Effects of early life adversity on cortisol/salivary alpha-amylase symmetry in free-ranging juvenile rhesus macaques

Early life adversity (ELA) affects physiological and behavioral development. One key component is the relationship between the developing Hypothalamic-Pituitary-Adrenal (HPA) axis and the Sympathetic Nervous System (SNS). Recent studies suggest a relationship between early life adversity and asymmetry in cortisol (a measure of HPA activation) and salivary alpha-amylase (sAA: a correlate of SNS activation) responses to stress among human children, but to our knowledge there have been no comparable studies in nonhumans. Here, we investigate the responses of these two analytes in “low stress” and “high stress” situations in free-ranging juvenile rhesus macaques (Macaca mulatta) on Cayo Santiago, Puerto Rico. Behavioral data on maternal maltreatment were collected during the first 3 months of life to determine individual rates of ELA, and saliva samples were collected from subjects noninvasively during juvenility. Irrespective of ELA, salivary alpha-amylase levels were lower in low stress situations and higher in high stress situations. For cortisol however, high ELA subjects exhibited higher low stress concentrations and blunted acute responses during high stress situations compared to moderate and low ELA subjects. Cortisol and sAA values were positively correlated among low ELA subjects, suggesting symmetry, but were uncorrelated or negatively correlated among moderate and high ELA subjects, suggesting asymmetry in these individuals. These findings indicate dysregulation of the stress response among juveniles maltreated during infancy: specifically, attenuated cortisol reactivity coupled with typical sAA reactivity characterize the stress response profiles of juveniles exposed to higher rates of ELA during the first 3 months of life.     

Do social disadvantage and early family adversity affect the diurnal cortisol rhythm in infants? The Generation R Study

Dysregulation of diurnal cortisol secretion patterns may explain the link between adversities early in life and later mental health problems. However, few studies have investigated the influence of social disadvantage and family adversity on the hypothalamic-pituitary-adrenal (HPA) axis early in life. In 366 infants aged 12-20 months from the Generation R Study, a population-based cohort from fetal life onwards, parents collected saliva samples from their infant at 5 moments over the course of 1 day. The area under the curve (AUC), the cortisol awakening response (CAR) and the diurnal cortisol slope were calculated as different composite measures of the diurnal cortisol rhythm. Information about social disadvantage and early adversity was collected using prenatal and postnatal questionnaires.We found that older infants showed lower AUC levels; moreover, infants with a positive CAR were significantly older. Both the AUC and the CAR were related to indicators of social disadvantage and early adversity. Infants of low income families, in comparison to high income families, showed higher AUC levels and a positive CAR. Infants of mothers who smoked during pregnancy were also significantly more likely to show a positive CAR. Furthermore, infants of mothers experiencing parenting stress showed higher AUC levels. The results of our study show that effects of social disadvantage and early adversity on the diurnal cortisol rhythm are already observable in infants. This may reflect the influence of early negative life events on early maturation of the HPA axis.     

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

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 posttraumatic 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.     

Antenatal glucocorticoids reset the level of baseline and hypoxemia-induced pituitary-adrenal activity in the sheep fetus during late gestation

This study examined the effects of dexamethasone treatment on basal hypothalamo-pituitary-adrenal (HPA) axis function and HPA responses to subsequent acute hypoxemia in the ovine fetus during late gestation. Between 117 and 120 days (term: approximately 145 days), 12 fetal sheep and their mothers were catheterized under halothane anesthesia. From 124 days, 6 fetuses were continuously infused intravenously with dexamethasone (1.80 +/- 0.15 microg.kg(-1).h(-1) in 0.9% saline at 0.5 ml/h) for 48 h, while the remaining 6 fetuses received saline at the same rate. Two days after infusion, when dexamethasone had cleared from the fetal circulation, acute hypoxemia was induced in both groups for 1 h by reducing the maternal fraction of inspired O2. Fetal dexamethasone treatment transiently lowered fetal basal plasma cortisol, but not ACTH, concentrations. However, 2 days after treatment, fetal basal plasma cortisol concentration was elevated without changes in basal ACTH concentration. Despite elevated basal plasma cortisol concentration, the ACTH response to acute hypoxemia was enhanced, and the increment in plasma cortisol levels was maintained, in dexamethasone-treated fetuses. Correlation of fetal plasma ACTH and cortisol concentrations indicated enhanced cortisol output without a change in adrenocortical sensitivity. The enhancements in basal cortisol concentration and the HPA axis responses to acute hypoxemia after dexamethasone treatment were associated with reductions in pituitary and adrenal glucocorticoid receptor mRNA contents, which persisted at 3-4 days after the end of treatment. These data show that prenatal glucocorticoids alter the basal set point of the HPA axis and enhance HPA axis responses to acute stress in the ovine fetus during late gestation.     

