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Abstract

The human organism is in a state of dynamic equilibrium, homeostasis. The stress system is activated when homeostasis is challenged by extrinsic or intrinsic forces, the stressors. This system, whose central component is the central nervous system (CNS) and includes corticotropin-releasing hormone (CRH) and noradrenergic neurons, respectively, in the hypothalamus and the brain stem, has as its peripheral limbs the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic (sympathetic) nervous system. Normal development and preservation of life and species are dependent on a normally functioning stress system. Maladaptive neuroendocrine responses, i.e., dysregulation of the stress system, may lead to disturbances in growth and development, and cause psychiatric, endocrine/metabolic, and/or autoimmune diseases or vulnerability to such diseases.

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... Glucocorticoid hormones, controlled by the Hypothalamic-Pituitary-Adrenal axis (HPA axis), are one of the major components of the stress response (Sapolsky 1992;Stratakis and Chrousos 1995;Wingfield et al. 1998;Sapolsky et al. 2000)-see Box 4.1 for a description of the principal systems regulating the stress response. Contrary to adrenaline and noradrenaline, glucocorticoids can easily cross the blood-brain barrier and bind to corticosteroid receptors in the brain (mainly glucocorticoid receptors and mineralocorticoid receptors) to influence brain function and cellular energetic signalling (Reul and Dekloet 1985;Datson et al. 2001). ...
... All vertebrate species elicit highly conserved, relatively nonspecific, behavioral, and physiological changes upon exposure to stressors. Within seconds to hours upon the perception of stressful cues, two endocrine systems are activated, one involving catecholamines, such as adrenaline (acting within seconds) from the adrenal medulla, and the other involving glucocorticoids (acting within minutes) secreted from the adrenal cortex (Stratakis and Chrousos 1995). The fastest component of the stress response, best known as the "fight or flight response" triggers a variety of physiological changes, including increased cardiovascular tone and respiration rate prompting the body for immediate reactions and muscular action (Cannon 1929). ...
Chapter
Exposure to challenging experiences during development, such as reduced parental care and food availability, can have profound effects on the adult phenotype with far-ranging consequences for individual performance. Traditionally, such early-life adversities have been assumed to lead to detrimental consequences for health and survival. Growing empirical evidence, however, pin point that early-life stress exposure can also promote adaptive coping mechanisms of resistance and resilience, and have beneficial long-lasting effects. Developmental timing, type, and severity of early-life stress exposure are hypothesized to be key features underlying subsequent phenotypic outcomes. In this book chapter, we provide an overview of the main molecular mechanisms and signals that may be driving the emergence of subsequent stress vulnerability or resilience. We focus on the actions of glucocorticoid hormones in shaping adult physiological stress responses, and in organizing key cellular and molecular mechanisms underlying senescence and life-history evolution, including telomeres, oxidative stress, and epigenetics. Finally, we critically appraise and identify gaps in our current knowledge and provide directions for future research.
... Therefore, the central stress system sits in a pivotal location on the base of the brain. According to Stratakis and Chrousos (2006) the key central coordinators of the stress system are the parvocellular corticotropin-releasing hormone (CRH, also termed corticotrophin-releasing factor CRF) and ...
... The SAM system is one of the major pathways mediating physiological responses in different organs and tissues in the body. It provides a rapidly responding mechanism that controls most of the acute response of the individual to a stressor (Melmed et al., 2015;Stratakis & Chrousos, 2006). The hypothalamus, in particular the PVN, controls both the SAM and the HPA axis response systems. ...
... 41 , 42 In response to stress, neurobiological systems activate to protect the body and promote adaptation, facilitated by the sympathetic adrenomedullary system and the hypothalamic-pituitary-adrenocortical (HPA) axis. [43][44][45] As part of the sympathetic nervous system, the sympathetic adrenomedullary system releases epinephrine, which signals the fight or flight response, 46 whereas the HPA axis is a component of the central nervous system and produces cortisol in response to stress. 43 Repeated or long-term exposure to stress creates a cumulative burden on the body, increasing its allostatic load and increasing the risk for disease. ...
... [43][44][45] As part of the sympathetic nervous system, the sympathetic adrenomedullary system releases epinephrine, which signals the fight or flight response, 46 whereas the HPA axis is a component of the central nervous system and produces cortisol in response to stress. 43 Repeated or long-term exposure to stress creates a cumulative burden on the body, increasing its allostatic load and increasing the risk for disease. 44 Maternal psychological distress during pregnancy has been associated with negative birth outcomes, such as low birth weight, preterm birth, and later risk for neurodevelopmental, psychiatric, cardiovascular, and metabolic disease. ...
