Hypothalamic-pituitary-adrenal Axis Dysfunction Research Articles

Adaptogenic action of diosgenin againsts chronic unpredictable mild stress-induced neuroimmune dysfunction of HPA axis reverses psychiatric behavior in mice

BackgroundStressful life experiences are associated with neurobehavioral abnormalities, such as anxiogenic-related depression and cognitive decline. Reportedly, adaptogens are well known to modulate stress-related responses and promote resilience. ObjectiveThis study aimed to assess the potential mechanisms and adaptogenic properties of diosgenin (DG), a phytosteroidal sapogenin with neuroendocrine protective effects, in chronic unpredictable mild stress (CUMS)-induced anxiogenic-depression and cognitive deficits in mice. MethodsDuring the 21-day study, mice were divided into five groups, and were daily treated with 5% dimethyl sulfoxide (control and CUMS model), diosgenin (25 mg/kg and 50 mg/kg) or fluoxetine (10 mg/kg) orally, respectively, followed by 21-item CUMS paradigm exposure, except for the control group. Mice were examined for anxiety, depression and cognitive-like features using relevant neurobehavioral paradigms. Biomarkers of oxidative stress, nitrite level, pro-inflammatory cytokines (TNF-α, IL-6), acetylcholinesterase (AChE), glutamic acid decarboxylase (GAD), and monoamine oxidase-B (MAOB) were measured in the prefrontal cortex, striatum, and hippocampal regions of the brain. Also, adrenal hypertrophy, serum corticosterone and glucose levels as a measure of hypothalamic pituitary adrenal (HPA) axis involvement were examined. ResultsDG ameliorated CUMS-induced behavioral anomaly, as characterized by the increased duration of grooming bouts in the sucrose preference test; decreased duration of immobility in the tail suspension and forced swim tests; anxiolytic effects in the elevated-plus maze, hole-board, light/dark compartment tests, as well as cognitive impairments indexed by the Y-maze and object recognition tests were reversed by DG respectively. DG remarkably decreased adrenal hypertrophy and elevated serum levels of corticosterone and glucose in CUMS mice. ConclusionConclusively, DG exhibits antidepressant-like and anxiolytic-like actions with memory enhancement in the CUMS mouse model, and thus could serve as an alternative agent for the management of depression and anxiety associated with cognitive decline in clinical settings.

Neurobehavioral and molecular changes in a rodent model of ACTH-induced HPA axis dysfunction

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is linked to the pathophysiology of depression. Although exogenous adrenocorticotropic hormone (ACTH) is associated with a depressive-like phenotype in rodents, comprehensive neurobehavioral and mechanistic evidence to support these findings are limited. Sprague-Dawley rats (male, n = 30; female, n = 10) were randomly assigned to the control (male, n = 10) or ACTH (male, n = 20; female n = 10) groups that received saline (0.1 ml, sc.) or ACTH (100 μg/day, sc.), respectively, for two weeks. Thereafter, rats in the ACTH group were subdivided to receive ACTH plus saline (ACTH_S; male, n = 10; female, n = 5; 0.2 ml, ip.) or ACTH plus imipramine (ACTH_I; male, n = 10; female, n = 5;10 mg/kg, ip.) for a further four weeks. Neurobehavioral changes were assessed using the forced swim test (FST), the sucrose preference test (SPT), and the open field test (OFT). Following termination, the brain regional mRNA expression of BDNF and CREB was determined using RT-PCR. After two-weeks, ACTH administration significantly increased immobility in the FST (p = 0.03), decreased interaction with the center of the OFT (p < 0.01), and increased sucrose consumption (p = 0.03) in male, but not female rats. ACTH administration significantly increased the expression of BDNF in the hippocampus and CREB in all brain regions in males (p < 0.05), but not in female rats. Imipramine treatment did not ameliorate these ACTH-induced neurobehavioral or molecular changes. In conclusion, ACTH administration resulted in a sex-specific onset of depressive-like symptoms and changes in brain regional expression of neurotrophic factors. These results suggest sex-specific mechanisms underlying the development of depressive-like behavior in a model of ACTH-induced HPA axis dysregulation.