Hypothalamic-pituitary-adrenal stress axis function and the relationship with chronic widespread pain and its antecedents

In clinic studies, altered hypothalamic-pituitary-adrenal (HPA) axis function has been associated with fibromyalgia, a syndrome characterised by chronic widespread body pain. These results may be explained by the associated high rates of psychological distress and somatisation. We address the hypothesis that the latter, rather than the pain, might explain the HPA results. A population study ascertained pain and psychological status in subjects aged 25 to 65 years. Random samples were selected from the following three groups: satisfying criteria for chronic widespread pain; free of chronic widespread pain but with strong evidence of somatisation ('at risk'); and a reference group. HPA axis function was assessed from measuring early morning and evening salivary cortisol levels, and serum cortisol after physical (pain pressure threshold exam) and chemical (overnight 0.25 mg dexamethasone suppression test) stressors. The relationship between HPA function with pain and the various psychosocial scales assessed was modelled using appropriate regression analyses, adjusted for age and gender. In all 131 persons with chronic widespread pain (participation rate 74%), 267 'at risk' (58%) and 56 controls (70%) were studied. Those in the chronic widespread pain and 'at risk' groups were, respectively, 3.1 (95% CI (1.3, 7.3)) and 1.8 (0.8, 4.0) times more likely to have a saliva cortisol score in the lowest third. None of the psychosocial factors measured were, however, associated with saliva cortisol scores. Further, those in the chronic widespread pain (1.9 (0.8, 4.7)) and 'at risk' (1.6 (0.7, 3.6)) groups were also more likely to have the highest serum cortisol scores. High post-stress serum cortisol was related to high levels of psychological distress (p = 0.05, 95% CI (0.02, 0.08)). After adjusting for levels of psychological distress, the association between chronic widespread pain and post-stress cortisol scores remained, albeit slightly attenuated. This is the first population study to demonstrate that those with established, and those psychologically at risk of, chronic widespread pain demonstrate abnormalities of HPA axis function, which are more marked in the former group. Although some aspects of the altered function are related to the psychosocial factors measured, we conclude that the occurrence of HPA abnormality in persons with chronic widespread pain is not fully explained by the accompanying psychological stress.     

Elevated Hair Cortisol Levels among Heroin Addicts on Current Methadone Maintenance Compared to Controls

Whether methadone maintenance treatment (MMT) can improve the basal function of the hypothalamic–pituitary–adrenal (HPA) axis, which is suppressed by long-term heroin consumption, is a matter of debate. The stress state and depression and anxiety symptoms may affect the basal activity of the HPA axis in MMT patients. However, the effect of psychological factors on HPA activity was not simultaneously controlled in previous studies. This study investigated differences in HPA basal activity between MMT patients and controls using psychological variables as covariates. The participants included 52 MMT patients and 41 age-matched, non-heroin-dependent controls. Psychological states were self-reported with the Perceived Stress Scale, Self-Rating Depression Scale and Self-Rating Anxiety Scale. The hair cortisol level was adopted as a biomarker of HPA basal activity and was determined with liquid chromatography tandem mass spectrometry. The results revealed that MMT patients had significantly higher hair cortisol levels than the controls (p<0.05), but the difference was not significant (p>0.05) when the perceived stress, depression and anxiety scores were used as covariates. We concluded that patients with long-term MMT showed higher basal activity of the HPA axis. The high chronic stress state and increase in depression and anxiety symptoms may mask the suppression effect of methadone on the HPA activity.     