Article
Purpose Despite recommendations from the World Health Organization and the American Academy of Pediatrics to exclusively breastfeed infants for their first 6 months of life, 75% of women do not meet exclusive breastfeeding guidelines, and 60% do not meet their own breastfeeding goals. Numerous observational studies have linked maternal psychological distress (eg, perceived stress, anxiety, and depression) with nonoptimal breastfeeding outcomes, such as decreased proportion and duration of exclusive breastfeeding. The physiological mechanisms underlying these associations, however, remain unclear. Methods For this narrative review, we evaluated the evidence of relationships between maternal psychological distress and lactation and breastfeeding outcomes in pregnancy and post partum and the possible physiological mechanisms that facilitate these relationships. We searched PubMed using the following terms: stress, anxiety, depression, breastfeeding, and lactation. Additional search by hand was conducted to ensure a thorough review of the literature. Findings Among the studies examined, methods used to assess maternal psychological distress were not uniform, with some studies examining perceived distress via a variety of validated tools and others measuring biological measures of distress, such as cortisol. Evidence supports a role for psychological distress in multiple breastfeeding outcomes, including delayed secretory activation and decreased duration of exclusive breastfeeding. One physiological mechanism proposed to explain these relationships is that psychological distress may impair the release of oxytocin, a hormone that plays a critical role in milk ejection during lactation. Continued impairment of milk ejection may lead to decreased milk production because of incomplete emptying of the breast during each feed. Maternal distress may also yield elevated levels of serum cortisol and decreased insulin sensitivity, which are associated with decreased milk production. The relationship between psychological distress and breastfeeding is likely to be bidirectional, however, in that breastfeeding appears to reduce maternal distress, again possibly via effects on the pleasure or reward pathway and calming effects of oxytocin on the mother. This finding suggests that interventions to support lactation and breastfeeding goals in women who score high on measures of psychological distress would be beneficial for both maternal and infant well-being. Implications Evidence to date suggests that maternal psychological distress may impair lactation and breastfeeding outcomes, but stronger study designs and rigorous assessment methods are needed. A better understanding of the physiological mechanisms leading to impaired lactation may assist in the development of early interventions for mothers experiencing distress. In addition, stress-reducing programs and policies should be investigated for their potential to improve breastfeeding outcomes.
... • Stress system is the neuroendocrine-immune complex, Adaptive stress system includes all physiological systems involved in the process of adaptation to stress. 133 • Homeostasis is a complex dynamic equilibrium/steady state, maintained by coordinated physiological processes in the organism. 132,134 In other words, homeostasis is the ability of a living organism or cell to maintain the state of internal balance despite changes in the conditions around it, while stress-is temporary inability to maintain this steady state. ...
Article
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Adaptogens comprise a category of herbal medicinal and nutritional products promoting adaptability, resilience, and survival of living organisms in stress. The aim of this review was to summarize the growing knowledge about common adaptogenic plants used in various traditional medical systems (TMS) and conventional medicine and to provide a modern rationale for their use in the treatment of stress-induced and aging-related disorders. Adapto-gens have pharmacologically pleiotropic effects on the neuroendocrine-immune system, which explain their traditional use for the treatment of a wide range of conditions. They exhibit a biphasic dose-effect response: at low doses they function as mild stress-mimetics, which activate the adaptive stress-response signaling pathways to cope with severe stress. That is in line with their traditional use for preventing premature aging and to maintain good health and vitality. However, the potential Med Res Rev. 2020;1-74. wileyonlinelibrary.com/journal/med | 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
... (12) 14) y el sistema hipotalámico-pituitario-adrenocortical (HPA). (15) El sistema SAM es una región de la división simpática del sistema nervioso autónomo, que libera epinefrina de la médula suprarrenal. El aumento de los niveles de epinefrina promueve la activación de la respuesta de lucha/huida (16) ; en cambio, el eje HPA, se encarga de la producción de glucocorticoides. ...
Article
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Stress is defined as the link mechanism between a stressor agent and its target organ, resulting in a psychophysiological response, characterized by glucocorticoid release. In this study, we review the main effects of stress on the nervous and endocrine systems, as well as the relationship between stress and diet. When experiencing a stressful event, an increase in the corticotropin releasing factor is generated in the hypothalamus, which upon reaching the anterior lobe of the pituitary promotes the secretion of adrenocorticotropic hormone, the latter will finally act on the adrenal gland cortex, inducing glucocorticoids release. The hypothalamic-pituitary-adrenocortical axis, when stimulated by stressful events, causes the increase in of glucocorticoids that promote food intake, particularly high-calorie foods. This intake turns out to be used by individuals as a way of coping with stress and finally inducing obesity.
