Basal Cortisol Research Articles

Relations of Lifetime Perceived Stress and Basal Cortisol With Hippocampal Volume Among Healthy Adolescents and Those at Clinical High Risk for Psychosis: A Structural Equation Modeling Approach

BackgroundHippocampal volume (HV) is sensitive to environmental influences. Under normative conditions in humans, HV increases linearly into childhood and asymptotes in early adulthood. Studies of humans and nonhuman animals have provided evidence of inverse relationships between several measures of stress and HV. MethodsUsing structural equation modeling, this study aimed to characterize the relationships of age, basal cortisol, biological sex, and lifetime perceived stress with bilateral HV in a sample of healthy adolescents and adolescents at clinical high risk for psychosis (CHR-P) (N = 571, 43% female; age range = 12–19.9 years). This sample included 469 individuals at CHR-P and 102 healthy comparison participants from the combined baseline cohorts of the second and third NAPLS (North American Prodrome Longitudinal Study). ResultsA structural model that constrained the individual effects of basal cortisol and perceived stress to single path coefficients, and freely estimated the effects of age and biological sex in group models, optimized model fit and parsimony relative to other candidate models. Significant inverse relationships between basal cortisol and bilateral HV were observed in adolescents at CHR-P and healthy comparison participants. Significant sex differences in bilateral HV were also observed, with females demonstrating smaller HV than males in both groups. ConclusionsMultigroup structural equation modeling revealed heterogeneity in the relationships of age and biological sex with basal cortisol, lifetime perceived stress, and bilateral HV in individuals at CHR-P and healthy comparison participants. Moreover, the findings support previous literature indicating that elevated basal cortisol is a nonspecific risk factor for reduced HV.

Cortisol levels associated with mortality in children with critical illness: a systematic review

Background Critically ill patients, including those with sepsis, have increased cortisol levels due to activation of the hypothalamic-pituitary-adrenal (HPA) axis or critical illness-related corticosteroid insufficiency (CIRCI).
 Objective To evaluate for a possible association between cortisol levels and mortality from sepsis in pediatric patients by systematic review of the literature.
 Methods A systematic review was conducted on studies involving critically ill children, including those with sepsis. We included studies published between 2011-2020 analyzing data on cortisol levels (total serum cortisol, serum-free cortisol, salivary cortisol, real-time free cortisol, basal serum cortisol and post-adrenocorticotropin hormone (ACTH) stimulation test, or basal salivary cortisol and post-ACTH stimulation test), the predictive score for mortality (Pediatric Logistic Organ Dysfunction/PELOD), Pediatric Risk of Mortality (PRISM), Pediatric Index of Mortality (PIM), Vasotropic Inotropic Score (VIS), or Pediatric Critical Illness Score (PCIS)], mortality (non-survivor percentage), and CIRCI percentage as an outcome in patients with critical illness, sepsis, and septic shock.
 Results Twenty-one observational studies were included in our systematic review, with a total of 2,212 subjects, 916 of whom had sepsis. Nineteen studies indicated a positive association between elevated cortisol levels and mortality in critically ill children, but 2 studies stated that there was no association with the CIRCI percentage of 32.3 and 84.3% respectively. The mortality percentage of critically ill patients with elevated cortisol levels and sepsis were 25.81 (2.7-60)% and 35.31 (6-60)%, respectively. The percentages of CIRCI in critically ill and sepsis patients were 21.91 (0-84.3)% and 21.35 (0-84.3)%, respectively.
 Conclusion Cortisol levels may increase or decrease in critically ill children. Elevated cortisol levels are associated with mortality in septic children. The effect of CIRCI on mortality in critically ill children cannot be concluded.

Environmental enrichment improves behaviors rather than the growth and physiology of rock bream Oplegnathus fasciatus.

Environmental enrichment has the potential to improve the welfare and post-release survival of hatchery fish stocked for conservation purposes. However, the effectiveness of environmental enrichment is partly dependent on the fish species, life stage, and specific enrichment structure used. To enhance the effectiveness of environmental enrichment, it is crucial to focus on characteristic differences in enrichment structures, such as type and level. This study investigated how differences in enrichment type and level affected physiological and behavioral aspects of the welfare of pre-release juvenile rock bream Oplegnathus fasciatus by evaluating growth performance, basal and stressed cortisol levels, antioxidant enzyme activities, and exploratory behaviors regarding anxiety and flexibility. Fish were reared for 4 weeks in different enrichment treatments: barren, low-level cover structure, high-level cover structure, low-level interference structure (LI), and high-level interference structure (HI). The results revealed that fish reared with the LI treatment showed less anxiety and greater flexibility with respect to exploratory behaviors, without oxidative damage being detected. Despite exhibiting less anxiety as well, fish reared in the HI treatment had oxidative damage, indicated by lower superoxide dismutase activity, compared to those in the barren treatment. In addition, none of these enrichment structures enhanced growth performance or mitigate chronic and acute stress responses. Overall, the low-level interference structure may be more favorable in promoting the behavioral welfare of the fish. Application of this type and level of enrichment may increase the survival of the hatchery fish after release, which is critical to stocking success.

