Adrenal Axis Research Articles

Inflammatory-like status and acute stress response in horses after road transport

This study aimed to evaluate the change of white blood cell count, serum concentration of cortisol, C-reactive protein, albumin and globulin fractions in horse after road transport, and to assess the linkage among hypothalamic–pituitary–adrenal axis (HPA) and inflammatory reaction. From 10 horses blood samples were collected at rest, before road transport (218 km) (BT); after unloaded (AT), 30 and 60 min after unloaded (AT30 and AT60) in order to assess white blood cell count (WBC), serum cortisol, C-reactive protein (CRP), total proteins, albumin, α1-, α-2, β1-, β2- and γ-globulins. WBC, cortisol, CRP, α1-, α-2 and β2-globulins values increased after road transport than rest condition (p < 0.001). Albumin and A/G ratio showed lower values after road transport than rest (p < 0.001). Pearson’s test showed a negative correlation between cortisol and the values of WBC, CRP, α1-, α2-, β1-, β2- globulins, and a positive correlation between WBC and serum concentration of CRP, α1- and α2-, β1-, β2-globulins at AT and AT30. The results showed that road transport evokes an inflammatory like-status in horses. Moreover, the activation of HPA and the onset of acute phase reaction in response to road transport seem to be interconnected with effects on horse’s immune status.

Hormones and Aging: An Endocrine Society Scientific Statement.

Multiple changes occur across various endocrine systems as an individual ages. The understanding of the factors that cause age-related changes and how they should be managed clinically is evolving. This statement reviews the current state of research in the growth hormone, adrenal, ovarian, testicular, and thyroid axes, as well as in osteoporosis, vitamin D deficiency, type 2 diabetes, and water metabolism, with a specific focus on older individuals. Each section describes the natural history and observational data in older individuals, available therapies, clinical trial data on efficacy and safety in older individuals, key points, and scientific gaps. The goal of this statement is to inform future research that refines prevention and treatment strategies in age-associated endocrine conditions, with the goal of improving the health of older individuals.

The Unique and Interactive Effects of Threat and Deprivation Adversity on Emerging Adults’ Latent Trait Cortisol (LTC)

The mechanisms through which early adversity predicts psychopathology differ for threat (e.g., assault) versus deprivation (e.g., neglect) adversity. Threat, but not deprivation, adversity is linked to hypothalamic pituitary adrenal (HPA) axis activity, but whether this effect is modified by co-occurring adversities has not been examined. Here we tested whether threat adversity, deprivation adversity, and their interaction were related to latent trait cortisol (LTC), and whether other co-occurring adversities modified effects. Emerging adults (n=90) provided saliva samples 4 times per day during three 3-day sampling waves spanning 13 weeks. Contextual stress interviews assessed early adversity before age 18. An across-wave LTC factor was identified (CFI=.93, RMSEA=.05). Path models revealed that threat, but not deprivation, adversity was related to the across-wave LTC. Specifically, a greater frequency of threat adversity was related to lower across-wave LTC (β= -.40; p=.04), regardless of level of co-occurring deprivation adversity (ps>.05). Greater severity of threat adversity was also related to lower LTC, but only when deprivation adversity was lower in severity (b= -.03; p=.04). Finally, the effect of threat adversity on the across-wave LTC was stronger when co-occurring non-threat adversity was lower in severity (b= -.03; p=.01) and frequency (b= -.03; p=.01). Findings suggest that the impact of threat adversity on LTC depends upon its conceptualization and the context in which it occurs. These results help to identify for whom and under what circumstances threat adversity predicts lower LTC, a potential pathway to later psychopathology.

