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ABSTRACT Objective Methods Results Conclusion Children with intellectual disability (ID) usually exhibit neuroendocrine functioning impairment, such as alterations in the hypothalamic–pituitary–adrenal (HPA) neuroendocrine axis, which can result in glucocorticoid cortisol release alterations. Indeed, many studies showed a positive association between ID and cortisol concentration. However, evidence is lacking on the relationship between child neurodevelopment and cortisol levels during adolescence in population‐based studies. We aimed to test the association between ID and hair cortisol concentration (HCC) during adolescence in a prospective population‐based cohort.Data from 1770 individuals in the 2004 Pelotas Birth Cohort were used. ID was diagnosed at age 6 through clinical examination. Hair cortisol was measured at age 15. Association was assessed using linear regression models adjusted for sex, socio‐economic factors, hair‐related variables and corticosteroid use.Higher HCC were observed in individuals with ID (β: 1.120; 95% CI: 1.012, 1.241) in the analysis adjusted for sex, hair‐related variables and corticosteroid use. Compared to the other aetiological groups, this was more evident in idiopathic ID. But this did not remain significant when demographics/socio‐economic variables were controlled for.Children with ID, particularly those with idiopathic ID, might exhibit dysfunction in the HPA axis or experience heightened stress levels during adolescence. [ABSTRACT FROM AUTHOR]

Post-COVID-19 condition (PCC) is frequently associated with multiple endocrine hormone disturbances, primarily involving the hypothalamic–pituitary–adrenal axis. However, the exact cause remains unclear, particularly concerning whether these symptoms result from hypothalamus damage. This study reports on the clinical characteristics and examination methods of five patients exhibiting multiple endocrine disorders during PCC following SARS-CoV-2 infections, as well as the corresponding treatment strategies. Insulin tolerance test (ITT), arginine stimulation test, rapid adrenocorticotropic hormone (ACTH) stimulation test, and supine–standing test were used to evaluate endocrine hormone disturbances. Magnetic resonance imaging of the pituitary and computed tomography of the adrenal gland on one patient were performed to reveal the pathology. All five patients had hypothalamic syndrome with secondary adrenal insufficiency, growth hormone (GH) deficiency, and secondary hyperaldosteronism. Treatment included ACTH injection, recombinant human GH injection, and/or oral administration of synthetic glucocorticoids (prednisone acetate or methylprednisolone) and mineralocorticoid receptor antagonist finerenone. Remarkable improvement was observed within one week for all patients. To assess disorders in the hypothalamic–pituitary–§adrenal axis, dynamic endocrine testing is recommended. Upon confirmation of a diagnosis, timely supplementation of ACTH, glucocorticoids, GH, and aldosterone antagonists can yield remarkable therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Background: Dysfunctions of the hypothalamic‐pituitary‐adrenal (HPA) axis can trigger multiple sclerosis (MS) symptoms. Mood disorders comorbid with MS are implicated in the HPA axis activation in most people with MS (pwMS). This study purposed to examine salivary cortisol (SC) levels and their association with mood disorders in pwMS. Methods: Forty‐three men as pwMS and sixteen men as healthy controls (HC) were included in this study. pwMS and HC completed the Beck Depression Inventory (BDI), 36‐Item Short Form Survey (SF‐36), Fatigue Severity Scale (FSS), Depression Anxiety and Stress Scale, and Hospital Anxiety and Depression Scale questionnaires. SC levels were also measured in pwMS and HC. A linear regression model was used to analyze the relationship between the Expanded Disability Status Scale (EDSS) and mood disorders and SC levels. Pearson's or Spearman's tests examined the correlation between SC levels and mood disorders. Results: The SC level, anxiety, depression, fatigue, and stress were significantly higher in pwMS than in HC (p < 0.05). pwMS also showed significant correlations between SC levels and role physical (r = 0.3, p < 0.05) and emotional (r = 0.34, p < 0.05) in SF‐36. Among SF‐36 domains, only general health (β = −0.72, p < 0.05) and physical functioning (β = −1.61, p < 0.05) were negatively associated with disease duration. No correlation was found between SC levels and anxiety, depression, and fatigue (p > 0.05). Conclusions: The pwMS showed mild to moderate depression, anxiety, and fatigue. Only general health and physical functioning as aspects of quality of life were related to disease duration, while SC levels, mood disorders, and other quality‐of‐life domains were not associated with clinical characteristics. Also, this study failed to find a significant role for SC as a valuable marker in approaching mood disorders in pwMS. [ABSTRACT FROM AUTHOR]

ABSTRACT We examined the feasibility of using the neofunctional deep breathing (NDB) technique to reduce the allostatic load following the Trier Social Stress Test (TSST). Forty‐four healthy subjects were randomised into experimental and control groups. Following the TSST procedure, participants underwent either a single session of NDB or an attention control intervention. The Procomp Infinity Biofeedback system measured breath per minute (BPM), respiratory amplitude, HRV linear domains, skin conductance, and trapezius muscle electromyographic activity. Cortisol and cytokine salivary concentrations, perceived stress, and anxiety levels were also assessed. These parameters were combined into an allostatic load index (ALI) to measure the intervention's effect. This pilot RCT demonstrated the feasibility of the study design and practicality of the intervention. The NDB group showed reduced ALI, increased respiratory abdominal amplitude, decreased BPM, increased HRV indicating parasympathetic activation, and decreased cortisol and inflammatory cytokines. This study highlighted the feasibility of testing the NDB technique in reducing allostatic load through a neurobiological and anti‐inflammatory response after exposure to psychosocial stress. This protocol can represent a non‐invasive therapeutic adjutant in disorders related to a dysregulation of the HPA axis or to an inflammatory state.Trial Registration: NCT04102813 [ABSTRACT FROM AUTHOR]

The relationship between neurotransmitters and oxidative stress in Major Depressive Disorder (MDD) patients, considering HPA axis activity and psychological and cognitive states, is unclear. This study examines changes in neurotransmitters (GABA, Glx) and antioxidants (GSH) in the dorsal anterior cingulate cortex (dACC) of MDD patients under varying levels of ACTH, and their relationship with psychological and cognitive conditions. Forty-five MDD patients were divided into high-ACTH (>65 pg/mL; n = 16) and normal-ACTH (7–65 pg/mL; n = 29) groups based on blood ACTH levels, along with 12 healthy controls (HC). All participants underwent HAM-D, HAM-A assessments, and most completed MMSE and MoCA tests. GABA+, Glx, and GSH levels in the dACC were measured using the MEGA-PRESS sequence. Intergroup differences and correlations between clinical factors, HPA axis activity, and metabolites were analyzed. Compared to HC, the normal ACTH group showed higher Glx and lower GSH levels. Glx and GSH were negatively correlated with MDD severity. In the high-ACTH MDD group, Glx positively correlated with delayed memory, and GSH positively correlated with abstraction. Factors influencing GABA included ACTH levels, depression duration, and negative events. Predictive factors for HAM-D scores were GSH and GABA. The sample size is small. MDD patients exhibit neurochemical differences in the brain related to HPA axis levels, MDD severity, and cognitive function. Clinical factors, neurotransmitters, and neuroendocrine levels significantly influence depression severity. [Display omitted] • Compared to healthy controls, the normal ACTH MDD patients had higher Glx and lower GSH levels • Glx and GSH levels were inversely related to MDD severity • In the high ACTH MDD group, Glx positively correlated with delayed memory, and GSH with abstraction • Neurochemical differences in MDD patients' brains at varying HPA axis levels are linked to MDD severity and cognitive function [ABSTRACT FROM AUTHOR]

The excessive secretion of glucocorticoids resulting from the overactivation of the hypothalamic-pituitary-adrenal axis is a crucial factor in the pathogenesis of depression. RIPK3 plays a significant role in apoptosis and necroptosis. Glucocorticoids have been implicated in directly regulating the expression of RIPK3, leading to apoptosis and necroptosis of osteoblasts. This suggests that RIPK3 may contribute to cell death induced by glucocorticoids. However, the precise involvement of RIPK3 in glucocorticoid-induced depression remains poorly understood. In this study, a mouse model of depression was established by repeated corticosterone injections to examine the impact of RIPK3 knockdown on depression-like behavior. Additionally, a corticosterone-induced HT22 injury model was also established to investigate the role of RIPK3 in corticosterone-induced neuronal cell death and underlying mechanisms. Our findings demonstrate that hippocampal RIPK3 knockdown effectively ameliorated depression-related symptoms and restored synaptic plasticity impairment caused by corticosterone. Furthermore, treatment with the RIPK3 inhibitor GSK872 in vitro successfully mitigated corticosterone-induced HT22 cell death. Additionally, the administration of a free radical scavenger alleviated neuronal death and effectively suppressed the expression of corticosterone-induced RIPK3. The limitation of this study is that only the changes of RIPK3 in the hippocampus of depressed male animals were studied. These results suggest that corticosterone may induce RIPK3-dependent neuronal cell death and impair synaptic plasticity through the generation of high levels of oxidative stress, ultimately leading to depression-like behavior. Excessive corticosterone levels resulted in RIPK3-dependent neuronal loss and impairment of synaptic plasticity, ultimately leading to depression-like behavior. Elevated levels of RIPK3 may be associated with increased intracellular oxidative stress caused by corticosterone. Moreover, there was a detrimental cycle of reciprocal reinforcement between RIPK3 and oxidative stress, exacerbating the damage induced by corticosterone. Knockdown of RIPK3 in the hippocampus effectively reversed the depression-like behavior, synaptic plasticity impairment, and neuronal loss induced by corticosterone. [Display omitted] • Corticosterone increases RIPK3-level in the hippocampus. • Elevated RIPK3 leads to depressive behavior through neuronal death promotion. • RIPK3 down-regulation prevents corticosterone-induced depression-like behavior. • A corticosterone-induced increase of RIPK3 is associated with excessive oxidative stress. • Targeting RIPK3 represents a new treatment strategy of depression. [ABSTRACT FROM AUTHOR]