... While the SNS has traditionally not been incorporated into the neural diathesis-stress model of psychosis, the control and function of the HPA-axis, and SNS are interdependent and dysregulation in one system has implications for the other (23)(24)(25). The SNS speed of onset is rapid while the duration of its action is short lasting, as opposed to the HPA axis' slow speed of onset and long lasting duration of action (26,27). The differential time-course of each system means that each provides unique and important information throughout the stress experience that can be overlooked if not studied in tandem (27,28). ...
Article
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Deficits in stress-response systems are a characteristic of schizophrenia and psychosis spectrum illnesses, and recent evidence suggests that this impairment may be evident in those at clinical high-risk (CHR) for the development of a psychotic disorder. However, there is limited research specifically investigating biological and subjective stress reactivity in CHR individuals. In the present study, 38 CHR individuals and group of 38 control individuals participated in the Trier Social Stress Test (TSST), an experimentally induced psychosocial stressor. Changes in salivary cortisol and alpha amylase, as well as self-reported units of distress (SUDS), were evaluated. Interestingly, the TSST did not induce a change in cortisol levels in either group, though the CHR group did show higher overall cortisol levels throughout the TSST (pre-anticipation period through recovery period). However, indicative of an effective task manipulation, the TSST did illicit an increase in alpha amylase in both groups. CHR participants exhibited higher levels of subjective stress prior to the stressor compared to the control group and CHR SUDs did not significantly increase in response to the stressor. In contrast, the control group showed an increase in SUDS in response to the stressor. Notably, SUDS for the control group post task mirrored the levels CHR youth endorsed prior to the stressor. Taken together, these findings suggest that there may be a functional relationship between persistently elevated cortisol and chronic high levels of subjective distress in CHR individuals.
... Stress plays a role in the development of physical and mental disorders [1][2][3]. A physical response to stress occurs owing to an imbalance in the autonomic nervous system; moreover, the associated chronic inflammation contributes to the development of physical diseases [4][5][6][7]. However, questionnaires are exclusively used to measure stress, and few "gold standard" measures of stress can be used simply in daily practice [1]. ...
Article
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While plasma arginase-1 has been suggested as a biomarker of mental status in healthy individuals, it has not been evaluated in patients with chronic liver disease. This cross-sectional study investigated the utility of plasma arginase-1 for screening mental status in patients with chronic liver disease. This study included outpatients with chronic liver disease who underwent regular check-ups at Okayama University Hospital between September 2018 and January 2019. In addition to the standard blood tests, the plasma arginase-1 level was analyzed. The patients’ mental status was assessed using the Japanese version of the General Health Questionnaire-28 (GHQ-28). The associations between mental status and various parameters, including plasma arginase-1, were investigated using logistic regression analysis. Among 114 participating patients, 8 were excluded, comprising 6 with insufficient blood samples for plasma arginase-1 measurement and 2 with incomplete questionnaires. Multivariate binomial logistic regression analysis revealed that plasma arginase-1 was significantly and negatively associated with the GHQ-total score, especially somatic symptoms. Therefore, plasma arginase-1 may be a useful biomarker for assessing the mental status of outpatients with chronic liver disease.
... For example, both systems are coordinated by a central autonomic network involving brainstem, subcortical, and cortical structures, which together indirectly regulate HPA axis activity via the amygdala and directly control PNS responsivity (Thayer and Sternberg, 2006). In addition, hypothalamic CRH and noradrenergic neurons have common inputs and are activated and inhibited by the same neurotransmitters; further, CRH and catecholaminergic neurons have reciprocal neural connections, allowing coordinated, counteracting patterns of activation between HPA and ANS (Stratakis and Chrousos, 1995). Thus, the HPA axis and ANS can become co-activated/inhibited, and each system can modulate the activity of the other system (Bauer et al., 2002). ...
Article
The development of child mental health problems has been associated with experiences of adversity and dysregulation of stress response systems; however, past research has largely focused on externalizing or internalizing problems (rather than their co-occurrence) and single physiological systems in high-risk adolescent samples. The present study examined whether cumulative family adversity, functioning in the hypothalamic-pituitary-adrenal axis (i.e., cortisol) and the parasympathetic nervous system (i.e., respiratory sinus arrhythmia [RSA]), and their interactions, predicted trajectories of co-occurring externalizing and internalizing problems among young children. Participants included 338 socioeconomically and racially diverse children (M age = 5.32 years, SD = .32; male = 51.8%) from a community sample. Family adversity (assessed with six measures) and child daily cortisol output and resting RSA were assessed in kindergarten. Parents, teachers, and children reported on children’s externalizing and internalizing psychopathology up to three times from kindergarten to grade 1. Latent class growth analyses identified stable trajectories of externalizing and internalizing psychopathology. Trajectories were combined to create groups: co-occurring externalizing and internalizing (13.1%), externalizing-only (14.0%), internalizing-only (11.3%), and low problems (61.3%). Family adversity and resting RSA significantly positively predicted co-occurring group membership. Tests for interactions showed adversity did not significantly interact with physiological indicators to predict group membership. However, the two physiological systems interacted, such that higher and lower daily cortisol predicted internalizing group membership for children with lower and higher resting RSA, respectively. Findings support the importance of considering family context and multiple physiological systems to inform understanding of the development of mental health problems, and their co-occurrence, in early childhood.