Natural Herbal Compounds Exerting an Antidepressant Effect through Hypothalamic-Pituitary-Adrenal Axis Regulation.

Depression is a common mental illness that damages the life and health of patients and causes economic burden, and HPA (hypothalamic-pituitary-adrenal) axis dysfunction is considered to be one of the important factors leading to depression. In this case, it is essential to explore possible treatment methods by using natural compounds with HPA axis regulating and antidepressant effects. However, no one has reviewed it so far. Therefore, the purpose of this review is to systematically sort out the related natural products that play an antidepressant role by regulating the function of the HPA axis. Natural products are divided into flavonoids, polyphenols, terpenoids, saponins, polysaccharides and so on according to their chemical structures, which play a variety of biological activities such as regulating the HPA axis, anti-inflammation and neuroprotection. These effects may provide a useful reference for the potential treatment of depression so as to develop new antidepressants.

Advancements Exploring Major Depressive Disorder: Insights on Oxidative Stress, Serotonin Metabolism, BDNF, HPA Axis Dysfunction, and Pharmacotherapy Advances

Major depressive disorder (MDD), a prevalent mental illness, is marked by a complex mixture of biological factors. This review focuses on the roles of oxidative stress, tryptophan-serotonin metabolism, brain-derived neurotrophic factor (BDNF), and the hypothalamic–pituitary–adrenal (HPA) axis in MDD’s pathophysiology. Oxidative stress, defined as an imbalance between pro-oxidants and antioxidants, is closely linked to MDD’s neurobiological changes. The tryptophan (TRP)-/serotonin (5-HT) metabolic pathway is also known to be crucial in mood regulation, with its dysregulation being a central aspect of MDD. Additionally, BDNF, key for neuronal growth and plasticity, often shows alterations in MDD patients, supporting its role in the disorder’s progression. Furthermore, the HPA axis, which manages stress response, is frequently disrupted in MDD, further contributing to its complex pathology. In addition to exploring these biological mechanisms, this review also explores the pharmacotherapy of MDD, including new advances. These advancements in treatment strategies are crucial for managing MDD effectively. Understanding these mechanisms and the latest pharmacological interventions is essential for developing more effective treatments for MDD.

Cortisol Dynamics, Quality of Life, and Fatigue following Traumatic Brain Injury in Childhood

Introduction: Traumatic brain injury (TBI) is a leading cause of acquired neurological morbidity. The prevalence of post-traumatic hypopituitarism and associated morbidity after childhood TBI is unclear. Our study investigated long-term hypothalamus-pituitary-adrenal (HPA) axis function, in a prospective childhood TBI and control cohort, using measures of cortisol/cortisone secretion (physiological and stimulated), HPA axis feedback, and exploring associations with fatigue, depression, and quality of life (QoL) outcomes. Methods: All TBI participants had data concerning severity and mechanism of TBI. All groups had clinical assessment, pituitary/brain MRI, questionnaire measures of QoL, fatigue, depression, and salivary cortisone profiles including dexamethasone suppression test. In addition, participants with moderate/severe TBI had ethical approval for baseline endocrine blood tests, overnight 12-h venous sampling of cortisol and growth hormone, and stimulated HPA axis evaluation with an insulin tolerance test (ITT). Results: Seventy-two participants with moderate/severe (n = 31, age 19.8 ± 4.2 years) or mild TBI (n = 24, age 17.8 ± 5.1 years) and matched controls (n = 17, age 18.5 ± 5.5 years) took part. Time post-TBI was 6.8–10.8 years. Baseline endocrine tests confirmed normal thyroid and posterior pituitary function. One female with moderate/severe TBI had hypogonadism. Pituitary neuroimaging was normal in all participants. In 2/25 ITT and 9/22 overnight serum profiles, peak cortisol was Conclusion: Although not as prevalent as previously reported, HPA axis dysfunction does occur in survivors of childhood TBI, confirming the need for endocrine surveillance. However, in most of our paediatric TBI survivors assessed 7–11 years post-TBI, HPA function and circadian rhythmicity were preserved or had recovered. Chronic fatigue is a common concern post-TBI, but in the majority, it is not associated with frank HPA axis dysfunction. Morning salivary cortisone levels were higher in TBI survivors (who have a high prevalence of fatigue) compared to healthy controls, despite the recognised association of chronic fatigue with cortisol hyposecretion.

