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1.  Levels and confounders of morning cortisol collected from adolescents in a naturalistic (school) setting 
Psychoneuroendocrinology  2008;33(9):1257-1268.
Summary
Salivary cortisol is widely used in research but little is known about the typical, or expected, functioning of the HPA-axis in adolescents in naturalistic settings, nor whether the extensive array of confounders documented in the literature is applicable in this situation.
In a school-based study, 2995 15-year-old pupils provided two saliva samples, 30 min apart, in morning sessions timed to capture peak cortisol decline. The collection protocol was a balance between the large sample size obtainable in a school situation and a limited number of samples, constrained by the school timetable. In addition, pupils completed a questionnaire containing items previously shown to be associated with cortisol levels (e.g. time since awakening and life events), and their height and weight were measured. Outcome measures were cortisol levels at Times 1 and 2, and change (per minute) in cortisol between the two time points.
Median (IQR) cortisol levels for males and females were 10.5 (8.1) and 11.6 (9.3) nmol/L at Time 1, and 8.2 (6.0) and 8.1 (6.5) nmol/L at Time 2. 73% had a decline in cortisol level of more than 10% across the two time points, compatible with the expected diurnal pattern. In bivariate analyses, cortisol sampled on Monday, times of measurement and since awakening, prior smoking and several life events were associated with cortisol levels at Times 1 and 2 in both sexes. However, in multivariate analysis, few of these variables remained after controlling for times of measurement and since awakening and, in addition, the final models differed between the sexes. Two events (friend dying and splitting with a boy/girlfriend) predicted cortisol levels in both sexes while age, maturity, recent eating and smoking were predictors only in males. Several factors associated with cortisol change differed from those observed for absolute levels. Further adjustment for school clustering affected some associations, particularly time of measurement.
This study managed many of the problems found in naturalistic research on cortisol and provides norms for morning cortisol levels in 15-year-old adolescents.
doi:10.1016/j.psyneuen.2008.06.010
PMCID: PMC2571963  PMID: 18691824
Hydrocortisone; Adolescent; Saliva; Stress; Cross-sectional studies; Social environment
2.  Gender Specific Effect of Psychological Stress and Cortisol Reactivity on Adolescent Risk Taking 
The purpose of this study was to evaluate how psychological stress, gender and cortisol response to stress relate to risk behavior among 132 14–18 year old adolescents. Participants completed a laboratory based risk task prior to and immediately after a computerized psychological stress task, and salivary cortisol was collected from pre-stress to 60 minutes following initial stress exposure. Results indicate that adolescent boys (n = 59) and girls (n = 73) demonstrate different patterns of risk taking (RT) in response to stress, such that boys evidenced an increase in RT following stress exposure, whereas girls evidenced a decrease in RT. In addition, a gender by cortisol interaction demonstrated that for boys, both a smaller total cortisol output (AUCg) and peak cortisol response to stress (PC) was associated with greater stress-induced RT. Both cortisol measures were unrelated to stress-induced RT among girls. Taken together, data suggest that among boys, a blunted cortisol response to stress underlies an increase in risk taking in the context of psychological stress. Further research with an additional behavioral stress task is needed prior to drawing conclusions regarding the relation between female gender, cortisol response to stress, and risk taking in the context of psychological stress.
doi:10.1007/s10802-013-9713-4
PMCID: PMC3681843  PMID: 23338478
Risk Taking; Gender; Cortisol; Stress; Adolescence
3.  Enhanced cortisol increase upon awakening is associated with greater pain ratings but not salivary cortisol or soluble tumor necrosis factor-α receptor II responses to acute pain 
The Clinical Journal of Pain  2012;28(4):291-299.
Objectives
The cortisol awakening response (CAR) is related with psychosocial factors and health in potentially significant ways, suggesting that it may be a distinctive marker of hypothalamic-pituitary-adrenal (HPA) axis function and dysfunction. This sought to expand upon previous work that examined the association between CAR and ratings of laboratory-evoked acute pain stimulation. In addition to evoked pain ratings, this study also tested whether CAR was prospectively related with salivary cortisol and soluble tumor necrosis factor-α receptor II (sTNFαRII) responses to acute pain stimulation.
Methods
This study included 36 healthy, pain-free volunteers of both sexes recruited via posted study flyers. Prior to completion of laboratory pain testing, salivary cortisol samples were obtained at home over the course of a single morning according to the following time frame: upon awakening, and 15, 30, and 60 min after awakening. Following collection of saliva, study participants brought their home saliva samples to the laboratory for assay and subsequently completed acute experimental pain testing procedures.
Results
Cluster analysis of CAR revealed two distinct groups with similar patterns of cortisol response to awakening; increased and flattened. Relative to flattened CAR, increased CAR was associated with greater ratings of pain intensity and unpleasantness. Salivary cortisol was significantly increased and sTNFαRII significantly decreased following pain testing, but neither of these responses differed as a function of increased versus flattened CAR.