Children today are immersed in electronic technology shortly after birth as they now begin regularly watching television earlier than they did in the past. Many new programs geared towards infants contain lots of lights, color, and sounds, which may constitute a form of sensory overstimulation (SOS) that leads to cognitive and behavioral changes in children and adolescents. Here, we examined the impact of early life SOS exposure on later life behavioral and cognitive function in rodents by exposing developing male and female rats to excessive audiovisual stimulation from postnatal days (PND) 10–40 and assessing anxiety-like behavior, social motivation, compulsive behavior, and spatial learning/cognition from PND 50–60. To evaluate potential SOS effects on hypothalamic–pituitary–adrenal (HPA)-axis function, levels of the stress hormone corticosterone (CORT) were measured at 3 timepoints (e.g., PND 23, 41, 61) post-SOS exposure. Sensory overstimulated males exhibited reduced anxiety-like and compulsive behavior compared to controls, whereas females exhibited reduced social motivation but enhanced spatial learning/cognition compared to controls. No differences in baseline CORT levels were found at any age tested, suggesting no impact of early life SOS on later life basal HPA-axis function. Our results demonstrate sex-specific effects of early life SOS on distinct behavioral domains in early adult rats. [ABSTRACT FROM AUTHOR]

Introduction: Children with Attention Deficit/Hyperactivity Disorder (ADHD) participated in a randomized clinical trial comparing animal-assisted intervention (AAI) to psychosocial treatment as usual (TAU). This brief report describes effects of AAI on acute HPA axis reactivity and regulation. Saliva was collected before, during, and after psychosocial intervention sessions with and without therapy dogs and later assayed for cortisol (ug/dL). Methodology: Thirty-nine participants (n = 39) with ADHD, aged 7-9 years (79% male) provided saliva at 3 points during 90-minute sessions; (i) upon arrival, (ii) +20 minutes, and (iii) 15 minutes prior to departure, on 3 occasions across an 8-week intervention (weeks 1, 4, and 8). Cortisol slopes calculated within each session were compared across the intervention weeks to determine within subject and between group effect sizes. Spearman's correlations between baseline individual neurodevelopmental symptoms and in-session acute cortisol responses were also evaluated. Results: No significant between group differences were observed in cortisol responsiveness at week-1. By week-4, in-session changes in cortisol were evident, with significantly greater decreases in the AAI group (Cohen's d = -.40). This pattern was also observed at week-8, with an even stronger effect-size (d = -0.60). Concurrent symptoms of autism were associated with the in-session acute cortisol response. Specifically, higher parent-reported symptom scores were associated with steeper decreases in cortisol across the session at week 1 (r = -0.42, p <.01) and week-8 (r = -0.34 p =.05). At week-8 this association was stronger in the AAI group (r = -0.53) versus TAU (r = -0.25), with Cohen's q = 0.413). Discussion: AAI may influence acute HPA reactivity and regulation for children with ADHD. Concurrent symptoms of ADHD and autism may be related to individual differences in the nature of the effect. Implications of these findings for AAI as an alternative, or complementary intervention for ADHD are discussed. Clinical trial registration: ClinicalTrials.gov, identifier NCT05102344. [ABSTRACT FROM AUTHOR]

Cannabinoid hyperemesis syndrome presents as a complex of symptoms and signs encompassing nausea, vomiting, abdominal pain, and hot water bathing behavior, most typically in a heavy cannabis user. Its presentation is frequently associated with hypothalamic-pituitary-adrenal axis activation with stress and weight loss. Recent investigation has identified five statistically significant mutations in patients distinct from those of frequent cannabis users who lack the symptoms, affecting the TRPV1 receptor, two dopamine genes, the cytochrome P450 2C9 enzyme that metabolizes tetrahydrocannabinol, and the adenosine triphosphate-binding cassette transporter. The syndrome is associated with escalating intake of high potency cannabis, or alternatively, other agonists of the cannabinoid-1 receptor including synthetic cannabinoids. Some patients develop environmental triggers in scents or foods that suggest classical conditioned responses. Various alternative "causes" are addressed and refuted in the text, including exposure to pesticides, neem oil or azadirachtin. Nosological confusion of cannabinoid hyperemesis syndrome has arisen with cyclic vomiting syndrome, whose presentation and pathophysiology are clearly distinct. The possible utilization of non-intoxicating antiemetic cannabis components in cannabis for treatment of cannabinoid hyperemesis syndrome is addressed, along with future research suggestions in relation to its genetic foundation and possible metabolomic signatures. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a complex heterogenous disorder manifesting with various reproductive, endocrine, and metabolic derangements such as insulin resistance and hyperglycemia. The arginine vasopressin peptide (AVP), also called or antidiuretic hormone (ADH), modulates metabolic functions such as glucose hemostasis, insulin sensitivity, and lipid metabolism via binding to two central and peripheral receptors (AVPR1A and AVPR1B). In the present study, we aimed to detect whether the AVPR1A and AVPR1B genes confer risk for PCOS. Methods: In peninsular Italian families, we tested 7 variants in the AVPR1B gene and 2 variants in the AVPR1A gene via Pseudomarker for linkage and linkage joint to association (i.e.., linkage disequilibrium) with PCOS. Results: We identified two risk variants in each gene, significantly associated with the risk of PCOS. Conclusion: To the best of our knowledge, this is the first study to report risk variants in AVPR1A and AVPR1B genes in association with PCOS. However, replication in other ethnic groups as well as functional studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

• Maternal and postnatal docosahexaenoic acid intake may play a role in brain function of infants. • Docosahexaenoic acid supplementation induces microbial shifts in the gut of infants. • Health benefits of docosahexaenoic acid on cognition may be through modulation of gut–brain axis. Perinatal stage represents a critical period for brain development. Docosahexaenoic acid (DHA) is a ω-3 polyunsaturated fatty acid preferentially accumulated in the brain that may benefit neurodevelopment. Microbial colonization and maturation parallel with the rapid development of infant metabolic and brain function that may influence the effects of DHA on neurological development. This review aims to summarize the current literature on the mediating effects of DHA on brain and gut microbiome development and attempts to reevaluate the efficacy of DHA from a gut microbiome–mediated perspective. Specifically, the regulatory roles of DHA on hypothalamic-pituitary-adrenal axis, inflammation, and neuroactive mediators may be partly moderated through gut microbiome. Consideration of the gut microbiome and gut–brain communication, when evaluating the efficacy of DHA, may provide new insights in better understanding the mechanisms of DHA and impart advantages to future development of nutritional therapy based on the nutrient-microbiome interaction. Potential mechanisms of DHA in shaping the gut microbiome to impact brain development and function. Abbreviations: DHA, docosahexaenoic acid; HPA, hypothalamic-pituitary-adrenal. Figure created with BioRender.com. [Display omitted] [ABSTRACT FROM AUTHOR]

The future of depression pharmacotherapy lies in a precision medicine approach that recognizes that depression is a disease where different causalities drive symptoms. That approach calls for a departure from current diagnostic categories, which are broad enough to allow adherence to the "one-size-fits-all" paradigm, which is complementary to the routine use of "broad-spectrum" mono-amine antidepressants. Similar to oncology, narrowing the overinclusive diagnostic window by implementing laboratory tests, which guide specifically targeted treatments, will be a major step forward in overcoming the present drug discovery crisis. A substantial subgroup of patients presents with signs and symptoms of hypothalamic-pituitary-adrenocortical (HPA) overactivity. Therefore, this stress hormone system was considered to offer worthwhile targets. Some promising results emerged, but in sum, the results achieved by targeting corticosteroid receptors were mixed. More specific are non-peptidergic drugs that block stress-responsive neuropeptides, corticotropin-releasing hormone (CRH), and arginine vasopressin (AVP) in the brain by antagonizing their cognate CRHR1-and V1b-receptors. If a patientʼs depressive symptomatology is driven by overactive V1b-signaling then a V1b-receptor antagonist should be first-line treatment. To identify the patient having this V1b-receptor overactivity, a neuroendocrine test, the so-called dex/CRH-test, was developed, which indicates central AVP release but is too complicated to be routinely used. Therefore, this test was transformed into a gene-based "near-patient" test that allows immediate identification if a depressed patient's symptomatology is driven by overactive V1b-receptor signaling. We believe that this precision medicine approach will be the next major innovation in the pharmacotherapy of depression. [ABSTRACT FROM AUTHOR]

