Child maltreatment and the developing HPA axis

The developing HPA axis is under strong social regulation in infancy and early childhood and is vulnerable to perturbation in the absence of sensitive, responsive caregiving. Child maltreatment has complex, long-term influences both on basal cortisol levels and on HPA responsivity to pharmacological and psychological stressors, depending on current psychiatric status, current life adversity, age, and most likely, genetic factors. Among the more consistent findings, maltreated children with internalizing problems have elevated basal cortisol most often detected in early AM concentrations, whereas adults maltreated as children often exhibit low basal cortisol levels and elevated ACTH response to psychological stressors. To disentangle these complicated interactions, future research must take the above qualifiers into account, study the transition to puberty, explore the moderating role of candidate genes, and utilize animal models and pharmacological challenges, when ethical, to localize changes in the HPA axis. Post-institutionalized children may provide a model to separate early adverse care histories from current adversity.     

Chronic maternal stress affects growth, behaviour and hypothalamo-pituitary-adrenal function in juvenile offspring

Maternal stress during pregnancy, particularly that combined with low socioeconomic status (SES), has been linked to an increased risk for impaired behavioural and emotional development and affective disorders in children. In animal models, acute periods of prenatal stress have profound effects on hypothalamo-pituitary-adrenal (HPA) function and behaviour. However, few studies have determined the impact of chronic exposure to stress in animal models. The objective of this study was to determine the effects of chronic maternal stress (CMS) during the 2nd half of pregnancy and nursing on growth, locomotor behaviour and HPA axis function in juvenile guinea pig offspring. Pregnant 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). CMS mothers displayed increased basal salivary cortisol levels in the later stages of pregnancy compared to control mothers (p < 0.05). The male offspring of CMS mothers had a lower bodyweight, which was maintained to weaning (p < 0.01). In open-field testing, CMS male offspring showed a decrease in activity compared to controls (p < 0.05). There was no effect of CMS on bodyweight or activity in female offspring. In contrast, both male and female offspring born to CMS mothers displayed increased (p < 0.05) basal salivary cortisol at pnd25, but a blunted adrenocortical response to exposure to the novel open-field enclosure. In conclusion, CMS leads to modification of growth trajectory, locomotor activity and adrenocortical responses to stress in juvenile offspring. Further, males appear considerably more vulnerable to these effects than females.     

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.     

High self-perceived stress and many stressors, but normal diurnal cortisol rhythm, in adults with ADHD (attention-deficit/hyperactivity disorder)

Attention-deficit/hyperactivity disorder (ADHD) in adults is associated with significant impairment in many life activities and may thus increase the risk of chronic stress in everyday life. We compared adults with a DSM-IV ADHD diagnosis (n = 28) with healthy controls (n = 28) regarding subjective stress and amounts of stressors in everyday life, diurnal salivary cortisol in the everyday environment and salivary cortisol before and after cognitive stress in a laboratory setting. The association between cortisol concentrations and impulsivity was also investigated. Consistent with assumptions, individuals with ADHD reported significantly more self-perceived stress than controls, and subjective stress correlated with the amount of stressors in everyday life. The two groups were comparable with respect to overall diurnal cortisol levels and rhythm, as well as in pre- and post-stress cortisol concentrations. Post-stress cortisol (but not baseline cortisol) concentration was positively correlated with impulsivity. The group with high post-stress cortisol also reported more symptoms of depression and anxiety, as well as self-perceived stress and stressors in every-day life. The diagnosis of ADHD significantly increased the risk of belonging to the group with high post-stress cortisol levels. The results in this study warrant a focus not only on the primary diagnosis of ADHD, but also calls for a broader assessment of stressors and subjective stress in everyday life, as well as support comprising stress management and coping skills.     

Modeling cortisol dynamics in the neuro-endocrine axis distinguishes normal, depression, and post-traumatic stress disorder (PTSD) in humans