Discussion
CAR may be a marker for stress sensitivity and/or the anticipation of impending stress, which could explain why the increased CAR cohort reported greater acute pain ratings.
doi:10.1097/AJP.0b013e31822cf542
PMCID: PMC3237812  PMID: 21904196
Cortisol awakening response; acute pain; inflammation; HPA axis; stress
4.  The Relationship Between Fluticasone Furoate Systemic Exposure and Cortisol Suppression 
Clinical Pharmacokinetics  2013;52:885-896.
Introduction
The inhaled corticosteroid (ICS) fluticasone furoate is in development, in combination with the long-acting beta2-agonist vilanterol for the once-daily treatment of asthma and chronic obstructive pulmonary disease and as a monotherapy treatment for asthma. Corticosteroids, including ICSs, have the potential to induce dose-dependent systemic effects on the hypothalamic–pituitary–adrenal (HPA) axis. Cortisol suppression has been observed in asthma patients with normal HPA axis function at baseline on receiving high doses of ICSs, and is associated with adverse effects on a number of physiological processes. The measurement of 24-h serum cortisol and 24-h urinary cortisol excretion are sensitive methods for assessing adrenocortical activity, and can evaluate cortisol suppression in a dose-dependent manner.
Objective
The purpose of the meta-analysis presented here was to characterize the population pharmacokinetic/pharmacodynamic relationship between fluticasone furoate systemic exposure [as measured by area under the concentration–time curve over 24 h postdose (AUC24)] and both 24-h weighted mean serum cortisol (WM24) and 24-h urine cortisol excretion in healthy subjects and subjects with asthma.
Methods
The serum cortisol meta-analysis integrated eight studies; five Phase I studies in healthy subjects, two Phase IIa studies, and one Phase III study in subjects with asthma. Each study included serial blood sampling for estimation of WM24. The urine cortisol meta-analysis integrated three studies: one Phase I study in healthy subjects, and one Phase IIb and one Phase III study in subjects with asthma. Each study included complete 0–24 h urine collection for estimation of urine cortisol excretion. All studies included blood sampling for estimation of fluticasone furoate AUC24. A sigmoid maximum effect (Emax) model was fitted to fluticasone furoate AUC24 and serum cortisol and urine cortisol data using nonlinear mixed-effect modeling with the computer program NONMEM®.
Results
Over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range, the relationship between fluticasone furoate AUC24 and WM24 and 24-h urine cortisol excretion was well described by an Emax model. The average estimate of AUC producing 50 % of maximum effect (AUC50) was similar for the serum cortisol and urine cortisol models with values of 1,556 and 1,686 pg·h/mL, respectively. Although formulation/inhaler was shown to be a significant covariate on the estimates of both WM24 at zero concentration (C0) and AUC50 in the serum cortisol model, the differences were small and believed to be due to study variability. Age was shown to be a significant covariate on the estimates of both C0 and AUC50 in the urine cortisol model, and was considered to be a reflection of lower urine cortisol excretion in adolescents.
Conclusion
A pharmacokinetic/pharmacodynamic model has been established over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range to both WM24 and 24-h urine cortisol excretion. The values of AUC50 of 1,556 and 1,686 pg·h/mL, respectively, are several times higher than average fluticasone furoate AUC24 values observed at clinical doses of fluticasone furoate (≤200 μg). The models predict a fluticasone furoate AUC24 of 1,000 pg·h/mL would be required to reduce 24-h serum cortisol or 24-h urine cortisol excretion by 20 and 17 %, respectively.
doi:10.1007/s40262-013-0078-1
PMCID: PMC3779313  PMID: 23719680
5.  Neonatal Pain-Related Stress and NFKBIA Genotype Are Associated with Altered Cortisol Levels in Preterm Boys at School Age 
PLoS ONE  2013;8(9):e73926.
Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm ≤32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-κB, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm.
doi:10.1371/journal.pone.0073926
PMCID: PMC3774765  PMID: 24066085
6.  Heritability of daytime cortisol levels and cortisol reactivity in children 
Psychoneuroendocrinology  2009;34(2):273-280.
Summary
Individuals differ widely in cortisol output over the day and cortisol reactivity to challenge, both of which are relevant to disease risk. There is limited evidence concerning the heritability of these differences, so we evaluated the heritability of cortisol levels in the afternoon and cortisol reactivity using a twin design. The study involved 80 monozygotic (MZ) and 70 dizygotic (DZ) same-sex twin pairs aged 11.2 years on average. Salivary cortisol was measured in the afternoon at home before and after playing a computer game. Ratings of excitement and upset were also obtained, and objective task performance was assessed. Salivary cortisol levels averaged 4.08 (S.D. 2.3) nmol/l at pretask baseline, and declined on average over the session to 3.45 (1.9) nmol/l immediately after the tasks and 2.87 (1.6) nmol/l 10 min later. There were, however, marked individual differences, with cortisol reactivity (difference between pretask baseline and post-task 1) ranging from +4.53 to −6.23 nmol/l. Intra-class correlations for all the cortisol parameters were substantially greater for MZ (range 0.41–0.57) than for DZ (0.11–0.29) twin pairs. Quantitative genetic modelling confirmed significant heritability for pretask baseline cortisol (58%), the two post-task values (60 and 56%), and cortisol reactivity (44%). The study lacked power for assessing sex differences. Subjective reports of excitement were also somewhat heritable, but there was little covariation of cortisol and subjective responses, so genetic influences on covariation could not be tested. These findings indicate that individual differences in children’s cortisol levels recorded before tasks and cortisol reactivity to behavioural challenges are influenced by genetic factors.
