Hypothalamic-pituitary-adrenal Axis Activity Research Articles

Cumulative trauma predicts hair cortisol concentrations and symptoms of depression and anxiety in pregnant women—an investigation of community samples from Greece, Spain and Perú

Exposure to traumatic experiences across lifespan shapes the functioning of the hypothalamic pituitary adrenal (HPA) axis and sets individuals at risk to develop symptoms of depression and anxiety. Particularly, HPA axis regulation and the psychological health of the expectant mother have been of interest, as the health of the unborn child may be affected through changes in gestational biology. The present study investigated the potential associations between lifetime trauma, current symptoms (depression and anxiety) and hair cortisol concentrations (HCC) in pregnant women. A total of 149 pregnant women were interviewed in public outpatient clinics with varying gestational age in Greece, Spain and Perú. Lifetime trauma exposure and current symptoms of depression and anxiety were assessed. HCC was measured in scalp-near hair segments (2 cm length) reflecting cumulative cortisol secretion of the past two months. Results showed that trauma load is negatively associated with HCC and higher symptoms of depression and anxiety. There was a negative association between HCC and symptoms. The present findings support the notion that cumulative trauma exposure exerts long-lasting effects on the expectant mother’s HPA axis activity functioning and mental health and may thereby potentially create risk trajectories for the unborn child via changes in gestational biology.

Genetic parameters of feather corticosterone and fault bars and correlations with production traits in turkeys (Meleagris gallopavo)

Robustness can refer to an animal’s ability to overcome perturbations. Intense selection for production traits in livestock has resulted in reduced robustness which has negative implications for livability as well as production. There is increasing emphasis on improving robustness through poultry breeding, which may involve identifying novel phenotypes that could be used in selection strategies. The hypothalamic–pituitary–adrenal (HPA) axis and associated hormones (e.g., corticosterone) participate in many metabolic processes that are related to robustness. Corticosterone can be measured non-invasively in feathers (FCORT) and reflects the average HPA axis activity over the feather growing period, however measurement is expensive and time consuming. Fault bars are visible feather deformities that may be related to HPA axis activity and may be a more feasible indicator trait. In this study, we estimated variance components for FCORT and fault bars in a population of purebred turkeys as well as their genetic and partial phenotypic correlations with other economically relevant traits including growth and efficiency, carcass yield, and meat quality. The estimated heritability for FCORT was 0.21 ± 0.07 and for the fault bar traits (presence, incidence, severity, and index) estimates ranged from 0.09 to 0.24. The genetic correlation of FCORT with breast weight, breast meat yield, fillet weight, and ultimate pH were estimated at −0.34 ± 0.21, −0.45 ± 0.23, −0.33 ± 0.24, and 0.32 ± 0.24, respectively. The phenotypic correlations of FCORT with breast weight, breast meat yield, fillet weight, drum weight, and walking ability were −0.16, −0.23, −0.18, 0.17, and 0.21, respectively. Some fault bar traits showed similar genetic correlations with breast weight, breast meat yield, and walking ability but the magnitude was lower than those with FCORT. While the dataset is limited and results should be interpreted with caution, this study indicates that selection for traits related to HPA axis activity is possible in domestic turkeys. Further research should focus on investigating the association of these traits with other robustness-related traits and how to potentially implement these traits in turkey breeding.

Variation of hair cortisol in two herds of migratory caribou (Rangifer tarandus): implications for health monitoring.

Migratory caribou (Rangifer tarandus sspp.) is an ecotype of conservation concern that is experiencing increased cumulative stressors associated with rapid climate change and development in Arctic Canada. Increasingly, hair cortisol concentrations (HCCs) are being used to monitor seasonal hypothalamic-pituitary-adrenal axis activity of ungulate populations; yet, the effect of key covariates for caribou (sex, season, sampling source, body location) are largely unknown. The objectives of this research were 4-fold: first, we assessed the impact of body location (neck, rump) sampling sites on HCC; second, we assessed key covariates (sex, sampling method, season) impacting HCCs of caribou; third, we investigated inter-population (Dolphin and Union (DU), Bluenose-East (BNE)) and inter-annual differences in HCC and fourth, we examined the association between HCCs and indices of biting insect activity on the summer range (oestrid index, mosquito index). We examined hair from 407 DU and BNE caribou sampled by harvesters or during capture-collaring operations from 2012 to 2020. Linear mixed-effect models were used to assess the effect of body location on HCC and generalized least squares regression (GLS) models were used to examine the impacts of key covariates, year and herd and indices of biting insect harassment. HCC varied significantly by body location, year, herd and source of samples (harvester vs capture). HCC was higher in samples taken from the neck and in the DU herd compared with the BNE, decreased linearly over time and was higher in captured versus hunted animals (P < 0.05). There was no difference in HCC between sexes, and indices of biting insect harassment in the previous year were not significantly associated with HCC. This study identifies essential covariates impacting the HCC of caribou that must be accounted for in sampling, monitoring and data interpretation.

