awakening at 0530hrs), cortisol awakening response (CAR=salivary cortisol from time of awakening to 30 min later), fasting serum cortisol and overnight urinary free cortisol.
Results
Using linear regression, salivary cortisol0530hrs and NCR were negatively associated with CIMT (βstandardized = −0.215 and −0.220, p<0.01) independent of age, height, percent body fat, ethnicity and systolic blood pressure. Nocturnal salivary cortisol2200hrs, morning serum cortisol, and overnight urinary free cortisol were not associated with CIMT. Using ANCOVA, participants with LOW NCR (NCR <0.44µg/dL, n=52) had significantly greater CIMT than those with HIGH NCR (NCR ≥0.91 µg/dL, n=52; 0.632±0.008 vs. 0.603±0.008mm p=0.01) after controlling for covariates. Ethnicity was independently associated with CIMT, whereby African-American children had greater CIMT than Latino children (−0.028±0.009, p=0.006). The relationships between cortisol measures and CIMT did not differ between the two ethnic groups (all pinteraction=0.28–0.97). CRP, IL-6 and TNF-α were not associated with CIMT (p>0.05). IL-6 was inversely related to NCR (r=−0.186, p=0.03), but it did not explain the relationship between NCR and CIMT.
Conclusions
Salivary cortisol0530hrs and NCR, but not CAR, nocturnal salivary cortisol 2200hrs, morning serum cortisol or overnight urinary free cortisol, were associated with CIMT, independent of relevant covariates, including inflammatory factors. A low awakening salivary cortisol or a blunted NCR may be related to increased atherosclerosis risk in overweight and obese minority youth. These findings support adult studies suggesting flattened daytime diurnal cortisol variation impacts cardiovascular disease risk.
doi:10.1016/j.psyneuen.2013.01.011
PMCID: PMC3722251  PMID: 23433749
Obesity; cardiovascular risk; carotid artery; intima media thickness; cortisol
8.  Comparing Cortisol, Stress and Sensory Sensitivity in Children with Autism 
Previously we reported that children with autism show significant variability in cortisol. The current investigation was designed to extend these findings by exploring plausible relationships between cortisol and psychological measures of stress and sensory functioning. Salivary cortisol values for diurnal rhythms and response to stress in children with and without autism were compared to parent-report measures of child stress, the Stress Survey Schedule (SSS), sensory functioning, Short Sensory Profile (SSP) and parenting stress (PSI). In autism, a negative relationship between morning cortisol and the SSS revealed that higher observed symptoms of stress were related to lower cortisol. Lower cortisol is seen in conditions of chronic stress and in social situations characterized by unstable social relationships. Sensory sensitivity painted a more complicated picture, in that some aspects of SSP were associated with higher while others were associated with lower cortisol. We propose that increased sensory sensitivity may enhance the autistic child’s susceptibility to the influence of zeitgeibers reflected in variable cortisol secretion. Evening cortisol were positively associated with SSS such that the higher the level of evening cortisol, the higher the child’s parent-reported daily stress, especially to changes, such as in daily routine. Regarding the response to stress, the psychological and parent variables did not differentiate the groups; rather, discrete subgroups of cortisol responders and non-responders were revealed in both the autism and neurotypical children. The results support a complex interplay between physiological and behavioral stress and sensory sensitivity in autism and plausible developmental factors influencing stress reactivity across the groups.
doi:10.1002/aur.64
PMCID: PMC2698454  PMID: 19358306
autism; cortisol; diurnal variation; stress; LHPA; sensory sensitivity
9.  Pain Intensity and Its Association with Negative Mood States in Patients with Spinal Cord Injury 
Pain and Therapy  2013;2(2):113-119.
Introduction
Chronic and persistent pain is a prevalent and debilitating secondary condition in patients with a neurological injury such as spinal cord injury (SCI). Patients with SCI have an increased risk of developing other co-morbid conditions such as elevated negative mood states. Arguably, the presence of chronic pain would act to intensify the chances of developing negative mood states as opposed to resilient mental states. The objective of this research was to investigate the association between pain intensity and levels of negative mood states in adult patients with SCI.
