Cortisol awakening response and psychosocial factors: A systematic review and meta-analysis

The magnitude of the cortisol awakening response, a relatively new indicator of hypothalamic–pituitary–adrenocortical (HPA) axis activation, has been related to a number of psychosocial factors. But findings have been inconsistent across studies. We systematically reviewed previous studies investigating the association between the cortisol awakening response and psychosocial factors. 147 eligible studies from 62 articles were identified. Separate analyses were carried out on the increase in cortisol following waking (CARi), and the integrated volume of cortisol released over the waking period (CARauc). We found that the CARi was positively associated with job stress and general life stress. It was negatively associated with fatigue, burnout, or exhaustion. There were less reliable negative associations between the CARi and positive affects. The CARauc was positively related to general life stress and negatively related to posttraumatic stress syndrome. This review concludes that different psychosocial factors are associated with an enhanced or reduced cortisol awakening response.     

Concurrent and longitudinal associations of basal and diurnal cortisol with mental health symptoms in early adolescence

Recent biosocial theories postulate that both biological risk and the social context influence the development of mental health problems [Boyce and Ellis (2005) Development and Psychopathology, 17(2), 271-301]. Guided by this framework, we examined whether basal cortisol and its diurnal rhythm were associated with mental health symptoms in early adolescence. Because cross-sectional and longitudinal investigations sometimes reveal different cortisol-mental health associations, we examined the association both concurrently and longitudinally when children transition to middle school, a time which entails a major change in social context from single to multiple teachers, classrooms, and sets of classmates. Salivary cortisol was measured three times a day (waking, afternoon, and bedtime) across 3 days when adolescents were 5th graders. Mental health was measured when adolescents were in 5th and 7th grades, just before and after the transition to middle school. To deal with the substantial comorbidity of internalizing and externalizing symptoms at this developmental stage, mental health measures distinguished overall symptom severity from the preponderance of internalizing versus externalizing symptoms (i.e., directionality). A three-level Hierarchical Linear Model was used to extract basal cortisol and its diurnal rhythm separate from the day-to-day and within-the-day fluctuations in cortisol in response to daily experiences. Results were specific to symptom severity, suggesting that cortisol is a nonspecific risk factor for mental health symptoms in young adolescents. At 5th grade, low basal cortisol was associated with concurrent symptom severity. However, longitudinally, it was adolescents with high cortisol at 5th grade who were at risk for increasing mental health symptoms by 7th grade. Flat diurnal rhythms in 5th grade were related to levels of symptom severity at both 5th and 7th grades. Considering the change in social context, as defined by the transition to middle school, helped resolve seemingly inconsistent evidence that both hypo- and hyper-arousal were associated with mental health symptoms in early adolescence.     

Allostasis model facilitates understanding race differences in the diurnal cortisol rhythm

The concept of allostasis suggests that greater cumulative stress burden can influence stress-responsive physiology. Dysregulation of allostatic mediators, including the hypothalamic-pituitary-adrenal (HPA) axis, is thought to precede many other signs of age-related pathology as the persistent burden of stressors accumulates over the individual's life span. We predicted that even in young adulthood, HPA regulation would differ between Blacks and Whites, reflecting, in part, higher rates of stressor exposure and greater potential for stressors to "get under the skin." We examined whether stressor exposure, including experiences with racism and discrimination, explained race differences in waking cortisol and the diurnal rhythm. We also examined whether HPA functioning was associated with mental health outcomes previously linked to cortisol. Salivary cortisol was assayed in 275 young adults (127 Blacks, 148 Whites, 19 to 22 years old), four times a day across 3 days. Hierarchical linear models revealed flatter slopes for Blacks, reflecting significantly lower waking and higher bedtime cortisol levels compared to Whites. Associations of HPA functioning with stressors were typically more robust for Whites such that more stress exposure created an HPA profile that resembled that of Black young adults. For Blacks, greater stressor exposure did not further impact HPA functioning, or, when significant, was often associated with higher cortisol levels. Across both races, flatter slopes generally indicated greater HPA dysregulation and were associated with poor mental health outcomes. These differential effects were more robust for Whites. These findings support an allostatic model in which social contextual factors influence normal biorhythms, even as early as young adulthood.     