Imaging a putative marker of brain cortisol regulation in alcohol use disorder

BackgroundStress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [18F]AS2471907 to measure 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls. MethodsWe imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11β-HSD1 inhibitor radiotracer [18F]AS2471907 as a bolus injection and were imaged for 150–180 min on the High-Resolution Research Tomograph. 11β-HSD1 availability was quantified by [18F]AS2471907 volume of distribution (VT; mL/cm3). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate. ResultsIndividuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [18F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [18F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02). ConclusionsThis is the first in vivo examination of 11β-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11β-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11β-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.

Bacopaside I alleviates depressive-like behaviors by modulating the gut microbiome and host metabolism in CUMS-induced mice

Bacopaside I (BSI) is a natural compound that is difficult to absorb orally but has been shown to have antidepressant effects. The microbiota-gut-brain axis is involved in the development of depression through the peripheral nervous system, endocrine system, and immune system and may be a key factor in the effect of BSI. Therefore, this study aimed to investigate the potential mechanism of BSI in the treatment of depression via the microbiota-gut-brain axis and to validate it in a fecal microbiota transplantation model. The antidepressant effect of BSI was established in CUMS-induced mice using behavioral tests and measurement of changes in hypothalamicpituitaryadrenal (HPA) axis-related hormones. The improvement of stress-induced gut-brain axis damage by BSI was observed by histopathological sections and enzyme-linked immunosorbent assay (ELISA). 16 S rDNA sequencing analysis indicated that BSI could modulate the abundance of gut microbiota and increase the abundance of probiotic bacteria. We also observed an increase in short-chain fatty acids, particularly acetic acid. In addition, BSI could modulate the disruption of lipid metabolism induced by CUMS. Fecal microbiota transplantation further confirmed that disruption of the microbiota-gut-brain axis is closely associated with the development of depression, and that the microbiota regulated by BSI exerts a partial antidepressant effect. In conclusion, BSI exerts antidepressant effects by remodeling gut microbiota, specifically through the Lactobacillus and Streptococcus-acetic acid-neurotrophin signaling pathways. Furthermore, BSI can repair damage to the gut-brain axis, regulate HPA axis dysfunction, and maintain immune homeostasis.

The exploration of neuroinflammatory mechanism by which CRHR2 deficiency induced anxiety disorder

Inflammation stimulates the hypothalamic-pituitary adrenal (HPA) axis and triggers glial neuroinflammatory phenotypes, which reduces monoamine neurotransmitters by activating indoleamine 2,3-dioxygenase enzyme. These changes can induce psychiatric diseases, including anxiety. Corticotropin releasing hormone receptor 2 (CRHR2) in the HPA axis is involved in the etiology of anxiety. Omega(n)-3 polyunsaturated fatty acids (PUFAs) can attenuate anxiety through anti-inflammation and HPA axis modulation. However, the underlying molecular mechanism by CRHR2 modulates anxiety and its correlation with neuroinflammation remain unclear. Here, we first constructed a crhr2 zebrafish mutant line, and evaluated anxiety-like behaviors, gene expression associated with the HPA axis, neuroinflammatory response, neurotransmitters, and PUFAs profile in crhr2+/+ and crhr2−/− zebrafish. The crhr2 deficiency decreased cortisol levels and up-regulated crhr1 and down-regulated crhb, crhbp, ucn3l and proopiomelanocortin a (pomc a) in zebrafish. Interestingly, a significant increase in the neuroinflammatory markers, translocator protein (TSPO) and the activation of microglia M1 phenotype (CD11b) were found in crhr2−/− zebrafish. As a consequence, the expression of granulocyte-macrophage colony-stimulating factor, pro-inflammatory cytokines vascular endothelial growth factor, and astrocyte A1 phenotype c3 were up-regulated. While microglia anti-inflammatory phenotype (CD206), central anti-inflammatory cytokine interleukin-4, arginase-1, and transforming growth factor-β were downregulated. In parallel, crhr2-deficient zebrafish showed an upregulation of vdac1 protein, a TSPO ligand, and its downstream caspase-3. Furthermore, 5-HT/5-HIAA ratio was decreased and n-3 PUFAs deficiency was identified in crhr2−/− zebrafish. In conclusion, anxiety-like behavior displayed by crhr2-deficient zebrafish may be caused by the HPA axis dysfunction and enhanced neuroinflammation, which resulted in n-3 PUFAs and monoamine neurotransmitter reductions.