doi:10.1016/j.psyneuen.2008.09.006
PMCID: PMC2637309  PMID: 18938040
Cortisol; Genetics; Reactivity; Twins; Children
7.  Salivary cortisol concentrations and behavior in a population of healthy dogs hospitalized for elective procedures 
Applied animal behaviour science  2012;141(3-4):10.1016/j.applanim.2012.08.007.
Identification of severe stress in hospitalized veterinary patients may improve treatment outcomes and welfare. To assess stress levels, in Study 1, we collected salivary cortisol samples and behavioral parameters in 28 healthy dogs hospitalized prior to elective procedures. Dogs were categorized into two groups; low cortisol (LC) and high cortisol (HC), based on the distribution of cortisol concentrations (< or ≥ 0.6 µg/dL). We constructed a stress research tool (SRT) based on three behaviors, (head resting, panting and lip licking) that were most strongly related to salivary cortisol concentrations. In Study 2, we collected salivary cortisol samples from 39 additional dogs, evaluated behavior/cortisol relationships, assigned each dog to an LC or HC group, and tested the ability of the SRT to predict salivary cortisol. Median (interquartile range) salivary cortisol concentrations were not different between Study 1 (0.43 µg/dL, 0.33 to 1.00 µg/dL) and Study 2 dogs (0.41 µg/dL, 0.28 to 0.52 µg/dL). The median salivary cortisol concentration was significantly lower (P ≤ 0.001) in LC versus HC dogs in each study; (Study 1 LC: 0.38 µg/dL, (0.19 to 0.44), n = 19, HC: 2.0 µg/dL, (1.0 to 2.8), n = 9, and Study 2 LC: 0.35 µg/dL, (0.25 to 0.48), n = 28, HC: 0.89 µg/dL, (0.66 to 1.4), n = 7). In Study 1, three behaviors were found to be associated with salivary cortisol concentrations. Duration of head resting was negatively associated with salivary cortisol (ρ = −0.60, P = 0.001), panting and lip licking were positively associated with cortisol (ρ = 0.39, P = 0.04, and 0.30, P = 0.05, respectively), Head resting (p = 0.001) and panting (p = 0.003) were also associated with LC/HC group assignment. In Study 2 dogs, the three behaviors correlated (but not significantly) with salivary cortisol concentration; of the three, only head resting was significantly associated with LC/HC group assignment (P = 0.03). The SRT derived from Study 1 was effective at prediction of salivary cortisol concentrations when applied to 20 min but not 2 min of behavioral data from Study 2. Additionally, we note that dexmedetomidine and butorphanol sedation more than 6 h prior to measurement was found to be significantly (P = 0.05) associated with lower salivary cortisol concentrations when compared to unsedated dogs. Our work offers support for eventual construction of a rating tool that utilizes the presence or absence of specific behaviors to identify higher salivary cortisol concentrations in dogs subjected to hospitalization, which may be tied to greater psychogenic stress levels. Future work to investigate the effects of stress on dogs and its mitigation in clinical situations may be approached by studying a combination o f parameters, and should consider the possible beneficial effects of sedatives.
doi:10.1016/j.applanim.2012.08.007
PMCID: PMC3817620  PMID: 24204086
Salivary cortisol; hospitalization; stress; dogs; dexmedetomidine; butorphanol
8.  Relationship of child perceptions of maternal pain to children’s laboratory and nonlaboratory pain 
Previous research has established links between parent and child pain. However, little is known about sex-specific parent-child pain relationships in a nonclinical population. A sample of 186 children aged eight to 18 years (49% female) provided information on maternal and self bodily pain, assessed by asking children about the presence and location of bodily pain experienced. Children also completed three laboratory pain tasks and reported on cold pressor pain intensity, pressure pain intensity and heat pain intensity. The presence of child-reported maternal pain was consistently correlated with daughters’ bodily and laboratory pain, but not with sons’ pain in bivariate analyses. Multivariate analyses controlling for child age and maternal psychological distress indicated that children of mothers with bodily pain reported more total bodily pain sites as well as greater pressure and cold pain intensity, relative to children of mothers without bodily pain. For cold pain intensity, these results differed for boys versus girls, in that daughters reporting maternal pain evidenced significantly higher cold pain intensity compared with daughters not reporting maternal pain. No such differences were found for boys. The findings suggest that children’s perceptions of maternal pain may play a role in influencing children’s own experience of pain, and that maternal pain models may affect boys and girls differently.