This series of three articles will explore the fundamentals related to anatomy, physiology and pathophysiology in relation to three important topics: the cardiac system, the respiratory system and the endocrine system. The series is intended to provide an informative and evidence-based summary of each topic for both students and clinicians. This third and final paper explores the maternal endocrine system, outlining the key physiological adaptations in pregnancy and summarising the key pathophysiological conditions that may occur. [ABSTRACT FROM AUTHOR]

There are currently no effective treatments to prevent, halt, or reverse Alzheimer's disease (AD), the most common cause of dementia in older adults. Melatonin, a relatively harmless over-the-counter supplement, may offer some benefits to patients with AD. Melatonin is known for its sleep-enhancing properties, but research shows that it may provide other advantages as well, such as antioxidant and anti-amyloidogenic properties. Clinical trials for melatonin use in AD have mixed results but, overall, show modest benefits. However, it is difficult to interpret clinical research in this area as there is little standardization to guide the administration and study of melatonin. This review covers basic biology and clinical research on melatonin in AD focusing on prominent hypotheses of pathophysiology of neurodegeneration and cognitive decline in AD (i.e., amyloid and tau hypotheses, antioxidant and anti-inflammation, insulin resistance and glucose homeostasis, the cholinergic hypothesis, sleep regulation, and the hypothalamic-pituitary-adrenal axis and cortisol). This is followed by a discussion on pending clinical trials, considerations for future research protocols, and open questions in the field. [ABSTRACT FROM AUTHOR]

Air pollution exposure is ranked as a leading environmental risk factor for not only cardiopulmonary diseases but also for systemic health ailments including diabetes, reproductive abnormalities, and neuropsychiatric disorders, likely mediated by central neural stress mechanisms. Current experimental evidence links many air pollution health outcomes with activation of neuroendocrine sympathetic-adrenal-medullary and hypothalamic–pituitary–adrenal (HPA) stress axes associated with resultant increases in adrenal-derived hormone levels acting as circulating mediators of multi-organ stress reactions. Epidemiological and experimental investigations also demonstrated sex-specific responses to air pollutant inhalation, which may be attributed to hormonal interactions within the stress and reproductive axes. Sex hormones (androgens and estrogens) interact with neuroendocrine functions to influence hypothalamic responses, subsequently augmenting stress-mediated metabolic and immune changes. These neurohormonal interactions may contribute to innate sex-specific responses to inhaled irritants, inducing differing individual susceptibility. The aim of this review was to: (1) examine neuroendocrine co-regulation of the HPA axis by gonadal hormones, (2) provide experimental evidence demonstrating sex-specific respiratory and systemic effects attributed to air pollutant inhalation exposure, and (3) postulate proposed mechanisms of stress and sex hormone interactions during air pollution-related stress. Highlights: Air pollution exposure responses are co-regulated by stress and sex hormones Hypothalamic and CNS stress reactions are sensitive to sex hormones Estrogen and testosterone influence HPA axis induction and glucocorticoid dynamics Neuroendocrine axes interactions mediate sex-specific air pollutant health effects [ABSTRACT FROM AUTHOR]

Research confirms that stress is associated with alcohol drinking and relapse in males and females and that there are sex differences in the alcohol-related adaptations of stress pathways. The predator stress (PS) model of traumatic stress produces an increase in alcohol drinking or self-administration in a subpopulation of rodents, so it is utilized as an animal model of comorbid alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD). Previous work determined that sensitivity to PS-enhanced drinking produced sex differences in proteins related to stress-regulating systems in the medial prefrontal cortex and hippocampus. The present studies examined whether male and female C57BL/6J mice differ in sensitivity to the ability of the corticotropin releasing factor receptor 1 antagonist CP-376395 to decrease PS-enhanced drinking. In control studies, CP-376395 doses of 5, 10, and 20 mg/kg dose-dependently decreased 4-h ethanol drinking. Next, CP-376395 doses of 5 and 10 mg/kg were tested for effects on ethanol drinking in mice with differential sensitivity to PS-enhanced drinking. Subgroups of "Sensitive" and "Resilient" male and female mice were identified based on changes in ethanol intake in an unrestricted-access ethanol-drinking procedure following four exposures to PS (dirty rat bedding). During the first 2 h post-injection of CP-376395, both doses significantly decreased ethanol licks versus vehicle in the females, with no significant interaction between subgroups, whereas the 10 mg/kg dose significantly decreased ethanol licks versus vehicle in the "Resilient" males. Thus, sensitivity to the suppressive effect of CP-376395 on stress-induced ethanol intake was greater in females versus males, whereas sensitivity and resilience to PS-enhanced drinking produced differential sensitivity to the ability of CP-376395 to decrease ethanol drinking only in male mice. Our results argue against greater efficacy of CRF-R1's ability to decrease ethanol intake in subjects with traumatic stress-enhanced ethanol drinking. • CRF-R1 antagonist CP-376395 decreased alcohol intake in control male and female mice. • This decrease was less alcohol-selective in male than in female mice. • CP-376395 decreased alcohol intake in female mice following repeated predator stress. • CP-376395 decreased such intake only in males resistant to stress-enhanced drinking. • Predator stress-enhanced alcohol drinking does not increase CRF-R1 sensitivity. [ABSTRACT FROM AUTHOR]

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths in women, with psychosocial stress commonly cited by patients as one of its causes. While there is conflicting epidemiological evidence investigating the association between psychosocial stress and breast cancer incidence and progression, there is reason to believe that interventions aimed at reducing stress pharmacologically or psychologically may improve breast cancer outcomes. The aim of this review is to discuss the molecular and biological mechanisms of stress-attributed breast cancer incidence and progression, including the induction of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS), as well as decreased immune function and stress hormone-induced resistance to chemotherapy. Moreover, these mechanisms have been cited as potential therapeutic targets of pharmacologic and psychological interventions that may improve the care, well-being and survival of breast cancer patients. Further research is recommended to investigate whether interventions in the primary care setting for women with risk factors for breast cancer development may lead to a decreased incidence of invasive breast tumors. [ABSTRACT FROM AUTHOR]

Adverse Childhood Experiences (ACEs) refer to early life stress events, including abuse, neglect, and other psychosocial childhood traumas that can have long-lasting effects on a wide range of physiological functions. ACEs provoke sex-specific effects, whereas women have been shown to display a strong positive correlation with obesity and cardiometabolic disease. Notably, rodent models of chronic behavioral stress during postnatal life recapitulate several effects of ACEs in a sex-specific fashion. In this review, we will discuss the potential mechanisms uncovered by models of early life stress that may explain the greater susceptibility of females to obesity and metabolic risk compared with their male counterparts. We highlight the early life stress-induced neuroendocrine shaping of the adrenal-adipose tissue axis as a primary event conferring sex-dependent heightened sensitivity to obesity. [ABSTRACT FROM AUTHOR]

Prohormone convertase 1/3 (PC1/3) is an endopeptidase required for the processing of neuropeptide and endocrine peptide precursors; it is expressed in neuroendocrine tissues as well as in immune cells. In response to endotoxemia, global PC1/3 knockout mice mount a cytokine storm and die rapidly. Further, immune cells isolated from these mice have a pro-inflammatory signature, suggesting that PC1/3 activates an unknown anti-inflammatory peptide precursor in immune cells. Here, we tested this hypothesis using tissue-specific PC1/3 ablation models. Knocking out PC1/3 in the myeloid or the hematopoietic compartment did not induce any phenotype. In contrast, proopiomelanocortin (POMC)-specific PC1/3 knockout mice phenocopied global PC1/3 knockout mice, including an enlarged spleen size and a hyperinflammatory sepsis phenotype in response to mild endotoxemia. This phenotype was prevented by steroid therapy and mimicked by blocking corticoid receptors in wild-type mice. Thus, our data suggest that sepsis hypersensitivity in PC1/3 deficiency is uncoupled from immune cell intrinsic PC1/3 expression and is driven by a lack of anti-inflammatory glucocorticoids due to an impairment in the hypothalamic-pituitary-adrenal axis. [ABSTRACT FROM AUTHOR]