Potential mechanisms of non-suicidal self-injury (NSSI) in major depressive disorder: a systematic review

BackgroundNon-suicidal self-injury (NSSI) is a frequent and prominent phenomenon in major depressive disorder (MDD). Even though its prevalence and risk factors are relatively well understood, the potential mechanisms of NSSI...

Electroacupuncture Ameliorates Hypothalamic‒Pituitary‒Adrenal Axis Dysfunction Induced by Surgical Trauma in Mice Through the Hypothalamic Oxytocin System.

Electroacupuncture (EA) can effectively reduce surgical stress reactions and promote postoperative recovery, but the mechanisms remain unclear. The present study aims to examine the effects of EA on the hyperactivity of the hypothalamic‒pituitary‒adrenal (HPA) axis and investigate its potential mechanisms. Male C57BL/6 mice were subjected to partial hepatectomy (HT). The results showed that HT increased the concentrations of corticotrophin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH) in the peripheral blood and upregulated the expression of CRH and glucocorticoid receptors (GR) proteins in the hypothalamus. EA treatment significantly inhibited the hyperactivity of the HPA axis by decreasing the concentration of CRH, CORT, and ACTH in peripheral blood and downregulating the expression of CRH and GR in the hypothalamus. Moreover, EA treatment reversed the HT-induced downregulation of oxytocin (OXT) and oxytocin receptor (OXTR) in the hypothalamus. Furthermore, intracerebroventricular injection of the OXTR antagonist atosiban blocked the effects of EA. Thus, our findings implied that EA mitigated surgical stress-induced HPA axis dysfunction by activating the OXT/OXTR signaling pathway.

From childhood adversity to latent stress vulnerability in adulthood: the mediating roles of sleep disturbances and HPA axis dysfunction.

Childhood adversity is a prominent predisposing risk factor for latent stress vulnerability, expressed as an elevated likelihood of developing stress-related psychopathology upon subsequent exposure to trauma in adulthood. Sleep disturbances have emerged as one of the most pronounced maladaptive behavioral outcomes of childhood adversity and are also a highly prevalent core feature of stress-related psychopathology, including post-traumatic stress disorder (PTSD). After reviewing the extensive literature supporting these claims, the current review addresses the notion that childhood adversity-induced sleep disturbances may play a causal role in elevating individuals' stress vulnerability in adulthood. Corroborating this, sleep disturbances that predate adult trauma exposure have been associated with an increased likelihood of developing stress-related psychopathology post-exposure. Furthermore, novel empirical evidence suggests that sleep disturbances, including irregularity of the sleep-wake cycle, mediate the link between childhood adversity and stress vulnerability in adulthood. We also discuss cognitive and behavioral mechanisms through which such a cascade may evolve, highlighting the putative role of impaired memory consolidation and fear extinction. Next, we present evidence to support the contribution of the hypothalamic-pituitary-adrenal (HPA) axis to these associations, stemming from its critical role in stress and sleep regulatory pathways. Childhood adversity may yield bi-directional effects within the HPA stress and sleep axes in which sleep disturbances and HPA axis dysfunction reinforce each other, leading to elevated stress vulnerability. To conclude, we postulate a conceptual path model from childhood adversity to latent stress vulnerability in adulthood and discuss the potential clinical implications of these notions, while highlighting directions for future research.

