Allopregnanolone serum concentrations and diurnal cortisol secretion in women with premenstrual dysphoric disorder

Most prior studies in patients with premenstrual dysphoric disorder (PMDD) indicate a blunted hypothalamus–pituitary–adrenal axis function. However, the relationship between neuroactive progesterone metabolites, such as allopregnanolone, and hypothalamus–pituitary–adrenal (HPA) axis function in PMDD patients is relatively sparsely studied. The primary aims of this study were to assess diurnal variation in circulating cortisol and low-dose dexamethasone suppression in PMDD patients and healthy controls, and the relationship between these two HPA axis indices and allopregnanolone serum concentrations. Twenty-six women with prospectively defined PMDD and 30 healthy controls were recruited. Participants underwent diurnal sampling for cortisol serum concentrations and a low-dose dexamethasone suppression test. In addition, morning allopregnanolone serum concentrations were determined. There was no difference in diurnal secretion of cortisol and degree of dexamethasone suppression of cortisol between PMDD patients and healthy controls. However, PMDD patients with high allopregnanolone levels displayed blunted nocturnal cortisol levels in comparison with healthy controls who had low allopregnanolone serum concentrations. In women with PMDD, diurnal secretion of cortisol may be influenced by allopregnanolone levels of the luteal phase. This finding may be attributed to timing of blood sampling in the late luteal phase as well as the individual level of allopregnanolone but could potentially explain the discrepancies in results between studies examining HPA axis function in women with PMDD.     

Morning cortisol Levels in preschool-aged foster children: differential effects of maltreatment type

Maltreated foster children are subjected to a range of early adverse experiences, including neglect, abuse, and multiple caregiver disruptions. Research suggests that such disturbances alter the development and subsequent functioning of the hypothalamic-pituitary-adrenocortical system. The current study was designed to investigate morning cortisol levels in 117 foster children and 60 low-income, nonmaltreated children. Maltreatment and foster care placement experiences were coded from official records. Analyses revealed that the foster children were significantly more likely than the nonmaltreated children to have low morning cortisol levels. Additionally, specific maltreatment experiences were significantly associated with the foster children's morning cortisol levels. Foster children with low morning cortisol levels experienced more severe physical neglect than the other foster children. In contrast, foster children with high morning cortisol levels experienced more severe emotional maltreatment. These results suggest that specific early adverse experiences have differential effects on the functioning of the hypothalamic-pituitary-adrenocortical system.     

Blunted HPA axis response to stress is related to a persistent Dysregulation Profile in youth

The Child Behavior Checklist Dysregulation Profile (DP) in youth has been shown to be a predictor of psychopathology later in life. We examined the activity of the hypothalamic pituitary adrenal (HPA) axis in youth with remitted, new, persistent, and no DP. Data from 489 youth (47% boys) participating in a Dutch longitudinal general population study were included (Wave 1 mean age = 11.5, Wave 2 = 14.2). Wave 2 diurnal cortisol patterns and levels in response to a laboratory stress paradigm were compared in youth with DP at Wave 1 only, Wave 2 only, both Waves, and neither Wave. Youth with the DP at Wave 2 only or at both time points showed blunted cortisol responses to stress relative to the other two groups. There were no group or sex differences in diurnal cortisol activity. More research is needed to determine how the association between DP symptoms and HPA axis functioning changes over time.     

Early deprivation and home basal cortisol levels: a study of internationally adopted children

Animal studies reveal that early deprivation impairs regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis, potentially increasing vulnerability to stressors throughout life. To examine early deprivation effects on basal HPA axis activity in humans, basal cortisol levels were examined in 164 internationally adopted children who had experienced varying degrees of preadoption deprivation. Duration of institutional care, age at adoption, and parent ratings of preadoption neglect indexed a latent factor of Deprived Care. Adoption measures of height and weight standardized to World Health Organisation norms indexed a latent factor of Growth Delay that was viewed as another reflection of deprivation. Cortisol samples were collected 3.3-11.6 years postadoption (Md = 7.3 years) at home on 3 days approximately 30 min after wakeup and before bedtime. Both early a.m. levels and the decrease in cortisol across the day were examined. A structural equation model revealed that preadoption Deprived Care predicted Growth Delay at adoption and Growth Delay predicted higher morning cortisol levels and a larger diurnal cortisol decrease.     