Methods
Participants included 107 adults with SCI living in the community who completed an assessment regimen in a relaxed environment. Mean pain intensity over a period of 1 week and the Profile of Mood States, a validated psychometric measure of mood states (anxiety, depressed mood, anger, vigor, fatigue, confusion and total negative mood score) were used to determine associations between pain intensity and mood states. The sample was divided into a low pain intensity sub-group (<4 where 0 = no pain; 10 = worst pain imaginable) and a clinically significant or high pain intensity sub-group (≥4), allowing negative mood to be compared between the sub-groups.
Results
Mean age was 47.1 years, and 87% of the sample was male. Clinically significant pain intensity over the week prior to assessment was found in 52% of the 107 participants. The high pain intensity sub-group was found to have significantly elevated anxiety, depressed mood, anger, fatigue, confusion and significantly reduced vigor.
Conclusion
These results provide further evidence that patients with SCI experience clinically elevated negative mood states if they have intense levels of pain over extended periods of time. In contrast, patients without intense pain have mood states similar to those in the able-bodied community. Implications for the treatment of SCI are discussed.
doi:10.1007/s40122-013-0017-8
PMCID: PMC4107910  PMID: 25135149
Anxiety; Depressed mood; Negative mood states; Pain intensity; Profile of Mood States; Spinal cord injury
10.  Salivary cortisol differs with age and sex and shows inverse associations with WHR in Swedish women: a cross-sectional study 
Background
Most studies on cortisol have focused on smaller, selected samples. We therefore aimed to sex-specifically study the diurnal cortisol pattern and explore its association with abdominal obesity in a large unselected population.
Methods
In 2001–2004, 1811 men and women (30–75 years) were randomly selected from the Vara population, south-western Sweden (81% participation rate). Of these, 1671 subjects with full information on basal morning and evening salivary cortisol and anthropometric measurements were included in this cross-sectional study. Differences between groups were examined by general linear model and by logistic and linear regression analyses.
Results
Morning and Δ-cortisol (morning – evening cortisol) were significantly higher in women than men. In both genders older age was significantly associated with higher levels of all cortisol measures, however, most consistently with evening cortisol. In women only, age-adjusted means of WHR were significantly lower in the highest compared to the lowest quartile of morning cortisol (p = 0.036) and Δ-cortisol (p < 0.001), respectively. Furthermore, when comparing WHR above and below the mean, the age-adjusted OR in women for the lowest quartile of cortisol compared to the highest was 1.5 (1.0–2.2, p = 0.058) for morning cortisol and 1.9 (1.3–2.8) for Δ-cortisol. All findings for Δ-cortisol remained after adjustments for multiple covariates and were also seen in a linear regression analysis (p = 0.003).
Conclusion
In summary, our findings of generally higher cortisol levels in women than men of all ages are novel and the stronger results seen for Δ-cortisol as opposed to morning cortisol in the association with WHR emphasise the need of studying cortisol variation intra-individually. To our knowledge, the associations in this study have never before been investigated in such a large population sample of both men and women. Our results therefore offer important knowledge on the descriptive characteristics of cortisol in relation to age and gender, and on the impact that associations previously seen between cortisol and abdominal obesity in smaller, selected samples have on a population level.
doi:10.1186/1472-6823-9-16
PMCID: PMC2711063  PMID: 19545400
11.  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
12.  Comparison of rehabilitation outcomes following vascular-related and traumatic spinal cord injury 
Background
Previous studies have noted similar outcomes between vascular-related spinal cord injury (VR-SCI) and those with traumatic SCI (T-SCI), despite significant difference in their demographics and clinical presentation (age, level of injury (LOI), and degree of incompleteness).
Objectives
To review demographic and clinical presentation of VR-SCI and to compare outcomes with a matched group with T-SCI.
Design
Analysis of 10-year prospective data collection including 30 consecutive patients admitted to an SCI rehabilitation unit with VR-SCI and comparison with 573 patients with T-SCI. Outcomes were further analyzed comparing VR-SCI to T-SCI (n = 30), matched for age, LOI, and ASIA (American Spinal Injury Association) Impairment Scale (AIS).
