Hypothalamic-pituitary-adrenal Axis Hormones Research Articles

Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine.

Subanesthetic doses of (R,S)-ketamine (ketamine) have demonstrated rapid and robust antidepressant effects in individuals with depression. However, individual variability in response to ketamine exists, and current biomarkers of ketamine treatment response are not entirely understood. Preclinical evidence suggests a link between hypothalamic-pituitary-adrenal (HPA) axis activation, a determinant of the stress response system, and ketamine's efficacy in stressed mice exhibiting enhanced antidepressant responses. Here, we assessed the relationship between HPA axis, major depression features, and antidepressant response to ketamine in humans. We investigated 42 participants following medication washout with treatment-resistant depression who participated in a randomized, placebo-controlled, crossover trial receiving intravenous ketamine. Plasma levels of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline. Ketamine's antidepressant effects were assessed using the Montgomery-Asberg Depression Rating Scale. We found that baseline HPA axis hormone levels did not significantly moderate the antidepressant effects of ketamine. However, a negative association was observed between ACTH and CRF levels and the overall duration of depressive episodes, suggesting potential biomarker implications. Also, a negative correlation between baseline depressive scores and age of onset was observed, suggesting that the severity of depression might be greater if it develops at a younger age, indicating more enduring stress on the brain and body. Although we did not find a moderation effect of the plasma HPA axis hormones on the antidepressant effects of ketamine, moderation effects of the brain HPA axis hormones cannot be precluded and warrants further investigation. Importantly, our results implicate HPA axis components as potential biomarkers for the duration of depressive episodes.

Monosodium glutamate induces hypothalamic–pituitary–adrenal axis hyperactivation, glucocorticoid receptors down-regulation, and systemic inflammatory response in young male rats: Impact on miR-155 and miR-218

Abstract Young children are attracted to flavored foods with enhancers, particularly monosodium glutamate (MSG). Experimental studies have proven that MSG can alter the hypothalamic–pituitary–adrenal (HPA) axis response in neonates. We, therefore, investigated the modulation of microRNAs (miRNAs) by dietary MSG and its association with the stimulation of the HPA axis and inflammatory response in young male rats. One-month-old male rats were fed chow enriched with MSG (3 g/kg) for 16 weeks. Feeding MSG to rats markedly up-regulated hypothalamic miR-218, Toll-like receptors-4, and nuclear factor-kB but down-regulated miR-155 and glucocorticoid receptors (GR). In addition, it triggered a remarkable elevation in adrenocortical lipid peroxidation and depletion of antioxidants. These changes were coupled with increased plasma levels of the HPA axis hormones, comprising corticotropin-releasing hormone, adrenocorticotropic hormone, corticosterone levels, and serum pro-inflammatory cytokines. Taken together, current findings indicated that MSG caused an activation of the HPA axis, a down-regulation of GRs, and a systemic inflammatory response. These disturbances were associated with modulating hypothalamic miRNAs, encompassing miR-218 and 155.

The association between neuroendocrine/glucose metabolism and clinical outcomes and disease course in different clinical states of bipolar disorders.

The treatment of bipolar disorder (BD) remains challenging. The study evaluated the impact of the hypothalamic-pituitary-adrenal (HPA) axis/hypothalamic-pituitary-thyroid (HPT) axis and glucose metabolism on the clinical outcomes in patients with bipolar depression (BD-D) and manic bipolar (BD-M) disorders. The research design involved a longitudinal prospective study. A total of 500 BD patients aged between 18 and 65 years treated in 15 hospitals located in Western China were enrolled in the study. The Young Mania Rating Scale (YMRS) and Montgomery and Asberg Depression Rating Scale (MADRS) were used to assess the BD symptoms. An effective treatment response was defined as a reduction in the symptom score of more than 25% after 12 weeks of treatment. The score of symptoms was correlated with the homeostatic model assessment of insulin resistance (HOMA-IR) index, the HPA axis hormone levels (adrenocorticotropic hormone (ACTH) and cortisol), and the HPT axis hormone levels (thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), free triiodothyronine (fT3), and free thyroxine (fT4)). In the BD-M group, the YMRS was positively correlated with baseline T4 (r = 0.349, p = 0.010) and fT4 (r = 0.335, p = 0.013) and negatively correlated with fasting insulin (r = -0.289, p = 0.013). The pre-treatment HOMA-IR was significantly correlated with adverse course (p = 0.045, OR = 0.728). In the BD-D group, the baseline MADRS was significantly positively correlated with baseline fT3 (r = 0.223, p = 0.032) and fT4 (r = 0.315, p = 0.002), while baseline T3 (p = 0.032, OR = 5.071) was significantly positively related to treatment response. The HPT axis and glucose metabolism were closely associated with clinical outcomes at 12 weeks in both BD-D and BD-M groups. If confirmed in further longitudinal studies, monitoring T3 in BD-D patients and HOMA-IR for BD-M could be used as potential treatment response biomarkers.