Associations between biomarkers and the psychophysiological impacts of teacher stress: a systematic review

Extensive literature demonstrates associations between occupational stress and adverse mental and physical health outcomes. Findings are inconsistent regarding the impacts of occupational stress on specific biomarkers/physiological systems among teachers. We conducted a PRISMA systematic electronic search to evaluate associations between biomarkers and occupational stress in teachers across education levels and identify gaps in the field. 38 papers met inclusion criteria from the initial search (N=3,290). Most papers were cross-sectional, with a subset using longitudinal or experimental designs (n=12). For Hypothalamic Pituitary Adrenal (HPA) axis biomarkers (n =29; salivary or hair cortisol), a third of studies found no association between stress and physiological alterations; the remaining HPA axis studies found associations between higher chronic stress (burnout) and blunted/hyporeactive HPA axis activation, and positive associations between acute stress (job strain, perceived stress) and increased HPA axis activation (higher diurnal cortisol, higher reactivity). Cardiovascular findings were mixed, with inconsistent relations between stress and cardiac function (n=10; HR, BP, HRV). For immunological studies (n=6; immune assays), chronic work stress was associated with increased pro-inflammatory and less effective anti-inflammatory activity, and mixed associations between burnout and inflammatory markers. Both acute and chronic occupational stress (burnout, perceived stress, job strain), negatively impact teacher health processes. More research will clarify associations between facets of occupational stress and physiology. We conclude with recommendations for improved methodology, a call for more experimental and intervention work, and more focus placed on teacher health and how teacher health impacts both teacher and child outcomes.

Context and Neuroendocrine Interplay in the Lab and Everyday Experiences: From Early Life to Adulthood

Context and Neuroendocrine Interplay in the Lab and Everyday Experiences: From Early Life to Adulthood

Latent Trait Cortisol: Considering the Interplay of Adversity and Cultural Resilience Factors in Latino Adolescents

Latent trait cortisol (LTC) has been established across multiple samples as a stable person-level indicator of hypothalamic pituitary adrenal (HPA) axis functioning. However, extant research among predominantly White samples linking early life adversity to LTC has produced inconsistent findings, likely due to methodological and demographic differences. Using a cultural neurobiological framework, this study examined whether cultural resilience factors (ethnic racial identity [ERI], bicultural competence) may promote healthier LTC levels and protect against the deleterious effects of exposure to early adversity among Latino adolescents. Salivary cortisol was collected five times a day across three weekdays in a sample of 206 Latino high school seniors (Mage=18.1; 64.4% female). Self-reported questionnaires assessing demographics, health behaviors, adverse experiences, ERI, and bicultural competence (i.e., comfort and facility subscales) were also collected. Confirmatory factor analysis identified an adequate theory-driven model of LTC using waking and 30-minute post-waking samples and estimating within-day sample covariation. Structural equation modeling revealed that greater early adversity predicted lower LTC (b=-.11, p=.01). ERI demonstrated neither promotive nor protective effects. Bicultural facility predicted greater LTC (b=.39, p=.004) but did not moderate the association between adversity and LTC. Consistent with hypo-arousal theories, early adversity contributed to reduced LTC among Latino adolescents, whereas the ease with which youth navigate host and heritage culture demands (i.e., bicultural facility) promoted robust HPA axis functioning. Burgeoning literature establishing LTC as a stable cortisol construct should continue to be contextualized by known risk factors as well as culturally salient processes.

Application of intranasal oxytocin and affectionate touch reduce subsequent cortisol concentrations in romantic couples: Results from an ecological momentary assessment study

Social interactions and particularly affectionate touch are vital for mental and physical health. Research shows that affectionate touch is associated with release of oxytocin and has calming and stress reducing effects suggesting a regulatory effect of oxytocin on the hypothalamic pituitary adrenal (HPA) axis. Here, we aimed to systematically investigate the effects of repeated intranasal oxytocin administration on salivary cortisol. Furthermore, we focused on the moderating role of couples’ affectionate touch on biopsychological stress outcomes in everyday life. 80 heterosexual romantic couples (N=160 individuals) completed ecologically momentary assessments over five days. Six times per day participants answered smartphone-based questions regarding affectionate touch and momentary stress levels providing concomitant saliva samples for cortisol assessment. Half of the sample was randomly assigned to an instructed positive appraisal task. In a randomized double-blind design, both partners self-administered oxytocin or placebo on five days twice during the early evening. Multilevel analyses showed that oxytocin administration was associated with higher cortisol in the following morning and stronger decreases during the day. Subjectively reported momentary stress was associated with increase of affectionate touch in couples. Moreover, results indicate that participants, who received affectionate touch from their partner showed significantly lower cortisol levels after oxytocin administration. These results suggest that oxytocin administration paired with affectionate touch in romantic couples can influence HPA axis regulation as indicated via diurnal cortisol levels. Thereby, the data shed light on the neuroendocrine underpinnings of the health-promoting effects of intimate social relationships.