A review on hypothalamo-pituitary- adrenal axis

The effector hormones of the hypothalamic-pituitary-adrenal axis neuroendocrine system are the glucocorticoid hormones cortisol and corticosterone.The level of corticosterone, a systemic intercellular signal, changes dynamically with environmental and psychological stressors and predictably varies with time of day. A wide range of physiological and mental health issues are linked to irregularities in the typical HPA axis activity profiles. Despite several investigations that have uncovered molecular, cellular, and systems-level glucocorticoid actions to date, more glucocorticoid actions, and connections with clinical state, need to be discovered. Hypothalamic-pituitary-adrenal (HPA) axis feedback regulation may be compromised due to reduced mineralocorticoid receptor (MR)-mediated feedback in the brain. Medicinal herbs and their compounds have been shown to have a preventative impact against depression through a variety of ways. Medicinal plants can provide fresh ideas for antidepressant medication research.

The mane factor: Compliance is associated with increased hair cortisol in the horse

Equine personality tests enable the selection of horses for roles based on their habitual behavioural responses to challenges, aiming to maximise performance and safeguard equine welfare. However, existing research has identified that behavioural responses to acute challenges do not correlate well with stress physiology in the horse. The aim of this study was to investigate whether chronic stress physiology is related to habitual compliance in horses. Hair cortisol concentration (HCC), a long-term biomarker of hypothalamic–pituitary–adrenal axis activity and stress, was assayed in mane hair from the withers, midpoint of the neck and poll of 24 riding school horses (66% male, mean age 13 ± 4 years). Three caregivers provided scores for Agreeableness, Neuroticism, Extroversion, Gregariousness Towards People and Gregariousness Towards Horses for all subjects using a validated equine personality questionnaire. A gamma GLMM was used to model HCC as a function of personality scores and potential confounders of HCC (age, sex, hair colour and sampling location). Individual horses were fitted as random intercepts in the model. Manual backward selection was used to identify the best-fitting plausible model. Mean HCC was 3.8 ± 1.2 pg/mg. The final model only retained Agreeableness and sampling location as explanatory variables of HCC. A positive association was found between Agreeableness (reflecting habitual compliance) and hair cortisol concentration (t = 2.7, p = 0.01). Basal cortisol levels are known to drive sensitivity to punishment in humans. Therefore, horses with higher basal cortisol may be more sensitive to the aversive cues associated with negative reinforcement and consequently be more compliant. However, it is also possible that habitually compliant behaviour leads to higher chronic stress levels through increased exposure to stressors, as more subtle expressions of discomfort are not recognised by handlers. This result has important implications for welfare in the context of horse-human interaction and warrants further investigation to clarify whether a causal link exists between habitual compliance and higher levels of chronic stress. There was also a weaker but significant impact of sampling location (t = 2.1, p = 0.03; higher HCC at the poll), highlighting the importance of carefully standardizing sampling location for HCC analysis.

Paternal Nicotine/Ethanol/Caffeine Mixed Exposure Induces Offspring Rat Dysplasia and Its Potential "GC-IGF1" Programming Mechanism.