Disentangling psychobiological mechanisms underlying internalizing and externalizing behaviors in youth: longitudinal and concurrent associations with cortisol

Research examining cortisol dysregulation is seemingly contradictory with studies showing that both internalizing and externalizing behaviors are related to high and low cortisol. One extant theory to explain divergent findings in the stress literature is that both hypo- and hyper-arousal of the hypothalamic-pituitary-adrenal (HPA) axis may be present depending on time since onset of the stressor. This theory may extend to the onset of internalizing and externalizing behaviors. Data from 96 youth participating in a longitudinal project were used to examine this possibility. Composite measures of internalizing and externalizing behaviors at both childhood and early adolescence were formed using mother and teacher reports. Multiple salivary cortisol samples were also collected over two consecutive days during early adolescence. Problematic behaviors were associated with cortisol and the direction of the association was dependent on amount of time passed since onset of the behaviors. When examined concurrently in adolescence, youth with more internalizing behaviors had higher morning cortisol; however, when examined longitudinally, youth with more internalizing behaviors in childhood had lower morning cortisol levels as adolescents. Youth with more externalizing behaviors in childhood had flattened diurnal cortisol rhythms as adolescents, and this finding persisted when examined in adolescence. Cortisol dysregulation was greatest in children with the most severe behavior problems. Findings support the theoretical model of blunting of the HPA axis over time. While the HPA axis may show hyper-arousal when youth first display behaviors, long-term exposure may lead to a hypo-arousal of the HPA axis which culminates in a dysregulated diurnal rhythm.     

Social and reproductive conditions modulate urinary cortisol excretion in black tufted-ear marmosets (Callithrix kuhli)

The links between psychosocial stress, social status, reproductive function, and urinary cortisol were assessed in social groups of black tufted-ear marmosets (Callithrix kuhli). Urinary cortisol excretion was monitored in cases of intrafamily conflict (“sibling fights”) and in daughters in four distinct social contexts: in the family group, while housed singly or in same-sex pairs, and while paired with a male pairmate. Cortisol excretion was elevated in participants in intra-family conflict on the day of and the day following the conflict, relative to concentrations a week prior to or following the conflict. Daughters in natal family groups had concentrations of cortisol that did not differ from reproductively active adult females. This finding held for daughters who were either anovulatory or undergoing ovulatory cycles while in the natal family group. Natal family members and male pairmates exerted buffering effects on levels of activity in the hypothalamic pituitary adrenal axis (HPA) in female C. kuhli. Placing females in solitary housing led to significantly increased cortisol excretion. In the 2 months subsequent to pairing with a male partner, excreted cortisol concentrations in females declined significantly. Daughters removed from their natal family group and housed with a sister did not exhibit increased cortisol levels. These data reveal that activity in the (HPA) axis in marmosets is sensitive to psychosocial stressors, and that urinary cortisol can provide a useful quantitative measure of HPA reactivity. As in other callitrichids, delayed breeding in daughters and reproductive anomalies in C. kuhli appear to be mediated by mechanisms other than elevated HPA activity. Am. J. Primatol. 42:253–267, 1997. © 1997 Wiley-Liss, Inc.     

Age-related changes in the dog hypothalamic-pituitary-adrenocortical system: neuroendocrine activity and corticosteroid receptors.

Aging is associated with a progressive dysfunctioning of the hypothalamic-pituitary-adrenocortical (HPA) axis. We have studied the response of the HPA axis to stress and a hormonal (ovine corticotropin releasing factor (o-CRF) challenge in young (1.5-2 years) and aged (greater than 11 years) dogs. Compared to the young dogs, the aged animals displayed an increased basal concentration of both ACTH and cortisol. In addition, in response to an o-CRF challenge (1 microgram/kg i.v.) or an electric footshock (1 mA, alternatively on/off for 2 s) or immobilization (45 min) stress, the aged dogs showed significantly larger increments in ACTH and cortisol. Following the challenge test, the young and aged dogs reached their respective basal hormone levels at the same time, except for the o-CRF test. In the latter case, in contrast to the young controls, the aged dogs still showed an increased plasma cortisol level compared to the pre-challenge basal hormone concentration. Concerning the effect of aging on the brain and hypophyseal corticosteroid receptors, a selective decline (minus 50-75%) in mineralocorticoid receptor (MR) was observed in all measured brain regions (dorsal and ventral hippocampus, septum, hypothalamus) and anterior pituitary, whereas no change was found in brain glucocorticoid receptor (GR) number. The GR level in the anterior pituitary was even increased by 70%. In light of the role that MR and GR seem to play in the regulation of the HPA axis, it is concluded that the diminished MR number in the aged dog brain may underly the increased basal hormone levels and the elevated responsiveness of the HPA axis in these animals. The observation that the stress-induced elevations of cortisol and ACTH were not prolonged at senescence suggests that the GR-mediated negative feedback action of glucocorticoids is not altered, which is in line with the unchanged brain GR numbers in the aged dogs.     