Dysregulated diurnal cortisol pattern is associated with glucocorticoid resistance in women with major depressive disorder

Dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis is believed to play a role in the pathophysiology of depression. To investigate mechanisms that may underlie this effect, we examined several indices of HPA axis function – specifically, diurnal cortisol slope, cortisol awakening response, and suppression of cortisol release following dexamethasone administration – in 26 pre-menopausal depressed women and 23 never depressed women who were matched for age and body mass index. Salivary cortisol samples were collected at waking, 30 min after waking, and at bedtime over three consecutive days. On the third day, immediately after the bedtime sample, participants ingested a 0.5 mg dexamethasone tablet; they then collected cortisol samples at waking and 30 min after waking the following morning. As predicted, depressed women exhibited flatter diurnal cortisol rhythms and more impaired suppression of cortisol following dexamethasone administration than non-depressed women over the three sampling days. In addition, flatter diurnal cortisol slopes were associated with reduced cortisol response to dexamethasone treatment, both for all women and for depressed women when considered separately. Finally, greater self-reported depression severity was associated with flatter diurnal cortisol slopes and with less dexamethasone-related cortisol suppression for depressed women. Depression in women thus appears to be characterized by altered HPA axis functioning, as indexed by flatter diurnal cortisol slopes and an associated impaired sensitivity of cortisol to dexamethasone. Given that altered HPA axis functioning has been implicated in several somatic conditions, the present findings may be relevant for understanding the pathophysiology of both depression and depression-related physical disease.     

Cortisol circadian rhythms and stress responses in infants at risk of allergic disease

BACKGROUND: The cortisol circadian rhythm and response to stressful stimuli are altered in children and adults with allergic disease, including asthma. It is not known whether these alterations precede or follow the onset of allergic disease. OBJECTIVE: We sought to evaluate the cortisol circadian rhythm and stress response among infants at risk for the development of allergic disease. METHODS: Infants with and without risk factors for allergic disease were evaluated at age 6 months. Saliva was obtained at 8 am, 2 pm, and 8 pm at home (n = 68) by parents when their infants were comfortable and in the clinic (n = 88) before and after their physical examination and vaccinations. Information regarding parental allergy and exposure to other children at home or in child care were obtained by questionnaire. RESULTS: In multivariate analysis the circadian rhythm of cortisol was flattened because of the lack of the expected morning surge of cortisol, resulting in decreased diurnal variation of cortisol in infants of mothers with allergy (P = .035) or asthma (P = .002) or an asthmatic father (P = .022). The cortisol stress response was greater in infants of mothers with allergy (P = .045) or asthma (P = .039), those with fewer siblings (P = .066), and those not entering day care early in life (P = .017). CONCLUSIONS: These alterations in both basal and stress levels of endogenous cortisol among infants predisposed to allergic disease might affect the development of allergic immune responses early in life through interactions with inflammatory mediators.     

Diurnal rhythms in plasma cortisol, insulin, glucose, lactate and urea in pigs fed identical meals at 12-hourly intervals

Diurnal rhythms in plasma cortisol, insulin, glucose, lactate and urea concentrations were investigated in eight catheterized pigs of approximately 35 kg BW. Pigs were fed isoenergetic/isoproteinic diets at a restricted level (2.5 x maintenance requirement for energy) in two daily rations (06:00 and 18:00 hours) in order to obtain equal intervals between feed intake. Preprandial plasma cortisol concentration was 22+/-3 ng/mL in the morning and 14+/-2 ng/mL in the evening (p<0.025), whereas the concentrations of insulin, glucose, lactate, and urea were similar. In the postprandial period in the morning (06:00-09:00 hours) plasma cortisol, insulin and lactate concentrations (expressed as the total area under the curve) were greater (p<0.001) compared to the evening (18:00-21:00 hours) by 100%, 42%, and 24%, respectively, while postprandial plasma glucose and urea concentrations were not affected by time of the meal. When postprandial plasma concentrations were expressed as a response over preprandial concentrations (decremental or incremental area under the curve), the diurnal rhythm was not observed for cortisol and glucose, persisted for insulin and lactate, and appeared for urea with a smaller postprandial urea response (p<0.05) in the morning compared to the evening. We conclude that the diurnal rhythm in plasma cortisol is independent of feeding whereas the diurnal rhythms in plasma insulin, lactate and urea are unveiled by the morning/evening meals in pigs. At equal 12-h intervals between meals, the postprandial responses of lactate and urea show diurnal variations, each in a specific manner, which suggest decreased postprandial efficiency of carbohydrate metabolism and increased postprandial efficiency of protein metabolism in the morning compared to the evening.     