Corticotropin-releasing factor-dopamine interactions in male and female macaque: Beyond the classic VTA.

Dopamine (DA) is involved in stress and stress-related illnesses, including many psychiatric disorders. Corticotropin-releasing factor (CRF) plays a role in stress responses and targets the ventral midbrain DA system, which is composed of DA and non-DA cells, and divided into specific subregions. Although CRF inputs to the midline A10 nuclei ("classic VTA") are known, in monkeys, CRF-containing terminals are also highly enriched in the expanded A10 parabrachial pigmented nucleus (PBP) and in the A8 retrorubral field subregions. We characterized CRF-labeled synaptic terminals on DA (tyrosine hydroxylase, TH+) and non-DA (TH-) cell types in the PBP and A8 regions using immunoreactive electron microscopy (EM) in male and female macaques. CRF labeling was present mostly in axon terminals, which mainly contacted TH-negative dendrites in both subregions. Most CRF-positive terminals had symmetric profiles. In both PBP and A8, CRF symmetric (putative inhibitory) synapses onto TH-negative dendrites were significantly greater than asymmetric (putative excitatory) profiles. This overall pattern was similar in males and females, despite shifts in the size of these effects between regions depending on sex. Because stress and gonadal hormone shifts can influence CRF expression, we also did hormonal assays over a 6-month time period and found little variability in basal cortisol across similarly housed animals at the same age. Together our findings suggest that at baseline, CRF-positive synaptic terminals in the primate PBP and A8 are poised to regulate DA indirectly through synaptic contacts onto non-DA neurons.

Gender-affirming hormone therapy effect on cortisol levels in trans males and trans females.

Previous studies have shown differences in baseline and stimulated cortisol levels between men and women. Whether this difference is secondary to sex hormones or to other factors, such as genetic or epigenetic changes, is unknown. We investigated the effect of gender-affirming hormone treatment (GAHT) on the hypothalamo-pituitary-adrenal axisof transgender subjects in an effort to throw light on this question. Ten transgender males (TM) and eighttransgender females (TF) underwent a low-dose (1 µg) adrenocorticotropic hormone (ACTH) stimulation test before and 6 months after GAHT initiation. Serum total, free and salivary cortisol (SC) levels were measured at baseline and at 20, 30and 40 min. For the TM, all three levels were significantly lower at several time points after ACTH injection compared to pretreatment levels following 6 months of treatment (p < .05). Likewise, the overall SCresponse as calculated by the area under the curve was significantly lower (p = .0053). For the TF, the basal total cortisol (TC) level increased after 6 months of treatment (p < .01) while ACTH-stimulated SClevels decreased significantly. The basal ACTH levels were significantly lower following hormonal therapy (p < .001). Stimulated salivary cortisol levels decreased significantly after 6 months of GAHT in both male and female transgender subjects, possibly reflecting a decreased state of anxiety associated with treatment initiation. Additionally, basal and stimulated serum TC levels increased after hormonal treatment in the TF, probably secondary to the effect of oestrogen on cortisol-binding globulin.

Defining the basal serum cortisol cut-off for weaning patients off glucocorticoids in suspected tertiary adrenal insufficiency

Defining the basal serum cortisol cut-off for weaning patients off glucocorticoids in suspected tertiary adrenal insufficiency

Are bold-shy personalities of European perch (Perca fluviatilis) linked to stress tolerance and immunity? A scope of harnessing fish behavior in aquaculture