PMCID: PMC2642517  PMID: 18592057
Children; Pain; Sex differences; Social learning
9.  Relationship of child perceptions of maternal pain to children's laboratory and non-laboratory pain 
Previous research has established links between parent and child pain. Yet little is known about sex-specific parent-child pain relationships in a non-clinical population. A sample of 186 children aged 8–18 years (49% female) provided information on maternal and self bodily-pain, assessed by asking children about the presence and location of bodily pain experienced. Children also completed three laboratory pain tasks and reported on cold pressor pain intensity, pressure pain intensity and heat pain intensity. The presence of child-reported maternal pain was consistently correlated with daughters’ bodily and laboratory pain, but not with sons’ pain in bivariate analyses. Multivariate analyses controlling for child age and maternal psychological distress indicated that children of mothers with bodily pain reported more total bodily pain sites as well as greater pressure and cold pain intensity, relative to children of mothers without bodily pain. For cold pain intensity, these results differed for boys vs. girls, in that daughters reporting maternal pain evidenced significantly higher cold pain intensity compared to daughters not reporting maternal pain. No such differences were found for boys. The findings suggest that children’s perceptions of maternal pain may play a role in influencing children’s own experience of pain and that maternal pain models may affect boys and girls differently.
PMCID: PMC2642517  PMID: 18592057
pain; sex differences; social learning; children
10.  Intimate partner violence exposure, salivary cortisol, and childhood asthma 
Child abuse & neglect  2012;36(0):596-601.
Objectives
Neuroendocrine alterations may help explain health differences between intimate partner violence (IPV) exposed children and non-exposed children. We sought to determine the feasibility of having families, recruited at a child asthma visit, collect at home and return via mail child salivary samples, and whether socio-demographic variables were associated with sample return. For those returning samples, we examined whether past-year IPV exposure was associated with total cortisol output (AUC) and the magnitude of the cortisol awakening response (CAR), and whether these cortisol values were associated with asthma control.
Methods
Fifty five families with an asthmatic child of any age were recruited from 2 pediatric asthma clinics. At the time of the visit, parents completed a survey packet which included a modified version of the Conflict Tactics Scale to assess IPV. Parents were given supplies to collect 3 child salivary cortisol samples (awakening, 30-minutes after awakening, bedtime) at home on a typical day, and return them via mail. Medical records also were abstracted.
Results
Fifty-three percent (n = 29) returned child salivary samples. Families who returned samples typically returned them within two weeks, most commonly before we made a reminder call. Parental male sex was associated (p = .06) with increased rate of return at the trend level. In multivariable models, a one-unit increase in IPV was significantly associated with a .93 SD increase in root-transformed total cortisol output (AUC) (un-standardized beta = 2.5; SE .59; p = 0.001). The odds of uncontrolled asthma were marginally higher for every nmol/l increase in CAR (OR 1.04; 95% CI 1.0, 1.1; p = .06).
Conclusions
This study provides support for the feasibility of obtaining a moderate return of salivary specimens from a convenience sample. Findings that IPV was associated with elevated total cortisol output and uncontrolled asthma was marginally associated with cortisol awakening response suggest that future studies should investigate whether cortisol mediates the IPV-child asthma relationship.
doi:10.1016/j.chiabu.2011.12.002
PMCID: PMC3424283  PMID: 22858093
11.  Relationship Between Resting Blood Pressure and Laboratory-Induced Pain Among Healthy Children 
Gender Medicine  2011;8(6):388-398.
Background
Adult studies have demonstrated that increased resting blood pressure (BP) levels correlate with decreased pain sensitivity. However, few studies have examined the relationship between BP and experimental pain sensitivity among children.
Objectives
This study investigated the association between resting BP levels and experimental pain tolerance, intensity, and unpleasantness in healthy children. We also explored whether these BP–pain relationships were age and gender dependent.
Methods
Participants underwent separate 4-trial blocks of cutaneous pressure and thermal pain stimuli, and 1 trial of a cold pain stimulus in counterbalanced order.
Results
A total of 235 healthy children (49.6% female; mean age 12.7 [2.9] years; age range 8–18 years) participated. The study revealed specific gender-based BP–pain relationships. Girls with higher resting systolic BP levels were found to have lower thermal intensity ratings than girls with lower resting systolic BP levels; this relationship was stronger among adolescent girls than among younger girls. Among young girls (8–11 years), those with higher resting diastolic BP (DBP) levels were found to have lower cold intensity and unpleasantness as well as lower thermal intensity ratings than did young girls with lower resting DBP levels; these DBP–pain response relationships were not seen among adolescent girls.