Early Childhood Education Teacher Psychophysiology and Teacher Stress: Prior Findings, Current Studies, and Future Directions

Early Childhood Education Teacher Psychophysiology and Teacher Stress: Prior Findings, Current Studies, and Future Directions

Daily Rumination and Diurnal Cortisol in Latino Adolescents: The Role of Bicultural Competence and Gender

Rumination is a transdiagnostic risk factor for internalizing disorders and is hypothesized to influence psychopathology through alterations in physiological stress systems (i.e., hypothalamic pituitary adrenal axis). The current study examined daily and spillover effects of rumination on diurnal cortisol patterns and investigated how bicultural competence and gender moderated those associations. Salivary cortisol was collected five times per day for three weekdays in a sample of 206 Latino adolescents (Mage=18.10, SD=0.41; 64.4% female). Daily diaries assessed daily rumination and perceived stress, and demographics and bicultural competence were assessed via self-report questionnaires. Diurnal cortisol patterns were modeled using three-level growth curve analyses. Illustrating spillover effects, ruminating more than usual about stress/problems one night was linked with flatter next-day diurnal slopes (γ=.119, p<.01). Gender significantly moderated associations between same-day rumination and diurnal cortisol patterns. When females ruminated more than usual about stress/problems, they exhibited a greater cortisol awakening response (CAR; γ=.046, p<.01). Males exhibited a smaller CAR on days when they ruminated more than usual about their feelings (γ=-.067, p<.05). Bicultural competence was not a significant moderator of associations. Findings suggest spillover effects and gender differences in the relation of rumination and diurnal cortisol activity in Latino adolescents. Efforts to identify adolescents at-risk for psychopathology should consider the interplay of detrimental emotion regulation styles and gender that contribute to greater physiological stress at a daily level.

Epigenetic modification of the hypothalamic–pituitary–adrenal (HPA) axis during development in the house sparrow (Passer domesticus)

Epigenetic modifications such as DNA methylation are important mechanisms for mediating developmental plasticity, where ontogenetic processes and their phenotypic outcomes are shaped by early environments. In particular, changes in DNA methylation of genes within the hypothalamic–pituitary–adrenal (HPA) axis can impact offspring growth and development. This relationship has been well documented in mammals but is less understood in other taxa. Here, we use target-enriched enzymatic methyl sequencing (TEEM-seq) to assess how DNA methylation in a suite of 25 genes changes over development, how these modifications relate to the early environment, and how they predict differential growth trajectories in the house sparrow (Passer domesticus). We found that DNA methylation changes dynamically over the postnatal developmental period: genes with initially low DNA methylation tended to decline in methylation over development, whereas genes with initially high DNA methylation tended to increase in methylation. However, sex-specific differentially methylated regions (DMRs) were maintained across the developmental period. We also found significant differences in post-hatching DNA methylation in relation to hatch date, with higher levels of DNA methylation in nestlings hatched earlier in the season. Although these differences were largely absent by the end of development, a number of DMRs in HPA-related genes (CRH, MC2R, NR3C1, NR3C2, POMC)—and to a lesser degree HPG-related genes (GNRHR2)—predicted nestling growth trajectories over development. These findings provide insight into the mechanisms by which the early environment shapes DNA methylation in the HPA axis, and how these changes subsequently influence growth and potentially mediate developmental plasticity.