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     

Chronic subcutaneous leptin infusion diminishes the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in female rhesus monkeys

The fat derived protein leptin has its anorexic action through a number of neuropeptides including an upregulation of corticotropin releasing hormone (CRH) expression in the hypothalamus. However, the influence of leptin on these neuropeptides may be different during stress. The present study used ovariectomized female rhesus monkeys (n=8) to further define the effect of leptin on HPA responsivity. To accomplish this, we assessed the effects of constant leptin infusion on cortisol and ACTH secretion in both a predictable and unpredictable situation as well as in response to dexamethasone suppression-CRH stimulation test. We hypothesized that leptin would attenuate the increase in cortisol and ACTH to a novel, unpredictable situation and would enhance glucocorticoid negative feedback and diminish the response to CRH. Animals were assessed under control placebo conditions and during a 28 day infusion with recombinant human leptin (6 microg/kg/day, SC). Within each treatment condition, HPA responsivity was assessed during no estradiol replacement and acute estradiol replacement that produced serum concentrations of approximately 40 pg/ml. However, the results indicated that neither estradiol alone or in combination with leptin had any consistent effect on the outcome measures. Compared to the control condition, leptin had no effect on the cortisol diurnal rhythm; however, evening but not morning plasma ACTH concentrations were significantly lower during leptin infusion. In contrast, the response in plasma cortisol and ACTH to an unpredictable situation was significantly attenuated by chronic leptin infusion. Furthermore, leptin enhanced glucocorticoid negative feedback and blunted CRH-induced increase in both cortisol and ACTH. Taken together, these data suggest that in the female monkey, leptin has little effect on basal cortisol. However, when the HPA axis is activated, leptin attenuates the neuroendocrine response by enhancing glucocorticoid negative feedback. These data underscore the potential importance of leptin in maintaining homeostasis through its diverse interaction with the HPA axis.     

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

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

Effects of an attachment-based intervention on the cortisol production of infants and toddlers in foster care

Studies with nonhuman primates and rodents, as well as with human children, have suggested that early separations from caregivers are often associated with changes in the functioning of the hypothalamus-pituitary-adrenal (HPA) axis. On the basis of these findings, we designed a relational intervention that was intended to normalize HPA functioning among children in foster care. This paper presents findings from a randomized clinical trial that assessed the effectiveness of a relational intervention (Attachment and Biobehavioral Catch-up [ABC]) with regard to HPA functioning. The ABC intervention was intended to enhance children's ability to regulate physiology and behavior. The control intervention (Developmental Education for Families) was intended to enhance children's cognitive skills. A comparison group of children who had never been in foster care was also included. Children's cortisol production was assessed upon arrival at the lab, and 15 and 30 min following the Strange Situation. Random effects analyses of variance were performed to assess differences in initial values and change between children in the two intervention groups. Children in the ABC intervention and comparison group children showed lower initial values of cortisol than children in the treatment control group, considering arrival at lab as initial values (p < .05). Groups did not differ significantly in change over time. These results suggest that the ABC intervention is effective in helping children regulate biology in ways more characteristic of children who have not experienced early adversity.     

Self- or parent report of (co-occurring) internalizing and externalizing problems,and basal or reactivity measures of HPA-axis functioning: A systematic evaluation of the internalizing-hyperresponsivity versus externalizing-hyporesponsivity HPA-axis hypothesis

Background

Previous research findings on the link between adolescents’ psychopathology and hypothalamic–pituitary–adrenal (HPA) axis activity have been heterogeneous.

Method

Adolescents (n = 211) with a preadolescent DSM-IV diagnosis participated in a lab-based social stress task. Saliva cortisol was assessed at awakening and during social stress. It was investigated if continuous measures of internalizing and externalizing problems and their interaction, using both self- and parent report, were associated with basal or reactivity measures of HPA-axis functioning

Results

During social stress, an enhanced total release of cortisol was associated with self-reported internalizing problems and a blunted total release of cortisol with self-reported externalizing problems. Post hoc analyses revealed that the association between enhanced cortisol output and internalizing problems held for boys but not for girls. Associations with morning cortisol measures were overall weak

Conclusions

Only in the context of stress, and particularly when based on self-report, blunted cortisol output was associated with externalizing and enhanced cortisol output with internalizing problems. Our broad approach demonstrates the importance of who reports on psychopathology, the use of dimensional measures of psychopathology, simultaneous analysis of internalizing and externalizing problems, and the use of awakening and social stress related measures of cortisol.     