Dysfunction of the hypothalamic-pituitary adrenal axis and its influence on aging: the role of the hypothalamus

As part of the hypothalamic-pituitary adrenal (HPA) axis, the hypothalamus exerts pivotal influence on metabolic and endocrine homeostasis. With age, these processes are subject to considerable change, resulting in increased prevalence of physical disability and cardiac disorders. Yet, research on the aging human hypothalamus is lacking. To assess detailed hypothalamic microstructure in middle adulthood, 39 healthy participants (35–65 years) underwent comprehensive structural magnetic resonance imaging. In addition, we studied HPA axis dysfunction proxied by hair cortisol and waist circumference as potential risk factors for hypothalamic alterations. We provide first evidence of regionally different hypothalamic microstructure, with age effects in its anterior–superior subunit, a critical area for HPA axis regulation. Further, we report that waist circumference was related to increased free water and decreased iron content in this region. In age, hair cortisol was additionally associated with free water content, such that older participants with higher cortisol levels were more vulnerable to free water content increase than younger participants. Overall, our results suggest no general age-related decline in hypothalamic microstructure. Instead, older individuals could be more susceptible to risk factors of hypothalamic decline especially in the anterior–superior subregion, including HPA axis dysfunction, indicating the importance of endocrine and stress management in age.

Biopsychological trait markers supporting the stress-diathesis model in functional neurological disorders. (S51.010)

<h3>Objective:</h3> To shed light on the underlying neurobiological mechanisms of functional neurological disorders (FND), we analysed the relationship between potential dysregulation of the Hypothalamic-Pituitary Adrenal (HPA) axis, trauma history, and structural brain abnormalities. <h3>Background:</h3> Stress is a well-known risk factor to develop FND. Only little is known about the biological stress regulation, and what might be the role of predisposing biological and psychosocial risk factors. <h3>Design/Methods:</h3> We set out to study the HPA axis analysing the cortisol awakening response and diurnal baseline cortisol in 86 patients with mixed functional neurological symptoms compared to 76 healthy controls. We then examined the association between cortisol regulation and severity and duration of traumatic life events. Finally, we analysed volumetric brain alterations in brain regions particularly sensitive to psychosocial stress, acting on the assumption of the neurotoxic effect of prolonged cortisol exposure. <h3>Results:</h3> Overall, patients had a significantly flatter cortisol awakening response (<i>P</i> &lt; 0.001) and reported longer (<i>P</i> = 0.01) and more severe (<i>P</i> &lt; 0.001) emotional neglect as compared to heathy controls. Moreover, volumes of bilateral hippocampus and amygdala were found to be reduced in patients. Using a partial least squares correlation, we found that in patients, emotional neglect plays a role in the multivariate pattern between trauma history and HPA axis dysfunction, whilst cortisol did not relate to reduced brain volumes. <h3>Conclusions:</h3> In summary, this study supports a stress-diathesis model for FND and showed an association between different attributes of trauma history and abnormalities in HPA-axis function. Moreover, we suggest that reduced hippocampal- and amygdalar volumes represent a biological ‘trait marker’ for FND patients, which might contribute to a reduced resilience to stress. <b>Disclosure:</b> Mrs. Weber has nothing to disclose. Mrs. Bühler has nothing to disclose. Mr. Loukas has nothing to disclose. Dr. Aybek has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Swiss Movement Disorder Foundation. The institution of Dr. Aybek has received research support from Swiss National Science Foundation.

Diurnal Cortisol Features and Type 2 Diabetes Risk in Patients With Hypertension and Obstructive Sleep Apnea: A Cohort Study.