Context Glucocorticoids suppress the hypothalamic–pituitary–adrenal (HPA) axis, resulting in tertiary adrenal insufficiency (AI). When weaning patients off glucocorticoids there is no consensus on whether to maintain patients on prednisolone or convert to hydrocortisone. Objective To investigate HPA axis recovery in patients on long-term prednisolone and assess outcome after hydrocortisone conversion. Methods This was a retrospective cohort study at an outpatient endocrine steroid clinic. Patients were on long-term prednisolone and referred for HPA axis testing between 2015 and 2022. The main outcomes measured were (1) HPA axis recovery rate in patients on prednisolone demonstrated by a normal adrenocorticotrophic hormone (ACTH) stimulation test (AST) and (2) HPA axis recovery rate subanalysis of dose-matched patients with confirmed tertiary AI on prednisolone or hydrocortisone were measured. Results In total, 206 patients on prednisolone were tested for tertiary AI. Of these, 176 remained on prednisolone while 30 were converted to hydrocortisone. The overall HPA axis recovery rate for patients on prednisolone after interval testing was 137/206 (66.5%). The HPA axis recovery rate in dose-matched prednisolone and hydrocortisone conversion groups was 7/10 (70%) and 2/13 (15%) (P =.008), respectively. There was no difference in mean (SD) age (67.1 [12.2] vs 63.4 [11.1] years; P =.464) and baseline cortisol (5.3 [4.2] vs 4.6 [3.1] µg/dL; P =.648) and median [interquartile, IQR] glucocorticoid duration (1213 [1114] vs 2316 [4808] days; P =.693) and baseline ACTH (20.5 [29.0] vs 16.3 [14.8] ng/L; P =.905) between dose-matched prednisolone and hydrocortisone groups. Follow-up duration in the prednisolone group was significantly lower (median [IQR] 348 [975] vs 667 [884] days; P =.012). Conclusion Patients with glucocorticoid-induced AI maintained on once-daily prednisolone can recover HPA axis function when weaning. There is no apparent advantage to recover HPA axis function in converting to multiple-dosing hydrocortisone. [ABSTRACT FROM AUTHOR]

The alterations of phenotypic traits (morphology, endocrine physiology, and behavior) in response to predictable environmental cues across life‐history stages in seasonally breeding birds enable successful culmination of reproduction. The present study elucidated the plasticity of the hypothalamic–pituitary–adrenal (HPA) axis in a subtropical free‐living finch, Amandava amandava amandava, and suggests the crucial role of the baseline corticosterone (CORT) to coordinate energetic readiness across life‐history stages. Birds were captured monthly from an area (25.1337° N 82.5644° E) in Uttar Pradesh, India, from June 2014 to May 2015. Only male birds were included in this study corresponding to different life‐history stages (6/life‐history stage; 2/month): pre‐breeding (June–August), breeding (September–November), post‐breeding (December–February), and quiescent phases (March–May). The pituitary expression of adrenocorticotropic hormone (ACTH), adrenal interrenal cell morphometry, and plasma level of the CORT showed varied patterns across life‐history stages. The density and immunointensity of the ACTH‐immunoreactive corticotropes and the interrenal cell number increased along with the significant plasma CORT elevation during the breeding cycle (both pre‐breeding and breeding phases). CORT might facilitate the energy demand for the display of sexual behavior (nest‐building, courtship), testicular recrudescence, and foraging of food for offspring during the breeding cycle. On the contrary, plasma CORT decrease in the post‐breeding and quiescent phases might enable the bird to molt avoiding the protein catabolic effect of the hormone. Given the complexity involved in the study of baseline CORT in free‐living birds, more studies are needed to better understand the crucial role of the HPA axis in the modulation of life‐history stages in this and other subtropical avian species. [ABSTRACT FROM AUTHOR]

Formula One (F1) racing has recently grown in popularity, extending well beyond its traditional European roots. However, there has been a paucity of scholarly research dedicated to the health of drivers and even less discussion of the prevalence of psychiatric symptoms, risk factors, and types of psychopathology in F1. This is notable given advancements in sports psychiatry and evidence of psychiatric disorders emerging across other sports. Accordingly, this perspective paper details the physiological conditions in F1 and the socioenvironmental pressures that a driver may encounter during their career, including heat stress, weight restrictions, harassment, and other factors. These extreme physiological and psychological stressors, both in racing and non-racing environments, alongside sport-specific psychosocial pressures, may cause HPA axis dysregulation and other issues in drivers, heightening vulnerabilities for mental health concerns. Additionally, F1 is still affected by stigmatizing attitudes and regressive sociocultural norms, which could inhibit progress toward promoting sustainable wellbeing. Consequently, drivers may be at risk for mental disorder and a decrease in overall health and wellbeing. Against this background, we thereby recommend mental health programs and regulatory actions that could better address these challenges and promote mental wellbeing across F1. [ABSTRACT FROM AUTHOR]

Objective: The mechanisms driving the progression of infantile spasms are not well understood. We aimed to investigate the changes and correlations of the gut microbiota, the hypothalamus-pituitary-adrenal (HPA) axis hormones, and the inflammatory cytokines in children with infantile spasms before and after treatment in order to provide a reference for future pathogenesis research. Methods: Children with infantile spasms who were admitted to our hospital were recruited into the case group. The case group was divided into the pre-treatment group (group A, n = 14), the 2 weeks after treatment group (group B), and the 1 month after treatment group (group C). On the other hand, healthy children with the same sex ratio as the case group were recruited into the control group (group D, n = 14). Three stool and blood samples were collected before treatment, 2 weeks after treatment, and 1 month after treatment. The serum samples were analyzed using cytometric bead array (CBA), enzyme-linked immunosorbent assay (ELISA), and chemiluminescent immunoassay (CLIA) to measure the levels of HPA axis hormones and inflammatory cytokines. The collected stool samples were sequenced using 16S rDNA. Results: The pre-treatment group demonstrated elevated levels of corticotropin-releasing hormone (CRH), interleukin 2 (IL-2), IL-4, IL-6, and IL-17a, which decreased with treatment. The level of CRH was lower in the effective group than that in the ineffective group. Sutterellaceae was lower in the pretreatment group than that in the control group. Lachnospiracea_incertae_sedis was positively associated with CRH concentration (p < 0.05). After treatment, Sutterellaceae was negatively associated with IL-2 and TNF-a (p < 0.05). Conclusion: This study found that imbalance of the gut microbiota may be involved in the pathogenesis of infantile spasms and is related to the response to adrenocorticotropic hormone (ACTH). Lachnospiraceae and Lachnospiracea_ incertae_sedis might be involved in the disease onset. Sutterellaceae might have a link to children's improved health. [ABSTRACT FROM AUTHOR]

Due to the heterogeneous nature of depression, the underlying etiological mechanisms greatly differ among individuals, and there are no known subtype-specific biomarkers to serve as precise targets for therapeutic efficacy. The extensive research efforts over the past decades have not yielded much success, and the currently used first-line conventional antidepressants are still ineffective for close to 66% of patients. Most clinicians use trial-and-error treatment approaches, which seem beneficial to only a fraction of patients, with some eventually developing treatment resistance. Here, we review evidence from both preclinical and clinical studies on the pathogenesis of depression and antidepressant treatment response. We also discuss the efficacy of the currently used pharmacological and non-pharmacological approaches, as well as the novel emerging therapies. The review reveals that the underlying mechanisms in the pathogenesis of depression and antidepressant response, are not specific, but rather involve an interplay between various neurotransmitter systems, inflammatory mediators, stress, HPA axis dysregulation, genetics, and other psycho-neurophysiological factors. None of the current depression hypotheses sufficiently accounts for the interactional mechanisms involved in both its etiology and treatment response, which could partly explain the limited success in discovering efficacious antidepressant treatment. Effective management of treatment-resistant depression (TRD) requires targeting several interactional mechanisms, using subtype-specific and/or personalized therapeutic modalities, which could, for example, include multi-target pharmacotherapies in augmentation with psychotherapy and/or other non-pharmacological approaches. Future research guided by interaction mechanisms hypotheses could provide more insights into potential etiologies of TRD, precision biomarker targets, and efficacious therapeutic modalities. [ABSTRACT FROM AUTHOR]