Salivary cortisol in pregnant women suffering from blood and injection phobia

Stress and/or anxiety during pregnancy affect maternal and fetal well-being and can cause premature delivery and postnatal pathology in the child. Women suffering from phobias related to blood and injections are prone to high levels of stress, including anxiety and sometimes panic attacks, during pregnancy. Cortisol is amongst the mediators through which the neurohormonal expressions of maternal psychological factors may be transduced to the fetus. The aim of this study was to investigate whether pregnant women suffering from blood and injection phobia have raised cortisol levels or are characterized by unusual diurnal salivary cortisol profiles compared with healthy controls. The sample consisted of 110 pregnant women with blood and injection phobia and 110 pregnant healthy controls. Both groups provided morning and evening saliva samples in weeks 25 and 36 for the assay of cortisol. In gestational week 25, when blood was drawn for the mandatory blood testing, extra blood was taken to analyze corticotrophin-releasing factor, adrenocorticotropic hormone, and cortisol in serum. The diurnal decline in salivary cortisol as well as increased cortisol levels were observed during pregnancy. Pregnant women suffering from blood and injection phobia had a higher output of cortisol compared with women without the phobia (F = 6.25, df = 1, p = 0.014), but no marked difference in the diurnal cortisol rhythm was found between groups. Our findings indicate that untreated blood and injection phobia during pregnancy increases cortisol concentrations. Blood and injection phobia is treatable, and cognitive behavioral therapy can be used. Women with blood and injection phobia during pregnancy therefore need to be recognized and offered treatment without delay in early pregnancy.     

A prospective study of diurnal cortisol responses to the social experience of school transition in four-year-old children: anticipation, exposure, and adaptation

This study examined psychosocial influences on hypothalamic-pituitary-adrenal axis activity in 105 4-year-old children transitioning to primary school. Measuring before, during, and after school transition over a period of up to 12 months, salivary cortisol was assessed on awakening and early evening. Parents reported child temperament and teachers recorded adaptive behavior. Whilst cortisol at awakening and early evening increased from baseline to school transition, effects were not significant. A significant decrease occurred between transition and follow-up and from baseline to follow-up for both awakening and evening cortisol. Poorer effortful control was associated with high morning and steeper diurnal slope of cortisol at transition whilst surgency/extroversion was associated individually with greater morning and evening cortisol at transition and adaptation. Greater increase in internalizing social isolation during the first 6 months of school in more surgent/extrovert children predicted higher morning and evening cortisol at follow-up. This study is the first to explore these adaptive relationships over a 12-month period and supports social isolation over time as a key element in developmental endocrine activation.     

Social support and salivary cortisol in women with metastatic breast cancer

OBJECTIVE: This study used a cross-sectional design to examine the relationships between social support, both quantity (number of people) and quality (appraisal, belonging, tangible, and self-esteem), and neuroendocrine function (mean and slope of diurnal salivary cortisol) among women with metastatic breast cancer. METHODS: Participants (N = 103) were drawn from a study (N = 125) of the effects of group therapy on emotional adjustment and health in women with metastatic breast cancer. They completed the Interpersonal Support Evaluation List and the Yale Social Support Index and provided saliva samples for assessment of diurnal cortisol levels on each of 3 consecutive days. Diurnal mean levels were calculated using log-transformed cortisol concentrations, and the slope of diurnal cortisol variation was calculated by regression of log-transformed cortisol concentrations on sample collection time. RESULTS: Mean salivary cortisol was negatively related to the Interpersonal Support Evaluation List subscales of appraisal, belonging, and tangible social support. No association was found between quantitative support or the esteem subscale of the Interpersonal Support Evaluation List and mean salivary cortisol. Measures of qualitative and quantitative social support were not associated with the diurnal cortisol slope. CONCLUSIONS: Results show that greater quality of social support is associated with lower cortisol concentrations in women with metastatic breast cancer, which is indicative of healthier neuroendocrine functioning. These results may have clinical implications in the treatment of breast cancer.     