The hypothalamic-pituitary-adrenal (HPA) axis may be associated with type 2 diabetes (T2D); however, whether HPA axis dysfunction is associated with incident T2D remains unclear in patients with hypertension and obstructive sleep apnea (OSA). To investigate the relationship between the diurnal cortisol features and the risk of incident T2D in patients with hypertension and OSA. Participants with cortisol rhythm test at baseline in the Urumqi Research on Sleep Apnea and Hypertension cohort were enrolled. The Cox regression model was used to evaluate the relationship between ln-transformed diurnal cortisol features and T2D risk. Stratified and sensitivity analyses were also performed. A total of 1478 patients with hypertension and OSA were enrolled in this study. During a median follow-up of 7.0 years, 196 participants developed T2D. Overall, a steep diurnal cortisol slope (DCS) was significantly associated with decreased T2D risk (per SD increase, HR 0.88, 95% CI 0.79-0.97, P = .014). Midnight cortisol was positively associated with increased T2D risk (per SD increase, HR 1.25, 95% CI 1.08-1.45, P = .003). Sensitivity analyses showed similar results. Neither DCS nor midnight cortisol was associated with incident T2D in the women's subgroup or participants with mild OSA. Steeper DCS and higher midnight cortisol levels are associated with lower and higher T2D risks in patients with hypertension and OSA, respectively, at least in men or participants with moderate to severe OSA. Diurnal cortisol features may represent an early prevention target for diabetes in this population.

Hypothalamic corticotrophin releasing hormone neurons in stress-induced psychopathology: Revaluation of synaptic contributions.

Stress has a strong influence on mental health around the world. Decades of research has sought to identify mechanisms through which stress contributes to psychiatric disorders such as depression, to potentially guide the development of therapeutics targeting stress systems. The hypothalamic pituitary adrenal (HPA) axis is the key endocrine system that is responsible for coordinating body-wide changes that are necessary for survival under stress, and much of the research aimed at understanding the mechanisms by which stress contributes to depression has focussed on HPA axis dysfunction. Corticotrophin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) sit at the apex of the HPA axis, integrating signals relevant to stress and external threats, to ensure HPA axis activity is appropriate for the given context. In addition to this, emerging research has demonstrated that neural activity in PVNCRH neurons regulates stress related behaviours via modulation of downstream synaptic targets. This review will summarize convergent evidence from preclinical studies on chronic stress and clinical research in mood disorders demonstrating changes in PVNCRH neural function, consider how this may influence synaptic targets of PVNCRH neurons, and discuss the potential role of these PVNCRH synaptic pathways in the development of maladaptive behaviours following chronic stress that are relevant to depression. We will also highlight important questions for future research aimed at precisely dissecting endocrine and synaptic roles of PVNCRH neurons in chronic stress, their potential interactions, and therapeutic opportunities for the treatment of stress related disorders.

Targeting the Arginine Vasopressin V1b Receptor System and Stress Response in Depression and Other Neuropsychiatric Disorders.

A healthy stress response is critical for good mental and overall health and promotes neuronal growth and adaptation, but the intricately balanced biological mechanisms that facilitate a stress response can also result in predisposition to disease when that equilibrium is disrupted. The hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system plays a critical role in the body's response and adaptation to stress, and vasopressinergic regulation of the HPA axis is critical to maintaining system responsiveness during chronic stress. However, exposure to repeated or excessive physical or emotional stress or trauma can shift the body's stress response equilibrium to a "new normal" underpinned by enduring changes in HPA axis function. Exposure to early life stress due to adverse childhood experiences can also lead to lasting neurobiological changes, including in HPA axis function. HPA axis impairment in patients with depression is considered among the most reliable findings in biological psychiatry, and chronic stress has been shown to play a major role in the pathogenesis and onset of depression and other neuropsychiatric disorders. Modulating HPA axis activity, for example via targeted antagonism of the vasopressin V1b receptor, is a promising approach for patients with depression and other neuropsychiatric disorders associated with HPA axis impairment. Despite favorable preclinical indications in animal models, demonstration of clinical efficacy for the treatment of depressive disorders by targeting HPA axis dysfunction has been challenging, possibly due to the heterogeneity and syndromal nature of depressive disorders. Measures of HPA axis function, such as elevated cortisol levels, may be useful biomarkers for identifying patients who may benefit from treatments that modulate HPA axis activity. Utilizing clinical biomarkers to identify subsets of patients with impaired HPA axis function who may benefit is a promising next step in fine-tuning HPA axis activity via targeted antagonism of the V1b receptor.