The pathogenesis of epilepsy is related to the microbiota-gut-brain axis, but the mechanism has not been clarified. The microbiota-gut-brain axis is divided into the microbiota-gut-brain axis (upward pathways) and the brain-gut-microbiota axis (downward pathways) according to the direction of conduction. Gut microorganisms are involved in pathological and physiological processes in the human body and participate in epileptogenesis through neurological, immunological, endocrine, and metabolic pathways, as well as through the gut barrier and blood brain barrier mediated upward pathways. After epilepsy, the downward pathway mediated by the HPA axis and autonomic nerves triggers "leaky brain "and "leaky gut," resulting in the formation of microbial structures and enterobacterial metabolites associated with epileptogenicity, re-initiating seizures via the upward pathway. Characteristic changes in microbial and metabolic pathways in the gut of epileptic patients provide new targets for clinical prevention and treatment of epilepsy through the upward pathway. Based on these changes, this review further redescribes the pathogenesis of epilepsy and provides a new direction for its prevention and treatment. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is progressively recognized as a stress-related disorder characterized by aberrant brain network dynamics, encompassing both structural and functional domains. Yet, the intricate interplay between these dynamic networks and their molecular underpinnings remains predominantly unexplored. Both structural and functional networks were constructed using multimodal neuroimaging data from 183 MDD patients and 300 age- and gender-matched healthy controls (HC). structural-functional connectivity (SC-FC) coupling was evaluated at both the connectome- and nodal-levels. Methylation data of five HPA axis key genes, including NR3C1, FKBP5, CRHBP, CRHR1, and CRHR2, were analyzed using Illumina Infinium Methylation EPIC BeadChip. We observed a significant reduction in SC-FC coupling at the connectome-level in patients with MDD compared to HC. At the nodal level, we found an imbalance in SC-FC coupling, with reduced coupling in cortical regions and increased coupling in subcortical regions. Furthermore, we identified 23 differentially methylated CpG sites on the HPA axis, following adjustment for multiple comparisons and control of age, gender, and medication status. Notably, three CpG sites on NR3C1 (cg01294526, cg19457823, and cg23430507), one CpG site on FKBP5 (cg25563198), one CpG site on CRHR1 (cg26656751), and one CpG site on CRHR2 (cg18351440) exhibited significant associations with SC-FC coupling in MDD patients. These findings provide valuable insights into the connection between micro-scale epigenetic changes in the HPA axis and SC-FC coupling at macro-scale connectomes. They unveil the mechanisms underlying increased susceptibility to MDD resulting from chronic stress and may suggest potential pharmacological targets within the HPA-axis for MDD treatment. • We replicated a significant SC-FC decoupling at the connectome level in MDD patients. • We identified disruptions in methylation levels at multiple CpG sites within key genes of the HPA axis in MDD patients. • We found a significant association between the methylation levels of disrupted CpG sites and the observed SC-FC decoupling. • Our findings support that chronic stress-related epigenetic changes play a pivotal role in the pathogenesis of MDD. [ABSTRACT FROM AUTHOR]

AIM: To investigate the ameliorative effect of nociceptin/orphanin （N/OFQ） on anxiety-like behavior in nicotine （NIC） withdrawal-induced rats and its regulatory mechanisms on the expression of neurotransmitters as sociated with the hypothalamic-pituitary-adrenal （HPA） axis and inflammatory factors. METHODS: Thirty-two adult-male Sprague-Dawley rats were randomly divided into 4 groups: normal control group, NIC withdrawal model group, low-dose N/OFQ treatment group, and high-dose N/OFQ treatment group, with 8 rats in each group. To establish NIC withdrawal model, the rats in the NIC model and N/OFQ treatment groups were subcutaneously injected with NIC （0. 4 mg/kg）, twice a day for 7 consecutive days followed by 3 days of withdrawal. During the withdrawal period, the rats in the low and high-dose N/OFQ treatment groups received intracerebroventricular injection of N/OFQ （1 nmol or 10 nmol） once per day for 3 consecutive days. Ten minutes after the third administration, all rats underwent open filed （OF） and elevated plus maze （EPM） tests to detect behavioral changes. The serum concentrations of corticotrophin-releasing hormone （CRH）, adrenocorticotropic hormone （ACTH）, corticosterone （CORT）, tumor necrosis factor-α （TNF-α）, interleukin-1β（ IL-1β） and IL-6 were measured by ELISA. The mRNA expression levels of TNF-α, IL-1β and IL-6 in the central nucleus of the amygdala （CeA） of the brain were detected by RT-qPCR. Histological changes in neuron morphology in the CA1 region of the hippocampus were observed under a light microscope following hematoxylin and eosin （HE） staining. Norepinephrine（ NE） levels in the CeA of the brain were determined by HPLC. The protein expression of tyrosine hydroxylase （TH） in the CeA of the brain was detected by Western blot. RESULTS: Compared with the NIC withdrawal model group, rats in the low and high-dose N/OFQ treatment groups showed significant increase in the distance and time spent in the central area of the open field（ P<0. 05 or P<0. 01）, as well as significant increase in the number of entries and the percentage of time spent in the open arms of the EPM （P<0. 05 or P<0. 01）. Furthermore, both low and high-dose N/OFQ treatment groups significantly inhibited serum concentrations of CRH, ACTH and CORT in NIC withdrawal rats （P< 0. 01）. N/OFQ administration also significantly reduced the levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 in the serum, as well as expression levels of TNF-α, IL-1β and IL-6 mRNA in the CeA（ P<0. 05 or P<0. 01）. The treatment with N/OFQ at both doses significantly alleviated neuronal damage in the CA1 region of the hippocampus and markedly reduced thelevels of NE and TH protein expression in the CeA of NIC withdrawal rats （P<0. 01）. CONCLUSION: N/OFQ alleviates anxiety-like behavior in NIC withdrawal rats through mechanisms related to the regulation of HPA axis hormone levels and inflammatory factors. [ABSTRACT FROM AUTHOR]

Background/Objectives: The dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis has been associated with various mental disorders. One of the most commonly described parameters of HPA axis functioning is the cortisol awakening response (CAR). To date, few studies have been conducted on the relationship between personality disorders and CAR. The present study aimed to compare the CAR between individuals with personality disorders and healthy controls. Moreover, the study aimed to assess the association of CAR with cognitive biases and psychopathological symptoms in people with personality disorders. Methods: A total of 43 individuals with personality disorders and 45 healthy controls were enrolled. Participants completed questionnaires measuring the severity of depressive symptoms, anxiety, cognitive biases, and psychotic-like experiences. Cortisol levels were measured in four morning saliva samples: immediately after awakening, and after 15, 30, and 45 min. Results: A significantly lower CAR was found among individuals with personality disorders, even after adjustment for age, sex, and the level of education. However, the receiver operating characteristic (ROC) curve analysis showed a relatively low area under the curve (AUC = 0.362). Furthermore, a significant negative correlation was observed between the CAR and the level of external attribution bias among individuals with personality disorders. No significant associations of the CAR with psychopathological symptoms and other cognitive biases were observed. Conclusions: Findings from this study indicate that the HPA axis activity might be altered in personality disorders. However, the clinical utility of this observation needs further studies in larger samples. External attribution might be related to the HPA axis alterations in this population. [ABSTRACT FROM AUTHOR]

Purpose: Our study aimed to explore the efficacy of Bifidobacterium breve 207-1 on specific neurotransmitters and hormones and the ability to regulate lifestyle behaviors in healthy adults. Methods: In total, 120 healthy adults with high mental stress, overweight, insomnia, and constipation were randomly assigned to receive low-dose B. breve 207-1 (LD, n = 40), high-dose B. breve 207-1 (HD, n = 40), or placebo (n = 40) for 28 days. Fecal and blood samples were collected and questionnaires were answered before and after the trial. Neurotransmitters and serum hormones were detected using enzyme-linked immunosorbent assay. The gut microbiota composition was assessed using 16 S rRNA sequencing. Short–chain fatty acids (SCFAs) concentrations were determined via gas chromatography–mass spectrometry (GC–MS). Results: The primary outcome of our study was changes in mental wellness, including neurotransmitters, the hypothalamic–pituitary–adrena (HPA) axis hormones, and the psychological scales. The results showed that γ-aminobutyric acid (GABA) increased significantly and the HPA axis hormones were suppressed overall in the probiotic groups while 5-hydroxytryptamine (5-HT) did not change significantly. However, there was no significant change in mood scale scores. The secondary outcome focused on the ability of 207-1 to regulate the body and lifestyle of healthy adults (e.g., sleep, diet, exercise, etc.). The PSQI scores in the probiotics groups significantly decreased, indicating improved sleep quality. Meanwhile, the probiotic groups had a slight increase in exercise consumption while dietary intake stabilized. By physical examination, the participants showed weight loss although no statistically significant difference was observed between the groups. Then, validated by gut microbiota, changes in the gut microbiota were observed under the effective intervention of 207-1 while short-chain fatty acids (SCFAs) increased in the LD group, particularly acetic and propionic acids. There was a slight decrease in alpha–diversity in the HD group. Conclusion: Bifidobacterium breve 207-1 entered the organism and affected neurotransmitter and the HPA axis hormone levels via the microbiome-gut-brain axis. Meanwhile, 207-1 supplementation improved daily lifestyle behaviors in healthy adults, which may in turn lead to changes in their bodies (e.g. weight and lipid metabolism). However, this study did not find significant mood-modulating efficacy. The mechanism of the overall study is unclear, but we hypothesize that SCFAs may be the key pathway, and more experiments are needed for validation in the future. Trial registration: This trial was retrospectively registered in the Chinese Clinical Trial Registry under the accession number ChiCTR2300069453 on March 16, 2023. [ABSTRACT FROM AUTHOR]