Maternal Sleep Quality and Diurnal Cortisol Regulation Over Pregnancy

Poor sleep in pregnancy is related to adverse neonatal health. Elevated maternal cortisol has been proposed as a pathway, yet the association in pregnancy is not well understood. The goals of the current study were to examine associations between (a) sleep and cortisol, (b) sleep, cortisol, and neonatal outcomes, and (c) variables that could explain these associations. Two hundred pregnant women completed the Pittsburgh Sleep Quality Index (PSQI; Buysse, Reynolds, Monk, Berman, & Kupfer, 1989) and provided diurnal salivary cortisol samples at two times over pregnancy. Poor sleep quality was associated with greater evening cortisol concentrations at 36 weeks’ gestation. This association was mediated by anxiety symptoms. Higher evening cortisol at 36 weeks’ gestation was associated with shorter gestation.     

Diurnal fluctuation of time perception under 30-h sustained wakefulness

Previous studies have reported that time perception in humans fluctuates over a 24-h period. Behavioral changes seem to affect human time perception, so that the fluctuation in human time perception may be the result of such changes due to self-determined activities. Recently, we carried out a study in which a healthy human cohort was asked to perform simultaneously loaded cognitive tasks under controlled conditions, and found that time perception decreased linearly from morning to evening. In addition, the variations in time perception were not a consequence of behavioral changes. It remains to be elucidated whether diurnal variations in time perception are a consequence of circadian rhythm or of some homeostatic changes that are attributable to accumulated wake time. The effects of circadian rhythm on time perception were investigated in eight healthy young male volunteers by conducting 10-s time production tasks under 30-h constant-routine conditions. Core body temperature and serum melatonin and cortisol levels were measured during the course of the study. Produced time exhibited a diurnal variation and was strongly correlated with circadian variations in core body temperature and serum melatonin levels. These results suggest that human short-term time perception is under the influence of the circadian pacemaker.     

Growth delay as an index of allostatic load in young children: predictions to disinhibited social approach and diurnal cortisol activity

The goal of this study was to examine whether growth delay can serve as an index of allostatic load during early development, as it is well known that the activity of stress-mediating systems inhibits growth. The participants were children adopted internationally from institutional care (n = 36), children adopted internationally from foster care (n = 26), and nonadopted children (n = 35). For the adopted children, height for age and weight for height were assessed at adoption; for all children, disinhibited social approach (DSA; termed elsewhere as "indiscriminate friendliness") and diurnal cortisol were assessed at 6-8 years (M = 6.9 years). For internationally adopted children in general, and postinstitutionalized children specifically, linear growth delay assessed at the time of adoption was associated with more dysregulated behavior in response to an unfamiliar adult (i.e., greater DSA) and a more dysregulated diurnal cortisol rhythm (i.e., higher late afternoon and evening values). Further, among the most growth-delayed children, higher cortisol levels later in the day were correlated with DSA. The potential for using growth delay as an allostatic load indicator and the possible problems and limitations in its use in child populations are discussed.     

Stress-buffering effects of psychosocial resources on physiological and psychological stress response in pregnant women

Sixty healthy pregnant women (aged 21-35 years), including 30 pregnant women at the beginning of second trimester and 30 women at the beginning of third trimester underwent a psychosocial stress test. Physiological (salivary free cortisol levels, salivary alpha-amylase levels) and psychological (perceived stress, mood, anxiety) responses to standardized psychosocial stress have been brought in association with psychosocial resources (self-efficacy and daily uplifts). Predictions revealed that higher resources predict lower physiological and psychological stress responses and higher mood levels. We conclude from our data that psychosocial resources appear to dampen psychological and physiological stress response during pregnancy.     