The sensitivity to stress and its impact on immunity are supposedly related to a fish's personality. In the present study, European perch (Perca fluviatilis) were exposed to an open-field and a novel-object test to identify distinctive shy and bold individuals. This series of cognitive tests revealed clear differences between proactive individuals with pronounced exploration behavior (bold personality) and reactive individuals that took a freeze-hide position (shy personality). A cohort of shy and bold perch was then exposed to elevated stocking density. Frozen activity and lower explorative behavior were related to higher basal and stocking-induced cortisol levels compared to proactive individuals. Since cortisol is a well-known modulator of immune-gene expression, we used multiplex real-time PCR to profile the differential immune responses to the intraperitoneal injection of Aeromonas hydrophila in the head kidney and peritoneal cells of bold and shy perch individuals. These expression differences between stimulated bold and shy perch were generally modest, except for the genes encoding the complement component c3 and the matrix metallopeptidase mmp9. The strong differential expression of these two bactericidal and inflammatory genes in the context of the modestly regulated features suggests that a fish's personality is linked to a particular immune-defense strategy. In conclusion, our approach, based on behavioral video observations, phagocytosis and enzyme assays, immunogene-expression profiling, and quantification of stress-relevant metabolites, revealed indications for divergent coping styles in cohorts of bold or shy European perch. This divergence could be exploited in future selective breeding programs.

FRI177 Cosyntropin Stimulation Testing Is More Selective Than Postoperative Day 1 Basal Cortisol for Diagnosing Secondary Adrenal Insufficiency Following Unilateral Adrenalectomy

Abstract Disclosure: S.H. Johnson: None. C. Zhang: None. P.T. Hangge: None. T.W. Yen: None. T. Shaik: None. K. Doffek: None. J.W. Findling: None. T.B. Carroll: None. D.B. Evans: None. S. Dream: None. T.S. Wang: None. Background: Secondary adrenal insufficiency (SAI) may occur in patients after unilateral adrenalectomy for adrenal-dependent hypercortisolism (HC) and/or primary aldosteronism (PA). Perioperative protocols include routine glucocorticoid replacement (GR) or selective GR based on postoperative day 1 (POD1) basal cortisol levels or cosyntropin stimulation testing (CST). This study aimed to assess if a POD1 basal cortisol level alone was predictive of an abnormal CST and the need for GR in patients following unilateral adrenalectomy for HC and/or PA. Methods: This is a single institution retrospective review of consecutive unilateral adrenalectomies performed for HC and/or PA from 9/2014-10/2022. Patients were grouped as overt hypercortisolism (OH;n=42), mild autonomous cortisol excretion (MACE;n=70), mixed PA/HC (n=22) or PA (n=73); 22 patients with PA did not have preoperative evaluation for HC. Preoperative morning cortisol after low-dose dexamethasone suppression testing (DST), was used to define MACE (1.8-4.9 µg/dL) and OH (≥5.0). POD1 CST was performed for all patients with HC and prior to 2021, all patients with PA. SAI was defined as basal cortisol ≤5 or stimulated ≤14 (≤18 before 4/2017). Receiver operating characteristic (ROC) curves and sensitivity analyses were performed to assess the sensitivity (SN) and specificity (SP) of cutoffs within the range of observed basal cortisol levels in predicting an abnormal CST and need for GR. Results: Of 207 patients, 152 had POD1 CST (93% OH, 96% MACE, 73% PA/HC, 41% PA). Of these, 80 (53%) had SAI (67% OH, 55% MACE, 44% PA/HC, and 33% PA). Of the 10 patients with PA and SAI, 5 did not have preoperative testing for HC. Overall, 81 patients were discharged on GR. Median (interquartile range [IQR]) duration of GR was 246 (127,557), 55 (38,207), 74 (16,185), and 26 (15,36) days in patients with OH, MACE, PA/HC, and PA, respectively. At a median follow-up of 142 days (IQR 42,617), 12 patients (5 OH, 6 MACE, 1 PA/HC) remained on GR. The SN/SP of a basal cortisol ≤10 in predicting GR was 92%/77% in patients with OH and 94%/73% of patients with MACE. Compared to initiation of GR based on basal cortisol ≤10, CST identified 4 patients with SAI in the combined OH and MACE cohorts who would not have received GR, and 11 in the combined cohort who did not require GR. For patients with PA and PA/HC, a basal cortisol ≤10 had SN of 100% and SP of 85% and 67%, respectively. The optimal basal cortisol for predicting SAI in patients with PA/HC was ≤5 (SN,SP 100%). Area under the curve for all ROC curves was &amp;gt;0.9. Conclusion: These results demonstrate that in patients who underwent unilateral adrenalectomy for HC, PA, or mixed PA/HC, POD1 CST improved identification of patients at risk for SAI compared to basal cortisol levels alone. While basal cortisol levels alone may be considered in patients with PA or mixed HC/PA, all other patients with HC should have POD1 CST to determine need for postoperative GR. Presentation: Friday, June 16, 2023

SAT626 The Use Of Salivary Cortisol Measurement By Mass Spectrometry To Identify Low Serum Cortisol Values In Healthy Volunteers Receiving CRN04894, A Melanocortin 2 Receptor (MC2R) Antagonist