Ovine corticotropin-releasing hormone stimulation test in patients with chronic renal failure: pharmacokinetic properties, and plasma adrenocorticotropic hormone and serum cortisol responses

The data on the status of the hypothalamic-pituitary-adrenal (HPA) axis in haemodialysis (HD) patients are conflicting. Moreover, a state reminiscent of Cushing's syndrome has been reported in this group of patients. Corticotropin-releasing hormone (CRH), that is produced by the hypothalamus and modulates the secretion of adrenocorticotropic hormone (ACTH), has been shown to be useful as a provocative test of the HPA axis. We investigated the effect of exogenous ovine CRH (oCRH) on plasma levels of ACTH and cortisol in 13 chronic HD patients. The plasma concentrations of immunoreactive CRH following oCRH administration were similar in patients and controls. In all patients, oCRH given intravenously as bolus injection caused a further increase in the already elevated levels of cortisol. The mean basal plasma levels of ACTH were within the normal range. There was, however, a blunted ACTH response to oCRH. We conclude that the HPA axis in chronic HD patients retains the ability to respond to exogenous oCRH. The patterns of the ACTH and cortisol response to this peptide resemble those observed in chronic stress (depression, anorexia nervosa). Besides, the kinetics of disappearance of oCRH indicate that the kidney may not be the major organ that metabolizes oCRH.     

Effects of chronic maternal stress on hypothalamo–pituitary–adrenal (HPA) function and behavior: No reversal by environmental enrichment

Maternal stress during pregnancy is linked to increased risk for impaired behavioral and emotional development and affective disorders in children. In animal models, acute periods of prenatal or postnatal stress have profound effects on HPA function and behavior in adult offspring. However, few animal studies have determined the impact of chronic exposure to stress throughout the perinatal period. The objective of this study was to determine the effects of chronic maternal stress (CMS) during the 2nd half of pregnancy and nursing on HPA function, locomotor behavior and prepulse inhibition in adult guinea pig offspring, as well as to determine whether environmental enrichment (EE) could reverse the effects of CMS. Guinea pigs were exposed to a random combination of variable stressors every other day over the 2nd half of gestation and from postnatal day (pnd) 1 until weaning (pnd25). Following weaning, offspring were housed in either standard conditions or EE. In both adult male and female offspring, there was no effect of CMS on basal or activated HPA function. CMS significantly increased locomotor activity in an open-field in male offspring, though no effect was observed in females. In female offspring, CMS disrupted PPI; however there was no effect on male PPI. EE had a number of effects on HPA function and behavior but in most cases these were independent of the influence of CMS. EE significantly elevated basal cortisol levels in male offspring at pnd70, whereas in female offspring, EE interacted with CMS to elevate basal cortisol levels from pnd35 to pnd70. In female offspring, EE decreased locomotor activity. In males, EE enhanced PPI; however in female offspring EE disrupted PPI. In conclusion, while CMS had minimal effects on HPA function, there were significant long-term sex-specific effects on behavior. EE did not reverse the effects observed as a result of CMS, but rather modified HPA function and behavior independently of CMS. Further, there was significant interaction of CMS with EE that resulted in elevation of basal HPA function in female offspring. These data, combined with previous studies from our laboratory, suggest that acute phases of maternal stress in late pregnancy may have greater long-term effects on HPA function and related behaviors than prolonged chronic maternal stress.     

Effects of chronic maternal stress on hypothalamo-pituitary-adrenal (HPA) function and behavior: no reversal by environmental enrichment