Sustained inflammation and high cortisol reactivity following an coronary event

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Heart and lung foundation Sweden. Background Over the last decades, significant improvements have been made in medical and lifestyle managements of patients with coronary artery disease (CAD). Nonetheless, "residual inflammatory risk" for recurrent cardiovascular events is high in this patient group and remains a diagnostic and therapeutic challenge. Activation of the NLRP3 inflammasome, involving release of interleukin (IL)-1β and IL-18 followed by their downstream target IL-6, is considered a major component of the inflammatory process in atherosclerosis. One major immunomodulator is the hypothalamic–pituitary–adrenal (HPA) axis. Interestingly, there is increasing evidence that cortisol exerts proinflammatory effects through the induction of NLRP3 expression. Purpose We investigated whether sustained inflammation was associated with altered HPA stress reactivity in patients with CAD. From 4 weeks up to 6 months after a coronary event, we measured systemic inflammation, with focus on inflammasome-related cytokines, and HPA axis hormones (ACTH and cortisol) before and after acute physical stress. Method We included 81 patients (mean age 62 years, 77 % males) and 30 controls (mean age 69 years, 67 % males). Patients underwent a standardized submaximal exercise stress test at 4 weeks (visit A) and 3-6 months after the coronary event (visit B) while controls performed one test only. Free cortisol was measured in saliva before, directly and 30 min after exercise. IL-18, IL-Ra (as a surrogate for IL-1 β), IL-6, ACTH and total cortisol were measured in plasma before and 30 min after exercise. Results At visit A, plasma levels of CRP (baseline only) and IL-6 did not differ between patients and controls while IL-18 and IL-1Ra were significantly higher in patients both before and after exercise, 500 (391-632) vs 386 (295-493), p=0.002; and 179 (141-267) vs 147 (117- 182), p=0.005, respectively(table 1). At visit B, CRP decreased while IL-18 and IL-1Ra levels remained at higher levels than controls. At both visits, patients showed a heightened cortisol reactivity (i.e. significant increase directly after exercise) while this did not occur in controls (Figure 1). At visit B, the relative increase in cortisol directly after exercise was even higher than at visit A (p=0.024). At both visits, ACTH decreased significantly after exercise in patients (p<0.01), probably due to negative feedback, while no change in ACTH was observed in controls. Conclusion Sustained elevations in IL-18 and IL-1Ra in CAD patients following a coronary event may indicate enhanced activity of NLRP3 inflammasome. Furthermore, patients exhibited a heightened cortisol stress reactivity, a phenomenon which has been associated with atherosclerosis progression and sedentary lifestyle in the population. It may be speculated that HPA axis alteration is directly associated with NLRP3 inflammasome activation in CAD, thus opening doors to new insights in prevention. However, this remains to be further investigated.