Cortisol, secreted in the adrenal cortex in response to stress, is an informative biomarker that distinguishes anxiety disorders such as major depression and post-traumatic stress disorder (PTSD) from normal subjects. Yehuda et al. proposed a hypothesis that, in humans, the hypersensitive hypothalamus-pituitary-adrenal (HPA) axis is responsible for the occurrence of differing levels of cortisol in anxiety disorders. Specifically, PTSD subjects have lower cortisol levels during the late subjective night in comparison to normal subjects, and this was assumed to occur due to strong negative feedback loops in the HPA axis. In the present work, to address this hypothesis, we modeled the cortisol dynamics using nonlinear ordinary differential equations and estimated the kinetic parameters of the model to fit the experimental data of three categories, namely, normal, depressed, and PTSD human subjects. We concatenated the subjects (n = 3) in each category and created a model subject (n = 1) without considering the patient-to-patient variability in each case. The parameters of the model for the three categories were simultaneously obtained through global optimization. Bifurcation analysis carried out with the optimized parameters exhibited two supercritical Hopf points and, for the choice of parameters, the oscillations were found to be circadian in nature. The fitted kinetic parameters indicate that PTSD subjects have a strong negative feedback loop and, as a result, the predicted oscillating cortisol levels are extremely low at the nadir in contrast to normal subjects, albeit within the endocrinologic range. We also simulated the phenotypes for each of the categories and, as observed in the clinical data of PTSD patients, the simulated cortisol levels are consistently low at the nadir, and correspondingly the negative feedback was found to be extremely strong. These results from the model support the hypothesis that high stress intensity and strong negative feedback loop may cause hypersensitive neuro-endocrine axis that results in hypocortisolemia in PTSD.     

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.     

An animal model of eating disorders associated with stressful experience in early life

Experience of childhood abuse is prevalent among patients with eating disorders, and dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in its pathophysiology. Neonatal maternal separation is considered as an animal model of stressful experience early in life. Many of studies have demonstrated its impact both on the activity of HPA axis and the development of psycho-emotional disorders later in life. In this paper, a series of our researches on developing an animal model of eating disorders is reviewed. An animal model of neonatal maternal separation was used; Sprague-Dawley pups were separated from dam daily for 180 min during the first 2 weeks of life (MS) or undisturbed. Anxiety-/depression-like behaviors were observed in MS rats at the age of two months with decreased serotonergic activity in the hippocampus and the raphe. Post-weaning social isolation promoted food intake and weight gain of adolescent MS pups, with impacts on anxiety-like behaviors. Sustained hyperphagia was observed in the MS pups subjected to a fasting/refeeding cycle repeatedly during adolescence, with increased plasma corticosterone levels. Anhedonia, major symptom of depression, to palatable food was observed in adolescent MS pups with blunted response of the mesolimbic dopaminergic activity to stress. Results suggest that neonatal maternal separation lead to the development of eating disorders when it is challenged with social or metabolic stressors later in life, in which dysfunctions in the HPA axis and the brain monoaminergic systems may play important roles.     

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.     

Psychopathic personality traits and cortisol response to stress: The role of sex, type of stressor, and menstrual phase

Previous research indicates that psychopathic personality traits are associated with lower cortisol secretion in response to stress in men but not in women. The current study explored whether prior null results for women were related to the latency of the cortisol stress response to two different types of stressors. Additionally, accuracy of self-reported menstrual phase was explored via salivary progesterone levels. A mixed-sex sample of 145 participants characterized by high (36 men, 37 women) and low (34 men, 38 women) scores on a screening measure of psychopathic personality traits were randomly assigned to either a performance-based stressor task or a social rejection stressor task. Salivary hormone samples were taken just prior to task onset (baseline) and at 0, 20, 40, and 60 min post-stressor. Results indicated that both men and women characterized by psychopathic personality traits exhibited lower stress-induced cortisol levels to the performance-based task in comparison with controls at 20 min post-stressor. The social rejection task produced a cortisol response 20 min post-stressor in the male controls only. Removal of women with low progesterone from the analyses strengthened the psychopathy group differences. Results could suggest that deficient cortisol production in response to stress might be another important neurobiological feature associated with psychopathic traits, and that biological verification of menstrual phase is an important aspect to obtaining accurate cortisol results in women.     

Pre-experience of social exclusion suppresses cortisol response to psychosocial stress in women but not in men

Lack of social support and social exclusion is associated with adverse effects for mental and physical health. Additionally, women appear to be more vulnerable to social triggers of health disturbances. The hypothalamus–pituitary–adrenocortical-axis (HPA axis) might play a key role in this context as it has been shown both to relate to psychosocial conditions and health outcomes and to respond differentially depending on gender. In a previous experiment we found no effects of exclusion alone (operationalized via Cyberball) on cortisol secretion. Here we examine the effects of a social exclusion pre-experience on psychological and cortisol responses to a public speaking stressor. Subjects (33 m, 34 f) were randomly assigned to social exclusion (SE) or one of two control conditions (exclusion attributed to technical default (TD) and social inclusion (SI)). Afterwards salivary cortisol and psychological responses to a public speaking paradigm were assessed. Exclusion pre-treatment does not affect psychological responses to public speaking stress though with respect to cortisol significant. Cyberball by gender and Cyberball by gender by time interactions are found. SE-women show a blunted cortisol stress response to public speaking while cortisol responses of SE-men fall between SI-men and TD-men. Pre-experience of social exclusion leads to a blunted cortisol response to stress in women but not in men. This factor might contribute to the higher vulnerability to social triggers of health disturbances observed in women.     