Conclusions
Age, rather than resting BP, was predictive of laboratory pain ratings in boys. The findings suggest that the relationship between BP and experimental pain is age and gender dependent. These aspects of cardiovascular relationships to pain in males and females need further attention to understand their clinical importance.
doi:10.1016/j.genm.2011.07.002
PMCID: PMC3319441  PMID: 22035675
blood pressure; children; gender differences; laboratory pain
12.  Sex differences in cortisol response to Corticotropin Releasing Hormone challenge over puberty: Pittsburgh Pediatric Neurobehavioral Studies 
Psychoneuroendocrinology  2011;36(8):1226-1238.
Summary
Objective
Consistent sex differences in regulation of the hypothalamic pituitary adrenocortical (HPA) axis have been shown in animal models and emerge over puberty. However, parallel work in humans is lacking despite implications for elucidating the emergence of sex differences in depression over puberty. We investigated sex differences in HPA response to corticotropin releasing hormone (CRH) challenge over puberty in a carefully screened normative sample.
Methods
Participants were 68 healthy children (41% girls), ages 6–16, with no personal or family history of psychiatric disorder. Pubertal maturation was determined by Tanner staging. Following 24 hours of adaptation, 9–10 plasma cortisol samples were collected over 30–40 minutes pre-infusion baseline, 1 μg/kg CRH infusion, and 90–180 minutes post-infusion recovery. Thirty-seven participants completed 2+ CRH challenges allowing inclusion of cross-sectional and longitudinal data in all analyses. The influence of gender and pubertal maturation on parameters of cortisol response to CRH challenge was investigated using nonlinear mixed model metholodogy.
Results
Girls showed increasing total cortisol output following CRH challenge over puberty, while boys showed little change in total cortisol output over puberty. Increased cortisol output in girls was explained by slower reactivity and recovery rates leading to prolonged time to reach peak cortisol and delayed return to baseline over puberty. Girls also showed increasing baseline cortisol over puberty, while boys showed declining baseline over puberty.
Conclusion
Results reveal subtle normative sex differences in the influence of pubertal maturation on HPA regulation at the pituitary level. This normative shift may tip the balance towards stress response dysregulation in girls at high risk for depression, and may represent one potential mechanism underlying elevated rates of depression among pubescent girls.
doi:10.1016/j.psyneuen.2011.02.017
PMCID: PMC3270708  PMID: 21489699
CRH challenge; cortisol; sex differences; puberty; depression; adolescent; children; HPA; gender differences
13.  Neonatal Procedural Pain and Preterm Infant Cortisol Response to Novelty at 8 Months 
Pediatrics  2004;114(1):e77-e84.
Objectives. Stress systems may be altered in the long term in preterm infants for multiple reasons, including early exposure to procedural pain in neonatal intensive care. This question has received little attention beyond hospital discharge. Stress responses (cortisol) to visual novelty in preterm infants who were born at extremely low gestational age (ELGA; ≤28 weeks), very low gestational age (VLGA; 29–32 weeks), and term were compared at 8 months of age corrected for prematurity (corrected chronological age [CCA]). In addition, among the preterm infants, we evaluated whether cortisol levels at 8 months were related to neonatal exposure to procedural pain and morphine in the neonatal intensive care unit.
Methods. Seventy-six infants, 54 preterm (≤32 weeks' GA at birth) and 22 term-born infants who were seen at 8 months CCA composed the study sample, after excluding those with major sensory, motor, or cognitive impairment. Salivary cortisol was measured before (basal) and 20 minutes after introduction of novel toys (post 1) and after developmental assessment (post 2).
Results. Salivary cortisol was significantly higher in ELGA infants at 8 months, compared with the VLGA and term groups before and after introduction of visual novelty. Term-born and VLGA infants showed a slight decrease in cortisol when playing with novel toys, whereas the ELGA group showed higher basal and sustained levels of cortisol. After controlling for early illness severity and duration of supplemental oxygen, higher basal cortisol levels in preterm infants at 8 months' CCA were associated with higher number of neonatal skin-breaking procedures. In contrast, cortisol responses to novelty were predicted equally well by neonatal pain or GA at birth. No relationship between morphine dosing and cortisol response was demonstrated in these infants.
Conclusions. ELGA preterm infants show a different pattern of cortisol levels before and after positive stimulation of visual novelty than more maturely born, VLGA preterm and term-born infants. Exposure to high numbers of skin-breaking procedures may contribute to “resetting” basal arousal systems in preterm infants.
PMCID: PMC1351380  PMID: 15231977
14.  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
15.  Stressor paradigms in developmental studies: What does and does not work to produce mean increases in salivary cortisol 
Psychoneuroendocrinology  2009;34(7):953-967.