Setting
A level 1 tertiary university trauma center.
Main outcome measures
Functional independence measure (FIM) score changes from admission to discharge. Secondary outcome measures included admission and discharge FIM scores, FIM efficiency, rehabilitation length of stay (LOS), and discharge disposition.
Results
Overall, individuals with VR-SCI were more likely (P < 0.0001) to be older (mean age 57.2 vs. 40.0 years) and have paraplegia (87 vs. 48%) than those with T-SCI. Common etiologies for VR-SCI were post-surgical complication (43%), arteriovenous malformation (17%), aortic dissection (13%), and systemic hypotension (13%). Common region of injury and AIS classification in VR-SCI was thoracic (73%) and AIS C (33%). Common SCI-related complications in VR-SCI included neurogenic bowel/bladder (93%), urinary tract infection (73%), pain (67%), pressure ulcers (47%), and spasticity (20%). Matched-group outcome comparisons did not reveal significant differences in FIM change, FIM efficiency, LOS, or disposition between VR-SCI and T-SCI.
Conclusion
VR-SCI leads to significant disability and is associated with common secondary SCI complications as well as medical co-morbidities. This study notes differing demographic and injury characteristics between VR-SCI and T-SCI groups. However, when matched for these differences, rehabilitation functional outcomes were not significantly different between the two groups.
doi:10.1179/2045772311Y.0000000016
PMCID: PMC3152813  PMID: 21903015
Spinal cord injuries; Vascular; Traumatic; Spinal cord ischemia; Aortic dissection; Post-surgical ischemia; Vascular embolism; Arteriovenous malformation; Systemic hypotension; Functional independence measure
13.  Diurnal Cortisol Dysregulation, Functional Disability, and Depression in Women With Ovarian Cancer 
Cancer  2010;116(18):4410-4419.
BACKGROUND
Multiple alterations in circadian rhythms have been observed in cancer patients, including the diurnal rhythm of the adrenal hormone cortisol. Diurnal cortisol alterations have been associated with cancer-related physiological processes as well as psychological stress. Here we investigate alterations in diurnal cortisol rhythm in ovarian cancer patients, and potential links with depression, life stress, and functional disability.
METHODS
Women (n = 177) with suspected ovarian cancer completed questionnaires and collected salivary cortisol 3× daily for 3 consecutive days before surgery. One hundred women were subsequently diagnosed with ovarian cancer and 77 with benign disease. In addition, healthy women (n = 33) not scheduled for surgery collected salivary cortisol at the same time points.
RESULTS
Ovarian cancer patients demonstrated significantly elevated nocturnal cortisol (P = .022) and diminished cortisol variability (P = .023) compared with women with benign disease and with healthy women (all P values <.0001). Among ovarian cancer patients, higher levels of nocturnal cortisol and less cortisol variability were significantly associated with greater functional disability, fatigue, and vegetative depression, but not with stress, distress, or depressed affect. There were no significant associations between functional or psychological variables and diurnal cortisol in women with benign disease.
CONCLUSIONS
Nocturnal cortisol and cortisol variability show significant dysregulation in ovarian cancer patients, and this dysregulation was associated with greater functional disability, fatigue, and vegetative depression. These findings suggest potential hypothalamic-pituitary-adrenal involvement in functional disability in ovarian cancer, and may have implications for disease progression.
doi:10.1002/cncr.25299
PMCID: PMC3118555  PMID: 20564155
cortisol; ovarian cancer; diurnal rhythm; fatigue; functional disability; depression; stress
14.  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
15.  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
16.  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
17.  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
18.  The Effects of Race-related Stress on Cortisol Reactivity in the Laboratory 
Background
The experience of race-related stressors is associated with physiological stress responses. However, much is unknown still about the complex relationship between how race-related stressors are perceived and experienced and potential moderators such as strength of racial identity.
Purpose
This research examines the impact of a real-life stressor and strength of race identity on physiological responses to a social evaluative threat induced in the laboratory.