High-Fat Diet Exacerbates Stress Responsivity in Juvenile Traumatic Brain Injury.

Abstract Traumatic brain injury (TBI) is one of the leading causes of death for children in the United States. Juveniles are more likely to sustain TBIs than most other age groups, and TBI has been shown to result in increased anxiety and stress behaviors. In addition, the hypothalamic-pituitary-adrenal (HPA) axis has previously been shown to become dysregulated after a TBI. Further, many children consume diets high in saturated fats and refined sugars, which are also connected to alterations in HPA axis function and behavior disorders. The goal of the current study was to identify a potential relationship between high-fat diet (HFD) consumption and TBI on HPA axis function in juvenile rats. In the present study, male juvenile Long-Evans rats were fed either a combination of an HFD with a high-fructose corn syrup solution or a standard chow diet. On post-natal Day 30, subjects sustained either a sham TBI or a TBI via the Closed-Head Injury Model of Engineered Rotational Acceleration (CHIMERA). Subjects participated in a trial of the open field test (OFT) following injury. In addition, some rats performed in an acute restraint stress test. All subjects were euthanized 7 days post-injury. Brain and blood plasma samples were collected for use in real-time polymerase chain reaction (RT-PCR), immunohistochemistry, and corticosterone or adrenocorticotropic hormone (ACTH) assays. Immediately following TBI, injured juveniles had increased time to righting and walking, with HFD-fed TBI rats having increased time to walking over Chow-fed TBI rats. HFD-fed TBI rats had a reduced number of entries to the center of the OFT, in addition to reduced time spent in the center compared with HFD Sham controls and Chow TBI rats. During the acute restraint stress test, HFD-fed TBI rats had elevated pre-stress ACTH and corticosterone and post-stress ACTH levels. Pre-stress ACTH levels were significantly elevated in HFD TBI compared with Chow TBI. Further, pre-stress ACTH:corticosterone ratios were elevated in HFD TBI compared with Chow TBI. cFos immunoreactivity in the paraventricular nucleus (PVN) of the hypothalamus following the acute restraint stress test was elevated in HFD-fed TBI rats. HFD TBI rats had greater activation of cFos in the PVN compared with Chow TBI. In addition, RT-PCR showed significantly reduced expression of relevant HPA axis genes, NR3C1, NR3C2, and CRHR2, in the hypothalamus of TBI subjects compared with Sham subjects. Further, AVP and CRHR2 in the hypothalamus were significantly reduced in HFD TBI compared with Chow TBI. These results offer evidence that TBI paired with high-fat diet consumption can cause HPA axis dysfunction, resulting in more anxiety-like behaviors.

Functional changes in the hypothalamic-pituitary-adrenal axis after successful cardiopulmonary resuscitation