Stress and psoriasis: Exploring the link through the prism of hypothalamo-pituitary-adrenal axis and inflammation

BackgroundPsoriasis is an immune-mediated, chronic inflammatory disease affecting mainly the skin. Chronic stress leads to the blunted hypothalamic-pituitary-adrenal axis (HPA) that might induce pro-inflammatory conditions. Hence, we assessed the blood levels of the HPA hormones and interleukin-17 (IL-17) and the effect of stress and emotional distress to understand the link between stress and psoriasis better. MethodsThis cross-sectional study included 45 patients with psoriasis and 45 age and gender-matched apparently healthy volunteers (n = 45). IL-17, cortisol, and adrenocorticotrophic hormone (ACTH) levels were assessed in both groups. Psoriasis Area Severity Index (PASI) was used to assess disease severity. Presumptive Stressful Life Events scale [PSLE], Perceived Stress scale [PSS] and Daily Hassles and Uplifts Scale [DHUS] scoring were used to assess stress levels and emotional distress. ResultsPatients with psoriasis had higher levels of IL-17 and ACTH and lower levels of cortisol, as compared to controls. Stress scores (PSS, PSLE & DHUS) were significantly elevated in cases, as compared to the controls. IL-17, ACTH and stress scores showed a significant positive correlation with one another and a significant negative correlation with cortisol levels. They also showed a significant positive correlation with PASI, while cortisol levels showed a significant negative correlation. ConclusionPsoriasis patients having high ACTH, IL-17 and stress scores had lower levels of cortisol, indicating a dysregulated HPA axis with the pro-inflammatory state. This might lead to exacerbation of psoriatic flares, which needs investigation in further prospective studies.

Guilt by Association: Inflammation and Shared Genetic Risk Between Stress-Related and Immune Disorders

Guilt by Association: Inflammation and Shared Genetic Risk Between Stress-Related and Immune Disorders

Hypothalamic-pituitary-adrenal axis and renin-angiotensin-aldosterone system in adulthood PTSD and childhood maltreatment history.

Accumulated evidence shows that psychological trauma and posttraumatic stress disorder (PTSD) are associated with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis. Besides the HPA axis hormones, recent evidence suggests that the renin-angiotensin-aldosterone (RAA) system and genetic factors may be involved in trauma/PTSD as well as in HPA axis regulation. This study attempted to better understand the HPA axis function in relation to PTSD and childhood maltreatment by simultaneously examining RAA system and genetic polymorphisms of candidate genes. Here we studied 69 civilian women with PTSD and 107 healthy control women without DSM-IV-based traumatic experience. Childhood maltreatment history was assessed with the Childhood Trauma Questionnaire. PTSD severity was assessed with the Posttraumatic Diagnostic Scale. Functional disability was assessed with the Sheehan Disability Scale. HPA axis was examined by measuring blood levels of cortisol, adrenocorticotropic hormone, and dehydroepiandrosterone-sulphate (DHEA-S). RAA system was examined by measuring blood renin and aldosterone levels. The FKBP5 rs1360780 and CACNA1C rs1006737 polymorphisms were genotyped. No significant differences were seen between patients and controls in any of the five hormone levels. DHEA-S levels were significantly negatively correlated with overall PTSD severity (p = 0.003) and functional disability (p = 0.008). A two-way analysis of variance with diagnostic groups and genotypes as fixed factors revealed that patients with the rs1006737 A-allele had significantly lower DHEA-S levels than patients with the GG genotype (p = 0.002) and controls with the A-allele (p = 0.006). Childhood maltreatment history was not significantly correlated with any of the five hormone levels. These results were generally unchanged after controlling for the potentially confounding effect of age, depression, and anxiety. Our findings suggest that lower DHEA-S levels could indicate more severe subtype of PTSD, the association of which might be partly modified by the CACNA1C polymorphism.

Níveis dos hormônios do eixo hipotálamo-pituitária-adrenal no líquido cefalorraquidiano de pacientes com CCL e demência devido à doença de Alzheimer: uma revisão sistemática