Maternal stress during pregnancy is linked to increased risk for impaired behavioral and emotional development and affective disorders in children. In animal models, acute periods of prenatal or postnatal stress have profound effects on HPA function and behavior in adult offspring. However, few animal studies have determined the impact of chronic exposure to stress throughout the perinatal period. The objective of this study was to determine the effects of chronic maternal stress (CMS) during the 2nd half of pregnancy and nursing on HPA function, locomotor behavior and prepulse inhibition in adult guinea pig offspring, as well as to determine whether environmental enrichment (EE) could reverse the effects of CMS. Guinea pigs were exposed to a random combination of variable stressors every other day over the 2nd half of gestation and from postnatal day (pnd) 1 until weaning (pnd25). Following weaning, offspring were housed in either standard conditions or EE. In both adult male and female offspring, there was no effect of CMS on basal or activated HPA function. CMS significantly increased locomotor activity in an open-field in male offspring, though no effect was observed in females. In female offspring, CMS disrupted PPI; however there was no effect on male PPI. EE had a number of effects on HPA function and behavior but in most cases these were independent of the influence of CMS. EE significantly elevated basal cortisol levels in male offspring at pnd70, whereas in female offspring, EE interacted with CMS to elevate basal cortisol levels from pnd35 to pnd70. In female offspring, EE decreased locomotor activity. In males, EE enhanced PPI; however in female offspring EE disrupted PPI. In conclusion, while CMS had minimal effects on HPA function, there were significant long-term sex-specific effects on behavior. EE did not reverse the effects observed as a result of CMS, but rather modified HPA function and behavior independently of CMS. Further, there was significant interaction of CMS with EE that resulted in elevation of basal HPA function in female offspring. These data, combined with previous studies from our laboratory, suggest that acute phases of maternal stress in late pregnancy may have greater long-term effects on HPA function and related behaviors than prolonged chronic maternal stress.     

What can we know from pituitary-adrenal hormones about the nature and consequences of exposure to emotional stressors?

Exposure to stress induces profound physiological and behavioral changes in the organisms and some of these changes may be important regarding stress-induced pathologies and animal models of psychiatric diseases. Consequences of stress are dependent on the duration of exposure to stressors (acute, chronic), but also of certain characteristics such as intensity, controllability, and predictability. If some biological variables were able to reflect these characteristics, they could be used to predict negative consequences of stress. Among the myriad of physiological changes caused by stress, only a restricted number of variables appears to reflect the intensity of the situation, mainly plasma levels of ACTH and adrenaline. Peripheral hypothalamic-pituitary-adrenal (HPA) hormones (ACTH and corticosterone) are also able to reflect fear conditioning. In contrast, the activation of the HPA axis is not consistently related to anxiety as evaluated by classical tests such as the elevated plus-maze. Similarly, there is no consistent evidence about the sensitivity of the HPA axis to psychological variables such as controllability and predictability, despite the fact that: (a) lack of control over aversive stimuli can induce behavioral alterations not seen in animals which exert control, and (b) animals showed clear preference for predictable versus unpredictable stressful situations. New studies are needed to re-evaluate the relationship between the HPA axis and psychological stress characteristics using ACTH instead of corticosterone and taking advantages of our current knowledge about the regulation of this important stress system.     

The Activity of the Hypothalamic‐Pituitary‐Adrenal Axis and the Sympathetic Nervous System in Relation to Waist/Hip Circumference Ratio in Men

Objective: To investigate possible differences, between generally and abdominally obese men, in activity and regulation of the hypothalamic‐pituitary‐adrenal (HPA) axis and the sympathetic nervous system. Research Methods and Procedures: Fifty non‐diabetic, middle‐aged men were selected to obtain two groups with similar body mass index (BMI) but different waist/hip circumference ratio (WHR). Measurements were performed of the activity of the HPA axis and the sympathetic nervous system, as well as metabolic and endocrine variables. Results: Men with a high WHR, in comparisons with men with a low WHR, had higher insulin, glucose, and triglyceride values in the basal state and higher glucose and insulin after an oral glucose tolerance test. Men with high WHR had elevated diurnal adrenocorticotropic hormone (ACTH) values but similar cortisol values, except lower cortisol values in the morning. Diurnal growth hormone concentrations showed reduced peak size. Stimulation of the HPA axis with corticotropin‐releasing hormone (CRH) and laboratory stress showed no difference in ACTH values between groups, but cortisol values were lower in men with high WHR. In comparison with men with a low WHR, men with a high WHR had elevated pulse pressure and heart rate in the basal state and after challenges by CRH and laboratory stress. They also had increased urinary excretion of catecholamine metabolites. Discussion: These results suggest a mild dysregulation of the HPA axis, occurring with elevated WHR independent of the BMI. The results also indicate a central activation of the sympathetic nervous system, such as in the early phases of hypertension, correlating with insulin resistance.     