Association analysis of gut microbiota-metabolites-neuroendocrine changes in male rats acute exposure to simulated altitude of 5500 m

Hyperactivation of hypothalamic–pituitary–adrenal (HPA) axis and hypothalamic–pituitary–thyroid (HPT) axis were found in acute high altitude challenge, but the role of gut microbiota and metabolites is unknown. We utilized adult male Sprague–Dawley rats at a simulated altitude of 5500 m for 3 days in a hypobaric-hypoxic chamber. ELISA and metabolomic analyses of serum and 16S rRNA and metabolomic analyses of fecal samples were then performed. Compared with the normoxic group, serum corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT), and thyroxine (tT4) were increased in the hypoxia group, whereas thyrotropin-releasing hormone (TRH) was decreased. Bacteroides, Lactobacillus,Parabacteroides,Butyricimonas,SMB53,Akkermansia,Phascolarctobacterium, and Aerococcus were enriched in hypoxia group, whereas [Prevotella], Prevotella,Kaistobacter,Salinibacterium, and Vogesella were enriched in normoxic group. Metabolomic analysis indicated that acute hypoxia significantly affected fecal and serum lipid metabolism. In addition, we found five fecal metabolites may mediate the cross-talk between TRH, tT4, and CORT with [Prevotella], Kaistobacter,Parabacteroides, and Aerococcus, and 6 serum metabolites may mediate the effect of TRH and tT4 on [Prevotella] and Kaistobacter by causal mediation analysis. In conclusion, this study provides new evidence that key metabolites mediate the cross-talk between gut microbiota with HPA and HPT axis under acute hypobaric hypoxia challenge.

Pharmacological Modulation of Energy and Metabolic Pathways Protects Hearing in the Fus1/Tusc2 Knockout Model of Mitochondrial Dysfunction and Oxidative Stress.

Tightly regulated and robust mitochondrial activities are critical for normal hearing. Previously, we demonstrated that Fus1/Tusc2 KO mice with mitochondrial dysfunction exhibit premature hearing loss. Molecular analysis of the cochlea revealed hyperactivation of the mTOR pathway, oxidative stress, and altered mitochondrial morphology and quantity, suggesting compromised energy sensing and production. Here, we investigated whether the pharmacological modulation of metabolic pathways using rapamycin (RAPA) or 2-deoxy-D-glucose (2-DG) supplementation can protect against hearing loss in female Fus1 KO mice. Additionally, we aimed to identify mitochondria- and Fus1/Tusc2-dependent molecular pathways and processes critical for hearing. We found that inhibiting mTOR or activating alternative mitochondrial energetic pathways to glycolysis protected hearing in the mice. Comparative gene expression analysis revealed the dysregulation of critical biological processes in the KO cochlea, including mitochondrial metabolism, neural and immune responses, and the cochlear hypothalamic-pituitary-adrenal axis signaling system. RAPA and 2-DG mostly normalized these processes, although some genes showed a drug-specific response or no response at all. Interestingly, both drugs resulted in a pronounced upregulation of critical hearing-related genes not altered in the non-treated KO cochlea, including cytoskeletal and motor proteins and calcium-linked transporters and voltage-gated channels. These findings suggest that the pharmacological modulation of mitochondrial metabolism and bioenergetics may restore and activate processes critical for hearing, thereby protecting against hearing loss.