Abstract Disclosure: A. Ayala: Employee; Self; Crinetics Pharmaceuticals Inc. C. LaCerte: Employee; Self; Crinetics Pharmaceuticals Inc. R. Luo: Employee; Self; Crinetics Pharmaceuticals Inc. C. Davidson: Employee; Self; Crinetics Pharmaceuticals Inc. J. Wang: Employee; Self; Crinetics Pharmaceuticals Inc. P. Trainer: Employee; Self; Crinetics Pharmaceuticals Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals Inc. Clinical trials of cortisol-lowering drug candidates would benefit from user-friendly methods to measure cortisol in an outpatient setting. CRN04894 is a potent, orally bioavailable, MC2R antagonist in development for the treatment of ACTH-dependent Cushing’s syndrome and congenital adrenal hyperplasia. We have previously reported results from a randomized, double-blinded, placebo-controlled (6 active:3 placebo/cohort), multiple (10-day) ascending dose (40 to 80 mg/day) study in healthy volunteers. Declines in basal and ACTH-stimulated serum cortisol levels and a median reduction of 75% in 24-hr urinary-free cortisol (UFC) were seen in the 80 mg cohort. Asymptomatic glucocorticoid deficiency (defined as 08:00 serum cortisol of &amp;lt;5 µg/dL) was the most commonly observed adverse event. Here we report the comparison of salivary cortisol measurements with serum cortisol day curves and 24-hr UFC observed in this study. We evaluated cortisol and ACTH data from the three cohorts dosed once daily (QD) at 22:00 with either 40, 60, or 80 mg. Cortisol (salivary &amp; serum) and ACTH day curves (results reported as the mean of 4 or 5 available samples collected at 22:00, 08:00, 12:00, 16:00 &amp; 20:00) studies were undertaken on days -1, 1, 4, and 9. Mean serum cortisol was moderately correlated with 24-hr UFC:creatinine ratio (ug/g) (r = 0.495) and strongly correlated (r = 0.734) with mean salivary cortisol. There was across all three doses of CRN04894 a consistent magnitude ranking change in measured cortisol analytes: serum (free plus bound) &amp;lt; saliva &amp;lt; urine, with substantial changes being seen within 24 hours of initiation of CRN04894 and no loss of cortisol suppression over 9 days despite median ACTH changes of &amp;gt;1000% from baseline (60 &amp; 80 mg doses). Time-matched individual saliva and serum cortisol values were used (without timepoint or visit restrictions) to explore the relationship between low serum cortisol and salivary levels. A saliva cutoff for cortisol deficiency was optimized for diagnostic accuracy (92.2%) using a serum cortisol value of &amp;lt;5 µg/dL as the reference. Four subjects had 08:00 serum cortisol &amp;lt;5 µg/dL and saliva cortisol data. All four cases were correctly identified as cortisol-deficient using a simultaneous saliva cortisol cutoff of &amp;lt;0.0491 µg/dL. In conclusion, CRN04894 effectively lowered cortisol measured in serum, saliva, and urine in healthy volunteers. Salivary cortisol measured by tandem mass spectrometry correlated well with serum cortisol day curves and may be useful in the diagnosis of biochemical cortisol deficiency in outpatient studies. Future studies will explore the use of salivary glucocorticoid measurement in patients with Cushing’s disease receiving CRN04894. Presentation: Saturday, June 17, 2023

Clinical insights of pregnancy management, adrenal insufficiency as a possible cause of elevated TSH: a pilot study of case series

BackgroundThe upper limit for thyroid-stimulating hormone has been strictly defined for pregnancy management, at which point levothyroxine replacement therapy will been initiated. However, it is essential to exclude adrenal insufficiency, including subclinical adrenal insufficiency, when initiating levothyroxine replacement therapy. However, in pregnancy management, it has rarely reported the incidence, clinical course, and characteristics of adrenal insufficiency as a possible cause of elevated thyroid-stimulating hormone.MethodsThis case series study included pregnant patients undergoing thyroid-stimulating hormone management in a single-center diabetes endocrinology department between 2017 and 2020. The primary study outcome was the incidence of newly diagnosed adrenal insufficiency. We reported the clinical course and assessed the adrenal insufficiency characteristics at baseline and delivery and compared them with those of hypothyroidism.ResultFifteen pregnant women were included for thyroid-stimulating hormone management; and nine were below the basal serum cortisol level, and four were newly diagnosed as having adrenal insufficiency (26.7%) with the endocrinological stimulation test. Among them, two cases exhibited nausea and hypoglycemic symptoms after the start of levothyroxine replacement therapy. In cases of adrenal insufficiency, the patients were successfully treated with appropriate steroid coverage.ConclusionsIn the management of elevated thyroid-stimulating hormone levels during pregnancy, the frequency of adrenal insufficiency suspecting hypothyroidism may be higher than expected; therefore, we must be careful about starting levothyroxine replacement therapy for hypothyroidism. These clinical insights can have a significant impact on the pregnancy outcomes.