... The response to a stressful situation is usually both psychological and physiological [8,9]. The physiological stress response, i.e., the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis and sympathetic nervous system [10], leads to altered secretion of cortisol and dehydroepiandrosterone sulfate (DHEAS) [11,12]. Cortisol and DHEAS are markers of HPA axis activation [12] and, thus in this study, are exploited as markers of either acute or chronic stress reactions [11][12][13][14]. ...
Article
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Background Psychological processes can be manifested in physiological health. We investigated whether acceptance and commitment therapy (ACT), targeted on psychological flexibility (PF), influences inflammation and stress biomarkers among working-age adults with psychological distress and overweight/obesity.Method Participants were randomized into three parallel groups: (1) ACT-based face-to-face (n = 65; six group sessions led by a psychologist), (2) ACT-based mobile (n = 73; one group session and mobile app), and (3) control (n = 66; only the measurements). Systemic inflammation and stress markers were analyzed at baseline, at 10 weeks after the baseline (post-intervention), and at 36 weeks after the baseline (follow-up). General PF and weight-related PF were measured with questionnaires (Acceptance and Action Questionnaire, Acceptance and Action Questionnaire for Weight-Related Difficulties).ResultsA group × time interaction (p = .012) was detected in the high-sensitivity C-reactive protein (hsCRP) level but not in other inflammation and stress biomarkers. hsCRP decreased significantly in the face-to-face group from week 0 to week 36, and at week 36, hsCRP was lower among the participants in the face-to-face group than in the mobile group (p = .035, post hoc test). Age and sex were stronger predictors of biomarker levels at follow-up than the post-intervention PF.Conclusion The results suggest that ACT delivered in group sessions may exert beneficial effects on low-grade systemic inflammation. More research is needed on how to best apply psychological interventions for the health of both mind and body among people with overweight/obesity and psychological distress.Trial RegistrationClinicalTrials.gov Identifier: NCT01738256, Registered 17 August, 2012
... During critical illness, excessive or inadequate adaptive responses evoked by intensive stress can have negative effects on the gut motility, mucosal blood flow, and mucosal permeability [19,[23][24][25][26]. Gut hyperpermeability and barrier dysfunction may lead to a systemic inflammatory response syndrome, a clinical state that is also called "gut-derived sepsis" [27]. ...
Article
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The gut is a complex organ that has played an important role in digestion, absorption, endocrine functions, and immunity. The gut mucosal barriers consist of the immunologic barrier and nonimmunologic barrier. During critical illnesses, the gut is susceptible to injury due to the induction of intestinal hyperpermeability. Gut hyperpermeability and barrier dysfunction may lead to systemic inflammatory response syndrome. Additionally, gut microbiota are altered during critical illnesses. The etiology of such microbiome alterations in critical illnesses is multifactorial. The interaction or systemic host defense modulation between distant organs and the gut microbiome is increasingly studied in disease research. No treatment modality exists to significantly enhance the gut epithelial integrity, permeability, or mucus layer in critically ill patients. However, multiple helpful approaches including clinical and preclinical strategies exist. Enteral nutrition is associated with an increased mucosal barrier in animal and human studies. The trophic effects of enteral nutrition might help to maintain the intestinal physiology, prevent atrophy of gut villi, reduce intestinal permeability, and protect against ischemia-reperfusion injury. The microbiome approach such as the use of probiotics, fecal microbial transplantation, and selective decontamination of the digestive tract has been suggested. However, its evidence does not have a high quality. To promote rapid hypertrophy of the small bowel, various factors have been reported, including the epidermal growth factor, membrane permeant inhibitor of myosin light chain kinase, mucus surrogate, pharmacologic vagus nerve agonist, immune-enhancing diet, and glucagon-like peptide-2 as preclinical strategies. However, the evidence remains unclear.
