Chronic Hypothalamic-pituitary-adrenal Axis Activity Research Articles

Abstract 12407: Hypothalamic-Pituitary Adrenal Axis Activation in Women With Takotsubo Syndrome

Introduction. Takotsubo Syndrome (TS) has been associated with acute stress exposure and excessive activation of the adrenergic nervous system. Less is known about the role of chronic stress and of the hypothalamic-pituitary-adrenal (HPA) axis in the pathophysiology of TS. Hair cortisol concentration (HCC) is a novel biomarker of chronic stress and HPA axis activation. Plasma cortisol is incorporated in growing hair (average growth rate = 1 cm/month), reflecting HPA axis activity over the preceding months. In this study we measured HCC in TS patients and explored associations between HCC, trigger status, and psychological characteristics at enrollment. Methods. HCC was measured in a group of patients admitted with a new TS diagnosis based on Mayo Clinic criteria (n=18). Demographics, perceived stress, depression, anxiety, PTSD symptoms, coping skills, and resilience (self-report questionnaires); trigger history (standardized in-person interview); and HCC were collected at the baseline visit. Hair strands were cut near the scalp from a posterior vertex position. HCC was measured in the first 3 cm of hair, which reflects plasma cortisol levels during the previous 3 months. Samples were washed, ground, extracted in HPLC-grade methanol, and quantified (pg/mg) using a high-sensitivity enzyme immunoassay (EIA) kit. Descriptive statistics were used to characterize the sample, and Spearman rho to examine associations. A p value (2-sided) < .05 was considered significant. Results. Participants were 65.6 (SD 9.4) years old, 100% female, 100% white, 10% Hispanic. 52% married/living as married. Median HCC was 6.35 pg/mg (IQR 3.6, 15.2). HCC was significantly higher in patients reporting no triggers vs. those reporting a trigger prior to the TS episode (14.9 vs. 6.8 pg/ml, p=0.03). No associations were found between psychological measures and HCC, except for a non-significant inverse association between HCC and PTSD symptoms (rho=-0.35; p=0.14). Conclusions. This first exploration of HCC levels in patients with a recent TS episode suggests that chronic HPA axis activation likely does not play a role in the pathophysiology of TS. Findings need to be confirmed in a controlled study with a larger and more diverse sample.

Chronic HPA activity in mothers with preterm delivery: A pilot nested case-control study.

Chronic hypothalamic-pituitary-adrenal (HPA) axis activity role in the pathogenesis of preterm birth (PTB) remains unclear due to inconsistent measures with limited ability to monitor long-term cortisol concentrations. We explored this relationship using the novel method of assessing cortisol in hair, which is a valid and reliable measure of chronic HPA axis activity. 137 participants (40 PTB cases and 97 controls from a birth cohort of pregnant women in Peru) were interviewed and invited to provide a 9-cm hair sample from the posterior vertex position of the scalp (mean = 13 weeks gestation). Hair cortisol concentration (HCC) was determined using luminescence immunoassay and values were natural-log transformed. PTB cases were defined as women who delivered before 37 gestational weeks. Case-control differences were assessed using multivariable linear and logistic regressions. Overall, combined pre-conception and first-trimester HCC was 13% lower among cases as compared with controls (p-value = 0.01). Compared with controls, maternal HCC among PTB cases were 14% (p = 0.11), 10% (p = 0.22) and 14% (p = 0.08) lower for 3-6 months pre-conception, 0-3 months pre-conception, and first trimester, respectively. After adjusting for putative confounders, a 1-unit increase in HCC was associated with 55% reduced odds of PTB (aOR = 0.45; 95% CI: 0.17-1.17). For a 1-unit increase in HCC in the scalp-intermediate and scalp-distal segments (representing HCC concentrations in 0-3 months pre-conception and first trimester), the corresponding odds for PTB were 0.53 (95% CI: 0.19-1.48) and 0.39 (95% CI: 0.13-1.13), respectively. Women who deliver preterm, as compared with those who deliver at term, have lower preconception and first trimester HCC. Our findings suggest that HPA axis activation, integral to the adaptive stress-response system, may be chronically dysregulated in women at increased risk of PTB.