Effects of a Soft Baby Carrier on Fathers’ Behavior and Hormones: A Randomized Controlled Trial

Increased father–infant physical contact may promote early paternal caregiving. This randomized controlled trial, preregistered on https://osf.io/qwe3a, tested the effects of a soft baby carrier intervention on fathers’ parenting behavior and hormonal levels. Eighty first-time fathers of 2- to 4-month-old infants were randomly assigned to a baby carrier intervention group (n = 41 fathers) or a control group receiving an infant seat (n = 39 fathers). Fathers were instructed to use the baby carrier or seat for 3 weeks. Fathers’ sensitive parenting behavior, involvement, salivary oxytocin and cortisol basal levels and reactivity to interacting with the infant were assessed at pre-test (on average 2 weeks before the intervention) and at post-test (on average 1 week after the intervention period ended). The results showed that the intervention did not enhance fathers’ sensitive parenting or involvement. Involvement operationalized as hours spent with the infant decreased over time for fathers in the carrier condition compared to fathers in the control condition. The baby carrier intervention had no effect on fathers’ basal oxytocin or cortisol levels, nor did it affect fathers’ oxytocin or cortisol reactivity to interacting with their infant. Our findings indicate that 3 weeks of using a baby carrier does not have immediate beneficial effects on fathers’ parenting behavior or hormonal functioning as assessed here. Future research may examine whether infant carrying has beneficial effects on the longer term or in different groups of fathers, and how fathers’ infant carrying affects their infants.

Associations between immune competence phenotype and stress response in sheep

Immune competence in domestic sheep is gaining more attention in genetic selection programs that seek to enhance flock immunity and animal welfare. A goal of many programs is to identify behavioral phenotypes that indicate stress-coping strength, as well as disease resilience. The current study set out to explore the relationship between immune responsiveness, physiological stress, and behavioral response among sheep that had been selected for ‘low’ (LR) or ‘high’ (HR) response to cell-mediated and antibody-mediate reactivity to a clostridial vaccine. Multiparous ewes were placed in four experiments which exposed the animals to various threats including, dog presence, human proximity, visual isolation from flock, and physical restraint. To evaluate the consistency of behavioral phenotypes, all ewes were placed in the test circuit one year later. Basal body temperature (via iButton) and serum cortisol concentrations were collected prior to and after the circuit each year. Immune group (HR vs. LR) was not found to be related to behavioral performance during the dog, human, isolation, or restraint challenge. Immune group categorization was also unrelated to pre- and post-cortisol concentrations, and the change in cortisol concentrations during testing. There was a negative relationship identified between response to visual isolation and change in cortisol response during testing, indicating that sheep which were more active or agitated during visual isolation from the flock experienced less of an increase in serum cortisol levels and were perhaps experiencing a negative, high arousal state compared to less reactive sheep (e.g., freeze behavior) (χ2(4, N=99) = 42.72, P &amp;lt;0.0001). There was also a post hoc, positive relationship identified between weight measurements and immune group, such that individuals with greater body weight were more likely to be in the high immune responsiveness group (P= 0.01). Specifically, for every unit increase in weight, there was a ~49% chance of being categorized in the HR group. This is relevant for selection programs because producers that seek to enhance immune responsiveness and performance may be able to select sheep that carry a greater body mass, and while not found in the present study, could lead to greater flock immunity.

