Influence of early life stress on later hypothalamic-pituitary-adrenal axis functioning and its covariation with mental health symptoms: a study of the allostatic process from childhood into adolescence

The hypothalamic-pituitary-adrenal (HPA) axis is a primary mechanism in the allostatic process through which early life stress (ELS) contributes to disease. Studies of the influence of ELS on children's HPA axis functioning have yielded inconsistent findings. To address this issue, the present study considers multiple types of ELS (maternal depression, paternal depression, and family expressed anger), mental health symptoms, and two components of HPA functioning (traitlike and epoch-specific activity) in a long-term prospective community study of 357 children. ELS was assessed during the infancy and preschool periods; mental health symptoms and cortisol were assessed at child ages 9, 11, 13, and 15 years. A three-level hierarchical linear model addressed questions regarding the influences of ELS on HPA functioning and its covariation with mental health symptoms. ELS influenced traitlike cortisol level and slope, with both hyper- and hypoarousal evident depending on type of ELS. Further, type(s) of ELS influenced covariation of epoch-specific HPA functioning and mental health symptoms, with a tighter coupling of HPA alterations with symptom severity among children exposed previously to ELS. Results highlight the importance of examining multiple types of ELS and dynamic HPA functioning in order to capture the allostatic process unfolding across the transition into adolescence.     

The salivary alpha amylase over cortisol ratio as a marker to assess dysregulations of the stress systems

Different factors have been associated with changes in the regulation of the two major stress response systems of the human body, the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. Changes in these systems have been associated with various (psycho)pathologies across adulthood, and are thus frequently assessed within the context of allostatic load. Early Life Adversity (ELA) has been identified as one such factor. Individuals with histories of ELA show evidence of elevated basal and reactive salivary alpha amylase (sAA) levels (a marker of SNS activity), blunted cortisol levels (a marker of HPA axis activity), and an asymmetrical relationship between the two variables. However, variable methods used in the past to measure each variable, and the relationship between the two systems, prevent us from drawing firm conclusions. This preliminary study investigated whether the ratio of reactive sAA over reactive cortisol would be more informative to investigate the relationship between the two stress systems than the ratio of cortisol over sAA, or either marker alone, and whether there is a systematic link between this marker and subjective indexes of chronic stress and depression. We studied this in a total of 37 subjects (n=20 with signs of early life adversity and n=17 without) exposed to the Trier social stress test. Using a specific formula to determine the ratio of sAA over cortisol, we found a systematically stronger positive relationship with indexes of chronic stress and depression when compared to cortisol over sAA, or either marker alone. Our findings suggest that the ratio of sAA over cortisol might be a better marker of stress systems dysregulation than the ratio of cortisol over sAA, sAA or cortisol alone. The usefulness of this marker for other chronic stress states as found in allostatic load is discussed.     

Cortisol levels in relation to maternal interaction and child internalizing behavior in preterm and full-term children at 18 months corrected age

Cortisol levels were compared in children born preterm at extremely low gestational age (ELGA; 24-28 weeks), very low gestational age (VGLA; 29-32 weeks), and full-term in response to cognitive assessment at 18 months corrected age (CA). Further, we investigated the relationship between maternal interactive behaviors and child internalizing behaviors (rated by the mother) in relation to child cortisol levels. EGLA children had higher "pretest" cortisol levels and a different pattern of cortisol response to cognitive assessment compared to VGLA and full-terms. Higher cortisol levels in ELGA, but not full-term, children were associated with less optimal mother interactive behavior. Moreover, the pattern of cortisol change was related to internalizing behaviors among ELGA, and to a lesser degree VLGA children. In conclusion, our findings suggest altered programming of the hypothalamic-pituitary-adrenal (HPA) axis in preterm children, as well as their greater sensitivity to environmental context such as maternal interactive behavior.     