Summary
The stress response system is comprised of an intricate interconnected network that includes the hypothalamic–pituitary–adrenocortical (HPA) axis. The HPA axis maintains the organism’s capacity to respond to acute and prolonged stressors and is a focus of research on the sequelae of stress. Human studies of the HPA system have been facilitated enormously by the development of salivary assays which measure cortisol, the steroid end-product of the HPA axis. The use of salivary cortisol is prevalent in child development stress research. However, in order to measure children’s acute cortisol reactivity to circumscribed stressors, researchers must put children in stressful situations which produce elevated levels of cortisol. Unfortunately, many studies on the cortisol stress response in children use paradigms that fail to produce mean elevations in cortisol. This paper reviews stressor paradigms used with infants, children, and adolescents to guide researchers in selecting effective stressor tasks. A number of different types of stressor paradigms were examined, including: public speaking, negative emotion, relationship disruption/threatening, novelty, handling, and mild pain paradigms. With development, marked changes are evident in the effectiveness of the same stressor paradigm to provoke elevations in cortisol. Several factors appear to be critical in determining whether a stressor paradigm is successful, including the availability of coping resources and the extent to which, in older children, the task threatens the social self. A consideration of these issues is needed to promote the implementation of more effective stressor paradigms in human developmental psychoendocrine research.
doi:10.1016/j.psyneuen.2009.02.010
PMCID: PMC2692557  PMID: 19321267
Salivary cortisol; Stressor paradigms; Human development
16.  Sex differences in salivary cortisol in response to acute stressors among healthy participants, in recreational or pathological gamblers, and in those with posttraumatic stress disorder 
Hormones and behavior  2009;57(1):35-45.
Sex differences in incidence and severity of some stress-related, neuropsychiatric disorders are often reported to favor men, suggesting that women may be more vulnerable to aberrant hypothalamic-pituitary-adrenal (HPA) axis responses to stress. In this review, we discuss several investigations that we, and others, have conducted assessing salivary cortisol as a measure of HPA function. We have examined basal cortisol among healthy men and women and also following acute exposure to stressors. Among healthy participants, men had higher basal cortisol levels than did women. In response to acute stressors, such as carbon dioxide or noise, respectively, cortisol levels were comparable between men and women or higher among women. We have also examined cortisol levels among those with problem eating, gambling, or post traumatic stress disorder (PTSD). Women with restrained eating habits have higher basal cortisol levels than do women without restrained eating habits. Pathological gamblers have more aberrant stress response to gambling stimuli than do recreational gamblers, and these effects are more prominent among men than women. Men who have motor-vehicle accident related PTSD, demonstrate more aberrant cortisol function, than do their female counterparts. Although these sex differences in cortisol seem to vary with type of stress exposure and/or pathophysiological status of the individual, other hormones may influence cortisol response. To address this, cortisol levels among boys and girls with different stress-related experiences, will be the subject of future investigation.
doi:10.1016/j.yhbeh.2009.06.003
PMCID: PMC2858325  PMID: 19538960
Cortisol; Gender Differences; Hypothalamic-Pituitary-Adrenal Axis; Hypothalamic-Pituitary-Gonadal Axis; Panic Attack
17.  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
18.  Hair Cortisol Predicts Object Permanence Performance in Infant Rhesus Macaques (Macaca mulatta) 
Developmental psychobiology  2009;51(8):706-713.
Although high circulating levels of glucocorticoids are associated with impaired cognitive performance in adults, less is known about this relationship in infancy. Furthermore, because studies have relied on acute cortisol measures in blood plasma or saliva, interpretation of the results may be difficult as acute measures may in part reflect emotional responses to testing procedures. In this study we examined whether hair cortisol, an integrated measure of HPA axis functioning, predicted performance of nursery-reared (NR) infant rhesus monkeys (N=32) on Piagetian object permanence tasks. Testing of NR infants began at 19.8±2.2 (mean±SE) days of age and continued for the next several months. Hair cortisol concentrations from the 32 NR monkeys were compared to those of 20 mother-peer-reared (MPR) infants. Hair was shaved at day 14, allowed to re-grow, and obtained again at month 6, thus representing integrated cortisol over a 5.5-month period of time. NR and MPR infants did not differ in month 6 hair cortisol values (t(50)=0.02, p=0.98). Linear regression revealed that hair cortisol predicted object permanence performance in the NR infants. Infants with higher hair cortisol reached criterion at later ages on the well (p<0.01), screen (p<0.05), and A-not-B (p<0.05) tasks and required more test sessions to complete the well (p<0.01) and screen tasks (p<0.05). These data are the first to implicate hair cortisol as a reliable predictor of early cognitive performance in infant macaque monkeys.
doi:10.1002/dev.20405
PMCID: PMC2797997  PMID: 19771550
Rhesus macaque; infant; cortisol; cognition; object permanence
19.  Posttraumatic stress symptoms related to community violence and children’s diurnal cortisol response in an urban community-dwelling sample 
Background
While community violence has been linked to psychological morbidity in urban youth, data on the physiological correlates of violence and associated posttraumatic stress symptoms are sparse. We examined the influence of child posttraumatic stress symptoms reported in relationship to community violence exposure on diurnal salivary cortisol response in a population based sample of 28 girls and 15 boys ages 7–13, 54% self-identified as white and 46% as Hispanic.