Clinical and animal studies suggest that paternal exposure to adverse environments (bad living habits and chronic stress, etc.) has profound impacts on offspring development; however, the mechanism of paternal disease has not been clarified. In this study, a meta-analysis was first performed to suggest that paternal exposure to nicotine, ethanol, or caffeine is a high-risk factor for adverse pregnancy outcomes. Next, we created a rat model of paternal nicotine/ethanol/caffeine mixed exposure (PME), whereby male Wistar rats were exposed to nicotine (0.1 mg/kg/d), ethanol (0.5 g/kg/d), and caffeine (7.5 mg/kg/d) for 8 weeks continuously, then mated with normal female rats to obtain a fetus (n = 12 for control group, n = 10 for PME group). Then, we analyzed the changes in paternal hypothalamic-pituitary-adrenal (HPA) axis activity, testicular function, pregnancy outcomes, fetal serum metabolic indicators, and multiple organ functions to explore the mechanism from the perspective of chronic stress. Our results demonstrated that PME led to enhanced paternal HPA axis activity, decreased sperm quality, and adverse pregnancy outcomes (stillbirth and absorption, decreased fetal weight and body length, and intrauterine growth retardation), abnormal fetal serum metabolic indicators (corticosterone, glucolipid metabolism, and sex hormones), and fetal multi-organ dysfunction (including hippocampus, adrenal, liver, ossification, and gonads). Furthermore, correlation analysis showed that the increased paternal corticosterone level was closely related to decreased sperm quality, adverse pregnancy outcomes, and abnormal offspring multi-organ function development. Among them, the decreased activity of the glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis may be the main mechanism of offspring development and multi-organ dysfunction caused by PME. This study explored the impact of common paternal lifestyle in daily life on offspring development, and proposed the GC-IGF1 programming mechanisms of paternal chronic stress-induced offspring dysplasia, which provides a novel insight for exploring the important role of paternal chronic stress in offspring development and guiding a healthy lifestyle for men.

Hypothalamic-pituitary-adrenal axis activity in patients with primary polydipsia compared to healthy controls.

Primary polydipsia is characterized by excessive fluid intake which may suppress vasopressin levels. It is speculated that suppressed vasopressin levels lead to a dysregulated hypothalamic-pituitary-adrenal (HPA) axis as vasopressin co-modulates the HPA axis. However, data are contradictory. The aim of this study was to investigate markers of the HPA axis in patients with primary polydipsia compared to healthy controls. Exploratory analysis combining data from two different prospective observational studies. We included 34 patients with primary polydipsia (68% females, median aged 29.5 years (interquartile range, IQR: 26.0, 38.8) and 20 healthy controls (55% females, median age 24.0 years [IQR: 22.0, 27.2]). The main outcome was difference in HPA axis activity assessed using circadian serum and salivary cortisol, 24-hurinary free cortisoland cortisol levels before and after adrenocorticotropic hormone (ACTH) stimulation; vasopressin suppression was assessed measuring fasting copeptin levels between patients with primary polydipsia and healthy controls using Wilcoxon rank-sum test. No difference was seen in circadian serum cortisol levels (p = .9), urinary free cortisol levels (p = .17)and serum cortisol in response to ACTH stimulation (p = .77) between groups. Circadian salivary cortisol levels were significantly lower in patients with primary polydipsia compared to healthy controls with an estimated difference of -3.7 nmol/L (95%CI: -5.5, -1.8 nmol/L, p < .001). Fasting copeptin levels were significantly lower in patients with primary polydipsia compared to healthy volunteers (p < 0.01). Our results suggest no difference in HPA axis activity between patients with primary polydipsia and healthy controls. The observed difference in salivary cortisol levels may be linked to a dilution effect in saliva rather than an altered stress axis considering the other findings.

Cortisol awake response imbalance as an indicator of acute central serous chorioretinopathy: Relationship with choriocapillaris and choroidal features.

The purpose of the present study was to measure in central serous chorioretinopathy (CSC) the salivary cortisol awake response (CAR) delta percentage (Δ%) variation, a distinct and robust indicator of cortisol rhythm during wakefulness, commonly proposed as a marker of hypothalamic-pituitary adrenal (HPA) axis activity, whose alteration is frequently associated with several adverse health outcomes. In the present cross-sectional observational study, salivary CAR Δ% variation was assessed in 17 adult male subjects affected by acute naïve CSC and compared to 17 matched healthy controls. Choroid vasculature metrics were assessed in the study population by measuring the subfoveal choroidal thickness (FCT) and the choroidal vascularity index (CVI) by the imaging technique of enhanced-depth imaging spectral-domain optical coherence tomography (EDI-SD-OCT). Furthermore, flow signal void area features of the choriocapillaris were evaluated in the study population using OCT angiography (OCTA). Both the control and CSC groups showed a physiological cortisol increase that occurred during the first 30 min after awaking. However, CSC adult male patients showed remarkably blunted CAR Δ% variation in comparison with controls, which might reflect a CSC-related imbalance of HPA axis activity. Statistically significant correlations were shown by Pearson's correlation test between salivary CAR Δ% and the selected choroidal and choriocapillaris imaging biomarkers (FCT, CVI, and flow signal void area) in the study population. In conclusion, alterations of the CAR Δ% increase, associated with choroidal-retinal metrics, might provide a window into the physiopathology of acute CSC, suggesting a possible common factor to explain the association between stress and CSC.