Measuring glucocorticoids such as cortisol is a useful tool for exploring relationships among behavior, physiology, and well‐being in primates. As cortisol circulates in blood, it moves into biological matrices such as hair, urine, feces, and saliva. Saliva sampling is a simple, noninvasive method to measure cortisol that can be easily implemented by training animals to voluntarily provide samples. The temporal lag between elevation of cortisol in the blood and elevation of cortisol in saliva likely varies by species and must be characterized to identify appropriate sampling regimens. In the present study we characterized the time course of cortisol changes in saliva following an acute psychological stressor in captive tufted capuchin monkeys (Sapajus apella). We trained eight free‐moving female tufted capuchin monkeys to voluntarily produce clean saliva samples. We exposed them to the acute stressor of a veterinary catch net and observed behavior pre and post exposure. We collected salivary samples immediately pre exposure (0 min) and 30, 45, 60, 75, 90, and 120 min after exposure. Salivary cortisol was quantified using a Salimetrics kit. Behavioral and cortisol measures were compared within individuals to a control condition in which no stressor was presented. Capuchins showed a clear behavioral response to the stressor by demonstrating increased freezing and pacing, decreased feed foraging, nonsocial play, and scratching, and decreased willingness to provide saliva samples after stressor presentation. After stressor presentation, average salivary cortisol began to increase at 30 min and continued to increase through the 120 min sample period. There was individual variation in absolute cortisol levels, the timing of the cortisol increase, and the timing of the peak. Our results suggest that no single time‐point can be reliably used to evaluate salivary cortisol response to an acute stressor across individuals, and instead we recommend the collection of a prolonged time series. Research Highlights: Capuchins showed a clear behavioral response to an acute stressor, decreasing feed foraging, nonsocial play, scratching, and willingness to provide saliva samples, and increasing freezing behavior.Average salivary cortisol began to increase 30 min after stressor presentation and continued to increase over 120 min, with individual variation in absolute cortisol levels and the timing of increase and peak.Salivary cortisol detects capuchin responses to acute stressors, but no single time‐point can be reliably used to compare the response across individuals; instead we recommend the collection of a prolonged time series. [ABSTRACT FROM AUTHOR]

Background: The perseverative cognition hypothesis stipulates that rumination (repetitive, passive, uncontrollable negative thinking) prolongs the experience of a stressor which impacts stress physiology. In line with this hypothesis, we proposed that in response to real-life experiences of social rejection, adolescent girls who ruminate would show a blunted diurnal cortisol slope the next day relative to girls who do not ruminate. We also examined the effects of social rejection and rumination on waking cortisol levels and the cortisol awakening response. Method: Participants were (n = 50) adolescent girls (mean age = 13.30, SD = 2.34) who varied on psychiatric risk and provided saliva samples 4 times a day for 3 days, as well as, daily diary reports of social rejection and rumination. A lagged multilevel model was utilized to examine the interactive effects of rejection and rumination on diurnal cortisol. Results: There was a significant interaction between social rejection and rumination. Specifically, rumination following social rejection was associated with a flatter diurnal cortisol slope. In the absence of rumination, social rejection was marginally associated with a steeper diurnal cortisol slope. The effects for waking cortisol levels and the cortisol awakening response were null. Conclusion: Findings support the perseverative cognition hypothesis and suggest that cognitive mechanisms such as rumination can impact stress physiology. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a complex psychiatric disorder associated with adverse long-term health outcomes, including cardiovascular disease (CVD). Despite growing evidence that PTSD is positively associated with CVD, the biological mechanisms underlying this association are poorly understood. This review provides an overview of the current state of science on the genetic association between PTSD and CVD. This scoping review identified studies from Pubmed, Embase, PsycINFO, and Web of Science. The search terms were a combination of PTSD, CVD/CVD-related traits, and a set of genetic molecules and related terms. This review followed the PRISMA Extension for Scoping Reviews guidelines. Eligible criteria included original studies that have genetic factors related to PTSD or CVD, conducted in humans, written in English, and published between 2003 and 2023 in peer-reviewed journals. A total of twenty-three studies were included; PTSD correlated with genetic variants in CVD-related traits and gene expression in regulatory pathways contributing to CVD development. Common CVD-related traits involved in genetic associations with PTSD were inflammation, cellular aging, increased blood pressure, hypothalamus-pituitary-adrenal axis dysregulation, metabolic syndrome, and oxidative stress. These traits may explain potential underlying mechanisms between PTSD and CVD. Evidence of a causal relationship between the two diseases was insufficient. PTSD and CVD/CVD-related traits are genetically associated. Further research is needed to comprehensively explore gene-environment interactions and the cumulative impact of behavioral and psychological factors on the pathophysiological mechanisms between PTSD and CVD. • Post-traumatic stress disorder (PTSD) is genetically correlated with cardiovascular diseases (CVD) and CVD-related traits. • There is no strong evidence for causal links between PTSD and CVD. • Six potential pathways contributing to the genetic associations between PTSD and CVD are identified. • Further research is needed to explore the cumulative impact of various factors on the associations between PTSD and CVD. [ABSTRACT FROM AUTHOR]

Biological sex affects the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, how androgen deprivation affects this axis remains largely unknown. In this study, we investigated the effect of androgen status on different components of the HPA axis in male mice. Two weeks of androgen deprivation did not affect total plasma corticosterone levels but led to increased pituitary ACTH levels. Stress-induced total plasma corticosterone levels were increased, whereas the suppression of corticosterone after dexamethasone treatment under basal conditions was attenuated. Androgen-deprived mice displayed a 2-fold increase in plasma levels of corticosteroid binding globulin (CBG). A similar increase in CBG was observed in global androgen receptor knock-out animals, compared to wild-type littermates. Androgen deprivation was associated with a 6-fold increase in CBG mRNA in the liver and enhanced transcriptional activity at CBG regulatory regions, as evidenced by increased H3K27 acetylation. We propose that the induction of CBG as a consequence of androgen deprivation, together with the unaltered total corticosterone levels, results in lower free corticosterone levels in plasma. This is further supported by mRNA levels of androgen-independent GR target genes in the liver. The reduction in negative feedback on the HPA axis under basal condition would suffice to explain the enhanced stress reactivity after androgen deprivation. Overall, our data demonstrate that, in mice, tonic androgen receptor activation affects CBG levels in conjunction with effects on gene expression and HPA-axis reactivity. [ABSTRACT FROM AUTHOR]

Context Maternal obesity, hypertensive pregnancy disorders, and gestational diabetes (GDM) are linked to an increased risk of negative offspring health outcomes. This association may be mediated by maternal hypothalamic-pituitary-adrenal axis (HPA axis) activity, resulting in elevated maternal cortisol levels and fetal exposure, but evidence remains scarce. Objective We (1) examined maternal diurnal cortisol profiles longitudinally across gestation, and (2) explored associations with maternal cardiometabolic complications. Methods Women in the InTraUterine sampling in early pregnancy (ITU) study (n = 667) provided 7 salivary cortisol samples from awakening to bedtime up to 3 times during pregnancy (median gestational week 19.3, 25.7, and 38.1; n = 9356 samples). Changes in cortisol awakening response (CAR) and diurnal slope (indicative of HPA axis activity) and their associations with maternal body mass index (BMI), hypertensive pregnancy disorders and GDM were examined using linear mixed models. Results The CAR declined in 60% to 67% of women, and the diurnal slope attenuated from early to late pregnancy (b = 0.006; P =.001). Higher BMI was associated with less decline in CAR (b = 0.031; P =.0004) and less attenuation in diurnal slope from early to late pregnancy (b = −0.001; P =.006). Hypertensive pregnancy disorders and GDM were not significantly associated with diurnal cortisol profiles. Conclusion The attenuation in CAR and diurnal slope support HPA axis hyporesponsivity during pregnancy. Less attenuation of both markers in women with a higher BMI may indicate reduced adaption of the HPA axis to pregnancy, presenting a mechanistic link to offspring health outcomes. [ABSTRACT FROM AUTHOR]

Major Depressive Disorder, or depression, has been extensively linked to dysregulated HPA axis function, chronic inflammation and cardiovascular diseases. While the former two have been studied in depth, the mechanistic connection between depression and cardiovascular disease is unclear. As major mediators of vascular homeostasis, vascular pathology and immune activity, endothelial cells represent an important player connecting the diseases. Exaggerated inflammation and glucocorticoid function are important topics to explore in the endothelial response to MDD. Glucocorticoid resistance in several cell types strongly promotes inflammatory signaling and results in worsened severity in many diseases. However, endothelial health and inflammation in chronic stress and depression are rarely considered from the perspective of glucocorticoid signaling and resistance. In this review, we aim to discuss (1) endothelial dysfunction in depression, (2) inflammation in depression, (3) general glucocorticoid resistance in depression and (4) endothelial glucocorticoid resistance in depression co-morbid inflammatory diseases. We will first describe vascular pathology, inflammation and glucocorticoid resistance separately in depression and then describe their potential interactions with one another in depression-relevant diseases. Lastly, we will hypothesize potential mechanisms by which glucocorticoid resistance in endothelial cells may contribute to vascular disease states in depressed people. Overall, endothelial-glucocorticoid signaling may play an important role in connecting depression and vascular pathology and warrants further study. [ABSTRACT FROM AUTHOR]