Maternal care and development of stress responses in baboons

The ability to mount a successful response to threats is critical for an organism's survival. A key element of the stress response is its nonspecificity toward the stress source, with similar endocrine and behavioral changes expected under a variety of stressors. In this project we utilized an experimental design that accounts for multiple sources of variation to further understand the nature of stress responsivity and its relationship to the early rearing environment. A sample of baboons (n=73) was observed during the early phase of life in their social group, and then tested as juveniles in a challenging situation. Maternal cortisol levels were measured during the peripartum period. The challenging situation (individuals were isolated for a few minutes in a single cage) was designed to be a moderate source of psychological stress. Patterns in individual differences during the stress test were "mapped" by means of multidimensional scaling (MDS). After the observation was made, the subject was sedated and a blood sample was taken to measure cortisol levels. Our results indicate that when juvenile baboons are confronted with a source of psychological stress, they show a multidimensional behavioral response, probably mediated by the activation and synergic interaction among different neurohormonal systems that, ultimately, act on the hypothalamus-pituitary-adrenal (HPA) axis. Different components of the multidimensional, or nonspecific, behavioral response are associated with the quality and quantity of interactions with their mothers during early life. Juveniles whose mothers displayed higher levels of positive interaction were characterized by vigilant but less active reactions to the stress test, whereas juveniles of mothers that displayed high levels of stress-related behaviors had higher cortisol and locomotion levels.     

Psychological stressors as a model of maternal adversity: diurnal modulation of corticosterone responses and changes in maternal behavior

Maternal adversity is associated with long-lasting consequences on cognitive development, behavior and physiological responses in rat offspring. Few studies have examined whether repeated maternal stress produces repeated activation of the hypothalamus-pituitary-adrenal (HPA) axis in mothers and whether it modifies maternal behavior. Here, we tested a novel model of perinatal stress using repeated exposure to "purely" psychological stressors throughout the gestation and lactation periods in rats. We first tested the diurnal influences of repeated 1-h strobe light exposure on maternal corticosterone secretion. Despite the hyporesponsiveness to stress documented in late pregnant and lactating mothers, we observed an enhanced response to strobe light in the afternoon compared to the morning in stressed mothers during lactation. Next, dams were exposed to 24-h forced foraging followed by 10-h wet bedding during the diurnal peak of corticosterone secretion. Although no corticosterone responses to forced foraging and wet bedding were observed, the combination of both stressors had a significant effect on maternal behavior. Mother-pup interactions were significantly altered during the first 8 days of lactation. Taken together, these findings suggest that lactating mothers maintain responsiveness to specific and repeated psychological stressors, in particular at the time of the diurnal peak in corticosterone secretion. Depending on the stressor applied, either neuroendocrine activation or changes in maternal behavior might be important determinants of the long-term consequences in the offspring. The combination of forced foraging, wet bedding and strobe light might represent a novel model of mild maternal adversity using "purely" psychological stressors.     

Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects

Pregnant guinea pigs were treated with dexamethasone (1 mg/kg) or vehicle on days 40--41, days 50--51, and days 60--61 of gestation. Adult offspring were split into two groups. Group 1 guinea pigs were catheterized, and the hypothalamo-pituitary-adrenal (HPA) axis was tested in basal and activated states. Group 2 guinea pigs were euthanized with no further manipulation. In male offspring, prenatal dexamethasone exposure resulted in a significant reduction in brain-to-body weight ratio. Dexamethasone-exposed male offspring exhibited reduced basal and activated plasma cortisol levels, which was associated with elevated hippocampal mineralocorticoid receptor (MR) mRNA and increased plasma testosterone. In females exposed to glucocorticoids in utero, basal and stimulated plasma cortisol levels were higher in the follicular and early luteal phases of the cycle, but this effect was reversed in the late luteal phase, indicating a significant interaction of sex steroids. In female offspring (at estrus), glucocorticoid receptor mRNA levels were lower in the paraventricular nucleus and pars distalis but higher in the hippocampus in animals exposed to dexamethasone in utero. Hippocampal MR mRNA levels were significantly lower (approximately 50%) than in controls. In conclusion, repeated antenatal glucocorticoid treatment programs HPA function in a sex-specific manner, and these changes are associated with modification of corticosteroid receptor expression in the adult brain and pituitary.     