The effects of hypercortisolism on the frequency and magnitude of sleep EEG waves in patients with Cushing syndrome: A spectral analysis study

ObjectivesOur aim was to investigate the effects of endogenous chronic hypercortisolism on sleep electroencephalogram (EEG) and differences between the adrenocorticotropic hormone (ACTH)-dependent and independent Cushing Syndrome (CS) patients through a sleep spectral analysis program. MethodsA total of 32 patients diagnosed as having endogenous CS (12 ACTH-dependent and 20 ACTH-independent) and a control group comprising 16 healthy individuals were included in the study. Polysomnographic analysis was performed. Blood samples were collected at 08:00 AM for analysis of ACTH and basal cortisol, and at 00:00 AM for midnight cortisol levels. The frequency and power of the slow wave activity (SWA), theta, alpha, and beta waves of the first and last non-rapid eye movement (NREM) cycles were measured with a spectral analysis program. ResultsThe CS patient group had higher SWA power, especially in the first NREM cycle. In the ACTH-dependent group, SWA maximum and mean power values were higher in the frontal channels in the first NREM, compared to the last NREM sleep stage (p<0.05). ConclusionCortisol has been found to be associated with SWA waves, making these waves higher in power, especially in the first NREM phase. This difference was much less pronounced in the final NREM sleep stage. The difference between the first and last NREM sleep stages with respect to the power of SWA in the frontal channel in the ACTH-dependent group suggests that not only cortisol but also high levels of ACTH affect the power of slow waves during sleep.

Intergenerational plasticity to cycling high temperature and hypoxia affects offspring stress responsiveness and tolerance in zebrafish.

Predicted climate change-induced increases in heat waves and hypoxic events will have profound effects on fishes, yet the capacity of parents to alter offspring phenotype via non-genetic inheritance and buffer against these combined stressors is not clear. This study tested how prolonged adult zebrafish exposure to combined diel cycles of thermal stress and hypoxia affect offspring early survival and development, parental investment of cortisol and heat shock proteins (HSPs), larval offspring stress responses, and both parental and offspring heat and hypoxia tolerance. Parental exposure to the combined stressor did not affect fecundity, but increased mortality, produced smaller embryos and delayed hatching. The combined treatment also reduced maternal deposition of cortisol and increased embryo hsf1, hsp70a, HSP70, hsp90aa and HSP90 levels. In larvae, basal cortisol levels did not differ between treatments, but acute exposure to combined heat stress and hypoxia increased cortisol levels in control larvae with no effect on larvae from exposed parents. In contrast, whereas larval basal hsf1, hsp70a and hsp90aa levels differed between parental treatments, the combined acute stressor elicited similar transcriptional responses across treatments. Moreover, the combined acute stressor only induced a marked increase in HSP47 levels in the larvae derived from exposed parents. Finally, combined hypoxia and elevated temperatures increased both thermal and hypoxia tolerance in adults and conferred an increase in offspring thermal but not hypoxia tolerance. These results demonstrate that intergenerational acclimation to combined thermal stress and hypoxia elicit complex carryover effects on stress responsiveness and offspring tolerance with potential consequences for resilience.

Machine Learning Approaches for Assessing Risk Factors of Adrenal Insufficiency in Patients Undergoing Immune Checkpoint Inhibitor Therapy.

Adrenal insufficiency is a rare, yet life-threatening immune-related adverse event of immune checkpoint inhibitors (ICIs). This study aimed to establish a risk scoring system for adrenal insufficiency in patients receiving anti-programmed cell death 1 (PD-1) or anti-programmed cell death-ligand 1 (PD-L1) agents. Moreover, several machine learning methods were utilized to predict such complications. This study included 209 ICI-treated patients from July 2015 to February 2021, excluding those with prior adrenal insufficiency, previous steroid therapy, or incomplete data to ensure data integrity. Patients were continuously followed up at Gyeongsang National University Hospital, with morning blood samples taken for basal cortisol level measurements, facilitating a comprehensive analysis of their adrenal insufficiency risk. Using a chi-squared test and logistic regression model, we derived the odds ratio and adjusted odds ratio (AOR) through univariate and multivariable analyses. This study utilized machine learning algorithms, such as decision trees, random forests, support vector machines (SVM), and logistic regression to predict adrenal insufficiency in patients treated with ICIs. The performance of each algorithm was evaluated using metrics like accuracy, sensitivity, specificity, precision, and the area under the receiver operating characteristic curve (AUROC), ensuring rigorous assessment and reproducibility. A risk scoring system was developed from the multivariable and machine learning analyses. In a multivariable analysis, proton pump inhibitors (PPIs) (AOR 4.5), and α-blockers (AOR 6.0) were significant risk factors for adrenal insufficiency after adjusting for confounders. Among the machine learning models, logistic regression and elastic net showed good predictions, with AUROC values of 0.75 (0.61-0.90) and 0.76 (0.64-0.89), respectively. Based on multivariable and machine learning analyses, females (1 point), age ≥ 65 (1 point), PPIs (1 point), α-blockers (2 points), and antipsychotics (3 points) were integrated into the risk scoring system. From the logistic regression curve, patients with 0, 1, 2, 4, 5, and 6 points showed approximately 1.1%, 2.8%, 7.3%, 17.6%, 36.8%, 61.3%, and 81.2% risk for adrenal insufficiency, respectively. The application of our scoring system could prove beneficial in patient assessment and clinical decision-making while administering PD-1/PD-L1 inhibitors.