Abstract Background Cardiac arrest (CA) is a terminal event that results in a range of pathophysiological changes in the body, most notably, systemic ischemia-reperfusion injury. The hypothalamic-pituitary-adrenal (HPA) axis is an important neuroendocrine system that modulates adrenocortical hormone release. This study was designed to investigate the changes in HPA-related hormone levels after successful cardiopulmonary resuscitation (CPR) and to explore possible etiologies to provide a basis for relevant clinical research. Methods We collected the clinical data of 96 patients with CA admitted to the Emergency Department of Beijing Chaoyang Hospital, Capital Medical University, between January 2016 and May 2017. Serum samples were collected 6, 24, and 72 hours after restoring spontaneous circulation (ROSC). The data were compared with those of the healthy control group (n = 50). An enzyme-linked immunosorbent assay (ELISA) was performed to measure copeptin, adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), and total cortisol. Demographic data were collected for both groups. For the CPR group, clinical data and the end-of-study cerebral performance category (CPC) were analyzed. Patients were followed up through day 28. Death or survival after day 28 was used as the study endpoint. Simple values were expressed as medians and quartiles or ratios (%) for statistical analysis. Continuous variables are expressed as mean ± standard deviation. Categorical variables were expressed as frequencies and percentages. The mean values of normally distributed measurement data were analyzed using 1-way analysis of variance (ANOVA) for among-group comparisons and the least significant difference (LSD) test for between-group comparisons. SPSS v17 (SPSS, Chicago, IL, USA) was used for statistical analysis, and P &lt; 0.05 was considered statistically significant. Results No significant between-group differences were observed in terms of age or sex. The 28-day mortality rate in the CPR group was 71%. ACTH and CRH levels were significantly lower in the CPR group than in the healthy control group (P &lt; 0.001). Copeptin and cortisol levels 6 hours after ROSC were significantly higher in the CPR group than in the healthy control group (P &lt; 0.001). No significant changes in any indicator were observed over time (6, 24, and 72 hours after ROSC) (P &gt; 0.05). The CPC score was 1–2 (good cerebral performance group) in 13 patients, 3–4 (poor cerebral performance group) in 17 patients, and 5 (brain death or clinical death) in 66 patients. Patients with significantly declining ACTH and CRH levels had higher CPC scores (P &lt; 0.05); however, no significant differences were found in other indicators (P &gt; 0.05). Conclusion After post-CA ROSC, ischemia-reperfusion injury may cause brain damage and HPA axis damage and dysfunction, the severity of which is associated with CPC score.

Premature adrenarche in Prader-Willi syndrome is associated with accelerated pre-pubertal growth and advanced bone age.

Prader-Willi syndrome (PWS) is characterized by obesity, growth hormone deficiency, hypogonadism, and a high prevalence of premature adrenarche despite reported hypothalamic-pituitary-adrenal axis dysfunction. While idiopathic premature adrenarche is associated with accelerated pre-pubertal growth and advanced bone age, the consequences of elevated adrenal androgens on growth and bone maturation in PWS remain unknown. This study therefore sought to describe age-related changes in dehydroepiandrosterone sulfate (DHEAS) and their effects on growth and bone maturation in PWS. This retrospective observational study included 62 children with PWS. Simple and multiple regression models were constructed to relate age and BMI-SDS with DHEAS levels. Height velocity was compared to age andsex-based norms with t-tests and two-way ANOVA. Patterns in bone age Z-score were examined with two-way ANOVA, and the contributions of age, BMI-SDS, and DHEAS to bone age Z-score were analyzed with multiple regression. DHEAS levels rose earlier and were less strongly correlated with age in males and females with PWS (R2=0.12 and 0.30) compared to healthy controls (R2=0.89 and 0.88) in a pattern unrelated to BMI-SDS (adjusted R2=0.076, p=0.10 for age, and 0.29 for BMI-SDS). Mid-childhood height velocity was increased in males and preserved in females with PWS before declining at the age of expected puberty (p<0.0001). Peri-adrenarchal bone age was advanced in a manner associated with DHEAS but not BMI-SDS (p<0.0001; adjusted R2=0.48, p=0.0014 for DHEAS, and 0.78 for BMI-SDS). An obesity-independent increase in adrenal androgens is associated with accelerated mid-childhood growth and bone maturation in PWS.

Immune checkpoint inhibitor related hypothalamus pituitary adrenal axis dysfunction: A retrospective study in Derriford Hospital

Immune checkpoint inhibitor related hypothalamus pituitary adrenal axis dysfunction: A retrospective study in Derriford Hospital