Static electric field exposure decreases white blood cell count in peripheral blood through activating hypothalamic–pituitary–adrenal axis

ABSTRACT With the development of ultra-high-voltage (UHV) direct-current (DC) transmission, the health risk from the static electric field (SEF) generated by UHV DC transmission lines has drawn public attention. To investigate the effect of SEF exposure on white blood cell (WBC) count, mice were exposed to 56.3 kV/m SEF. Results revealed that total WBC count and lymphocyte count significantly decreased and serum levels of corticotropin-releasing hormone, adrenocorticotropic hormone and corticosterone (CORT) significantly increased after the exposure of 7d and 14d. All indices above recovered after the exposure of 21d. Analysis showed that the exposure of 7d and 14d could activate hypothalamic-pituitary-adrenal (HPA) axis. The increased CORT could bind to the glucocorticoid receptor (GR) in lymphocytes, and then promote the migration and apoptosis of lymphocytes. After the exposure of 21d, the magnitude of HPA axis activation declined through CORT-mediated negative feedback and the regulation of stress-related neural circuitry, so WBC count recovered.

Restricted cafeteria feeding and treadmill exercise improved body composition, metabolic profile and exploratory behavior in obese male rats

The aim of this study was to evaluate, in male Long-Evans rats, whether a restricted-cafeteria diet (CAFR), based on a 30% calorie restriction vs continuous ad libitum cafeteria (CAF) fed animals, administered alone or in combination with moderate treadmill exercise (12 m/min, 35 min, 5 days/week for 8 weeks), was able to ameliorate obesity and the associated risk factors induced by CAF feeding for 18 weeks and to examine the changes in circadian locomotor activity, hypothalamic–pituitary–adrenal (HPA) axis functionality, and stress response elicited by this dietary pattern. In addition to the expected increase in body weight and adiposity, and the development of metabolic dysregulations compatible with Metabolic Syndrome, CAF intake resulted in a sedentary profile assessed by the home-cage activity test, reduced baseline HPA axis activity through decreased corticosterone levels, and boosted exploratory behavior. Both CAFR alone and in combination with exercise reduced abdominal adiposity and hypercholesterolemia compared to CAF. Exercise increased baseline locomotor activity in the home-cage in all dietary groups, boosted exploratory behavior in STD and CAF, partially decreased anxiety-like behavior in CAF and CAFR, but did not affect HPA axis-related parameters.

High salt intake activates the hypothalamic-pituitary-adrenal axis, amplifies the stress response, and alters tissue glucocorticoid exposure in mice.

High salt intake is common and contributes to poor cardiovascular health. Urinary sodium excretion correlates directly with glucocorticoid excretion in humans and experimental animals. We hypothesized that high salt intake activates the hypothalamic-pituitary-adrenal axis activation and leads to sustained glucocorticoid excess. In male C57BL/6 mice, high salt intake for 2-8 weeks caused an increase in diurnal peak levels of plasma corticosterone. After 2 weeks, high salt increased Crh and Pomc mRNA abundance in the hypothalamus and anterior pituitary, consistent with basal hypothalamic-pituitary-adrenal axis activation. Additionally, high salt intake amplified glucocorticoid response to restraint stress, indicative of enhanced axis sensitivity. The binding capacity of Corticosteroid-Binding Globulin was reduced and its encoding mRNA downregulated in the liver. In the hippocampus and anterior pituitary, Fkbp5 mRNA levels were increased, indicating increased glucocorticoid exposure. The mRNA expression of the glucocorticoid-regenerating enzyme, 11β-hydroxysteroid dehydrogenase Type 1, was increased in these brain areas and in the liver. Sustained high salt intake activated a water conservation response by the kidney, increasing plasma levels of the vasopressin surrogate, copeptin. Increased mRNA abundance of Tonebp and Avpr1b in the anterior pituitary suggested that vasopressin signalling contributes to hypothalamic-pituitary-adrenal axis activation by high salt diet. Chronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells.