Stress hormone levels of children of depressed mothers

Research suggests that disruptions in early caretaking can have long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response. Children of depressed mothers are at increased risk for developing internalizing problems in part because of disruptions in their caretaking environment. The present study investigated whether children of depressed mothers exhibit elevated salivary cortisol levels. Salivary cortisol samples were collected from 45 7- to 8-year-old children of mothers with a history of depression and 29 children of nondepressed mothers. Samples were collected soon after arrival to the laboratory and after a mild laboratory stressor and at home after wakeup and before bedtime. Children who had elevated levels of intemalizing symptoms and whose mothers had a history of depression showed elevated laboratory baseline cortisol levels. Children who were reported to have clinically significant internalizing symptoms were also more likely to show an elevated stress response to a mild laboratory stressor. When the longitudinal history of maternal depression was examined, matemal depression during the child's first 2 years of life was the best predictor of elevations in baseline cortisol at age 7 years. This study provides evidence that internalizing symptoms exist in conjunction with a more reactive hormonal stress system in children of depressed mothers. The results also provide preliminary evidence that exposure to maternal depression in the first 2 years of life may be related to children's cortisol levels later in life.     

Prenatal maternal emotional complaints are associated with cortisol responses in toddler and preschool aged girls

Associations between prenatal maternal emotional complaints and child behavioral and cognitive problems have been reported, with different relations for boys and girls. Fetal programming hypotheses underline these associations and state that the early development of the HPA‐axis of the children may have been affected. In the present study, differences in cortisol responses of prenatally exposed and nonexposed children are examined for both sexes separately. Cortisol response patterns of a group preschool aged children that were prenatally exposed to high levels of maternal emotional complaints (N = 51) were compared to a nonexposed group (N = 52). Child saliva was collected at the start of a home visit (T1), 22 min after a mother–child interaction episode (T2), and 22 min after a potentially frustrating task (T3). Repeated measures analyses showed that prenatally exposed girls showed higher cortisol levels across the three episodes compared to nonexposed girls. No differences were found in boys. Maternal prenatal emotional complaints might be related to child HPA‐axis functioning differently for boys and girls. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 51: 553–563, 2009.     

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.     

Children's internalizing symptoms: the role of interactions between cortisol and respiratory sinus arrhythmia

We examined interactions between children's physiological activity across two systems, the hypothalamic-pituitary-adrenal (HPA)-axis and the parasympathetic nervous system (PNS), as predictors of child-reported internalizing symptoms (depression, anxiety). HPA activity was indexed by baseline salivary cortisol, and PNS activity was indexed by baseline respiratory sinus arrhythmia (RSA). Study 1 consisted of 57 children (54% girls; M age = 8.81 years ±.34), and Study 2 included 219 children (51% girls; M age = 9.31 years ±.79). Cortisol interacted with RSA to explain unique variance in children's internalizing symptoms. Across the two studies, children with higher cortisol levels in conjunction with higher RSA levels tended to exhibit the lowest levels of depression and anxiety symptoms. Findings demonstrate that contemporaneous consideration of physiological activity across multiple systems can advance understanding of internalizing symptoms in children.     

Prenatal cortisol exposure predicts infant cortisol response to acute stress

Experimental animal findings suggest that early stress and glucocorticoid exposure may program the function of the hypothalamic–pituitary–adrenal (HPA) axis in the offspring. The extension of these findings to human development is not yet clear. A prospective longitudinal study was conducted on 125 mothers and their normally developing children. Amniotic fluid was obtained at, on average, 17.2 weeks gestation; infant behavior and cortisol response to a separation–reunion stress was assessed at 17 months. Amniotic fluid cortisol predicted infant cortisol response to separation–reunion stress: infants who were exposed to higher levels of cortisol in utero showed higher pre‐stress cortisol values and blunted response to stress exposure. The association was independent of prenatal, obstetric, and socioeconomic factors and child–parent attachment. The findings provide some of the strongest data in humans that HPA axis functioning in the child may be predicted from prenatal cortisol exposure. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 145–155, 2013     

Maternal early-life trauma and affective parenting style: the mediating role of HPA-axis function

A history of childhood trauma is associated with increased risk for psychopathology and interpersonal difficulties in adulthood and, for those who have children, impairments in parenting and increased risk of negative outcomes in offspring. Physiological and behavioral mechanisms are poorly understood. In the current study, maternal history of childhood trauma was hypothesized to predict differences in maternal affect and HPA axis functioning. Mother-infant dyads (N?=?255) were assessed at 6 months postpartum. Mothers were videotaped during a 3-min naturalistic interaction, and their behavior was coded for positive, neutral, and negative affect. Maternal salivary cortisol was measured six times across the study visit, which also included an infant stressor paradigm. Results showed that childhood trauma history predicted increased neutral affect and decreased mean cortisol in the mothers and that cortisol mediated the association between trauma history and maternal affect. Maternal depression was not associated with affective measures or cortisol. Results suggest that early childhood trauma may disrupt the development of the HPA axis, which in turn impairs affective expression during mother-infant interactions in postpartum women. Interventions aimed at treating psychiatric illness in postpartum women may benefit from specific components to assess and treat trauma-related symptoms and prevent secondary effects on parenting.     