Plasma cortisol responses to stress in lactating and nonlactating female rhesus macaques

Lactating female rats without their pups exhibit lower HPA responsiveness to stress than nonlactating females. However, responsiveness to stress is similar when lactating females are tested with their pups and the stressor involves a potential threat to the offspring. This study constitutes the first comparison of stress responsiveness in lactating and nonlactating female nonhuman primates. Subjects were 53 multiparous female free-ranging rhesus macaques. Approximately half of the females were lactating and half were nonpregnant/nonlactating. Blood samples were obtained after capture and after overnight housing in an individual cage. Lactating females were tested with their infants. Lactating females had significantly higher plasma cortisol levels than nonlactating females on both days. Having or not having an infant was also a better predictor of plasma cortisol levels among all females than their age, dominance rank, group of origin, time of day at which the sample was obtained, and time elapsed since beginning of the sampling procedure or since anesthesia. Plasma cortisol levels of lactating females were not significantly correlated with post-partum stage or with the cortisol levels of their infants. Capture, handling, and individual housing in a cage are powerful psychological stressors for free-ranging primates. We suggest that the higher plasma cortisol levels exhibited by lactating females reflect greater responsiveness to stress associated with perception of risks to infants. Hyporesponsiveness to stress may not be a general characteristic of lactation in all mammalian species, but a short-term effect of infant suckling that is most apparent with stressors unrelated to the offspring.     

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.     

The potential role of hypocortisolism in the pathophysiology of PTSD and psoriasis

Different physical, chemical and psychological stressors can provoke a unique but different endocrine response involving activation of the hypothalamo-pituitary-adrenal (HPA) axis. Inability of adequate compensatory reaction can lead to many disorders. The aim of our study was comparison of cortisol values in diseases provoked by various stressors. Our investigation included 34 posttraumatic stress disorder (PTSD) patients, as an example of disorder caused by extremely strong, acute stressful stimulus, 19 psoriatic patients, as an example of chronic stress stimulus and 17 healthy volunteers. In each patient we determined 24-hour urinary cortisol, serum cortisol at 8 a.m. and 5 p.m., and cortisol in dexamethasone suppression test by the standard radioimmunoassay (RIA) method. PTSD patients showed lower urinary 24-hour cortisol values, (361 +/- 28 nmol/24 h), "stronger" circadian rhythm of serum cortisol (595 +/- 57 nmol/l at 8 a.m. and 242 +/- 23 nmol/l at 5 p.m.) and attenuated suppression of cortisol in dexamethasone suppression test (197 +/- 45 nmol/l) in comparison to healthy volunteers (590 +/- 87 nmol/24 h urine, 590 +/- 32 nmol/l at 8 a.m., 402 +/- 31 nmol/l, and < 86 nmol/l in dexa test). Psoriatic patients showed markedly lower 24-hour cortisol values (150 +/- 98 nmol/24 h), even in comparison to PTSD patients, then serum cortisol values (404 +/- 138 nmol/l at 8 a.m., 187 +/- 80 nmol/l at 5 p.m.) and enhanced suppression of cortisol (23 +/- 5 nmol/l). The model of attenuated feedback inhibition in PTSD patients shows that they are unusually reactive to stress and represents an alternative model of acute stress reaction to extremely strong stressful stimulus. Unusually low cortisol values in psoriatic patients correlate to our hypothesis that in chronic stress-related disease, as psoriasis is, exists, by still undefined mechanism, altered HPA axis function, which is obviously incompetent to realise its immunoregulatory function, so consequentially, clinical signs of psoriasis persist.     