Association between Hpa Axis Functioning and Mental Health in Maltreated Children and Adolescents: A Systematic Literature Review.

Previous studies have demonstrated that children who experience maltreatment show a more elevated risk of psychopathological disorders than children from the general population. The HPA (hypothalamic-pituitary-adrenal) axis is not mature at birth and undergoes strong social regulation during the first years of life. Consequently, early exposure to stress could modify the usual adaptative response to stress. In stressful situations, perturbations in both cortisol response and cortisol circadian rhythm have been observed. Nevertheless, studies that have evaluated the links between child abuse, dysregulation of the HPA axis, and mental disorders have shown diverse results. Because of the variety of methods employed in the different studies, no formal comparisons have been made. In this systematic review, we have brought together these results. We conducted a systematic review of studies analyzing the correlation between child abuse, mental disorders, and HPA axis activity in patients aged between 6 and 16 years. PubMed, Scopus, Cochrane, and Google Scholar were searched using relevant keywords and inclusion/exclusion criteria (from 2000 to 2020). Fifteen studies from the 351 identified were included. Most patients were children in the child welfare system. Children who had experienced child abuse presented with more severe mental disorders (particularly in the dimensional measure) than children who had not been abused. HPA axis activity was assessed by measuring basal cortisol for some studies and cortisol reactivity for other studies. For children experiencing child abuse, there was a possible association between abuse and a decrease in the reactivity of the HPA axis. In addition, early life stress could be associated with lower matinal cortisol. However, the association between mental disorders and cortisol secretion in maltreated children did not seem obvious. This systematic review demonstrates that mental disorders are more frequent and severe in cases where child abuse has occurred. Moreover, children who experienced child abuse seem to present changes in the reactivity of the HPA axis. Nevertheless, the potential correlation between these changes in the reactivity of the HPA axis and mental disorders in this population needs to be evaluated in further studies.

Longitudinal association between saliva and hair cortisol concentration: A systematic comparison

Cortisol assays from hair have become increasingly common in psychoneuroendocrinological research as indicators of long-term output relevant to stress and health outcomes. Comparisons of hair cortisol concentration (HCC) with salivary samples have produced mixed findings, and it remains unclear which aspects of the diurnal salivary profile correspond most closely to HCC, and what time intervals between saliva and hair sampling are most relevant, taking the rate of hair growth into account. This longitudinal study aimed to evaluate the correspondence between HCC and parameters of total salivary cortisol output in the morning (CARauc and CARi) and during the rest of the day excluding the early morning period (DAYauc), by systematically studying three time periods – two weeks, four weeks, and six weeks – before hair sampling. At each time period, 54 female university students (mean age: 20.85 ± 1.16 years) provided three saliva cortisol samples on day 1 at 11 am, 3 pm, at bedtime, then two samples the following day on waking and 30 min after awakening. Hair strand collection (1 cm nearest the scalp) took place two weeks after the last saliva sample. Results of multivariable regressions indicate that HCC was consistently associated with DAYauc for all three time periods and with the aggregate DAYauc across days after adjusting for age, body mass index, smoking, oral contraceptive use, hair washing frequency and hair treatments. The strongest associations were found for DAYauc two weeks before hair sampling (β = 0.578, p < 0.001) and the aggregated DAYauc across all three time periods (β = 0.596, p < 0.001), although the confidence intervals overlapped those for four and six week analyses. There was no significant association between HCC and either CARauc or CARi. Our study confirms that hair cortisol could be a reliable retrospective biomarker of basal and long-term cortisol output secretion at least up to six weeks earlier. The results contribute to a better understanding of the different associations between HCC and salivary cortisol in the morning and the rest of the day, while also having implications for the use of HCC as an outcome measure in intervention and treatment research.

Activated Wake Systems in Narcolepsy Type 1.