Thyroid, Gonadal and Adrenal Dysfunction in Kidney Transplant Recipients: A Review for the Clinician

While chronic kidney disease-associated mineral and bone disorders (CKD-MBD) prevail in the endocrinological assessment of CKD patients, other endocrine abnormalities are usually overlooked. CKD is associated with significant thyroid, adrenal and gonadal dysfunction, while persistent and de novo endocrinological abnormalities are frequent among kidney transplant recipients (KTR). Low T3 levels prior to transplantation may help identify those at risk for delayed graft function and are often found in KTR. Thyroid surveillance after kidney transplantation should be considered due to structural anomalies that may occur. Despite the rapid recovery of gonadal hormonal secretion after renal transplantation, fertility is not completely restored. Testosterone may improve anemia and general symptoms in KTR with persistent hypogonadism. Female KTR may still experience abnormal uterine bleeding, for which estroprogestative administration may be beneficial. Glucocorticoid administration suppresses the hypothalamic-pituitary–adrenal axis in KTR, leading to metabolic syndrome. Patients should be informed about signs and symptoms of hypoadrenalism that may occur after glucocorticoid withdrawal, prompting adrenal function assessment. Clinicians should be more aware of the endocrine abnormalities experienced by their KTR patients, as these may significantly impact the quality of life. In clinical practice, awareness of the specific endocrine dysfunctions experienced by KTR patients ensures the correct management of these complications in a multidisciplinary team, while avoiding unnecessary treatment.

Electroacupuncture at ST 36 ameliorates cognitive impairment and beta-amyloid pathology by inhibiting NLRP3 inflammasome activation in an Alzheimer’s disease animal model

BackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disorder leading to cognitive impairment in the elderly, and no effective treatment exists. Increasing evidence has demonstrated that physical therapy and electroacupuncture (EA) effectively improve spatial learning and memory abilities. Nevertheless, the mechanism underlying the effects of EA on AD pathology is largely unexplored. Acupuncture at Zusanli (ST 36) has previously been shown to improve cognitive impairment in AD, but the mechanism is unclear. According to recent studies, EA drives the vagal–adrenal axis from the hindlimb ST 36 acupoint but not from the abdominal Tianshu (ST 25) to curb severe inflammation in mice. This study examined whether ST 36 acupuncture improves cognitive dysfunction in AD model mice by improving neuroinflammation and its underlying mechanism. MethodsMale 5xFAD mice (aged 3, 6, and 9 months) were used as the AD animal model and were randomly divided into three groups: the AD model group (AD group), the electroacupuncture at ST 36 acupoint group (EA-ST 36 group), and the electroacupuncture at ST 25 acupoint group (EA-ST 25 group). Age-matched wild-type mice were used as the normal control (WT) group. EA (10 Hz, 0.5 mA) was applied to the acupoints on both sides for 15 min, 5 times per week for 4 weeks. Motor ability and cognitive ability were assessed by the open field test, the novel object recognition task, and the Morris water maze test. Thioflavin S staining and immunofluorescence were used to mark Aβ plaques and microglia. The levels of NLRP3, caspase-1, ASC, interleukin (IL)-1β, and IL-18 in the hippocampus were assayed by Western blotting or qRT-PCR. ResultsEA at ST 36, but not ST 25, significantly improved motor function and cognitive ability and reduced both Aβ deposition and microglia and NLRP3 inflammasome activation in 5×FAD mice. ConclusionEA stimulation at ST 36 effectively improved memory impairment in 5×FAD mice by a mechanism that regulated microglia activation and alleviated neuroinflammation by inhibiting the NLRP3 inflammatory response in the hippocampus. This study shows that ST 36 may be a specific acupoint to improve the condition of AD patients.

Areca catechu L. ameliorates chronic unpredictable mild stress-induced depression behavior in rats by the promotion of the BDNF signaling pathway