... Plasma triiodothyronine (T 3 ) has been used as a biomarker of stress as Stratakis and Chrousos (1995) reported that there is a suppressed secretion of thyroid-stimulating hormone and decreased conversion of the relatively inactive T 4 to more biologically active T 3 during stress. There was, however, no significant difference in the plasma T 3 of the birds across the treatment groups at the different weeks of observation. ...
Article
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Commercialisation of helmeted guinea fowl production in Africa is still in its rudimentary stage and there is a dearth of information on the optimal stocking density of the birds. This study was conducted to evaluate the effect of stocking density on the physiological responses and performance of guinea fowl. A total of 240 indigenous guinea fowl were used for this study. The birds were weighed and assigned to different stocking densities of 14, 16, 18 and 20 birds/m2 (SD1, SD2, SD3 and SD4, respectively) at four weeks of age. Feed and water were provided ad libitum . Data were collected on growth performance, haematochemical profile and plasma triiodothyronine of the birds. The results showed that from the 7 th to the 13 th week, birds stocked at 14 and 16 birds/m ² were significantly ( P < 0.05) heavier than birds stocked at 18 and 20 birds/m ² , while at weeks 14 and 15, body weight of the birds was in the order 14 birds / m ² > 16 birds / m ² > 18 birds/m ² > 20 birds/m ² . Feed conversion ratios of the birds increased with stocking densities. Heterophil/lymphocyte ratio significantly increased with stocking density. It was concluded that stocking density of helmeted guinea fowl higher than 16 birds/m ² adversely affected growth performance and welfare of the birds.
... Patients with cancer tend to suffer chronic stress triggered by psychological disorders during the course of therapy and follow-up 32 . It has been well-reported that chronic stress could promote the release of stress-related hormone like NE through the activation of sympathetic nervous system or hypothalamic-pituitary-adrenal axis 33 . Prolonged exposure to stress-related hormones contributes to tumor growth, invasive capacity, and angiogenesis in various cancers 10,[34][35][36] . ...
Article
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Chronic stress could induce cancer metastasis by constant activation of the sympathetic nervous system, while cellular mechanism remains obscure. The aim of this research is to explore the metastasis associated negative effect of chronic stress. The analysis of transcriptome sequencing implied that activation of STAT3 signaling pathway by downregulated miR-337-3p might be a potential mechanism to induce epithelial to mesenchymal transition (EMT) of cancer cell and promote metastasis under chronic stress. We also verified this biological process in further experiments. Downregulation of miR-337-3p could downregulate E-cadherin expression and upregulate vimentin expression in vitro and in vivo. STAT3, related signal pathways of which are involved in metastasis regulation, was directly targeted by miR-337-3p. In conclusion, the above results denoted that activation of miR-337-3p/STAT3 axis might be a potential pathway for the increasing metastasis of breast cancer under chronic stress.
... This stimulates glucocorticoid release (GR) from the adrenal cortex and through sympathetic stimulation, causes the adrenal medulla to release the catecholamines known as adrenaline and noradrenaline (Brown, 1994). Glucocorticoids are steroids, of which cortisol is the dominant form in primates and most mammals, whereas corticosterone is dominant in rodents and birds (Stratakis and Chrousos, 1995). Cortisol then acts as a negative feedback on the hypothalamus and the anterior pituitary ( Figure 3). ...
... As its name would suggest, the HPA axis includes the hypothalamus, the pituitary, and the adrenals. These structures are connected via a complex signaling cascade, in which the the paraventricular nucleus (PVN) of the hypothalamus secretes corticotropin releasing factor (CRF), thereby prompting the pituitary to produce adrenocorticotropic hormone (ACTH; Gunnar & Vazquez, 2006;Stratakis & Chrousos, 1995). ACTH binds to receptors on the adrenal cortex, promoting the production of glucocorticoids (GCs), including cortisol, which are released into the blood stream (Gunnar, 1992). ...
Article
Self-regulation in early childhood encompasses both “top down,” volitional processes, as well as the “bottom up” activity of three neurophysiological systems: the parasym- pathetic nervous system (PNS), the sympathetic nervous system (SNS), and the hy- pothalamic-pituitary-adrenal (HPA) axis. In this paper we briefly review the structure, function, and early development of each of these systems and then explain why neu- rophysiological self-regulation is most accurately defined as a function of their joint activity. We note that while there are a number of predictive models that employ this definition, the field would benefit from a straightforward heuristic and aligned methods of visualization and analysis. We then present one such heuristic, which we call neurophysiological space, and outline how it may facilitate a new, collaborative approach to building a better understanding of self-regulation in early childhood. We conclude with a presentation of early education as one setting in which our heuristic and methods could be applied.