Optimism,positive affectivity,and salivary cortisol

Objectives. Research on stress and salivary cortisol has focused almost exclusively on the effects of negative psychological conditions or emotional states. Little attention has been drawn to the impact associated with positive psychological conditions, which have been shown recently to have significant influences on neuroendocrine regulation. The aim of this study is to examine the impact of optimism and positive affect on salivary cortisol with the effects of their negative counterparts controlled for. Design. Optimism and pessimism, and positive and negative affectivity were studied in relation to the diurnal rhythm of salivary cortisol in a group of 80 Hong Kong Chinese, who provided six saliva samples over the course of a day on two consecutive days. The separate effects of optimism and positive affect on two dynamic components of cortisol secretion, awakening response, and diurnal decline were examined. Methods. Optimism and pessimism were measured using the Chinese version of the revised Life Orientation Test while generalized affects and mood states were assessed by the Chinese Affect Scale. An enzyme‐linked immunoabsorbent assay kit (EIA) developed for use in saliva was adopted for the biochemical analysis of cortisol. Testing of major group differences associated with positive psychological conditions was carried out using two‐way (group by saliva collection time) ANOVAs for repeated measures with negative psychological conditions and mood states as covariates. Results. Participants having higher optimism scores exhibited less cortisol secretion in the awakening period when the effect of pessimism and mood were controlled. This effect was more apparent in men than in women who had higher cortisol levels in the awakening period. Optimism did not have similar effect on cortisol levels during the underlying period of diurnal decline. On the other hand, higher generalized positive affect was associated with lower cortisol levels during the underlying period of diurnal decline after the effects of negative affect and mood states had been controlled. Generalized positive affect did not significantly influence cortisol secretion during the awakening period. Conclusions. These findings suggest that positive psychological resources including optimism and generalized positive affect had higher impact on cortisol secretion than their negative counterparts, and point to the need for increased attention to the potential contribution of positive mental states to well‐being.     

Fos immunoreactivity in hypocretin-synthesizing and hypocretin-1 receptor-expressing neurons: effects of diurnal and nocturnal spontaneous waking,stress and hypocretin-1 administration

Hypocretin/orexin modulates sleep-wake state via actions across multiple terminal fields. Within waking, hypocretin may also participate in high-arousal processes, including those associated with stress. The current studies examined the extent to which alterations in neuronal activity, as measured by Fos immunoreactivity, occur within both hypocretin-synthesizing and hypocretin-1 receptor-expressing neurons across varying behavioral state/environmental conditions associated with varying levels of waking and arousal. Double-label immunohistochemistry was used to visualize Fos and either prepro-hypocretin in the lateral hypothalamus or hypocretin-1 receptors in the locus coeruleus and select basal forebrain regions involved in the regulation of behavioral state/arousal. Animals were tested under the following conditions: 1). diurnal sleeping; 2). diurnal spontaneous waking; 3). nocturnal spontaneous waking; and 4). high-arousal waking (diurnal novelty-stress). Additionally, the effects of hypocretin-1 administration (0.07 and 0.7 nmol) on levels of Fos were examined within these two neuronal populations. Time spent awake, scored for the 90-min preceding perfusion, was largely comparable in diurnal spontaneous waking, nocturnal spontaneous waking and high-arousal waking. Nocturnal spontaneous waking and high-arousal waking, but not diurnal spontaneous waking, were associated with increased levels of Fos within hypocretin-synthesizing neurons, relative to diurnal sleeping. Within hypocretin-1 receptor-expressing neurons, only high-arousal waking was associated with increased levels of Fos. Hypocretin-1 administration dose-dependently increased levels of Fos within hypocretin-1 receptor-expressing neurons to levels comparable to, or exceeding, levels observed in high-arousal waking. Combined, these observations support the hypothesis that hypocretin neuronal activity varies across the circadian cycle. Additionally, these data suggest that waking per se may not be associated with increased hypocretin neurotransmission. In contrast, high-arousal states, including stress, appear to be associated with substantially higher rates of hypocretin neurotransmission. Finally, these studies provide further evidence indicating coordinated actions of hypocretin across a variety of arousal-related basal forebrain and brainstem regions in the behavioral state modulatory actions of this peptide system.     