Methods
Salivary cortisol measures were collected throughout a stressor protocol. African-American participants were also randomized to one of two conditions designed to promote either racial identification or student identification, before the experimental task. Unexpectedly, a highly publicized real-life racial stressor, the Duke Lacrosse (LaX) scandal, occurred during the course of the data collection. This allowed for pre-post LaX comparisons to be made on cortisol levels.
Results
These comparisons showed that across both priming conditions, participants post-LaX had highly elevated cortisol levels that were nonresponsive to the experimental stress task, while their pre-LaX counterparts had lower cortisol levels that exhibited a normal stress response pattern. Furthermore, this effect of LaX was significantly moderated by gender, with women having lower mean cortisol levels pre-LaX but significantly greater cortisol levels than all other groups post-LaX.
Conclusions
These results suggest that recent exposure to race-related stress can have a sustained impact on physiological stress responses for African Americans.
doi:10.1007/s12160-007-9013-8
PMCID: PMC2763623  PMID: 18347910
Cortisol; Racial Stressors; Identity
19.  Differences in Salivary Alpha-Amylase and Cortisol Responsiveness following Exposure to Electrical Stimulation versus the Trier Social Stress Tests 
PLoS ONE  2012;7(7):e39375.
Background
Cortisol is an essential hormone in the regulation of the stress response along the HPA axis, and salivary cortisol has been used as a measure of free circulating cortisol levels. Recently, salivary alpha-amylase (sAA) has also emerged as a novel biomarker for psychosocial stress responsiveness within the sympathetic adrenomedullary (SAM) system.
Principal Findings
We measured sAA and salivary cortisol in healthy volunteers after exposure to the Trier Social Stress Test (TSST) and electric stimulation stress. One hundred forty-nine healthy volunteers participated in this study. All subjects were exposed to both the TSST and electric stimulation stress on separate days. We measured sAA and salivary cortisol levels three times immediately before, immediately after, and 20 min after the stress challenge. The State (STAI-S) and Trait (STAI-T) versions of the Spielberger Anxiety Inventory test and the Profile of Mood State (POMS) tests were administered to participants before the electrical stimulation and TSST protocols. We also measured HF, LF and LF/HF Heart Rate Variability ratio immediately after electrical stimulation and TSST exposure. Following TSST exposure or electrical stimulation, sAA levels displayed a rapid increase and recovery, returning to baseline levels 20 min after the stress challenge. Salivary cortisol responses showed a delayed increase, which remained significantly elevated from baseline levels 20 min after the stress challenge. Analyses revealed no differences between men and women with regard to their sAA response to the challenges (TSST or electric stimulations), while we found significantly higher salivary cortisol responses to the TSST in females. We also found that younger subjects tended to display higher sAA activity. Salivary cortisol levels were significantly correlated with the strength of the applied electrical stimulation.
Conclusions
These preliminary results suggest that the HPA axis (but not the SAM system) may show differential response patterns to distinct kinds of stressors.
doi:10.1371/journal.pone.0039375
PMCID: PMC3408464  PMID: 22859941
20.  Brain white matter integrity and cortisol in older men: the Lothian Birth Cohort 1936☆ 
Neurobiology of Aging  2015;36(1):257-264.
Elevated glucocorticoid (GC) levels are hypothesized to be deleterious to some brain regions, including white matter (WM). Older age is accompanied by increased between-participant variation in GC levels, yet relationships between WM integrity and cortisol levels in older humans are underexplored. Moreover, it is unclear whether GC-WM associations might be general or pathway specific. We analyzed relationships between salivary cortisol (diurnal and reactive) and general measures of brain WM hyperintensity (WMH) volume, fractional anisotropy (gFA), and mean diffusivity (gMD) in 90 males, aged 73 years. Significant associations were predominantly found between cortisol measures and WMHs and gMD but not gFA. Higher cortisol at the start of a mild cognitive stressor was associated with higher WMH and gMD. Higher cortisol at the end was associated with greater WMHs. A constant or increasing cortisol level during cognitive testing was associated with lower gMD. Tract-specific bases of these associations implicated anterior thalamic radiation, uncinate, and arcuate and inferior longitudinal fasciculi. The cognitive sequelae of these relationships, above other covariates, are a priority for future study.