Background: The mechanisms at the basis of depression are still matter of debate, but several studies in the literature suggest common pathways with dementia (genetic predispositions, metabolic and inflammatory mechanisms, neuropathological changes) and other geriatric syndromes. Aims: To evaluate the role of cortisol (as marker of the HPA, hypothalamus–pituitary–adrenal axis hyperactivity) in elderly subjects with depressive symptoms (by the means of the AGICO, AGIng and COrtisol, study), in relationship to the presence of the major geriatric syndromes. Methods: The AGICO study enrolled patients from ten Geriatric Units in Italy. Every subject received a comprehensive geriatric assessment or CGA (including the Mini Mental State Examination or MMSE, Geriatric Depression Scale or GDS and Cornell Scale for Depression in Dementia or CSDD), the neurological examination (with a computed tomography scan or magnetic resonance imaging of the brain), the assessment of the metabolic syndrome (MetS), the evaluation of the cortisol activity by two consecutive urine collections (diurnal and nocturnal), a CGA-derived frailty index (FI) and a modified measure of allostatic load (AL). Results: The MMSE scores were significantly and inversely related to the values of GDS (p < 0.001) and CSDD (p < 0.05), respectively. The patients with depressive symptoms (GDS/CSDD > 8) showed significantly increased disability, MetS, inflammation, FI and AL and significantly reduced MMSE and renal function. The diurnal and nocturnal urinary cortisol levels in the patients with depressive symptoms (GDS/CSDD > 8) were higher with respects to controls (p < 0.05 for nocturnal difference). Discussion: The AGICO study showed that the stress response is activated in the patients with depression. Conclusion: The depression in elderly patient should be reconsidered as a systemic disease, with coexisting major geriatric syndromes (disability, dementia, frailty) and combined pathogenetic mechanisms (metabolic syndrome, impaired renal function, low-grade inflammation, and allostatic load). Cortisol confirmed its role as principal mediator of the aging process in both dementia and metabolic syndrome. [ABSTRACT FROM AUTHOR]

Objectives: We investigated salivary biomarkers of stress, more specifically, cortisol and alpha-amylase, to evaluate effects of individualized music listening (IML) in people with dementia. Method: Participants were N = 64 nursing home residents with dementia (meanage = 83.53 ± 7.71 years, 68.8% female). Participants were randomly assigned to either listening to their favorite music every other day for a period of six weeks (intervention), or standard care (control). Using the Saliva Children's Swab (SCS), saliva was collected before, after, and 20 min after IML sessions at the beginning and end of the intervention period for the analysis of salivary alpha-amylase and cortisol. Results: Using the SCS was feasible in people with dementia. Nevertheless, there was no effect of IML on salivary stress markers. Discussion: Although using SCS was feasible, active patient engagement is required. Future studies need to corroborate findings in larger samples. Trial registration: German Clinical Trials Register: DRKS00015641, ISRCTN registry: ISRCTN59052178. [ABSTRACT FROM AUTHOR]

The results we obtained earlier indicate the potential for corrective effects on the negative consequences of social isolation on the functioning of the body through an enriched environment. The aim of the present study was to investigate the influence of housing conditions for rats –standard conditions, social isolation, and an enriched environment—on the activity of the hypothalamic–pituitary–adrenocortical (HPA) axis, focusing on HPA axis stress reactivity, pain sensitivity, and rat behavior following exposure to an ulcerogenic stressor. The experiments were conducted on male Sprague–Dawley rats. Thirty-day-old rats, after being weaned from their mothers, were placed in different housing conditions for four weeks: standard environment (SE), isolation (SI), or an enriched environment (EE). After four weeks, rats from each group were exposed to an ulcerogenic stressor (US): 3 hours of cold immobilization (10°C). Starting the day after US exposure, for one week, all groups of rats were sequentially assessed for somatic pain sensitivity (in the "hot plate" test), behavior (in the "open field" and "elevated plus maze" tests), and HPA stress reactivity (based on corticosterone levels in response to mild procedural stress). According to the results, SI conditions in our experimental setup led to a faster increase in body weight with age, higher anxiety levels, depressive-like reactions in half of the animals studied, and increased sensitivity to painful stimuli. At the same time, rats kept in the EE showed higher HPA axis stress reactivity, greater motor and exploratory activity, lower anxiety, and lower sensitivity to painful stimuli. The obtained results provide new evidence supporting our previous conclusion that SI exerts maladaptive effects on the overall functional state of the rats' bodies, while EE, on the contrary, leads to adaptive changes in the body. This study highlights the importance of an integrative approach when studying the effects of SI and EE on the body. [ABSTRACT FROM AUTHOR]

Perinatal depression is a prevalent mental disorder among pregnant women, characterized by sleep disturbances, appetite changes, negative emotions, cognitive impairment, and suicidal or homicidal tendencies. These symptoms severely compromise personal well-being, disrupt family life, and burden society. Early detection and intervention are thus crucial. The tryptophan-kynurenine (TRP-KYN) pathway is central to the inflammatory hypothesis of depression and has gained significant attention in perinatal depression research. This pathway encompasses numerous metabolic enzymes and neuroactive metabolites that interact with other physiological systems, influencing neurotransmitter synthesis and neuronal development. Through these interactions, the TRP-KYN pathway exerts psychotropic effects. This article reviews the key metabolites and enzymes of the TRP-KYN pathway and examines its intersection with immune inflammation, hormones, and gut microbiota. [ABSTRACT FROM AUTHOR]

Acute and chronic stress each have physical manifestations in the human body that can lead to many negative health impacts. Today, reported stress levels worldwide are at an all-time high, spurring the search for non-pharmaceutical interventions to maintain healthy stress levels. In this study, we examined whether a pet dog's presence influences healthy adults' acute stress responses as assessed through self-reports, heart rate, plasma cortisol, and salivary alpha-amylase. Participating pet dog owners were randomly assigned to undergo the Trier Social Stress Test either with their pet dog or alone. While there was no group difference in perceived anxiety levels, participants undergoing the acute psychological stressor with their pet dogs present had significantly lower heart rates, lower plasma cortisol responses, and higher salivary alpha-amylase responses than people without their dogs. Those who participated without their dogs had a statistically flat alpha-amylase response, which is typically associated with extreme or pathological stress. These findings extend the potential effects of pet dogs beyond merely lowering their owner's stress levels to maintaining a healthier, balanced response across the sympathoadrenal medullary axis and hypothalamic–pituitary-adrenal axis. [ABSTRACT FROM AUTHOR]

(1) Background: Insomnia is a neurological illness that poses a significant threat to both physical and mental health. It results in the activation of neuroglial cells, heightened neuroinflammation, oxidative stress, and disruptions in the Hypothalamic–Pituitary–Adrenal (HPA) axis. Ligusticum Chuanxiong (CX) and Finger citron (FC) are frequently utilized botanicals for addressing sleeplessness. Both herbs possess notable anti-inflammatory properties in their volatile oils. However, their effectiveness is hindered by the nasal mucosal irritation and instability they exhibit. (2) Methods: This study involved the preparation of a nanofiber composite system using carbon nanofiber (CNF) suspensions containing essential oils of Ligusticum chuanxiong–Finger citron (CXEO-FCEO-CNF). The effects and mechanisms of these essential oils in improving insomnia were investigated using an insomnia mouse model after encapsulation. (3) Results: The CXEO-FCEO-CNF had an average particle size of 103.19 ± 1.64 nm. The encapsulation rates of essential oils of Ligusticum chuanxiong (CXEO) and essential oils of Finger citron (FCEO) were 44.50% and 46.15%, respectively. This resulted in a considerable improvement in the stability of the essential oils over a period of 30 days. The essential oils effectively decreased the irritation of the nasal mucosa following encapsulation. Furthermore, CXEO-FCEO-CNF enhanced voluntary activity and sleep in mice with insomnia, notably boosted the activity of superoxide dismutase (SOD), reduced the concentration of lipoxidized malondialdehyde (MDA), decreased the levels of hormones associated with the HPA axis, and regulated the levels of neurotransmitters, resulting in a beneficial therapeutic outcome. CXEO-FCEO-CNF contains a total of 23 active ingredients, such as alpha-Asarone, (E)-methyl isoeugenol, and Senkyunolide. These ingredients primarily work by modulating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling system to decrease oxidative stress and inflammatory reactions. (4) Conclusions: This study presented initial evidence that the combination of CXEO and FCEO in nanofiber formulations effectively reduces the nasal mucosal irritation and instability of essential oils. Furthermore, it demonstrated the potential anti-neuroinflammatory and therapeutic effects of these formulations in treating insomnia. Overall, this study provides a theoretical foundation for developing new essential oil formulations derived from herbs. [ABSTRACT FROM AUTHOR]