Interactive effects of corticotropin releasing hormone receptor 1, serotonin transporter linked polymorphic region, and child maltreatment on diurnal cortisol regulation and internalizing symptomatology

Within an allostatic load framework, the effect of Gene × Environment (G × E) interactions on diurnal cortisol regulation and internalizing symptomatology were investigated. Variation in the corticotropin releasing hormone receptor 1 (CRHR1) TAT haplotype and serotonin transporter linked polymorphic region (5-HTTLPR) was determined in a sample of maltreated (n = 238, 21.4% with early physical and sexual abuse) and nonmaltreated (n = 255) children (M age = 10.08) participating in a summer research camp. Internalizing and depressive symptoms were assessed by other and self-report. G × E effects for CRHR1 and maltreatment and early abuse on diurnal cortisol regulation were observed; CRHR1 variation was related to cortisol dysregulation only among maltreated children. Early abuse and high internalizing symptoms also interacted to predict atypical diurnal cortisol regulation. The interaction of CRHR1, 5-HTTLPR, and child maltreatment (G × G × E) identified a subgroup of maltreated children with high internalizing symptoms who shared the same combination of the two genes. The findings support an allostatic load perspective on the effects of the chronic stress associated with child maltreatment on cortisol regulation and internalizing symptomatology as moderated by genetic variation.     

Distress conditions during pregnancy may lead to pre-eclampsia by increasing cortisol levels and altering lymphocyte sensitivity to glucocorticoids

Psychological stress may affect up to 18% of all pregnant women, altering the function of both neuroendocrine and immune systems. Distress conditions may directly change the hypothalamic-pituitary-adrenal (HPA) axis, leading to increased cortisol levels and associated changes in cellular immunity. Psychological events such as high stress levels, anxiety or depression may directly or indirectly affect pregnancy and may thus lead to pre-eclampsia (PE). Here, we suggest that distress conditions during pregnancy may lead the development of PE by enhancing in vivo cortisol levels. High cortisol levels are associated with hypertension and endothelial dysfunction, features often observed in patients with PE. Lymphocytes from patients with high cortisol levels may have a reduced sensitivity to the synthetic glucocorticoid dexamethasone (DEX). Stress-related steroid resistance may disrupt the HPA axis, leading to post-natal detrimental effects such as increased allostatic load, increased pro-inflammatory cytokine levels and even depression in the offspring.     

Clinical variables and hypothalamic-pituitary-adrenal function in depression. The importance of mood reactivity

Forty outpatients with major depressive disorder were studied with the 1 mg DST and the Afternoon Cortisol Test. No relationship was found between hypothalamic-pituitary-adrenal (HPA) axis function and Research Diagnostic Criteria subtypes of depression, with the exception of higher log post-dexamethasone cortisol levels in endogenous depressives. Patients with mood reactivity had lower cortisol values on all assessments. The data suggest that the presence of mood reactivity may be useful as a predictor of normal HPA function in depression.     

Hair cortisol levels as a retrospective marker of hypothalamic-pituitary axis activity throughout pregnancy: comparison to salivary cortisol

Maternal stress during pregnancy is associated with negative maternal/child outcomes. One potential biomarker of the maternal stress response is cortisol, a product of activity of the hypothalamic-pituitary-adrenal axis. This study evaluated cortisol levels in hair throughout pregnancy as a marker of total cortisol release. Cortisol levels in hair have been shown to be easily quantifiable and may be representative of total cortisol release more than single saliva or serum measures. Hair cortisol provides a simple way to monitor total cortisol release over an extended period of time. Hair cortisol levels were determined from each trimester (15, 26 and 36 weeks gestation) and 3 months postpartum. Hair cortisol levels were compared to diurnal salivary cortisol collected over 3 days (3 times/day) at 14, 18, 23, 29, and 34 weeks gestational age and 6 weeks postpartum from 21 pregnant women. Both salivary and hair cortisol levels rose during pregnancy as expected. Hair cortisol and diurnal salivary cortisol area under the curve with respect to ground (AUCg) were also correlated throughout pregnancy. Levels of cortisol in hair are a valid and useful tool to measure long-term cortisol activity. Hair cortisol avoids methodological problems associated with collection other cortisol measures such as plasma, urine, or saliva and is a reliable metric of HPA activity throughout pregnancy reflecting total cortisol release over an extended period.     