Sex-dependent effects of paternal deprivation and chronic variable stress on novel object recognition in adult California mice (Peromyscus californicus)

Early-life stress exposure can confer vulnerability for development of psychiatric illnesses and impaired cognition in adulthood. It is well-known that early-life stress can dysregulate the hypothalamic-pituitary-adrenal (HPA) axis in a sex-dependent manner. Specifically, uniparental rodent models of prolonged disrupted mother-offspring relationships (e.g., maternal separation) have demonstrated greater alterations in stress responsivity in adult males, compared to females. Also, chronic early-life stressors (e.g., limited bedding model) impair cognitive function in males more than females. However, the sex-dependent effects of early-life stress and later-life chronic HPA axis activation on cognition have not been well-characterized. Here, we utilized the biparental California mouse (Peromyscus californicus) to model the early-life adversity of paternal deprivation (PD). Fathers either remained in the nest (biparental care) or were permanently removed (PD) on postnatal day (PND) 1. Adult offspring were exposed to daily handling (control) or chronic variable stress (CVS; three stressors for seven days). Twenty-four hours after the final stressor, the novel object recognition (NOR) task commenced, followed by serum collection for corticosterone (CORT) analysis. Independent of sex or rearing, CVS increased CORT. Exploration during acquisition for the NOR task was increased as a result of CVS and PD. During NOR testing, non-stressed females exhibited greater difference scores (i.e., increased recognition memory), compared to non-stressed males. However, the addition of CVS diminished difference scores in females – an effect not observed in CVS-exposed males. Overall, these data suggest that neonatal paternal experience, sex, and chronic stress contribute to exploratory behavior, cognition, and stress hormone concentrations in a biparental species.

Hair cortisol concentrations as an indicator of potential HPA axis hyperactivation in risk for psychosis

A chronic hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is assumed to be an important indicator of vulnerability for psychosis. Despite the considerable research on this topic, putative social origins of HPA axis hyperactivation have received little attention in the literature so far. Also, the inconsistency of previous findings calls for new and reliable methods in the assessment of HPA axis activation. To address these issues, we used hair cortisol concentrations as an indicator of chronic HPA axis activation in participants at elevated risk for psychosis (clinical risk: n = 43, familial risk: n = 32) and low-risk controls (n = 35), and assessed its relation with a variety of social stressors. We also tested the interaction effect between social stressors and familial risk status on hair cortisol concentrations (moderation analysis). Participants at elevated risk for psychosis did not show significantly higher hair cortisol concentrations than low-risk controls. However, severe social stressors (child abuse experiences, traumatic events) predicted hair cortisol concentrations in the total sample. This relationship was not significantly moderated by familial risk status (as a marker of genetic risk). The results challenge the assumption that HPA axis hyperactivation is an early vulnerability indicator for psychosis but leave the possibility that it manifests only at more severe risk stages. Furthermore, the findings suggest that acquired experiences contribute to the emergence of HPA axis hyperactivation, which might occur via a gene-environment correlation rather than via a gene-environment interaction.

Alterations of hair cortisol and dehydroepiandrosterone in mother-infant-dyads with maternal childhood maltreatment

BackgroundChild maltreatment (CM) has severe effects on psychological and physical health. The hypothalamic-pituitary-adrenal (HPA) axis, the major stress system of the body, is dysregulated after CM. The analysis of cortisol and dehydroepiandrosterone (DHEA) in scalp hair presents a new and promising methodological approach to assess chronic HPA axis activity. This study investigated the effects of CM on HPA axis activity in the last trimester of pregnancy by measuring the two important signaling molecules, cortisol and DHEA in hair, shortly after parturition. In addition, we explored potential effects of maternal CM on her offspring’s endocrine milieu during pregnancy by measuring cortisol and DHEA in newborns’ hair.MethodsCM was assessed with the Childhood Trauma Questionnaire (CTQ). Cortisol and DHEA were measured in hair samples of 94 mothers and 30 newborns, collected within six days after delivery. Associations of maternal CM on her own and her newborn’s cortisol as well as DHEA concentrations in hair were analyzed with heteroscedastic regression models.ResultsHigher CM was associated with significantly higher DHEA levels, but not cortisol concentrations in maternal hair. Moreover, maternal CM was positively, but only as a non-significant trend, associated with higher DHEA levels in the newborns’ hair.ConclusionsResults suggest that the steroid milieu of the mother, at least on the level of DHEA, is altered after CM, possibly leading to non-genomic transgenerational effects on the developing fetus in utero. Indeed, we observed on an explorative level first hints that the endocrine milieu for the developing child might be altered in CM mothers. These results need extension and replication in future studies. The measurement of hair steroids in mothers and their newborns is promising, but more research is needed to better understand the effects of a maternal history of CM on the developing fetus.