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) &lt; .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.

Evaluation of psychological stress, cortisol awakening response, and heart rate variability in patients with chronic prostatitis/chronic pelvic pain syndrome complicated by lower urinary tract symptoms and erectile dysfunction.

Mental stress and imbalance of its two neural stress systems, the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis, are associated with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED). However, the comprehensive analyses of psychological stress and stress systems are under-investigated, particularly in CP/CPPS patients complicated by lower urinary tract symptoms (LUTS) and ED. Participants were 95 patients in CP/CPPS+ED group, 290 patients in CP/CPPS group, 124 patients in ED group and 52 healthy men in control group. The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), the International Index of Erectile Function-5 (IIEF-5) and the International Prostate Symptom Score (IPSS) were used for assessing the disease severity of CP/CPPS, LUTS and ED. Psychometric self-report questionnaires including the Beck Anxiety Inventory (BAI), Perceived Stress Scale (PSS), Type A Personality Test (TAPT) and Symptom Checklist 90 (SCL-90) were completed for distress from physical symptoms. Twenty-five subjects per group were randomly selected for further investigating the changes of the HPA axis and ANS. Saliva samples were taken on 3 consecutive days at 8 specific times with strict reference to time of morning awakening for evaluation of free cortisol. Heart rate variability (HRV) as marker of the ANS was measured using 24 h electrocardiography, and time-and frequency-domain variables were analyzed. The BAI and SCL-90 scores were significantly higher in the CP/CPPS+ED, CP/CPPS and ED groups compared with the control group (p < 0.01). The PSS scores of both groups with ED were significantly higher than the control group (p < 0.01). Compared with the CP/CPPS group, the differences of PSS, SCL-90 and TAPT scores were statistically significant in CP/CPPS+ED patients (p < 0.01). The IPSS scores were shown to have significantly positive correlations with BAI (r = 0.32, p < 0.0001), PSS (r = 0.18, p < 0.01) and SCL-90 (r = 0.19, p < 0.01) in the CP/CPPS patients. However, in all subjects, the IIEF-5 scores were shown to have significantly negative correlations with BAI (r = -0.17，p < 0.001), PSS (r = -0.25，p < 0.0001), SCL-90 (r = -0.20，p < 0.001) and quality of life score in NIH-CPSI (r = -0.14，p = 0.0075). Cortisol awakening response (CAR) parameters and diurnal cortisol levels did not significantly vary between the four groups. Time-dependent parameters of HRV also did not differ significantly across groups. In the frequency domain analysis, low frequency (LF) was significantly lower in ED patients when compared with CP/CPPS+ED patients (p = 0.044) and healthy controls (p = 0.005), high frequency (HF) power was significantly higher in healthy controls compared to patients with ED (p < 0.001), CP/CPPS (p < 0.001) and CP/CPPS+ED (p < 0.001), and the CP/CPPS+ED group had significantly higher LF/HF ratio than the control group (p = 0.001). CP/CPPS and ED patients score exceedingly high on most psychosocial variables. The symptom scores of LUTS and ED positively correlate with the severity of psychological stress. Our findings also suggest that the ANS sympathovagal imbalance is associated with ED and LUTS in CP/CPPS, whereas HPA axis activity is not.

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.

Peripheral glucocorticoid receptor antagonism by relacorilant with modest HPA axis disinhibition.

Glucocorticoid stress hormones are produced in response to hypothalamic-pituitary-adrenal (HPA) axis activation. Glucocorticoids are essential for physiology and exert numerous actions via binding to the glucocorticoid receptor (GR). Relacorilant is a highly selective GR antagonist currently undergoing a phase 3 clinical evaluation for the treatment of endogenous Cushing's syndrome. It was found that increases in serum adrenocorticotropic hormone (ACTH) and cortisol concentrations after relacorilant treatment were substantially less than the increases typically observed with mifepristone, but it is unclear what underlies these differences. In this study, we set out to further preclinically characterize relacorilant in comparison to the classical but non-selective GR antagonist mifepristone. In human HEK-293 cells, relacorilant potently antagonized dexamethasone- and cortisol-induced GR signaling, and in human peripheral blood mononuclear cells, relacorilant largely prevented the anti-inflammatory effects of dexamethasone. In mice, relacorilant treatment prevented hyperinsulinemia and immunosuppression caused by increased corticosterone exposure. Relacorilant treatment reduced the expression of classical GR target genes in peripheral tissues but not in the brain. In mice, relacorilant induced a modest disinhibition of the HPA axis as compared to mifepristone. In line with this, in mouse pituitary cells, relacorilant was generally less potent than mifepristone in regulating Pomc mRNA and ACTH release. This contrast between relacorilant and mifepristone is possibly due to the distinct transcriptional coregulator recruitment by the GR. In conclusion, relacorilant is thus an efficacious peripheral GR antagonist in mice with only modest disinhibition of the HPA axis, and the distinct properties of relacorilant endorse the potential of selective GR antagonist treatment for endogenous Cushing's syndrome.