... Cortisol acts upon the cells by way of binding to nuclear glucocorticoid receptors (GR). In this way, the GC/GR system mediates the response to stress through modulation of metabolic, cardiovascular and immune function (Sapolsky, Romero, & Munck, 2000;Stratakis & Chrousos, 1995). Thus, several stress-responsive genes have been reported as modulated by glucocorticoid receptor activation, suggesting that elevation in cortisol level during stressor exposure maybe a key signal for target tissue molecular programming (Aluru & Vijayan, 2009). ...
Article
Anaesthetics are widely used in aquaculture, fisheries, and biological research as a method to minimize fish stress and injury during handling and transport. Considerations such as efficacy, cost and environmental effect as well as its toxicity to fish are evaluated to choose a suitable anaesthetic. In the same way, several fish anaesthetic agents have been reported in fish including their safe dosage; however, scarce information is available about gene expression under anaesthetic stages. In this work, gene expression of hypoxia‐inducible factor 1 alpha (HIF1a) and the glucocorticoid receptor (GlucoR) was assessed as indicators of stress in the Colombian native fish species red‐bellied pacu (Piaractus brachypomus) under anaesthesia with menthol (50 mg/L) and eugenol (40 mg/L). Results of this study indicated that the exposure of red‐bellied pacu fingerlings to effective concentrations of the menthol generated a differential gene expression of HIF1a mRNA that was significantly higher in the liver for menthol group, and in the case of GlucoR mRNA, it was significantly higher in gills and blood of fish under eugenol anaesthesia. This is the first report of gene expression in this native fish species.
... This can have far-reaching consequences if, in the long term, new skills are not being learned or are being learned incorrectly. The human stress response is associated with the activation of different physiological pathways (e.g., [9,10]). The first, fast stress response is the activation of the sympathetic nervous system (SNS), which leads to the release of the catecholamines epinephrine and norepinephrine. ...
Article
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In this study, we investigated the associations between implicit associative learning with the cortisol and salivary alpha-amylase (sAA) stress response to an acute stressor as well as their associations with attention. Eighty one healthy adults (25 male) participated and either performed the socially evaluated cold-pressor test (SECPT) or a warm-water control task (WWT). Either prior to or immediately after the SECPT/WWT, participants implicitly learned digit-symbol pairs. A not-previously announced recall test was conducted about 20 min after the SECPT/WWT. Attention was assessed by means of a Stroop task at nine time points over the course of the experiment. Memory recall performance was not significantly associated with the acquisition time point (pre or post stressor) and did not significantly differ between the responder groups (i.e., non-responders, sAA-and-cortisol responders, only sAA responders, and only cortisol responders). Attentional performance increased throughout the experiment (i.e., reaction times in the Stroop task decreased). No differences in the attentional time course were found between the responder groups. However, some associations were found (puncorrected < 0.05) that did not pass the multiple comparison adjusted alpha level of αadjusted = 0.002, indicating different associations between attention and implicit learning between the responder groups. We conclude that the associations of sAA and cortisol responses with implicit learning are complex and are related to each other. Further studies in which both (sAA and cortisol responses) are selectively (de-) activated are needed. Furthermore, different learning tasks and less—potentially stressful—attentional assessments should be used in future research. Moreover, field studies are needed in which the associations between acute stress and implicit associative learning are investigated in everyday life.
... The original definition of stress, proposed by Selye (1936), is "the nonspecific response of the body to any demand"; that is, any disruption to the body's homeostasis and the response of the animal. When a noxious stimulus is perceived by an individual, there are both behavioural and physiological responses, such as heightened alertness, the suppression of reproductive and feeding processes, increased heart rate and blood pressure, and the redirection of energy reserves (Stratakis and Chrousos, 1995;Vingerhoets and Perski, 2000). Physiologically, two main response axes are activated; firstly, the sympatho-adrenal axis which causes the release of catecholamines from the adrenal medulla in the fight-or-flight response Arun, 2006) and secondly, the hypothalamic-pituitary-adrenal (HPA) axis, which results in the secretion of glucocorticoids (GCs) (Dedovic et al., 2009). ...