Evaluation of physiological stress in free-ranging bears: current knowledge and future directions

Stress responses, which are mediated by the neurogenic system (NS) and hypothalamic–pituitary–adrenal (HPA) axis help vertebrates maintain physiological homeostasis. Fight-or-flight responses are activated by the NS, which releases norepinephrine/noradrenaline and epinephrine/adrenaline in response to immediate stressors, whilst the HPA axis releases glucocorticoid hormones (e.g. cortisol and corticosterone) to help mitigate allostatic load. There have been many studies on stress responses of captive animals, but they are not truly reflective of typical ranges or the types of stressors encountered by free-ranging wildlife, such as responses and adaptation to environmental change, which are particularly important from a conservation perspective. As stress can influence the composition of age and sex classes of free-ranging populations both directly and indirectly, ecological research must be prioritised towards more vulnerable taxa. Generally, large predators tend to be particularly at risk of anthropogenically driven population declines because they exhibit reduced behavioural plasticity required to adapt to changing landscapes and exist in reduced geographic ranges, have small population sizes, low fecundity rates, large spatial requirements and occupy high trophic positions. As a keystone species with a long history of coexistence with humans in highly anthropogenic landscapes, there has been growing concern about how humans influence bear behaviour and physiology, via numerous short- and long-term stressors. In this review, we synthesise research on the stress response in free-ranging bear populations and evaluate the effectiveness and limitations of current methodology in measuring stress in bears to identify the most effective metrics for future research. Particularly, we integrate research that utilised haematological variables, cardiac monitors and Global Positioning System (GPS) collars, serum/plasma and faecal glucocorticoid concentrations, hair cortisol levels, and morphological metrics (primarily skulls) to investigate the stress response in ursids in both short- and long-term contexts. We found that in free-ranging bears, food availability and consumption have the greatest influence on individual stress, with mixed responses to anthropogenic influences. Effects of sex and age on stress are also mixed, likely attributable to inconsistent methods. We recommend that methodology across all stress indicators used in free-ranging bears should be standardised to improve interpretation of results and that a wider range of species should be incorporated in future studies.     

Differences in Salivary Alpha-Amylase and Cortisol Responsiveness following Exposure to Electrical Stimulation versus the Trier Social Stress Tests

Background

Cortisol is an essential hormone in the regulation of the stress response along the HPA axis, and salivary cortisol has been used as a measure of free circulating cortisol levels. Recently, salivary alpha-amylase (sAA) has also emerged as a novel biomarker for psychosocial stress responsiveness within the sympathetic adrenomedullary (SAM) system.

Principal Findings

We measured sAA and salivary cortisol in healthy volunteers after exposure to the Trier Social Stress Test (TSST) and electric stimulation stress. One hundred forty-nine healthy volunteers participated in this study. All subjects were exposed to both the TSST and electric stimulation stress on separate days. We measured sAA and salivary cortisol levels three times immediately before, immediately after, and 20 min after the stress challenge. The State (STAI-S) and Trait (STAI-T) versions of the Spielberger Anxiety Inventory test and the Profile of Mood State (POMS) tests were administered to participants before the electrical stimulation and TSST protocols. We also measured HF, LF and LF/HF Heart Rate Variability ratio immediately after electrical stimulation and TSST exposure. Following TSST exposure or electrical stimulation, sAA levels displayed a rapid increase and recovery, returning to baseline levels 20 min after the stress challenge. Salivary cortisol responses showed a delayed increase, which remained significantly elevated from baseline levels 20 min after the stress challenge. Analyses revealed no differences between men and women with regard to their sAA response to the challenges (TSST or electric stimulations), while we found significantly higher salivary cortisol responses to the TSST in females. We also found that younger subjects tended to display higher sAA activity. Salivary cortisol levels were significantly correlated with the strength of the applied electrical stimulation.

Conclusions

These preliminary results suggest that the HPA axis (but not the SAM system) may show differential response patterns to distinct kinds of stressors.     

Perceived stress, common health complaints and diurnal patterns of cortisol secretion in young, otherwise healthy individuals

Research has frequently linked perceived stress with changes in subjective and objective measures of ill health; however, additional assessment should consider the physiological mechanisms mediating these effects. This study investigated whether differential patterns of cortisol secretion might partially mediate perceived stress related disparities in common health complaints in young, otherwise healthy individuals. To capture the kinds of health complaints commonly reported in this population, the Pennebaker Inventory of Limbic Languidness (PILL) was selected. To capture important parameters of the diurnal profile, cortisol was sampled at waking, 30 minutes post waking, 1200 h and 2200 h on three consecutive weekdays. Results revealed flatter diurnal cortisol slopes and elevated mean diurnal output (characterised by HPA hyperactivity in the evening) for participants in the higher stress group. Participants that reported higher perceived levels of stress also reported experiencing common health complaints with markedly greater frequency; however, these disparities were abolished when mean diurnal output of cortisol was statistically controlled. While dysregulation of basal HPA activity has been implicated in the aetiologies of chronic illness, findings reported here implicated hypersecretion of cortisol as one physiological pathway, partially mediating perceived stress related disparities in the kinds of common health complaints that typically affect young, otherwise healthy individuals.     