Mental health outcomes of cocaine-exposed children at 6 years of age

OBJECTIVE: To assess 6-year-old cocaine- and noncocaine-exposed children's mental health outcomes controlling for potential confounders. METHODS: The sample consisted of 322 children [169 cocaine exposed (CE) and 153 noncocaine exposed (NCE)] enrolled in a longitudinal study since birth. At age 6, children were assessed for mental health symptoms using the Dominic Interactive (DI), a child self-report measure, and the Child Behavior Checklist (CBCL), a caregiver report of behavioral problems. RESULTS: CE children were more likely to self-report symptoms in the probable clinical range for oppositional defiant disorder (ODD) and attention deficit hyperactivity disorder (ADHD). In contrast, prenatal cocaine exposure was not related to child behavior based on the CBCL. After control for exposure, CE children in adoptive or foster care were rated as having more problems with aggression, externalizing behaviors, and total behavioral problems than NCE children and CE children in maternal or relative care. Also, CE children in adoptive or foster care self-reported more externalizing symptoms than CE children in maternal or relative care and NCE children. Findings could not be attributed to caregiver intelligence or depressive symptoms, or to the quality of the home environment. CONCLUSIONS: CE children report more symptoms of ODD and ADHD than nonexposed children. Adoptive or foster caregivers rated their CE children as having more behavioral problems than did maternal or relative caregivers of CE children or parents of NCE children. Although further studies are needed to understand the basis for the more negative ratings by adoptive or foster caregivers of their CE children, the self-report of CE children indicates a need for psychological interventions.     

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

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

The sound of stress: blunted cortisol reactivity to psychosocial stress in tinnitus sufferers

Clinical observations suggest that tinnitus is modulated by stress. However, there is little empirical data to support the link between stress and tinnitus. In this study, we measured the stress hormone cortisol to examine the reactivity of the hypothalamic-pituitary-adrenal (HPA) axis in tinnitus participants as well as in healthy controls without tinnitus. Eighteen participants with tinnitus and 18 controls without tinnitus were exposed to the Trier Social Stress Task and cortisol sampling and subjective ratings were obtained at regular intervals. Tinnitus participants displayed a blunted cortisol response to psychosocial stress, in comparison with healthy controls who had a typical cortisol release about 30 min after the beginning of the experiment. The blunted cortisol response displayed by the tinnitus participants suggests that they have an anomaly along the HPA axis. Their cortisol response is similar to that found in other bodily stress-related diseases and thus suggests that tinnitus is related to stress. However, tinnitus intensity might not be modulated by stress in a concurrent manner.     

Maternal attachment avoidance is linked to youth diurnal cortisol slopes in children with asthma

ABSTRACT

Prior evidence suggests that an individual’s attachment orientation is linked to the health and health-related biology of his/her romantic relationship partners. The current study examined whether this effect extends to parent–child relationships. Specifically, we investigated the association between maternal attachment anxiety and avoidance and diurnal cortisol of offspring. In a sample of 138 youth with asthma and their primary caregivers, caregivers reported their attachment orientations, and their children (aged 10–17) supplied four saliva samples per day over four days to assess diurnal cortisol patterns. Growth curve analyses revealed no links to caregiver attachment anxiety, but caregiver attachment avoidance was significantly associated with children’s diurnal cortisol slopes, such that greater attachment avoidance predicted flatter diurnal cortisol slopes. Maternal warmth did not mediate this link. These results support the possibility that an individual’s adult attachment orientation may “get under the skin” of family members to influence their health-related biology. Future research should seek to determine the causal direction of this association and mechanisms of this effect.     

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.     

Normalizing the development of cortisol regulation in maltreated infants through preventive interventions

Longitudinal effects of child maltreatment on cortisol regulation in infants from age 1 to 3 years were investigated in the context of a randomized preventive intervention trial. Thirteen-month-old infants from maltreating families (N = 91) and their mothers were randomly assigned to one of three intervention conditions: child-parent psychotherapy, psychoeducational parenting intervention, and a control group involving standard community services (CS). A fourth group of infants from nonmaltreating families (N = 52) and their mothers comprised a nonmaltreated comparison (NC) group. The two active interventions were combined into one maltreated intervention (MI) group for statistical analyses. Saliva samples were obtained from children at 10:00 a.m. before beginning a laboratory observation session with their mothers when the children were 13 months of age (preintervention), 19 months (midintervention), 26 months (postintervention), and 38 months (1-year postintervention follow-up). At the initial assessment, no significant differences among groups in morning cortisol were observed. Latent growth curve analyses examined trajectories of cortisol regulation over time. Beginning at midintervention, divergence was found among the groups. Whereas the MI group remained indistinguishable from the NC group across time, the CS group progressively evinced lower levels of morning cortisol, statistically differing from the MI and NC groups. Results highlight the value of psychosocial interventions for early child maltreatment in normalizing biological regulatory processes.     

Adrenocortical activity in at-risk and normally developing adolescents: individual differences in salivary cortisol basal levels, diurnal variation, and responses to social challenges

The purpose of this study was to examine adrenocortical activity (basal, diurnal variation, and responses to social stressors) in adolescents at risk for psychopathology. Salivary cortisol levels were examined in normally developing and at-risk youth with internalizing and externalizing symptoms ranging from subclinical to clinical levels. Adolescents showed expected patterns of diurnal variation, with high early morning cortisol levels and a pattern of decline throughout the day. Females showed higher midday and late afternoon levels than males, and these patterns interacted with risk status. Internalizing problems sometimes were associated with gradual rather than steep declines in basal cortisol production. Both immediate and delayed cortisol reactivity to a social performance stressor were associated with internalizing symptoms. There was no evidence of relations between externalizing problems and underarousal of the hypothalamic-pituitary-adrenal (HPA) system. These and other results suggest that gender is an important moderating factor linking psychopathology. development, and context with HPA axis functioning in adolescence.     