ABSTRACT Underlying the neuropsychological manifestations of Alzheimer’s disease (AD), hypothalamic-pituitary-adrenal (HPA) axis dysregulation and subsequent hypercortisolemia have been proposed as major mechanisms driving AD progression from mild cognitive impairment (MCI) to the onset of dementia. Nonetheless, changes in cerebrospinal fluid (CSF) levels of HPA axis hormones remain controversial despite their potential in AD diagnosis and prognosis testing. Objective: This study aimed to review the evidence of the variation in CSF levels of CRH, ACTH, and cortisol in subjects with mild cognitive impairment (MCI) and AD compared with subjects without cognitive disorders. Methods: A systematic review was conducted in MEDLINE, EMBASE, and Web of Science databases on July 5, 2022. Results: Seventeen observational studies were included. The results from the compiled investigations showed that individuals with AD exhibit a significant elevation of CSF cortisol levels which appear to correlate with the presence of the ApoE-ε4 allele, being higher in those homozygous for this allele. The variation of CSF CRH and ACTH levels in AD, on the other hand, is still inconclusive. Moreover, most studies found no significant difference in CSF cortisol levels in individuals with MCI compared to healthy subjects and patients with AD. Conclusion: The findings gathered in this review disclose a significant elevation of CSF cortisol levels in AD. Future investigations are warranted to elucidate the potential use of CSF cortisol as a biomarker in AD-associated dementia.

New View on the Impact of the Low-Frequency Electromagnetic Field (50 Hz) on Stress Responses: Hormesis Effect

Introduction: Low-frequency electromagnetic field (50 Hz) (EMF) can modify crucial neuronal processes. Existing data indicate that exposure to EMF may represent a mild stressor and contribute to disturbances of the hypothalamic-pituitary-adrenal (HPA) axis. The important regulatory pathways controlling HPA axis activity include two types of corticosteroid receptors: mineralocorticoid receptors (MRs) and glucocorticoid receptors. They are particularly abundant in the hippocampus, a key locus of HPA axis feedback control. The research aimed at determining whether (1) EMF exhibits hormesis, it means bidirectional action depending on EMF intensity (1 or 7 mT) and (2) repeated EMF exposure changes stress response to subsequent stress factors. Methods: The exposure (7 days, 1 h/day) of adult rats to EMF (1 mT and 7 mT) was repeated 3 times. HPA axis hormones and their receptors were analysed after each following exposure. Moreover, the impact of EMF exposure on hormonal and behavioural responses to subsequent stress factor – open-field test was evaluated. Results: Our data suggest that exposure to EMF can establish a new “set-point” for HPA axis activity. The direction and dynamics of this process depend on the intensity of EMF and the number of exposures. EMF of 1 mT induced an adaptive stress response, but 7 mT EMF caused sensitization. Consequently, EMF changed the vulnerability of the organism to a subsequent stress factor. We have also shown the increase in MR mRNA abundance in the hippocampus of 1 mT EMF-exposed rats, which can represent the possible neuroprotective response and suggest therapeutic properties of EMFs.

The Value of HPA Axis Hormones as Biomarkers for Screening and Early Diagnosis of Postpartum Depression: Updated Information About Methodology.

Because of the high prevalence of postpartum depression (PPD) and the suffering involved, early diagnosis is urgent; however, current screening tools and diagnosis are inadequate. In addition to conventional methods such as the Edinburgh Postnatal Depression Scale and clinical interviews, several hormones in the hypothalamic–pituitary–adrenal (HPA) axis, such as corticotrophin-releasing hormone, adrenocorticotropic hormone, and cortisol, have been considered because of their critical roles in stress regulation in the mothers. The study designs are complicated, however, and so the effectiveness of these hormones as biomarkers for PPD is still controversial. Such inconsistency may have resulted from the variation in methodology between studies. The methodology problems in the investigation of PPD and HPA axis hormones have not been reported extensively. We therefore sought to summarize the methodological problems of studies published in the past decade, including the strengths and weaknesses of the examinations and the technological difficulties involved. Our findings suggest that (a) suitable samples and appropriate detection methods would reduce heterogeneity among trials; (b) the cutoff value of the scale test should be carefully selected for determining the performance of biomarker tests; (c) evaluation methods and criteria should be chosen with consideration of the tools feasible for use in local hospitals and population; and (d) the cost of diagnosis should be reduced. We hope that these findings provide insight for future investigations of HPA axis hormones as biomarkers for screening and early diagnosis of PPD.