Associations between early life experience, chronic HPA axis activity, and adult social rank in rhesus monkeys

ABSTRACTEarly life experience and socioeconomic status (SES) are well-established predictors of health outcomes in people. Both factors likely influence health outcomes via hypothalamic-pituitary-adrenal (HPA) axis regulation. However, it is unclear how early experience and HPA axis activity influence adult social status. We studied differentially reared female rhesus monkeys (Macaca mulatta, N = 90) as models to test the hypothesis that chronic HPA axis activity assessed via hair cortisol concentrations (HCCs) mediated the relationship between early life experience and adult social rank. We found that mother-peer-reared (MPR) monkeys acquired higher social ranks than either of the two nursery-reared (NR) groups (peer-reared, PR, or surrogate-peer-reared, SPR monkeys) (β = −0.07, t(89) = −2.16, p = 0.034). We also found that MPR HCCs were lower during the juvenile period at 18 months (F(2,25) = 3.49, p = 0.047). Furthermore, for MPR but not NR monkeys, changes in HCCs from 18 to 24 months (r(s) = −0.627, p = 0.039) and adult HCCs (r(s) = −0.321, p = 0.03) were negatively correlated with adult social rank. These findings suggest that chronic HPA axis regulation in juvenility, and perhaps in adulthood, may influence adult social status for primates that experience typical early rearing. However, early life adversity may result in dissociation between neuroendocrine stress regulation and adult social competence, which may be risk factors for adverse health outcomes.

Responses to the Human Intruder Test are related to hair cortisol phenotype and sex in rhesus macaques (Macaca mulatta).

Measurement of cortisol in hair provides a chronic index of hypothalamic-pituitary-adrenal (HPA) axis activity and has been applied to assessments of temperament (stable behavioral differences between individuals). However, the extent to which chronically high HPA axis activity relates to a correspondingly high degree of behavioral reactivity is as yet unknown. Therefore, the goal of the present experiment was to assess the relationship between hair cortisol and a reactive temperament. We administered the Human Intruder Test (HIT) twice to 145 (80 male) rhesus macaques (Macaca mulatta) in order to assess behavioral reactivity. The HIT presents monkeys with an unfamiliar experimenter and is composed of a Baseline phase (no intruder) followed by three experimental phases in which the orientation of the intruder changes (Profile, Stare, Back). Behavioral responses to the test were videotaped and behaviors thought to reflect a reactive response to the intruder were scored for duration. Hair samples collected within ±1 month of the first HIT session were analyzed for cortisol by enzyme immunoassay. Subjects were assigned to three groups based on hair cortisol concentration: high, intermediate, and low cortisol phenotypes. Monkeys with the high cortisol phenotype were more reactive to the presence of the intruder than those with the low cortisol phenotype: they were more aggressive, scratched more, and spent more time in the back half of the cage. Males yawned significantly more while females spent more time immobile and in the back of the cage. Overall, monkeys with higher hair cortisol demonstrated an exaggerated response to the presence of the human intruder, supporting a relationship between high levels of chronic HPA axis activity and a reactive temperament. These results indicate that high levels of HPA axis activity, which may result from either genetic variation or environmental stress, correspond with heightened behavioral responses to a stressful experience. Am. J. Primatol. 79:e22526, 2017. © 2016 Wiley Periodicals, Inc.