Gut microbiota mediated inflammation, neuroendocrine and neurotrophic functions involved in the antidepressant-like effects of diosgenin in chronic restraint stress

BackgroundDiosgenin is a well-known steroid saponin possessing neuroprotective activities. However, it is unknown whether diosgenin could alleviate depression-like symptoms. MethodsThe antidepressant-like effect of diosgenin was investigated in mice induced by chronic restraint stress. The effects of diosgenin on behaviors, inflammation, neuroendocrine, neurotrophic function, and gut microbiota were evaluated. ResultsThe results showed that diosgenin alleviated the depressive-like behaviors in mice. In addition, diosgenin was found to reduce serum concentrations of proinflammatory cytokines and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Besides, diosgenin could activate hippocampal brain-derived neurotrophic factor (BDNF)/TrkB/ERK/CREB signaling pathway and improve the expression of postsynaptic protein PSD95. Meanwhile, the neurogenesis which was inhibited by chronic restraint stress, was totally reversed by diosgenin. Moreover, diosgenin increased the abundance of phylum Firmicutes and the genus Lactobacillus in stressed mice. The results further showed that diosgenin caused a strong correlation between gut microbiota composition and inflammation, the HPA axis activity, or hippocampus neurotrophic function. LimitationsOnly male mice were used for evaluation in the present study, which limits the understanding of effects of diosgenin on the both sexes. In addition, the results only indicate microbiota at the phylum or genus mediate the regulation of neuroinflammation, neuroendocrine, and neurotrophic function, but does not elucidate how microbiota modulate the systems via their primary or secondary metabolites. ConclusionsThe present study shows that diosgenin exerts the antidepressant activity, which is associated with the enhancement of neurotrophic function and the inhibition of inflammatory and neuroendocrine activities via the regulation of gut microbiota.

Subjective memory complaints in young people: the role of resilience

Objective Little is known about the origin and associated factors of subjective memory complaints (SMCs) in the young population, although they might be closely related to the psychophysiological states produced by stress exposure, such as anxiety and depression. In this regard, resilience has been related to a reduction in these negative states, as well as to more adaptive hypothalamic-pituitary-adrenal (HPA) axis functioning. We aimed to investigate the importance of depression, anxiety, and HPA axis activity in SMCs in the young population. We also analysed the relationship between resilience and SMCs through the mediation of depression, anxiety, and the cortisol awakening response (CAR). Design To do so, we measured SMCs, depression and anxiety states, resilience, and the CAR in 77 healthy young people. Results Both depression and anxiety were associated with SMCs. In addition, greater resilience was related to fewer SMCs through depression and anxiety. However, the CAR was not related to SMCs, and it did not mediate the relationship between resilience and SMCs. Conclusion These results suggest that negative affective states have greater importance in SMCs than HPA functioning in this age group, and they also highlight the importance of resilience in the psychological adjustment to stressful situations.

Delayed effects of neonatal immune activation on brain neurochemistry and hypothalamic-pituitary-adrenal axis functioning.

During the postnatal period, the brain is highly sensitive to stress and inflammation, which are hazardous to normal growth and development. There is increasing evidence that inflammatory processes in the early postnatal period increase the risk of psychopathologies and cognitive impairment later in life. On the other hand, there are few studies on the ability of infectious agents to cause long-term neuroinflammation, leading to changes in the hypothalamic-pituitary-adrenal axis functioning and an imbalance in the neurotransmitter system. In this review, we examine short- and long-term effects of neonatal-induced inflammation in rodents on glutamatergic, GABAergic and monoaminergic systems and on hypothalamic-pituitary-adrenal axis activity.