Diethyl phosphate disrupts hypothalamus-pituitary-adrenal axis endocrine hormones via nuclear receptors GR and Nur77: Integration of evidences from in vivo, in vitro and in silico approaches

Plenty of population epidemiology and cohort studies have found dialkyl phosphates (DAPs) in the urine were related to endocrine hormone disorders. However, we did not know whether these effects were caused by parent organophosphorus pesticides (OPs) or metabolite DAPs, especially the non-specific metabolite diethyl phosphate (DEP), which was the metabolic end product of most widely used diethyl OPs. In this study, animal experiments (in vivo), cell experiments (in vitro), small molecule-protein binding interaction experiments and computer molecular simulations (in silico) were used to explore the disturbing effects and molecular mechanisms of DEP on the hypothalamic-pituitary-adrenal (HPA) axis endocrine hormones. The animal experiments showed that chronic DEP exposure significantly disturbed the serum contents of HPA axis hormones in adult male rats. The target genes of glucocorticoid receptor (GR) in rat liver, including 11β-hsd1 and Pepck1 and PEPCK protein expressions, were down-regulated. Moreover, the gluconeogenic abilities of rats were impaired. However, it did not affect the expression of GR in the rat hypothalamus. These results indicated that the physiological functions of glucocorticoids and GR were damaged. Furthermore, spectroscopy experiments, cell experiments, molecular docking and molecular dynamics simulations also suggested that DEP can bind to nuclear receptors GR and Nur77, affecting their transcription factor functions, and the transcriptional expression levels of their downstream target genes were reduced. The biosynthesis and secretion of adrenocorticotropic hormone and glucocorticoids were blocked. Therefore, DEP can inhibit the production and physiological functions of HPA axis endocrine hormones by disrupting these related proteins and antagonizing nuclear receptors. These results were considered to provide a theoretical basis for strictly controlling the residue limits of OPs and their metabolites in foods, agricultural products and the environment. They also revealed new targets for evaluating the toxicities and risks of pesticide metabolites.

Early developmental stage glucocorticoid exposure causes DNA methylation and behavioral defects in adult zebrafish

Post-traumatic stress disorder (PTSD) is a psychiatric disorder caused by genetic and environmental factors. It is closely related to a dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, in which the epigenetic modification of the nr3c1 plays an important role. It is well known that nr3c1 methylation in offspring is reportedly related to early adverse life experiences, prenatal stress response, and early nursing conditions; however, the methylation location and extent of the nr3c1 are not sufficiently elucidated. In order to study the internal mechanism of PTSD caused by early adverse life experience, we used zebrafish to construct a psychopathological model. We found that early developmental stage prednisolone exposure caused HPA axis negative feedback dysfunction and hormone secretion disorder in adult male zebrafish. By analyzing nr3c1 promoter, we found that cytosine-guanine island (CpGI) 2 was highly methylated in adult male zebrafish, which affected the expression of glucocorticoid receptor, resulting in abnormal behavior and anxiety like phenotype of adult male zebrafish. Therefore, we believed that an early exposure of zebrafish larvae to prednisolone may be recorded through a change of CpGI 2 methylation in the nr3c1 promoter region, causing abnormal adult male zebrafish behavior. Moreover, the establishment of the zebrafish psychopathological model may facilitate the study of the clinical management of patients with PTSD.

Defects in NLRP6, autophagy and goblet cell homeostasis are associated with reduced duodenal CRH receptor 2 expression in patients with functional dyspepsia