ObjectivesIn this study, we have investigated the anti-depressant effects of the fruit Areca catechu L. (ACL) and elucidated its potential underlying mechanism using a rat model of chronic unpredictable mild stress (CUMS). MethodsCUMS was induced in rats to establish a depression animal model for 28 days. According to the baseline sucrose preference, the male rats were divided into 6 different groups. They were treated with paroxetine hydrochloride, ACL, and water once a day until the behavioral tests were performed. The levels of corticosterone (CORT), malondialdehyde (MDA), catalase (CAT), and total superoxide dismutase (T-SOD) in serum were detected using a commercial kit, and the concentrations of 5-hydroxytryptamine (5-HT) and dopamine (DA) monoamine neurotransmitters in the brain tissues were detected by liquid chromatography-tandem mass spectrometry. doublecortin (DCX) expression in the hippocampal dentate gyrus (DG) was determined by immunofluorescence, and the relative abundance of brain-derived neurotrophic factor (BDNF), TrkB, PI3K, p-AKT/AKT, PSD-95, and p-GSK-3β/GSK-3β of brain tissues were assayed by western blot. ResultsACL markedly increased sucrose preference, decreased the immobility time, and shortened the feeding latency of CUMS-induced rats. CUMS induction resulted in marked changes in the contents of the monoamine neurotransmitters (5-HT and DA) in the hippocampus and cortex of brain tissues and the levels of CORT, MDA, CAT, and T-SOD in serum, whereas ACL administration alleviated these considerable changes. ACL promoted DCX expression in DG and increased the protein levels of BDNF, TrkB, PI3K, p-AKT/AKT, PSD-95, and p-GSK-3β/GSK-3β in the brains of CUMS-induced rats. ConclusionsOur results indicated that ACL may improve depression-like behaviors in CUMS-induced rats by decreasing the hyperfunction and oxidative stress of the hypothalamic–pituitary–adrenal axis, stimulating hippocampal neurogenesis, and activating the BDNF signaling pathway.

Sustained inflammation and high cortisol reactivity following an coronary event

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

Effects of 20-hydroxyecdysone on UVB-induced photoaging in hairless mice

We recently reported that exposure of skin to ultraviolet B (UVB) irradiation for 2 weeks induces stress and accelerates skin aging. Interestingly, aldosterone synthase is known to be crucial in generating UVB-induced stress-related responses, suggesting that drugs that regulate its activity can be used as skin antiaging agents. Through extensive drug screening, we have identified 20-hydroxyecdysone (20E), a steroidal prohormone secreted by the prothoracic glands of insects, as a potent inhibitor of UVB-induced aging. Although 20E has been shown to exert antistress and anti-collagenase effects in vitro, its effects in vivo remain unexplored. Furthermore, the pharmacological and physiological effects of 20E on UVB-mediated photoaging are poorly understood. Therefore, in this study, we investigated the effects of 20E on aldosterone synthase and UVB-induced photoaging and skin lesions in hairless mice, focusing on the stress-related hypothalamic–pituitary–adrenal axis. We confirmed that 20E inhibited aldosterone synthase and reduced corticosterone levels. When applied to a UV-induced skin aging animal model, it ameliorated UV-induced stress and protected against the decrease in collagen levels. Importantly, when the aldosterone synthase inhibitor osilodrostat, an FDA-approved drug, was applied to the UV-induced skin aging model, the stress-reducing and antiaging effects of 20E were not observed. Thus, we conclude that 20E inhibits UVB-induced skin aging by blocking aldosterone synthase and is a potential candidate to prevent skin aging.

Adrenal Failure: An Evidence-Based Diagnostic Approach.

The diagnosis of adrenal insufficiency (AI) requires a high index of suspicion, detailed clinical assessment including detailed drug history, and appropriate laboratory evaluation. The clinical characteristics of adrenal insufficiency vary according to the cause, and the presentation may be myriad, e.g. insidious onset to a catastrophic adrenal crisis presenting with circulatory shock and coma. Secondary adrenal insufficiency (SAI) often presents with only glucocorticoid deficiency because aldosterone production, which is controlled by the renin angiotensin system, is usually intact, and rarely presents with an adrenal crisis. Measurements of the basal serum cortisol at 8 am (<140 nmol/L or 5 mcg/dL) coupled with adrenocorticotrophin (ACTH) remain the initial tests of choice. The cosyntropin stimulation (short synacthen) test is used for the confirmation of the diagnosis. Newer highly specific cortisol assays have reduced the cut-off points for cortisol in the diagnosis of AI. The salivary cortisol test is increasingly being used in conditions associated with abnormal cortisol binding globulin (CBG) levels such as pregnancy. Children and infants require lower doses of cosyntropin for testing. 21-hydoxylase antibodies are routinely evaluated to rule out autoimmunity, the absence of which would require secondary causes of adrenal insufficiency to be ruled out. Testing the hypothalamic-pituitary-adrenal (HPA) axis, imaging, and ruling out systemic causes are necessary for the diagnosis of AI. Cancer treatment with immune checkpoint inhibitors (ICI) is an emerging cause of both primary AI and SAI and requires close follow up. Several antibodies are being implicated, but more clarity is required. We update the diagnostic evaluation of AI in this evidence-based review.