The effect of confinement during lactation on the hypothalamic-pituitary-adrenal axis and behaviour of primiparous sows

Commercial sows are typically confined in crates before and during parturition and remain there throughout lactation. In various animal species including non-lactating pigs, confinement over similar periods leads to adaptive changes in the HPA axis, consistent with chronic stress. To investigate evidence for chronic stress in lactating sows, primiparous sows (gilts) were kept in behaviourally confining crates with straw bedding (CS, n = 8) or without bedding (C, n = 8) or in larger strawed pens (PS, n = 16) between 5 days before parturition until 29 days postpartum (piglets were weaned on day 28). Behavioural and physiological recordings (Plasma ACTH and cortisol) were taken at intervals (baseline), and CRH injections were given on five occasions (days 2, 8, 15, 22 and 29 postpartum). The PS gilts spent more time in substrate-directed behaviour and lying ventrally, and less time lying laterally and sitting than the two crated treatments (C and CS) throughout lactation. Baseline plasma ACTH and cortisol levels showed no treatment differences, although we confirmed that a diurnal pattern exists, with morning (1000 h) cortisol being higher than later in the day. CRH challenge tests suggested changes in the HPA axis, consistent with chronic stress, by the end of the lactation period. Cortisol response to CRH tended to be higher in CS than PS across all days, and by day 29 cortisol response to CRH was significantly higher in CS compared to PS and tended to be higher in C than PS. Cortisol/ACTH ratio following CRH challenge also tended to be higher in the crate treatments (C and CS) by day 29. These data suggest that prolonged confinement in farrowing crates may have a negative impact on sow welfare.     

Hypothalamic-pituitary-adrenal reactivity in boys with attention deficit hyperactivity disorder

The hypothesis 'whether subjects with attention-deficit/ hyperactivity disorder (ADHD), who showed under-reactivity of the hypothalamic-pituitary-adrenal (HPA) axis to stress, would make more commission errors in attention tasks', was examined. Forty-three boys, with ADHD, who visited the psychiatric outpatient clinic, at Kangbuk Samsung Hospital, were the subjects of this study. Both pre- and post-test morning saliva samples were collected from the patients at the Korean Educational Development Institute-Wechsler Intelligence Scale for Children (KEDI-WISC), and Tests of Variables of Attention (T.O.V.A.) performed. The Standard scores of the T.O.V.A were compared between the patients with decreases, or increases, in the salivary cortisol levels after the test. Decreases, or increases in the salivary cortisol levels after the test were shown in 28 and 15 patients, respectively. The patients with decreased cortisol levels after the test tended to make more commission errors in compared with those with increased cortisol levels. The patients with the decreased cortisol levels after test had more omission errors in the first quarter of the test, and more commission errors in the second half of the test compared to those with the increased cotisol levels. Subjects who show decreased salivary cortisol levels after stress make more commission errors in attention tests. This suggests that the blunted HPA axis response to stress is related to the impulsivity in patients with ADHD.     

Stress responsivity in children with externalizing behavior disorders

Patterns of lower autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis activity have been found in children with oppositional defiant disorder (ODD). The aim of the present study was to investigate whether children with attention-deficit/hyperactivity disorder (ADHD) differ from ODD children with (OD/AD) or without comorbid ADHD in ANS and HPA axis activity under baseline and stressful conditions. The effects of stress on cortisol, heart rate (HR), and skin conductance level (SCL) were studied in 95 children (26 normal control [NC] children and 69 child psychiatric patients referred for externalizing behavior problems [15 ODD, 31 OD/AD, and 23 ADHD]). No baseline differences were found in cortisol between the four groups. However, the ODD and OD/AD groups showed a significantly weaker cortisol response to stress compared to the ADHD and NC groups; the ADHD group had a similar cortisol response as the NC group. Within the ODD group this pattern of low cortisol responsivity was most clearly present in the more severely affected inpatients. With respect to HR, the ODD group had a significantly lower HR during baseline and stressful conditions. The higher HR levels in the OD/AD and ADHD groups were likely to be caused by methylphenidate. The externalizing groups had significantly lower SCL levels, and no differences were found between these groups. It was concluded that differences in cortisol responsivity during stress exposure are important in distinguishing within a group of children with externalizing behavior between those with ODD and ADHD.