Functional dyspepsia (FD) affects up to 15% of the population and is characterised by recurring upper gastrointestinal (GI) symptoms occurring in the absence of clinically identifiable pathology. Psychological stress is a key factor associated with the onset of FD and locally acting hypothalamic–pituitary–adrenal (HPA) axis hormones have been implicated in GI motility and barrier dysfunction. Recent pre-clinical work has identified mechanistic pathways linking corticotropin-releasing hormone (CRH) with the innate epithelial immune protein NLRP6, an inflammasome that has been shown to regulate GI mucus secretion.We recruited twelve FD patients and twelve healthy individuals to examine whether dysregulation of hypothalamic-pituitary adrenal (HPA) axis hormones and altered NLRP6 pathways were evident in the duodenal mucosa. Protein expression was assessed by immunoblot and immunohistochemistry in D2 duodenal biopsies. Plasma HPA axis hormones were assayed by ELISA and enteroid and colorectal cancer cell line cultures were used to verify function. FD patients exhibited reduced duodenal CRH-receptor 2, compared to non-GI disease controls, indicating a dysregulation of duodenal HPA signalling. The loss of CRH-receptor 2 correlated with reduced NLRP6 expression and autophagy function, processes critical for maintaining goblet cell homeostasis. In accordance, duodenal goblet cell numbers and mucin exocytosis was reduced in FD patients compared to controls. In vitro studies demonstrated that CRH could reduce NLRP6 in duodenal spheroids and promote mucus secretion in the HT29-MTX-E12 cell line. In conclusion, FD patients exhibit defects in the NLRP6-autophagy axis with decreased goblet cell function that may drive symptoms of disease. These features correlated with loss of CRH receptor 2 and may be driven by dysregulation of HPA signalling in the duodenum of FD patients.

Hypothalamic-Pituitary-Adrenal axis dysfunction by early life stress

Evidence indicates that early life stress (ELS) may act as a risk factor for the development and maintenance of adulthood severe mental health disorders due to persistent dysregulation within the hypothalamic–pituitary-adrenal (HPA) axis. It is now broadly accepted that psychological stress may change the internal homeostatic state of an individual. The dysregulation seems to be a byproduct of changes noted in the HPA axis hormone’s ability to bind to the glucocorticoid and mineralocorticoid receptors, crucial in maintaining homeostasis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behavior, and they influence the process of adaptation or ‘allostasis’. The HPA axis response to stress can be thought of as a mirror of the organism's response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. Evidence indicates that early-life stress can induce persistent changes in the ability of the HPA axis to respond to stress in adulthood This review aims to examine and summarise the existing literature exploring the relationship between ELS with regards specifically to HPA axis functioning. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of HPA hormones through binding to mineralocorticoid (MR) and glucocorticoid (GR) receptors limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals.

Periconceptional ethanol exposure alters hypothalamic-pituitary-adrenal axis function, signalling elements and associated behaviours in a rodent model

Alcohol consumption throughout pregnancy has been associated with mental illness, hyperactivity and social difficulties in offspring. This may be due in part to programmed disruption of the hypothalamic-pituitary-adrenal axis (HPA) activity and responsiveness. However, it is unknown if the HPA is affected and similar behavioural outcomes occur following alcohol exposure limited to the time around conception, the periconceptional (PC) period. Female Sprague-Dawley rats were treated with PC:EtOH (12.5 % v/v EtOH liquid diet) or a control diet from four days before conception, until embryonic day 4. Offspring at 3-months of age underwent the forced swim test (FST) and social interaction test. HPA reactivity tests (combined dexamethasone suppression test (DST) and corticotropin-releasing hormone test (CST), 30-minute restraint stress) were performed at 5 months of age and then pituitary and adrenal glands were collected for expression of genes involved in HPA regulation.PC:EtOH exposure significantly increased immobility (p < 0.05) in both sexes in the FST. PC:EtOH also increased the duration of affiliative behaviour (p < 0.05) within the social interaction test in female offspring. PC:EtOH programmed HPA hyperactivity in both sexes during the DST/CST test (p < 0.05); however, there was no impact of PC:EtOH on plasma corticosterone concentration in response to restraint stress. There was no significant impact of PC:EtOH on mRNA expression in glucocorticoid signalling genes in the pituitary gland or the steroidogenic pathway in the adrenal gland.This study suggests that alcohol exposure, even when limited to a short period around conception, can program mental illness-like phenotypes, and this was associated with alterations in HPA responsiveness. This study further highlights that consumption of alcohol even prior to implantation may impact the long-term health of offspring.