DIETS THAT HAVE POTENTIAL TO STIMULATE THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN SPRAGUE DAWLEY RATS

The pituitary gland is the master gland which regulates the body hormones. From the corticotrophs of the anterior pituitary gland, adrenocorticotrophic hormone (ACTH) is secreted and influences corticosterone production in rodents via the hypothalamic–pituitary–adrenal axis (HPA axis). ACTH and corticosterone are frequently used as a hormonal marker of stress level. Disturbance in ACTH and corticosterone were observed in many diseases especially Addison’s disease, Cushing’s syndrome, and metabolic syndrome. Our objective is to observe which diet produces the most and least stress to the Sprague Dawley rat’s physiology. Method: Thirty-five Sprague Dawley rats were grouped into five groups (n=7) and were given five different types of diets (control, high-fat, high-protein, high-sugar, and high-starch) with tap water supplied as drinking water ad libitum. By the end of eight weeks, the rat’s blood was collected, and serum separated. The individual components of ACTH and corticosterone from the blood was extracted, purified, identified, and quantified using the High-Performance Liquid Chromatography (HPLC) with photodiode array (PDA) analysis method. Result: The analytical studies revealed a high -sugar diet registered highest ACTH blood level. It was also revealed that the high-fat and high-sugar diet group presented with the highest peak for corticosterone. Conclusion: Consumption of high-fat and high-sugar diet for eight weeks is suggested to induce physiologic and metabolic stress in Sprague Dawley rats as evidenced by the HPA activation.

Targeting PDK2 rescues stress-induced impaired brain energy metabolism.

Depression is a mental illness frequently accompanied by disordered energy metabolism. A dysregulated hypothalamus pituitary adrenal axis response with aberrant glucocorticoids (GCs) release is often observed in patients with depression. However, the associated etiology between GCs and brain energy metabolism remains poorly understood. Here, using metabolomic analysis, we showed that the tricarboxylic acid (TCA) cycle was inhibited in chronic social defeat stress (CSDS)-exposed mice and patients with first-episode depression. Decreased mitochondrial oxidative phosphorylation was concomitant with the impairment of the TCA cycle. In parallel, the activity of pyruvate dehydrogenase (PDH), the gatekeeper of mitochondrial TCA flux, was suppressed, which is associated with the CSDS-induced neuronal pyruvate dehydrogenase kinase 2 (PDK2) expression and consequently enhanced PDH phosphorylation. Considering the well-acknowledged role of GCs in energy metabolism, we further demonstrated that glucocorticoid receptors (GR) stimulated PDK2 expression by directly binding to its promoter region. Meanwhile, silencing PDK2 abrogated glucocorticoid-induced PDH inhibition, restored the neuronal oxidative phosphorylation, and improved the flux of isotope-labeled carbon (U-13C] glucose) into the TCA cycle. Additionally, in vivo, pharmacological inhibition and neuron-specific silencing of GR or PDK2 restored CSDS-induced PDH phosphorylation and exerted antidepressant activities against chronic stress exposure. Taken together, our findings reveal a novel mechanism of depression manifestation, whereby elevated GCs levels regulate PDK2 transcription via GR, thereby impairing brain energy metabolism and contributing to the onset of this condition.