Article
Over the last century, wild tiger (Panthera tigris) numbers have declined from over 100 000 individuals to fewer than 4000, with animals now confined to less than 5% of their historic range due to habitat loss, persecution, inadequate management, and poaching. In contrast, 15 000 - 20 000 tigers are estimated to be housed in captivity, experiencing conditions vastly different than their wild counterparts. A total of 280 tigers are currently held at 44 different facilities within South Africa, including zoos, semi-captive 're-wilded' populations, and pets; these animals provide a unique opportunity to measure the impact of extrinsic factors, found in exotic habitats, on the adrenocortical activity of tigers. By monitoring and comparing stress-related faecal glucocorticoid metabolite (fGCM) concentrations of tigers housed at different locations, and free ranging tigers in natural tiger reserves, this project aimed to get a better understanding of the impact of extrinsic factors on adrenocortical function as a measure of stress. The results of this study showed no significant difference in fGCM concentrations between captive, re-wilded, and free-ranging tigers with the exception of one site. Furthermore, factors such as sex and season were not significant drivers of fGCM concentrations. One study group had elevated fGCM concentrations, showing population variation in the stress response. This indicates that populations are able to cope with exotic environments, however, as population-specific differences in the stress response exist, we suggest management protocols be created for each population. This study offered the unique opportunity to see how well tigers are faring outside of their native range and if having re-wilded tigers in exotic locations is a potential welfare-acceptable management option for tiger conservation globally.
... The sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis are the two main branches involved in the human stress response. During acute stress, the autonomic nervous system (ANS), consisting of the SNS and the parasympathetic nervous system (PNS), induces immediate rapid bodily changes through modulation of noradrenergic and cholinergic neuronal communication and the quick release of adrenaline via the sympatho-adrenal medullary system (SAM; Charmandari et al., 2005;Stratakis and Chrousos, 1995). The SNS is involved in the so-called 'fight or flight' responsethe immediate reaction to a stressor, while the complementary PNS regulates 'rest and digest' processes. ...
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The neurophysiological mechanisms underlying executive function deficits in very preterm born children still remain unclear. Moreover, evidence on factors that can be modified by behavior and exert an influence these deficits is lacking. The present case-control study examined the association between very preterm birth and neurophysiological indices of response inhibition (i.e. the N200-P300 complex) as well as the potential mediation of this association by aspects of physical fitness. 54 children born very preterm completed a submaximal cycling ergometer test and a motor skill test battery. Event-related potentials elicited by a Go/NoGo task were recorded using electroencephalography. Cases were then matched to full-term children (age: 11 ± 0.7 y). A higher error rate on NoGo trials was found in children born very preterm compared to those born full-term. Path-analyses further revealed that very preterm birth was associated with decreased NoGo P300 amplitude. Motor skills, but not aerobic fitness, fully mediated this association. In early adolescence, very preterm birth is associated with less effective recruitment of attentional resources for stimulus evaluation processes. The improvement of motor skills rather than cardiorespiratory fitness appears promising for reducing this specific impairment in cognitive control.
... Early life stress has long-term consequences, making children more vulnerable to physical and mental health problems in adulthood [1]. The main stress response system is the Hypothalamic Pituitary Adrenal (HPA) axis [2], which is immature at birth and sensitive to early experiences [3]. Cortisol is the final product of the HPA axis. ...
Article
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Several preclinical and clinical studies suggest that maternal psychosocial stress and anxiety during pregnancy may have persistent consequences for the long-term health of the offspring. The aim of our study was to evaluate possible associations between maternal cortisol levels, gestational age, baby’s birth weight and umbilical cord blood cortisol concentration. 145 women who attended the Obstetrics’ Service, Hospital de Clinicas “José de San Martín”, at the time of delivery, were included in this study. The population was divided into two groups: group 1 was constituted by 89 healthy women (26.5 ± 7.0 years) while group 2 was made up of 56 women (29 ± 7.8 years) who presented different pathologies. Total population was also divided according to the type of birth (cesarean section or vaginal). Group 2 was divided considering baby’s APGAR 5/10 score and birth weight. Cortisol was measured by a chemoluminiscent method (Immulite 2000 Siemens). Umbilical cord blood cortisol concentration correlated with pregnancy week (r=0.451, p=0.0001), birth weight (r=0.284, p=0.010) and maternal cortisol concentration; (r=0.424, p=0.0001). After dividing the population according to the type of birth, significant differences were found in umbilical cord blood cortisol concentration (p=0.003), pregnancy week (p=0.0001) and birth weight, (p=0.002), were found. A linear regression analysis was performed showing that maternal cortisol and pregnancy week were associated with umbilical cord blood cortisol concentrations (F=6.502, p=0.004) even after adjusting for birth weight. The correlation found between maternal cortisol and umbilical cord blood cortisol levels could be related to a probable fetal programming of the hypothalamic-pituitary-adrenal axis.
... The interplay between the HPA and HPG axes is a potential route through which ELS could impact pubertal timing (Marceau et al., 2014(Marceau et al., , 2015Negriff et al., 2015). There is evidence for inverse coupling of the HPA and HPG axes in adulthood, such that stress hormones suppress gonadal hormones (Stratakis and Chrousos, 1995;Romeo, 2005;Terburg et al., 2009). However, some evidence suggests that, unlike in adulthood, there is a positive coupling between the HPA and HPG axes during adolescence (Marceau et al., 2014), which may be more robust in girls than boys (Marceau et al., 2015). ...