Highlights
•We correlated salivary cortisol and brain white matter (WM) measures in older males.•Cortisol was measured diurnally and in reaction to a cognitive challenge.•Diffusion tensor magnetic resonance imaging (fractional anisotropy and mean diffusivity) and total hyperintensity volume measured WM integrity.•WM-cortisol relations were found for mean diffusivity and hyperintensity volume but not fractional anisotropy.•Higher cortisol in response to cognitive stressor denoted lower WM integrity.
doi:10.1016/j.neurobiolaging.2014.06.022
PMCID: PMC4274312  PMID: 25066239
Cortisol; Glucocorticoid; White matter; Aging; Brain structure; Tractography
21.  Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: The role of stress and of antipsychotic treatment 
Schizophrenia research  2009;116(2-3):234-242.
First-episode psychosis (FEP) patients show hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, but the mechanisms leading to this are still unclear. The aim of this study was to investigate the role of stress and antipsychotic treatment on diurnal cortisol levels, and on cortisol awakening response, in FEP. Recent stressful events, perceived stress and childhood trauma were collected in 50 FEP patients and 36 healthy controls using structured instruments. Salivary cortisol was obtained at awakening, at 15, 30, and 60 min after awakening, and at 12 and 8 pm. Patients experienced more recent stressful events, perceived stress and childhood trauma than controls (p < 0.001). Patients had a trend for higher diurnal cortisol levels (p=0.055), with those with less than two weeks of antipsychotics showing significantly higher cortisol levels than both patients with more than two weeks of antipsychotics (p=0.005) and controls (p=0.002). Moreover, patients showed a blunted cortisol awakening response compared with controls, irrespectively of antipsychotic treatment (p=0.049). These abnormalities in patients were not driven by the excess of stressors: diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=−0.36, p=0.014), and cortisol awakening response was positively correlated with a history of sexual childhood abuse (r=0.33, p=0.033). No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response. Our study shows that antipsychotics normalize diurnal cortisol hyper-secretion but not the blunted cortisol awakening response in FEP; factors other than the excess of psychosocial stress explain HPA axis abnormalities in FEP.
doi:10.1016/j.schres.2009.08.013
PMCID: PMC3513410  PMID: 19751968
First-episode psychosis; Cortisol; Stress; Antipsychotic; Childhood trauma; HPA axis
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.  Decreased Spinothalamic and Dorsal Column Medial Lemniscus-Mediated Function Is Associated with Neuropathic Pain after Spinal Cord Injury 
Journal of Neurotrauma  2012;29(17):2706-2715.
Abstract
Neuropathic pain (NP) after spinal cord injury (SCI) can significantly and negatively affect quality of life and is often refractory to currently available treatments. In order to find more effective therapeutic avenues, it would be helpful to identify the primary underlying pathophysiological mechanisms in each individual. The aim of the present study was to assess the relationship between the presence and severity of NP after SCI and measures of somatosensory function mediated via the dorsal column medial lemniscal (DCML) pathway and the spinothalamic tract (STT). Vibratory, mechanical, thermal, and pain thresholds measured in areas at and below the neurological level of injury (LOI) in persons with SCI and NP (SCI-NP, n=47) and in persons with SCI without NP (SCI-noNP, n=18) were normalized to data obtained from able-bodied pain-free control subjects (A-B, n=30). STT-mediated function at and below the LOI was significantly impaired in both SCI groups compared with A-B controls (p<0.001), but not significantly different between the two SCI groups (NP vs. no-NP). In contrast, the SCI-NP group had significantly greater impairment of DCML-mediated function at the LOI, as reflected by greater vibratory detection deficits (z=−3.89±0.5), compared with the SCI-noNP group (z=−1.95±0.7, p=0.034). Within the SCI-NP group, NP severity was significantly associated with increased thermal sensitivity below the LOI (r=0.50, p=0.038). Our results suggest that both impaired STT and DCML-mediated function are necessary for the development of NP after SCI. However, within the SCI-NP group, greater NP severity was associated with greater sensitivity to thermal stimuli below the LOI. This finding concurs with other studies suggesting that STT damage with some sparing is associated with NP.
doi:10.1089/neu.2012.2343
PMCID: PMC3510448  PMID: 22845918
NP; pain measurement; pain threshold; sensory thresholds; SCI
24.  Do vascular risk factors contribute to the prevalence of pressure ulcer in veterans with spinal cord injury? 
Objective
The overall goal of this observational study was to determine whether modifiable vascular risk factors contribute to the prevalence of pressure ulcers (PrU) in veterans with traumatic spinal cord injury (SCI).