Association of maternal depression and home adversities with infant hypothalamic-pituitary-adrenal (HPA) axis biomarkers in rural Pakistan

BackgroundEach year, almost 35% of children are exposed to maternal depression and more grow up in persistent poverty, increasing the risk for stress-related disease and other socio-developmental deficits later in life. These impacts are likely related to chronic stress via the hypothalamic-pituitary-adrenal (HPA) axis. However, there is little evidence relating early windows of child HPA axis activity to multiple exposures. MethodsWe investigated chronic measures of hair-derived HPA axis hormones (cortisol and dehydroepiandrosterone (DHEA)) in 104 one-year old infants from rural Pakistan and longitudinal measures of maternal depression, intimate partner violence (IPV), socio-economic status (SES), and the home environment. ResultsEstimates from adjusted linear mixed effects models did not reveal consistent significant associations between infant cortisol and maternal depression or home adversities. By contrast, infants exposed to maternal depression during pregnancy had lower DHEA levels (ß= -0.18 95% confidence interval [CI]: -0.34, -0.02) as did those whose mothers experienced multiple types of IPV (ß=-4.14 95% CI: -7.42, -0.79) within one year postpartum. Higher SES had a significant positive association with infant DHEA levels (ß= 0.77 95% CI: 0.08, 1.47). Depression severity and chronicity at one year postpartum had near significant associations with infant DHEA. Measures of home environment had no observable impacts on infant HPA axis activity. LimitationsLimitations include the modest sample size and aggregation of hair samples for analysis. ConclusionResults point to possible early HPA axis dysregulation driven by changes in DHEA activity, but not cortisol at one year of age. Findings contribute to growing research examining intergenerational transmissions of maternal depression, IPV, and household environment on infant stress-response systems.

Glucocorticoid receptor sensitivity in early pregnancy in an African American cohort.

Disruption in homeostatic feedback loops between inflammatory mediators and the hypothalamic-pituitary-adrenal (HPA) axis is a key mechanism linking chronic stress to inflammation and adverse health outcomes, including those occurring during pregnancy. In particular, alterations in glucocorticoid sensitivity may occur as a result of chronic stress, including that due to racial discrimination, and may be implicated in the persistent adverse maternal and infant health outcomes experienced by African Americans. While there are a few large-scale studies in human pregnancy that measure both cytokines and HPA axis hormones, to our knowledge, none directly measure glucocorticoid sensitivity at the cellular level, especially in an African American population. We measured the full range of the dexamethasone (DEX) dose-response suppression of TNF-α in first-trimester blood samples from 408 African American women and estimated leukocyte cell type contribution to the production of TNF-α. The mean (SD) DEX level needed to inhibit TNF-α production by 50% (ie, DEX IC50 ) was 9.8 (5.8) nmol/L. Monocytes appeared to be the main driver of Uninhibited TNF-α production, but monocyte counts explained only 14% of the variation. Monocyte counts were only weakly correlated with the DEX IC50 (r=-.11, P<.05). Moreover, there was no statistically significant correlation between the DEX IC50 and circulating pro-inflammatory (CRP, IL-6, IFN-γ) or anti-inflammatory (IL-10) mediators (P>.05). These findings challenge some prior assumptions and position this comprehensive study of glucocorticoid sensitivity as an important anchor point in the growing recognition of interindividual variation in maternal HPA axis regulation and inflammatory responses.

The enhanced serotonin (5-HT) synthesis and anti-oxidative roles of Trp oligopeptide in combating anxious depression C57BL/6 mice

Abstract This study compared enhanced serotonin (5-HT) synthesis roles of γ-[Glu]n-Trp (EW) and whey protein hydrolysate (WPH, Val-Ala-Gly-Thr-Trp-Tyr, Val-Ala-Gly-Thr-Trp, Ser-Ala-Trp-Tyr, Trp-Tyr-Ser, Gly-Thr-Trp) using anxious depression C57BL/6 mice. As an index of serotonergic activity, we assessed 5-HT levels in response to Trp oligopeptide ingestion. The neuroprotective and hypothalamic-pituitaryadrenal (HPA) axis hormones were examined in order to characterize the suggested improvements of anxious depression observed in mice after ingestion Trp oligopeptide. The 5-HT levels were increasingly enhanced by the EW and WPH diet, with the EW being more effective. But WPH had higher capacity on anti-oxidative than EW. EW and WPH could normalize the levels of HPA axis hormones, and promote brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling. In conclusion, Trp oligopeptide ingestion neuroprotective and HPA regulation effects possibly related to serotonergic activation and anti-oxidation. Consumed Trp oligopeptide diets may induce beneficial effects on anxious depression.