Serotonin transporter gene variation, infant abuse, and responsiveness to stress in rhesus macaque mothers and infants

A functional polymorphism in the promoter region of the serotonin transporter (5-HTTLPR) gene has been associated with variation in anxiety and hypothalamus-pituitary-adrenal (HPA) axis function in humans and rhesus macaques. Individuals carrying the short allele are at a higher risk for developmental psychopathology, and this risk is magnified in short allele carriers who have experienced early life stress. This study investigated the relationship between 5-HTTLPR allelic variation, infant abuse, and behavioral and hormonal responses to stress in rhesus macaques. Subjects were 10 abusive mothers and their infants, and 10 nonabusive mother-infant pairs. Mothers and infants were genotyped for the rh5-HTTLPR, and studied in the first 6 months of infant life. For mothers and infants, we measured social group behavior, behavioral responses to handling procedures, and plasma concentrations of ACTH and cortisol under basal conditions and in response to stress tests. The proportion of individuals carrying the short rh5-HTTLPR allele was significantly higher among abusive mothers than controls. Among mothers and infants, the short allele was associated with higher basal cortisol levels and greater hormonal stress responses in the infants. In addition, infants who carried the short rh5-HTTLPR allele had higher anxiety scores than infants homozygous for the long allele. The rh5-HTTLPR genotype also interacted with early adverse experience to impact HPA axis function in the infants. These results are consistent with those of previous studies which demonstrate associations between serotonergic activity and anxiety and stress reactivity, and add additional evidence suggesting that genetic variation in serotonergic function may contribute to the occurrence of abusive parenting in rhesus macaques and modulate emotional behavior and HPA axis function.     

Ethnic differences in adrenocorticotropic hormone, cortisol and corticotropin-releasing hormone during pregnancy

Significant ethnic disparities exist in reproductive outcomes. A potential contributing factor may be the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and placenta during pregnancy. In the present study, levels of cortisol, ACTH and CRH were determined longitudinally from the plasma of 310 African American, Hispanic and non-Hispanic White women at 18-20, 24-26 and 30-32 weeks' gestation. During pregnancy, African American women exhibited lower levels of cortisol than non-Hispanic women and higher levels of ACTH than Hispanic women. The trajectory of CRH increase also differed by ethnicity, with African Americans exhibiting the lowest levels both early and late in pregnancy. Higher levels of cortisol at 18-20 weeks were associated with higher levels of CRH at 30-32 weeks among the African American and Hispanic women, but not among non-Hispanic women. Ethnic differences persisted when adjusting statistically for sociodemographic and biomedical factors. The findings are consistent with the possibility that ethnic disparities in adverse birth outcomes may be due, in part, to differences in HPA axis and placental function.     

Sex difference in the relationship between the hypothalamic-pituitary-adrenal axis and sex hormones in obesity

Objective: This study was carried out to investigate the role of sex in the regulation of the hypothalamic‐pituitary‐adrenal (HPA) axis and its relationship with testosterone levels in male and female obesity. Research Methods and Procedures: Twenty‐two obese men (OB‐M) and 29 obese women (OB‐W) participated in the study. Two groups of normal weight men (NW‐M) and women (NW‐W), respectively, served as controls. In basal conditions, blood concentrations of major androgens, sex hormone—binding protein, and gonadotropins were assessed, and the free androgen index (testosterone ×100/ sex hormone‐binding globulin) was calculated. All subjects underwent a combined corticotropin‐releasing hormone plus arginine‐vasopressin stimulation test. Results: OB‐M and NW‐M had higher basal adrenal cortical tropic hormone (ACTH) and cortisol levels than their female counterparts. In addition, ACTH, but not cortisol basal, levels were significantly higher in obese than in normal weight controls in both sexes. OB‐W had a higher response than OB‐M to the combined corticotropin‐releasing hormone plus arginine‐vasopressin test of both ACTH and cortisol [expressed as incremental percentage of area under the curve (AUC%)]. The same finding was present between NW‐W and NW‐M. Basal luteinizing hormone levels were negatively correlated to ACTH_AUC% in both OB‐W and OB‐M. In the OB‐W, however, a positive correlation was found between cortisol_AUC% and testosterone (r = 0.48; p = 0.002), whereas a tendency toward a negative correlation was present in OB‐M. Discussion: In conclusion, we have shown a significant positive relationship between the activity of the HPA axis and testosterone in obese women, which suggests a partial responsibility of increased HPA axis activity in determining testosterone levels. In addition, it clearly seems that, as reported in normal weight subjects, a sex difference in the HPA axis activity still persists even in the presence of obesity.