Integrated Inflammatory Stress (ITIS) Model

During the last decade, there has been an increasing interest in the coupling between the acute inflammatory response and the Hypothalamic–Pituitary–Adrenal (HPA) axis. The inflammatory response is activated acutely by pathogen- or damage-related molecular patterns, whereas the HPA axis maintains a long-term level of the stress hormone cortisol which is also anti-inflammatory. A new integrated model of the interaction between these two subsystems of the inflammatory system is proposed and coined the integrated inflammatory stress (ITIS) model. The coupling mechanisms describing the interactions between the subsystems in the ITIS model are formulated based on biological reasoning and its ability to describe clinical data. The ITIS model is calibrated and validated by simulating various scenarios related to endotoxin (LPS) exposure. The model is capable of reproducing human data of tumor necrosis factor alpha, adrenocorticotropic hormone (ACTH) and cortisol and suggests that repeated LPS injections lead to a deficient response. The ITIS model predicts that the most extensive response to an LPS injection in ACTH and cortisol concentrations is observed in the early hours of the day. A constant activation results in elevated levels of the variables in the model while a prolonged change of the oscillations in ACTH and cortisol concentrations is the most pronounced result of different LPS doses predicted by the model.     

Post-traumatic Stress Disorder in children and adolescents: from Sigmund Freud's "trauma" to psychopathology and the (Dys)metabolic syndrome.

Post-traumatic Stress Disorder (PTSD) is an anxiety syndrome that develops after exposure to traumatic life events. Symptoms include re-experience of the initial trauma, avoidance of stimuli associated with the trauma and symptoms of excessive arousal. Neuroendocrine studies in adults with PTSD have demonstrated that basal cerebrospinal fluid (CSF) CRH levels are elevated and urinary cortisol levels are variable--low in the majority of cases--whereas other studies demonstrate no differences in urinary and plasma cortisol concentrations. Urinary catecholamine excretion is higher in PTSD patients than those of control subjects and other psychiatric disorders. Children may differ from adults in their psychologic and physiologic responses to severe stressors. Also, exposure to stress during critical periods of development may have irreversible effects on behavioral maturation and may affect specific vulnerable brain areas, altering CNS development. Similar to findings in adult studies, PTSD in children is characterized by increased sympathetic nervous system (SNS) activity, as indicated by elevated norepinephrine levels in the periphery. High cortisol levels in urine or saliva have been reported in most studies of childhood PTSD, while prospective longitudinal studies concerning the natural history of neuroendocrine changes in pediatric PTSD after an acute stressor are limited. The identification of neurobiologic changes in response to early adverse experiences is of major importance for the prognosis, prevention, management, and treatment of children and adolescents at risk for or suffering from PTSD.     

Is HPA axis reactivity in childhood gender-specific? A systematic review

Background

In adults, hypothalamus–pituitary–adrenal (HPA) axis activity shows sexual dimorphism, and this is thought to be a mechanism underlying sex-specific disease incidence. Evidence is scarce on whether these sex differences are also present in childhood. In a meta-analysis, we recently found that basal (non-stimulated) cortisol in saliva and free cortisol in 24-h urine follow sex-specific patterns. We explored whether these findings could be extended with sex differences in HPA axis reactivity.

Methods

From inception to January 2016, PubMed and EMBASE.com were searched for studies that assessed HPA axis reactivity in healthy girls and boys aged ≤18 years. Articles were systematically assessed and reported in the categories: (1) diurnal rhythm, (2) cortisol awakening response (CAR), (3) protocolled social stress tests similar or equal to the Trier Social Stress Test for children (TSST-C), (4) pharmacological (ACTH and CRH) stress tests, and (5) miscellaneous stress tests.

Results

Two independent assessors selected 109 out of 6158 records for full-text screening, of which 81 studies (with a total of 14,591 subjects) were included. Studies showed that girls had a tendency towards a more variable diurnal rhythm (12 out of 29 studies), a higher CAR (8 out of 18 studies), and a stronger cortisol response to social stress tests (9 out of 21 studies). We found no evidence for sex differences in cortisol response after a pharmacological challenge or to miscellaneous stress tests.

Discussion

Sex differences in HPA axis reactivity appear to be present in childhood, although evidence is not unequivocal. For a better evaluation of sex differences in HPA axis reactivity, standardization of protocols and reports of stress tests is warranted.