So-Ochim-Tang-Gamibang, a Traditional Herbal Formula, Ameliorates Depression by Regulating Hyperactive Glucocorticoid Signaling In Vitro and In Vivo.

So-ochim-tang-gamibang (SOCG) is a Korean traditional medicine; it has previously been shown to be safe and effective against depression. Persistently increased levels of circulating glucocorticoids have been considered as a pathological mechanism for depression and associated with decreased neurotrophic factors in the hippocampus. This study investigated whether SOCG controls the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and the molecular mechanisms underlying its effects in vivo and in vitro. Wistar Kyoto (WKY) rats were subjected to restraint stress, where SOCG was orally administered to the animals for 2 weeks. An open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were performed to explore the antidepressant activity of SOCG in WKY rats. Plasma levels of HPA axis hormones were measured by ELISA or western blotting analysis. The expression levels or activation of HPA axis-related signaling molecules such as brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), extracellular regulated kinase (ERK), and glucocorticoid receptors (GRs) in the brain were determined by real-time PCR and western blotting analysis. Furthermore, a corticosterone- (CORT-) induced cell injury model was established using SH-SY5Y cells to explore the antidepressive effects of SOCG in vitro. The results of the OFT, FST, and SPT revealed that SOCG ameliorated depressive-like behaviors in the WKY rats. The blood plasma levels of HPA axis hormones such as CORT, CORT-releasing hormone (CRH), and adrenocorticotrophic hormone were downregulated by SOCG. On the other hand, SOCG upregulated the phosphorylation of CREB and ERK in both the rat hippocampus and CORT-treated SH-SY5Y cells. Moreover, it also increased the GR expression. These results suggested that SOCG may improve depression by controlling hyperactive glucocorticoid signaling via the downregulation of HPA axis hormones and upregulation of GR.

Dispositional Mindfulness Profiles in Adolescents and their Associations with Psychological Functioning and Hypothalamic-Pituitary-Adrenal Axis Hormones.

Adolescence is often accompanied by an increase in stress and depression. Although there is considerable consensus about the benefits of mindfulness-based interventions to reduce these problems, the results for the role of dispositional mindfulness facets have been mixed. Recent studies have contributed to clarifying this role by identifying subtypes of individuals according to their profiles in mindfulness facets and examining the functioning of these profiles in relation to several self-reported indicators of wellbeing and health. The current study extends previous research by exploring mindfulness profiles in adolescents and by providing several sources of indicators (self-reports, parent-reports, and hypothalamic-pituitary-adrenal axis hormones) to examine the adaptive role of these profiles. A sample of 571 adolescents (50.61% girls; 12-17 years old) completed measures of mindfulness, depression, maladaptive schemas, and temperament (neuroticism, extraversion, and effortful control), and provided salivary samples for cortisol and dehydroepiandrosterone sulfate. In addition, 331 adolescents' parents completed measures of their children' temperaments. The results of latent profile analyses supported a three-profile solution: (1) moderate mindfulness (65.5%), (2) judgmental observing (24.2%), and (3) nonjudgmentally aware (10.3%). The judgmental observing profile was associated with a worse adjustment, indicated by higher depressive symptoms, maladaptive schemas, perceived stress, stress-associated hormones, and neuroticism, as well as lower scores on extroversion and effortful control. This profile was more frequent among the oldest adolescents. In contrast, the nonjudgmentally aware group presented a better adjustment and was more frequent among the youngest adolescents. These findings have implications for preventive interventions. Analyzing the specific profile of each adolescent can help improve individual intervention, taking into account the strengths and weaknesses of each adolescent.