Population density-dependent hair cortisol concentrations in rhesus monkeys (Macaca mulatta)

Population density is known to influence acute measures of hypothalamic-pituitary-adrenal (HPA) axis activity in a variety of species, including fish, deer, birds, and humans. However, the effects of population density on levels of chronic stress are unknown. Given the fact that exposure to chronically elevated levels of circulating glucocorticoids results in a host of health disparities in animals and humans alike, it is important to understand how population density may impact chronic stress. We assessed hair cortisol concentrations (HCCs), which are reliable indicators of chronic HPA axis activity, in rhesus monkeys (Macaca mulatta) to determine the influence of population density on these values. In Experiment 1, we compared HCCs of monkeys living in high-density (HD; 1 monkey/0.87m(2)) and low-density (LD; 1 monkey/63.37m(2)) environments (N=236 hair samples) and found that HD monkeys exhibited higher hair cortisol across all age categories (infant, juvenile, young adult, adult, and aged) except infancy and aged (F(5)=4.240, p=0.001), for which differences were nearly significant. HD monkeys also received more severe fight wounds than LD monkeys (χ(2)=26.053, p<0.001), though no effects of dominance status emerged. In Experiment 2, we examined how HCCs change with fluctuating population levels across 5 years in the adult LD monkeys (N=155 hair samples) and found that increased population density was significantly positively correlated with HCCs in this semi-naturalistic population (r(s)=0.975, p=0.005). These are the first findings to demonstrate that increased population density is associated with increased chronic, endogenous glucocorticoid exposure in a nonhuman primate species. We discuss the implications of these findings with respect to laboratory research, population ecology, and human epidemiology.

What are the links between maternal social status, hippocampal function, and HPA axis function in children?

The association of parental social status with multiple health and achievement indicators in adulthood has driven researchers to attempt to identify mechanisms by which social experience in childhood could shift developmental trajectories. Some accounts for observed linkages between parental social status in childhood and health have hypothesized that early stress exposure could result in chronic disruptions in hypothalamic-pituitary-adrenal (HPA) axis activation, and that this activation could lead to long-term changes. A robust literature in adult animals has demonstrated that chronic HPA axis activation leads to changes in hippocampal structure and function. In the current study, consistent with studies in animals, we observe an association between both maternal self-rated social status and hippocampal activation in children and between maternal self-rated social status and salivary cortisol in children.

1526 – Attenuation of the hypothalamic-pituitary-adrenal axis as a consequence of childhood adversity - a possible mechanism of sex-specific vulnerability for psychiatric disorders in adolescence?

Introduction Alterations of the Hypothalamic-Pituitary-Adrenal Axis (HPAA) may be related to the development of psychiatric disorders, especially in the context of childhood adversity. The “attenuation hypothesis” postulates that chronic childhood adversity leads to initial hyperactivation of the HPAA, which subsequently may turn into hypoactivation during adolescence, and support the development of emotional and behavioural problems. However, studies investigating this hypothesis during the course of adolescence are rare. Methods The sample comprised 49 adolescents (f/m 19/30), subsampled from a larger longitudinal study on adolescent development. Assessments were performed at three points in time (T1-T3). Pituitary Gland Volume (PGV) as an estimate of chronic HPAA activity was measured by MRI at T1 (mean age 12.5) and T3 (mean age 16.5). HPAA functioning was assessed via multiple salivary cortisol measures at T2 (mean age 15.5). The Cortisol Awakening Response (CAR) was calculated as a measure of HPAA activity. Additionally, childhood adversity was assessed at T2 using the Childhood Trauma Questionnaire (CTQ). Results There was a significant sex-specific association of PGV at T1 and HPAA activity at T2. While PGV was positively predicting HPAA activity in boys, girls showed a reverse pattern (attenuation of the HPAA). A blunted CAR in girls was significantly related to their report of childhood adversity. Conclusions The results show that girls may have a higher tendency of attenuation of the HPAA in the context of childhood adversity and initial hyperactivation of the HPAA. This may contribute to their higher risk for diverse psychiatric disorders during adolescence.