Background
Given the increasingly limited financial resources in hospitals and clinics, identifying risk factors associated with the development of PrU in persons with SCI will be a major step in reducing the cost of care for these individuals, and may improve their quality of life.
Method
We retrospectively reviewed the electronic charts of 87 veterans with SCI who are being followed regularly in our SCI clinic and are enrolled in the SCI registry. The data collected included the basic demographics, presence of modifiable vascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and current smoking; presence of incontinence and depression; and results from blood drawn for hemoglobin level, blood urea nitrogen, creatinine, and albumin levels and lipid profile on veteran's initial enrollment. Local Institution Review Board approval was obtained for the protocol.
Results
Of the 87 veterans with SCI, 27 had PrU. Comparisons between those with and without PrU found no significant differences for the demographic variables of age, gender, age of SCI onset, or SCI duration, but there was a trend for the groups to differ in ethnicity (P = 0.05). Similarly, the presence of modifiable vascular risk factors including hypertension, diabetes mellitus, hyperlipidemia, and current smoking did not differ between those with and without PrU. There were 36 pressure ulcer sites observed in 27 people. The proportion of pressure ulcer sites (of the 36) significantly differed by SCI severity based on the American Spinal Injury Association (ASIA) score (P < 0.0001).
Conclusion
This study suggests that the presence of PrU was influenced by the severity of the SCI without any contribution from modifiable vascular risk factors.
doi:10.1179/107902610X12923394765652
PMCID: PMC3066489  PMID: 21528626
Spinal cord injury; Pressure ulcer; Vascular risk factors
25.  Hypothalamic-Pituitary-Adrenal Axis Function: Relative Contributions of Perceived Stress and Obesity in Women 
Journal of Women's Health  2008;17(10):1647-1655.
Abstract
Objective
A range of behavioral and psychosocial factors may contribute to a chronically stimulated hypo-thalamic-pituitary-adrenal (HPA) axis and subsequently altered diurnal patterns. The goal of this cross-sectional study was to examine associations among diurnal cortisol levels, perceived stress, and obesity patterns.
Methods
Seventy-eight women (aged 24–72 years) employed in a rural public school system completed the perceived stress scale, collected diurnal saliva samples, and underwent anthropometric assessments. Reduced peak-to-nadir cortisol values across the day were considered a sign of impairment in HPA function. A series of linear regression models determined the best predictors of diurnal cortisol variation.
Results
There was a marginal linear trend in stress levels across body mass index (BMI) categories, with obese women reporting the highest levels of stress (p = 0.07). Perceived stress was the only significant predictor of the degree of flattening of the diurnal cortisol curve in the sample as a whole (β = −0.042, R2 = 0.11, F = 8.6, p = 0.005), indicating reduction in the normal diurnal pattern. Among overweight women (BMI = 25–29.9 kg/m2), stress and waist circumference combined predicted 35% of the variability in diurnal cortisol. In contrast, among obese women (BMI ≥ 30 kg/m2), BMI predicted 31% of the variability in diurnal cortisol (F = 13.8, p = 0.001), but stress was no longer significantly related to diurnal cortisol.
Conclusions
Psychological stress predicts a significant portion of HPA axis functioning. In overweight women, perceived stress and waist circumference were of approximately equal importance in predicting adrenal cortisol secretion. However, among obese women, a major portion of the diurnal cortisol variation was predicted by BMI alone, not stress or waist circumference. This may help elucidate the mechanisms linking obesity to increased risk of cardiovascular disease (CVD).
doi:10.1089/jwh.2008.0866
PMCID: PMC2945932  PMID: 19049359

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