Do infants show a cortisol awakening response?

Upon awakening from sleep, combined processes of deactivation of the hippocampus and activation of suprachiasmatic nucleus result in a marked increase in cortisol release from structures within the hypothalamic–pituitary–adrenal axis. This phenomenon, termed the cortisol awakening response (CAR), has been studied extensively in adults. In the current study, we examine this phenomenon for the first time in infancy. Saliva samples were collected by 32 mothers from themselves and their infants (13 males; 7.8–17.4 months of age) at the infant's AM waking (and 30 min later), and upon waking from the infant's first nap (and 30 min later). In contrast to what has been observed with the CAR in adults, cortisol levels declined from AM waking to 30 min post‐waking. Moreover, cortisol levels did not significantly rise or fall following naps. Consistent with prior research, both group‐level and dyadic‐level analyses showed that cortisol levels for mother–infant dyads were associated. © 2011 Wiley Periodicals,Inc. Dev Psychobiol 54: 736–743, 2012.     

Positive affect is associated with cardiovascular reactivity, norepinephrine level, and morning rise in salivary cortisol

Positive affect was examined as a predictor of (1) cardiovascular reactivity during a sadness and an anger recall task and recovery following the protocol, (2) epinephrine (EPI) and norepinephrine (NOREPI) reactivity and level during the recall protocol, and (3) the diurnal pattern of salivary cortisol. Sample was 328 individuals. Negative affect, age, race, sex, smoking status, income, and BMI were adjusted. During sadness recall, positive affect was inversely related to systolic blood pressure ( p =.007) and diastolic blood pressure ( p =.049) reactivity, and unrelated to heart rate ( p =.226). Positive affect was unrelated to reactivity during anger recall ( p s>.19), and was unrelated to recovery at the end of the recall protocol. Positive affect was inversely related to the mean level of NOREPI ( p =.046), and unrelated to EPI ( p =.149). Positive affect was inversely related to the increase in cortisol 30 min post awakening ( p =.042), and unrelated to the evening decline in cortisol levels ( p =.174). Positive emotions may be relevant to good health.     

Good Self- Rated Health is Related to Psychosocial Resources and a Strong Cortisol Response to Acute Stress: The LiVicordia Study of Middle- Aged Men

Self- rated health (SRH) is a strong predictor for disease and death. The relations among SRH, psychosocial factors, and cortisol dynamics were tested using pooled data from the LiVicordia study of 50- year- old men in Lithuania (n = 94) and Sweden (n = 89), controlling for effect of residence. SRH was assessed by “How would you assess your own health?” A standardized laboratory stress test included measures of cortisol in serum and saliva.Good SRH related to high scale scores of decision latitude, social support at work, coping, self- esteem, and sense of coherence; itto low scores of overcommitment (all p < .01) and vital exhaustion (r = - 0.40, p < 0.001); to low concentrations of saliva baseline cortisol (r = - .26, p = .001); and to a strong cortisol response to stress (r = .27, p = .001).Findings that good SRH related to favorable psychosocial characteristics and to a dynamic cortisol stress response indicate a possible explanation for observed lower risk for disease and death in this state.     

Altered stress patterns and increased risk for postpartum depression among low-income pregnant women

Postpartum depression (PPD) has been associated with a number of negative maternal and infant health outcomes. Despite these adverse health effects, few studies have prospectively examined patterns of pre- and postnatal stress that may increase a woman’s risk for PPD. The current study examined whether the timing of altered salivary cortisol patterns and perceived stress levels during pregnancy and at 3 months postpartum was associated with PPD symptoms among 100 low-income mothers. Higher levels of PPD were found among women with a lower cortisol awakening response (first and second trimester), lower average daily cortisol (second trimester), a flatter diurnal cortisol pattern (second and third trimester and at 3 months postpartum), and a less abrupt drop in both cortisol and perceived stress from the third trimester to 3 months postpartum. These results support the need for early screening and regulation of stress levels to promote depression prevention efforts in at-risk populations.