Methods
Mothers’ reported on the child’s exposure to community violence using the Survey of Children’s Exposure to Community Violence and completed the Checklist of Children’s Distress Symptoms (CCDS) which captures factors related to posttraumatic stress; children who were eight years of age or greater reported on their own community violence exposure. Saliva samples were obtained from the children four times a day (after awakening, lunch, dinner and bedtime) over three days. Mixed models were used to assess the influence of posttraumatic stress symptoms on cortisol expression, examined as diurnal slope and Area Under the Curve (AUC), calculated across the day, adjusting for socio-demographics.
Results
In adjusted analyses, higher scores on total traumatic stress symptoms (CCDS) were associated with both greater cortisol AUC and with a flatter cortisol waking to bedtime rhythm. The associations were primarily attributable to differences on the intrusion, arousal and avoidance CCDS subscales.
Conclusions
Posttraumatic stress symptomatology reported in response to community violence exposure was associated with diurnal cortisol disruption in these community-dwelling urban children.
doi:10.1007/s12529-009-9044-6
PMCID: PMC3094100  PMID: 19319691
community violence; cortisol rhythm; posttraumatic stress symptoms
20.  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
21.  Cortisol response to low dose versus standard dose (back-to-back) adrenocorticotrophic stimulation tests in children and young adults with thalassemia major 
Background:
Thalassemia major patients with repeated blood transfusion have high prevalence of endocrinopathies due to iron overload.
Materials and Methods:
We examined the adrenocortical function in 23 thalassemic patients (10 children and 13 young adults) aged 8-26 years. Serum cortisol and dehydroepiandrosterone sulfate (DHEA-S) concentrations were determined in each subject before blood transfusion both in basal condition and after low dose (LD) (1 μg), followed by standard dose (SD) (250 μg, respectively) with synthetic corticotrophin beta 1-24 ACTH (Synacthen, Ciba). Normal controls were a group of 13 age- and sex-matched normal subjects.
Results:
Using a peak total cortisol cutoff level of 550 nmol/L and increments of 200 μg above basal cortisol, adrenal insufficiency (AI) was demonstrated in 8 patients (34.7%) after the LD ACTH and in 2 patients (8.7%) after SD cosyntropin (ACTH) test, but none of the controls. Using a peak total cortisol cutoff level of 420 nmol/L and increments of 200 μg above basal cortisol, AI was demonstrated in 5 patients (21.7%) after the LD ACTH and in 2 patients after SD ACTH test (8.7%), but none of controls. All patients with biochemical AI were asymptomatic with normal serum sodium and potassium concentrations and had no history suggestive of adrenal pathology. The peak cortisol concentrations in thalassemic patients with impaired adrenal function both after 1 μg and 250 μg cosyntropin (294 ± 51 nmol/L and 307 ± 58.6) were significantly lower than those with patients with normal (454 ± 79.7 nmol/L and 546.1 ± 92.2 nmol/L, respectively) and controls (460.2 ± 133.4 nmol/L and 554.3 ± 165.8 nmol/L, respectively). Adolescents and young adults, but not children with thalassaemia, had significantly lower peak cortisol concentration after SD ACTH versus controls. Peak cortisol response to LD ACTH was correlated significantly with peak cortisol response to SD in all patients (r = 0.83, P < 0.0001). In adolescents and young adults with thalassemia, DHEA-S levels before and after LD ACTH stimulation were significantly lower and the cortisol/DHEA-S ratios were significantly higher than the controls.
Conclusion:
The use of LD ACTH test diagnoses more adrenal abnormalities versus SD ACTH in thalassemic patients. The relatively high prevalence of AI in thalassemic adolescents and young adults necessitates that these patients have to be investigated for AI before major surgery and those with impaired cortisol secretion should receive stress doses of corticosteroids during the stressful event.
doi:10.4103/2230-8210.122620
PMCID: PMC3872683  PMID: 24381882
Cortisol; dehydroepiandrosterone sulfate; low dose adrenocorticotropic hormone test; standard dose adrenocorticotropic hormone test; thalassemia
22.  Sex differences in the relationship between maternal negative life events and children’s laboratory pain responsivity 
Objective
Prior research has demonstrated links between psychosocial factors, including negative life events (NLE) and pain in children. The present study examined sex differences in the relationship between mother-reported NLE, child NLE, mother somatization and children’s laboratory pain responses for heat, cold and pressure pain tasks. We predicted that maternal NLE would be moderately associated with girls’ pain responses, but would not be associated with boys’ pain responses.
Method
Participants were 176 non-clinical children (89 boys) aged 8–18 years (mean = 12.2, SD = 2.7) and their mothers. Mothers and children completed questionnaires assessing their perceptions of NLE experienced in the previous 12 months.
Results
Contrary to predictions, maternal NLE were related to pain responses in both boys and girls, although in opposite directions. Thus, increased maternal stress was associated with increased pain responses in girls but with decreased pain responses in boys. In addition, the impact of maternal NLE was only apparent for heat and pain tasks, indicating differential effects for various types of pain.