Maternal depression and cortisol in pregnancy predict offspring emotional reactivity in the preschool period

Prenatal exposures to higher levels of maternal cortisol and depression have been linked to a variety of adverse physiological, neurological, and behavioral outcomes, such as dysregulated cortisol production, structural and functional differences in limbic areas of the brain, and greater negative emotionality. This study investigated prospective associations between maternal prepartum depression/cortisol levels and offspring emotional reactivity in 163 mother–child pairs. Women were assessed repeatedly during pregnancy, and later participated in a laboratory visit with their preschool‐aged children. Mothers self‐reported on depressive symptomatology during pregnancy and provided saliva samples for cortisol assay. Offspring emotional reactivity was assessed through multiple measures, including caregiver reports, cortisol response following a stressor, and laboratory observations of behavior. The findings suggest potential prenatal timing effects, with depression and maternal cortisol measured in the first and second trimesters being more strongly associated with child emotional reactivity. Sex was found to moderate associations between maternal prepartum depression/cortisol and child emotional reactivity, with the general pattern reflecting positive associations in girls, and negative associations in boys.     

Age effects on cortisol levels in depressed patients with and without comorbid post-traumatic stress disorder, and healthy volunteers

BACKGROUND: Post-traumatic stress disorder (PTSD) and major depression are frequently comorbid. Age and major depression are associated with higher cortisol levels and dexamethasone resistance, whereas PTSD is associated with lower cortisol and dexamethasone supersensitivity. Therefore, we examined the effect of age on the hypothalamic-pituitary-adrenal (HPA) system in depressed patients with and without PTSD. METHODS: Thirty-one depressed patients without PTSD, 12 depressed patients with PTSD, and 23 healthy volunteers were studied on 2 days. Subjects received single-blind placebo on day 1 and fenfluramine on day 2. Cortisol levels were drawn before challenge and for 5 h thereafter. RESULTS: Cortisol levels increase with age in depressed patients without PTSD but not in depressed patients with PTSD or in healthy volunteers. Number of previous major depressive episodes was a predictor of the cortisol response to fenfluramine administration in depressed patients without PTSD. CONCLUSIONS: The results of our study highlight the importance of considering age in psychobiology. Further research is needed to fully delineate the role of age in abnormalities of the HPA axis found in major depression and PTSD.     

Co-activation of SAM and HPA responses to acute stress: A review of the literature and test of differential associations with preadolescents’ internalizing and externalizing

Understanding co-activation patterns of the hypothalamic-pituitary-adrenal axis (HPA) and sympathetic adrenal medullary (SAM) during early adolescence may illuminate risk for development of internalizing and externalizing problems. The present study advances empirical work on the topic by examining SAM-HPA co-activation during both the reactivity and recovery phases of the stress response following acute stress exposure. Fourth and fifth grade boys and girls (N = 149) provided cortisol and alpha-amylase via saliva at seven times throughout a 95-min assessment in which they were administered the modified Trier Social Stress Test. Parents reported on adolescents’ life stress, pubertal development, medication use, and externalizing problems. Adolescents reported their own internalizing symptoms. Multiple linear regressions tested both direct and interactive effects of SAM and HPA reactivity and recovery on internalizing and externalizing problems. Results from these analyses showed that whereas SAM and HPA reactivity interacted to predict internalizing symptoms, it was their interaction during the recovery phase that predicted externalizing. Concurrent high SAM and HPA reactivity scores predicted high levels of internalizing and concurrently low SAM and HPA recovery scores predicted high levels of externalizing. Implications of the findings for further study and clinical application are discussed.     

Kindergarten stressors and cumulative adrenocortical activation: the "first straws" of allostatic load?