Dysregulation of the Th1/Th2 cytokine profile is associated with immunosuppression induced by hypothalamic-pituitary-adrenal axis activation in mice

Hypothalamic-pituitary-adrenal (HPA) axis activation-induced immunosuppression is associated with increased concentration of circulating corticosterone and impaired cellular immune responses. The purpose of this study was to investigate the effect of chronic HPA axis activation on the cellular immune response, Th1/Th2 cytokine profile, and concentration of corticosterone. Mice were divided into two groups: a control group comprised of healthy, untreated mice that received no stress, and an HPA axis-activated group that received stress through electric shock (ES). The delayed-type hypersensitivity reaction to dinitrofluorobenzene, splenocyte proliferative response to mitogens Concanavalin A and lipopolysaccharide, Th1 and Th2 profile, and TGF-β1 production were measured in plasma and in culture supernatants. The corticosterone concentration was also measured in plasma. In the ES group, elevated plasma corticosterone concentration was associated with immunosuppression and a significant decrease in plasma concentrations of IL-2, IL-4, and TGF-β1. In vitro IL-2 production in response to Con A was significantly lower in the ES group than in the control group. TGF-β1 production in nonstimulated and stimulated cultures in response to either mitogen was significantly lower in the ES group than in the control group. Plasma concentrations of IFN-γ and IL-10 did not differ significantly between groups. The concentrations of IFN-γ, IL-4, and IL-10 in the supernatants of splenocytes stimulated with either mitogen and IL-4 production by nonstimulated cells were significantly higher in the ES group than in the control group. These results suggest that corticosterone mediates the immunosuppression induced by HPA axis activation, and induces dysregulation of the Th1/Th2 cytokine profile.

Cognitive-behavioral stress management reduces distress and 24-hour urinary free cortisol output among symptomatic HIV-infected gay men

Stress management interventions can reduce symptoms of distress as well as modulate certain immune system components in persons infected with human immunodeficiency virus (HIV). These effects may occur in parallel with reductions in hypothalamic-pituitary-adrenal (HPA) axis hormones such as cortisol, which has been related in other work to a down-regulation of immune system components relevant to HIV infection. The present study tested the effects of a multimodal cognitive-behavioral stress management (CBSM) intervention on 24-hour urinary free cortisol levels and distressed mood in symptomatic HIV+ gay men. Symptomatic HIV-infected gay men who were randomized to either a 10-week group-based CBSM intervention or a 10-week wait-list period provided psychological responses and urine samples pre-post intervention. Of the 59 participants providing matched questionnaire data, men assigned to CBSM (n = 40) showed significantly lower posttreatment levels of self-reported depressed affect, anxiety, anger, and confusion than those in the wait-list control group (n = 19). Among the 47 men providing urine samples (34 CBSM, 13 controls), those assigned to CBSM revealed significantly less cortisol output as compared to controls. At the individual level, depressed mood decreases paralleled cortisol reductions over this period across the entire sample. A time-limited CBSM intervention reduced distress symptoms and urinary free cortisol output in symptomatic HIV+ gay men and greater reductions in some aspects of distress, especially depressed mood, paralleled greater decreases in cortisol over the intervention period. If persisting stressors and depressed mood contribute to chronic HPA axis activation in HIV-infected persons, then interventions such as CBSM, which teaches them to relax, alter cognitive appraisals, use new coping strategies, and access social support resources, may decrease distress and depressed mood and normalize HPA axis functioning.

Detrimental effects of chronic hypothalamic-pituitary-adrenal axis activation. From obesity to memory deficits.

Increasing evidence suggests that the detrimental effects of glucocorticoid (GC) hypersecretion occur by activation of the hypothalamic-pituitary-adrenal (HPA) axis in several human pathologies, including obesity, Alzheimer's disease, AIDS dementia, and depression. The different patterns of response by the HPA axis during chronic activation are an important consideration in selecting an animal model to assess HPA axis function in a particular disorder. This article will discuss how chronic HPA axis activation and GC hypersecretion affect hippocampal function and contribute to the development of obesity. In the brain, the hippocampus has the highest concentration of GC receptors. Chronic stress or corticosterone treatment induces neuropathological alterations, such as dendritic atrophy in hippocampal neurons, which are paralleled by cognitive deficits. Excitatory amino acid (EAA) neurotransmission has been implicated in chronic HPA axis activation. EAAs play a major role in neuroendocrine regulation. Hippocampal dendritic atrophy may involve alterations in EAA transporter function, and decreased EAA transporter function may also contribute to chronic HPA axis activation. Understanding the molecular mechanisms of HPA axis activation will likely advance the development of therapeutic interventions for conditions in which GC levels are chronically elevated.