Conclusion
The current findings underscore the importance of family variables in understanding sex differences in children’s pain. Future research is needed to examine the mechanisms within the parent-child relationship that contribute to sex-differentiated pain outcomes, particularly under conditions of exacerbated parental stress.
doi:10.1097/DBP.0b013e3181b0ffe4
PMCID: PMC2813770  PMID: 19668092
negative life events; children’s laboratory pain; sex differences
23.  Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin 
PLoS Genetics  2014;10(7):e1004474.
Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30–60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
Author Summary
Cortisol is a steroid hormone from the adrenal glands that is essential in the response to stress. Most cortisol in blood is bound to corticosteroid binding globulin (CBG). Diseases causing cortisol deficiency (Addison's disease) or excess (Cushing's syndrome) are life-threatening. Variations in plasma cortisol have been associated with cardiovascular and psychiatric diseases and their risk factors. To dissect the genetic contribution to variation in plasma cortisol, we formed the CORtisol NETwork (CORNET) consortium and recruited collaborators with suitable samples from more than 15,000 people. The results reveal that the major genetic influence on plasma cortisol is mediated by variations in the binding capacity of CBG. This is determined by differences in the circulating concentrations of CBG and also in the immunoreactivity of its ‘reactive centre loop’, potentially influencing not only binding affinity for cortisol but also the stability of CBG and hence the tissue delivery of cortisol. These findings provide the first evidence for a common genetic effect on levels of this clinically important hormone, suggest that differences in CBG between individuals are biologically important, and pave the way for further research to dissect causality in the associations of plasma cortisol with common diseases.
doi:10.1371/journal.pgen.1004474
PMCID: PMC4091794  PMID: 25010111
24.  Physiological differences between burnout patients and healthy controls: blood pressure, heart rate, and cortisol responses 
Occupational and Environmental Medicine  2003;60(Suppl 1):i54-i61.
Objectives: To investigate differences between burnout patients and healthy controls regarding basal physiological values and physiological stress responses. Measures of the sympathetic-adrenergic-medullary (SAM) axis and the hypothalamic-pituitary-adrenal (HPA) axis were examined.
Methods: SAM axis and HPA axis activity was compared between 22 burnout patients and 23 healthy controls. SAM axis activity was measured by means of heart rate (HR) and blood pressure (BP). HPA axis activity was investigated by means of salivary cortisol levels. Resting levels of HR, BP, and cortisol were determined as well as reactivity and recovery of these measures during a laboratory session involving mental arithmetic and speech tasks. In addition, morning levels of cortisol were determined.
Results: Burnout patients showed higher resting HR than healthy controls. BP resting values did not differ between burnout patients and healthy controls, nor did cardiovascular reactivity and recovery measurements during the laboratory session. Basal cortisol levels and cortisol reactivity and recovery measures were similar for burnout patients and healthy controls. However, burnout patients showed elevated cortisol levels during the first hour after awakening in comparison to healthy controls.
Conclusions: The findings provided limited proof that SAM axis and HPA axis are disturbed among burnout patients. Elevated HR and elevated early morning cortisol levels may be indicative of sustained activation.
doi:10.1136/oem.60.suppl_1.i54
PMCID: PMC1765727  PMID: 12782748
25.  Effects of Seasonal Differences in Testosterone and Cortisol Levels on Pain Responses Under Resting and Anxiety Conditions 
Yonsei Medical Journal  2013;55(1):216-223.
Purpose
This study investigated whether hormones and pain perception are associated with exam anxiety, and also whether exam anxiety is affected by seasonal differences in testosterone and cortisol levels.
Materials and Methods
Forty-six healthy males were recruited from a medical college. Anxiety was induced by having participants perform the Objective Structured Clinical Examination. Pressure was applied to the participants to induce pain. Pain thresholds, pain ratings, anxiety ratings, blood pressure, heart rate, salivary testosterone and cortisol levels were measured under resting and anxiety conditions in the spring and summer. Data were collected from 46 participants during the spring (n=25) and summer (n=21).
Results
Pain thresholds and testosterone levels were significantly lower under anxiety than at rest for all participants (n=46), while cortisol levels, pain ratings, and anxiety ratings were significantly higher under anxiety than at rest. In the spring (n=25), testosterone levels were significantly higher at rest than under anxiety, while there was no difference in cortisol levels between resting and anxiety conditions. In the summer (n=21), cortisol levels were significantly higher under anxiety than at rest, while there was no difference in testosterone levels between resting and anxiety conditions. There were no significant seasonal differences in pain and anxiety ratings and pain threshold.
Conclusion
These results indicate that seasonal differences in testosterone and cortisol levels under anxiety and at rest may affect pain responses. These results also suggest that acute clinical pain may be relieved by managing anxiety that is related to a decrease of testosterone in spring and a large increase of cortisol in summer.
doi:10.3349/ymj.2014.55.1.216
PMCID: PMC3874911  PMID: 24339310
Cortisol; testosterone; pain; seasonal differences

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