Effect of Vitamin D3 Treatment on Genes Expression of Corticotrophin Releasing Hormone (CRH), CRH Receptor 1 (CRH-R1) and Connexin-43 (CON-43) in PHM1-41 Cell Line that Induced by Hypoxia

Introduction: Hypothalamic-Pituitary-Adrenal (HPA) axis activity is one of pathophysiologic mechanism that caused preterm labor. Biologic maternal stress, for instance hypoxia condition, is one of the causes that can trigger preterm birth occasion through the activation of HPA axis. It increases Corticotrophin Releasing Hormone (CRH), CRH receptor 1 (CRH-R1), and Connexin-43 (CON-43) as the trigger of the contraction process. Vitamin D as a source of Ca2+ ion is needed for myometrium smooth muscle’s concentrations and relaxation mechanism. The aim of this study was to determine the effect of vitamin D3 in PHM1-41 cell line. Materials and Methods: The human smooth muscle uterine myometrium cell line PHM1-41 as an in vitro model experimental subject, treated by hypoxia oxidative stress condition and added by vitamin D3 (5, 10, 50 and 150 nM). The dichlorodihydrofluorescein diacetate (DCFDA) fluorescent was used to measure the level of intracellular reactive oxygen species (ROS). In addition, RNA of treated PHM1-41cells was isolated for analyzing gene expressions such as CRH, CRH-R1, and CON-43 as a profile of contractility regulation. Results: ROS level effectively decrease in the cells that treated by 150 nM vitamin D3 group compared to the control hypoxia cell group (7.16 ± 0.23 and 19.49 ± 1.76, respectively). Expression of CRH, CRH-R1, and CON-43 genes are also decrease by treated with 150 nM vitamin D3 to the cells. Pearson (parametric) correlation analysis evidenced a negative correlation between the vitamin D3 additional treated to the lower of ROS level, CRH, CRH-R1, and CON-43 genes expression on PHM1-41 cell line that induced by oxidative stress condition. Conclusion: The concentration of 150 nM vitamin D3 was a prominent potency to prevent the incidence of preterm labor.&#x0D; HIGHLIGHTS&#x0D; &#x0D; Hypothalamic-Pituitary-Adrenal (HPA) axis is one of the causes of preterm birth that marked by high level of intracellular ROS leads to increasing of Corticotrophin Releasing Hormone (CRH) which has significant role in aterm and preterm labor&#x0D; PHMI-41 cells can describe the Corticotrophin Releasing Hormone (CRH), CRH receptor 1 (CRH-R1), and Connexin-43 (CON-43) genes expression level so it was used as model of human pregnancy condition&#x0D; Vitamin D3 is one of antioxidant agent that can decrease ROS level also CRH, CRH-R1, and CON-43 genes expression on PHM1-41 cell especially at doses of 150 nM which shown a prominent potency to prevent the preterm labor incidence&#x0D; &#x0D; GRAPHICAL ABSTRACT

Does stress predict the development of internalizing symptoms in middle childhood? An examination of additive, mediated, and moderated effects of early family stress, daily interpersonal stress, and physiological stress.

Early life stress, daily life experiences, and the stress responsive hypothalamic-pituitary-adrenal (HPA) axis have each been examined as predictors of the development of psychopathology. Rarely have researchers attempted to understand the covariation or interaction among these stress domains using a longitudinal design in the prediction of symptoms of internalizing psychopathology, particularly during childhood. This study examined early family stress, daily interpersonal stress, indicators of diurnal cortisol, and internalizing symptoms in a racially/ethnically and socioeconomically diverse sample of twins (N = 970 children; Mage at outcome = 9.73; 52% female; 23.7% Hispanic/Latino, 58.8% White; 30% below middle class; Lemery-Chalfant et al., 2019). An additive model of stress, a stress mediation model, and a stress sensitization framework model each delineated potential pathways linking stress and internalizing symptoms. Supporting additive pathways, multilevel models showed that all 3 stress indicators uniquely predicted internalizing symptoms. There was a significant indirect path from early family stress to 9 year internalizing symptoms through interpersonal stress, supporting stress mediation. Family stress moderated the association between interpersonal stress and internalizing symptoms, though not in the direction that would support stress sensitization. Child stress, including daily interpersonal stress and HPA axis activity, and internalizing symptoms are prevalent and family stress is a significant precursor to child internalizing symptoms across child development. (PsycInfo Database Record (c) 2022 APA, all rights reserved).