This literature review, in light of the presented case report, explores the complex interplay between gabapentin (GBP), a gamma-aminobutyric acid (GABA) analog, and the hypothalamic–pituitary–adrenal (HPA) axis in patients undergoing major surgical procedures. It specifically investigates the potential impact of GBP on cortisol levels, stress responses, and infection risk, illustrated by a detailed clinical case. This review combines a comprehensive literature search with a case report of a 17-year-old male with osteosarcoma who experienced transient adrenal insufficiency and infections while receiving GBP. The case is analyzed in the context of the existing literature on GBP and the HPA axis. The findings highlight the intricate relationship between GBP use, adrenal insufficiency, and infection susceptibility. It underscores the need for further research and clinical vigilance when prescribing GBP to patients with underlying medical conditions, particularly in the context of major surgical procedures. The review underscores the need for further research and clinical vigilance when prescribing GBP, particularly in perioperative settings. In conclusion, GBP's effects on the HPA axis and immune responses are complex and multifaceted. Clinicians should exercise caution when prescribing GBP, especially for patients with underlying conditions undergoing major surgery. Further research is needed to elucidate the mechanisms of GBP's influence on cortisol levels and stress responses. [ABSTRACT FROM AUTHOR]

Depression is a prevalent mental disorder, but the side effects of antidepressants also make depressed patients resistant. Effective and safe antidepressants should be developed from traditional herbs, with the aim of reducing the side effects of antidepressants and improving the efficacy of drugs. In this study, the new macamide compound‐4 (NMC‐4) was synthesized for the first time, addressing the problem of difficult extraction, isolation, and low content of natural macamide. NMC‐4 was characterized using mass spectrometry, nuclear magnetic resonance, and infrared spectroscopy. The protective effect of NMC‐4 against cell injury was demonstrated to be stronger than that of natural macamide (N‐benzylhexadecanamide, XA) using a PC12 cell injury model. The study explored the effects of NMC‐4 on chronic unpredictable mild stress (CUMS)‐induced depressive symptoms. NMC‐4 significantly improved depressive‐like behaviors. NMC‐4 ameliorated CUMS‐induced depressive‐like behaviors by mitigating neuroinflammation and modulating the NF‐κB/Nrf2 and BDNF/PI3K/Akt pathways. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCH) is a mental disorder that requires long-term antipsychotic treatment. SCH patients are thought to have an increased sensitivity to stress. The dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, observed in SCH, could include altered levels of glucocorticoids, glucocorticoid receptors (GRs), and associated proteins. The perinatal administration of phencyclidine (PCP) to rodents represents an animal model of SCH. This study investigated the effects of perinatal PCP exposure and subsequent haloperidol/clozapine treatment on corticosterone levels measured by ELISA and the expression of GR-related proteins (GR, pGR, HSP70, HSP90, FKBP51, and 11β-Hydroxysteroid dehydrogenase-11β-HSD) determined by Western blot, in different brain regions of adult rats. Six groups of male rats were treated on the 2nd, 6th, 9th, and 12th postnatal days (PN), with either PCP or saline. Subsequently, one saline and one PCP group received haloperidol/clozapine from PN day 35 to PN day 100. The results showed altered GR sensitivity in the rat brain after PCP exposure, which decreased after haloperidol/clozapine treatment. These findings highlight disturbances in the HPA axis in a PCP-induced model of SCH and the potential protective effects of antipsychotics. To the best of our knowledge, this is the first study to investigate the effects of antipsychotic drugs on the HPA axis in a PCP animal model of SCH. [ABSTRACT FROM AUTHOR]

Purpose: Diet-related factors are of great significance in the regulation of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonad (HPG) axes. In this study, we aimed to investigate the effects of chronic exposure to a high fat diet (HFD), fructose or sucralose on the endocrine functions. Methods: Male, Sprague-Dawley rats received a normal chow diet, HFD, 10% fructose or 0.02% sucralose for 10 weeks. Behavioral changes were assessed by open field (OFT) and elevated plus-maze (EPM) tests at week 8. H&E staining was used to observe pathological changes in adrenal cortex, testis and perirenal adipose tissue. Serum hormone concentrations were quantified via enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of genes along the HPA and HPG axes were determined using real-time PCR. Results: All types of dietary interventions increased body weight and disturbed metabolic homeostasis, with anxiogenic phenotype in behavioral tests and damage to cell morphology of adrenal cortex and testis being observed. Along the HPA axis, significantly increased corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) concentrations were observed in the HFD or 0.02% sucralose group. For HPG axis, gonadotropin-releasing hormone (GnRH) and estradiol (E2) concentrations were significantly increased in all dietary intervention groups, while decreased concentrations of follicle-stimulating hormone (FSH) and testosterone (T) were also detected. Moreover, transcriptional profiles of genes involved in the synthesis of hormones and corresponding hormone receptors were significantly altered. Conclusion: Long-term consumption of HFD, fructose or sucralose manifested deleterious effects on endocrine system and resulted in the dysregulation of HPA and HPG axes. [ABSTRACT FROM AUTHOR]

Background: The stress‐sensitive maternal hypothalamic–pituitary–adrenal (HPA) axis through the end‐product cortisol, represents a primary pathway through which maternal experience shapes fetal development with long‐term consequences for child neurodevelopment. However, there is another HPA axis end‐product that has been widely ignored in the study of human pregnancy. The synthesis and release of dehydroepiandosterone (DHEA) is similar to cortisol, so it is a plausible, but neglected, biological signal that may influence fetal neurodevelopment. DHEA also may interact with cortisol to determine developmental outcomes. Surprisingly, there is virtually nothing known about human fetal exposure to prenatal maternal DHEA and offspring neurodevelopment. The current study examined, for the first time, the joint impact of fetal exposure to prenatal maternal DHEA and cortisol on infant emotional reactivity. Methods: Participants were 124 mother–infant dyads. DHEA and cortisol were measured from maternal hair at 15 weeks (early gestation) and 35 weeks (late gestation). Observational assessments of positive and negative emotional reactivity were obtained in the laboratory when the infants were 6 months old. Pearson correlations were used to examine the associations between prenatal maternal cortisol, prenatal maternal DHEA, and infant positive and negative emotional reactivity. Moderation analyses were conducted to investigate whether DHEA might modify the association between cortisol and emotional reactivity. Results: Higher levels of both early and late gestation maternal DHEA were linked to greater infant positive emotional reactivity. Elevated late gestation maternal cortisol was associated with greater negative emotional reactivity. Finally, the association between fetal cortisol exposure and infant emotional reactivity was only observed when DHEA was low. Conclusions: These new observations indicate that DHEA is a potential maternal biological signal involved in prenatal programming. It appears to act both independently and jointly with cortisol to determine a child's emotional reactivity. Its role as a primary end‐product of the HPA axis, coupled with the newly documented associations with prenatal development shown here, strongly calls for the inclusion of DHEA in future investigations of fetal programming. [ABSTRACT FROM AUTHOR]

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). To do so, we measured SMCs, depression and anxiety states, resilience, and the CAR in 77 healthy young people. 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. 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. [ABSTRACT FROM AUTHOR]

The article explores the effectiveness and potential of aromatherapy for managing anxiety. It discusses the impact of anxiety in social, occupational and other areas of life. It examines the impact of essential oils and aromatherapy on various anxiety disorders including anxiety in academic and work environment, reproductive anxiety, pregnancy and labor/maternity anxiety, preoperative and surgery anxiety, dental anxiety, procedural anxiety and anxiety in cancer and palliative care.

The way that living cells respond to non-ionizing electromagnetic fields (EMF), including static/extremely-low frequency and radiofrequency electromagnetic fields, fits the pattern of 'cellular stress response' – a mechanism manifest at the cellular level intended to preserve the entire organism. It is a set pattern of cellular and molecular responses to environmental stressors, such as heat, ionizing radiation, oxidation, etc. It is triggered by cellular macromolecular damage (in proteins, lipids, and DNA) with the goal of repairing and returning cell functions to homeostasis. The pattern is independent of the type of stressor encountered. It involves cell cycle arrest, induction of specific molecular mechanisms for repair, damage removal, cell proliferation, and cell death if damage is too great. This response could be triggered by EMF-induced alternation in oxidative processes in cells. The concept that biological response to EMF is a 'cellular stress response' explains many observed effects of EMF, such as nonlinear dose- and time-dependency, increased and decreased risks of cancer and neurodegenerative diseases, enhanced nerve regeneration, and bone healing. These responses could be either detrimental or beneficial to health, depending on the duration and intensity of the exposure, as well as specific aspects of the living organism being exposed. A corollary to electromagnetic hypersensitivity syndrome (EHS) could be an inappropriate response of the hippocampus/limbic system to EMF, involving glucocorticoids on the hypothalamic-pituitary-adrenal axis. [ABSTRACT FROM AUTHOR]