Narcolepsy type 1 (NT1) is assumed to be caused solely by a lack of hypocretin (orexin) neurotransmission. Recently, however, we found an 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN). We assessed the remaining CRH neurons in NT1 to determine whether they co-express vasopressin (AVP) to reflect upregulation. We also systematically assessed other wake-systems, since current NT1 treatments target histamine, dopamine, and norepinephrine pathways. In postmortem tissue of people with NT1 and matched controls, we immunohistochemically stained and quantified neuronal populations expressing: CRH and AVP in the PVN, and CRH in the Barrington nucleus; the key neuronal histamine-synthesizing enzyme, histidine decarboxylase (HDC) in the hypothalamic tuberomammillary nucleus (TMN); the rate-limited-synthesizing enzyme, tyrosine hydroxylase (TH), for dopamine in the mid-brain and for norepinephrine in the locus coeruleus (LC). In NT1, there was: a 234% increase in the percentage of CRH cells co-expressing AVP, while there was an unchanged integrated optical density of CRH staining in the Barrington nucleus; a 36% increased number of histamine neurons expressing HDC, while the number of typical human TMN neuronal profiles was unchanged; a tendency toward an increased density of TH-positive neurons in the substantia nigra compacta; while the density of TH-positive LC neurons was unchanged. Our findings suggest an upregulation of activity by histamine neurons and remaining CRH neurons in NT1. This may explain earlier reports of normal basal plasma cortisol levels but lower levels after dexamethasone suppression. Alternatively, CRH neurons co-expressing AVP neurons are less vulnerable. ANN NEUROL 2023;94:762-771.

Functional Additives in a Selected European Sea Bass (Dicentrarchus labrax) Genotype: Effects on the Stress Response and Gill Antioxidant Response to Hydrogen Peroxide (H2O2) Treatment.

Functional ingredients have profiled as suitable candidates for reinforcing the fish antioxidant response and stress tolerance. In addition, selective breeding strategies have also demonstrated a correlation between fish growth performance and susceptibility to stressful culture conditions as a key component in species domestication processes. The aim of the present study is to evaluate the ability of a selected high-growth genotype of 300 days post-hatch European sea bass (Dicentrarchus labrax) juveniles to use different functional additives as endogenous antioxidant capacity and stress resistance boosters when supplemented in low fish meal (FM) and fish oil (FO) diets. Three isoenergetic and isonitrogenous diets (10% FM/6% FO) were supplemented with 200 ppm of a blend of garlic and Labiatae plant oils (PHYTO0.02), 1000 ppm of a mixture of citrus flavonoids and Asteraceae and Labiatae plant essential oils (PHYTO0.1) or 5000 ppm of galactomannan-oligosaccharides (GMOS0.5). A reference diet was void of supplementation. The fish were fed the experimental diets for 72 days and subjected to a H2O2 exposure oxidative stress challenge. The fish stress response was evaluated through measuring the circulating plasma cortisol levels and the fish gill antioxidant response by the relative gene expression analysis of nfΚβ2, il-1b, hif-1a, nd5, cyb, cox, sod, cat, gpx, tnf-1α and caspase 9. After the oxidative stress challenge, the genotype origin determined the capacity of the recovery of basal cortisol levels after an acute stress response, presenting GS fish with a better pattern of recovery. All functional diets induced a significant upregulation of cat gill gene expression levels compared to fish fed the control diet, regardless of the fish genotype. Altogether, suggesting an increased capacity of the growth selected European sea bass genotype to cope with the potential negative side-effects associated to an H2O2 bath exposure.

Perceived discrimination and stress response profiles among Mexican-origin Adolescents

The hypothalamic-pituitary-adrenal (HPA) axis is one of the major stress response systems in the human body and it is sensitive to social evaluative stress. The functioning of HPA axis is commonly measured with cortisol. Research on cortisol has focused on cortisol reactivity and its diurnal rhythm using salivary cortisol to inform short-term stress responses. Cortisol can also be measured through hair, which tracks individuals’ cumulative stress response. To more comprehensively understand cortisol levels and responses to stress, this study used a person-centered approach to examine stress response profiles based on individuals’ cortisol reactivity, diurnal cortisol rhythms, and hair cortisol concentration. Participants were 290 Mexican-origin adolescents (Mage = 17.38; 52% female). Latent profile analysis was used to characterize stress response profiles identified using three daily salivary samples across four days, seven saliva samples throughout the Trier Social Stress Test, and hair cortisol. The resulting profiles were examined in relation to discrimination and covariates. Analyses identified two stress response profiles. Most of the participants (88%) were in the “lower” profile (blunted diurnal cortisol rhythm and lower pattern of cortisol reactivity) and the remainder were in the “higher” profile (elevated diurnal cortisol rhythm and increased pattern of cortisol reactivity). Adolescents in the “lower” group reported more discrimination than those in the “higher” group. Findings of the study demonstrate the first attempt to integrate different aspects of stress responses in the HPA axis. Results also highlight the blunting effects of discrimination on Mexican-origin adolescents’ basal cortisol and responses to stress.