Using an ethnically diverse longitudinal sample of 338 kindergarten children, this study examined the effects of cumulative contextual stressors on children's developing hypothalamic-pituitary-adrenocortical (HPA) axis regulation as an early life indicator of allostatic load. Chronic HPA axis regulation was assessed using cumulative, multiday measures of cortisol in both the fall and spring seasons of the kindergarten year. Hierarchical linear regression analyses revealed that contextual stressors related to ethnic minority status, socioeconomic status, and family adversity each uniquely predicted children's daily HPA activity and that some of those associations were curvilinear in conformation. Results showed that the quadratic, U-shaped influences of family socioeconomic status and family adversity operate in different directions to predict children's HPA axis regulation. Results further suggested that these associations differ for White and ethnic minority children. In total, this study revealed that early childhood experiences contribute to shifts in one of the principal neurobiological systems thought to generate allostatic load, confirming the importance of early prevention and intervention efforts. Moreover, findings suggested that analyses of allostatic load and developmental theories accounting for its accrual would benefit from an inclusion of curvilinear associations in tested predictive models.     

Intervention effects on foster parent stress: associations with child cortisol levels

Foster children exhibit high rates of atypical neuroendocrine functioning compared to children in the general population. In particular, alterations in the daytime diurnal activity of the hypothalamic-pituitary-adrenal (HPA) axis have been observed in foster children, often characterized by blunted salivary cortisol levels (i.e., low morning levels that remain low throughout the day). There is emerging evidence that therapeutic interventions for foster children can affect this pattern of HPA axis activity, but the specific intervention components responsible for change have not been fully explicated. Within a randomized trial to evaluate a therapeutic intervention for foster preschoolers (n = 57 intervention condition; n = 60 comparison condition; n = 60 community comparison condition), the present study examined whether diurnal cortisol activity was associated with caregiver self-reported stress in response to child problem behavior. Results showed immediate reductions in caregiver stress that were sustained through 12 months postbaseline in the intervention condition. In contrast, caregivers in the regular foster care condition showed higher rates of stress across time and increased stress sensitivity to child problem behaviors. In addition, among caregivers in regular foster care, higher self-reported stress was associated with lower morning cortisol levels and more blunted diurnal cortisol activity. These results provide evidence that interventions can simultaneously impact caregiver stress and buffer children from the negative impacts of caregiver stress on HPA axis regulation.     

Effects of prenatal depressive symptoms on maternal and infant cortisol reactivity

Prenatal depression is associated with adverse offspring outcomes, and the prevailing mechanistic theory to account for mood-associated effects implicates alterations of the maternal and foetal hypothalamic-pituitary adrenal (HPA) axes. Recent research suggests that depression may be associated with a failure to attenuate cortisol reactivity during early pregnancy. The aim of the current study is to investigate whether this effect continues into mid and late gestation. A further aim is to test whether maternal prenatal cortisol reactivity directly predicts infant cortisol reactivity. One hundred three pregnant women were recruited during either the second or third trimester. Depressive symptoms were assessed by self-report, and maternal salivary cortisol responses to a stressor (infant distress film) were measured. Approximately 2 months after birth, mothers (n?=?88) reported postnatal depression and infant salivary cortisol responses to inoculation were measured. Prenatal depression was not associated with cortisol reactivity to acute stress in mid and late pregnancy. Similarly, neither prenatal depression nor maternal prenatal cortisol reactivity predicted infant cortisol reactivity to inoculation at 2 months. If the effects of prenatal depression on foetal and infant development are mediated by alterations of the maternal and foetal HPA axes, then early pregnancy may be a particularly vulnerable period. Alternatively, changes to HPA reactivity may not be as central to this association as previously thought.     

Return to school accompanied by changing associations between family ecology and cortisol

This study examines everyday family life as a social regulator of child adrenocortical activity during the normative challenge of return to school. If positive family function facilitates child adaptation, we expected that mother-child relationships following school entry would predict individual differences in evening cortisol, a context-sensitive marker for the response to concurrent demands. Among 28 children followed longitudinally, late in pre-kindergarten those living with single and/or employed mothers had higher evening cortisol. Yet early during the following school year, children with poorer mother-child relationships had higher evening cortisol. Cortisol awakening response, a comparatively stable marker of anticipated demands, was higher with maternal employment, single parents, and busier child schedules before school re-entry, and with maternal employment afterwards. We argue for a layered ecological approach to social regulation, recognizing that family structure, family functioning, and proximal features of everyday life within the family moderate child adrenocortical activity differently across contexts.