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Recent research has linked early life stress (ELS), such as trauma exposure, with early puberty. Early puberty has also been identified as a risk factor for poor mental health outcomes. However, these two paths have primarily been examined independently. In addition, more studies have examined these associations in girls than boys, and findings for boys remain mixed. We hypothesized that early puberty (relative to peers) would be positively associated with both prior trauma exposure and concurrent anxiety symptoms. We anticipated that these associations might differ by sex. We tested these hypotheses within a cross-sectional sample of 133 8- to 13-year-old Black girls and boys with trauma exposure. The association between trauma and accelerated pubertal timing was sex-specific: it was positive for girls and negative for boys. We stratified subsequent analyses by sex. Regression analyses indicated that early puberty relative to peers predicted more anxiety symptoms for girls but not boys, after accounting for trauma exposure. A statistical mediation analysis indicated that, for girls, the positive association between trauma exposure and anxiety was partially mediated by pubertal timing. These results indicate that trauma exposure may have sex-specific effects on pubertal timing and anxiety risk in Black children. We also found that, for girls, trauma may increase risk for adverse outcomes by prompting earlier puberty, which is linked to higher anxiety. These findings are consistent with cascading effects of trauma across development, and highlight the need for further study of sex-specific mechanisms.
... The term 'adaptogen' was coined by the Russian scientist, Lazarev, in 1947 while working on dibazol (2 benzyl-benzimidazole), a synthetic compound found to stimulate nonspecific resistance of organisms (Brekhman & Dardymov, 1969;Todorova et al., 2021). The term Adaptogen was defined as "state of nonspecific resistance" in stress (Brekhman & Dardymov, 1969;Panossian, 2003)a physiological condition that is linked with various disorders of the neuro endocrine-immune system (Stratakis & Chrousos, 1995). This definition has been updated as "Adaptogenic substances have the capacity to normalize body functions and strengthen systems compromised by stress. ...
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Adaptogens are natural (herbs) or synthetic compounds (levamisole) used to maintain stability in human body. The plant based adaptogens were mainly used to enhance the physical endurance and metal health of patients. However, adaptogens are widely studied for their ability to protect and cope up the body against physical, chemical and biological stress and related diseases. Panax ginseng and Withania somnifera are natural adaptogens, used to attenuate stress & related disorders without increasing oxygen consumption. This review deals with a detailed description of adaptogenic potential of Panax ginseng and Withania somnifera in improving human health. It also focuses on the similarity and mechanism of action of Panax ginseng and Withania somnifera as adaptogens on human stress induced disorders.
... In mammalian physiology, the hypothalamus plays the roles in the regulation of water balance, energy balance, body temperature, reproductive function, body size and other homeostatic functions (Becú-Villalobos et al., 1994;Kopp et al., 1992;Rettori et al., 1994;Stratakis and Chrousos, 1995). In this region of the brain, there are many nuclei consisting of subsets of neurons that perform such a wide array of functions (Swaab et al., 1993). ...
... In general, the acute physiological stress response is associated with a variety of processes, such as activation of the sympathetic nervous system (SNS), down regulation of the parasympathetic nervous system (PNS; Ulrich-Lai & Herman, 2009), activation of the hypothalamic-pituitary adrenal (HPA) axis (Fulford & Harbuz, 2005;Selye, 1950), as well as with complex effects of the immune system with up-regulation of some components (most importantly inflammatory pathways) and down-regulation of others (most importantly cellular immunity; Chrousos, 2009;Morey et al., 2015). These processes are related with physiological changes that can be measured in humans: SNS and PNS responses are associated with changes in heart rate, heart rate variability, blood pressure, breathing frequency, skin temperature, and electrodermal activity (Chrousos & Gold, 1992;Stratakis & Chrousos, 1995). All these indicators can be assessed by means of technical devices such as heart rate or blood-pressure monitors. ...
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In the age of digitization, multitasking requirements are ubiquitous, especially in the workplace. Multitasking (MT) describes the activity of performing multiple (at least two) tasks at the same time. Dual tasking (DT) refers to the sequential switching between two tasks. The aim of our systematic review and meta-analysis was first to investigate whether physiological stress systems become activated in response to or during MT/DT and, secondly, whether this (re-)activity is higher compared to single tasking. We focused on the Sympathetic Nervous System (SNS), the Parasympathetic Nervous System (PNS), the hypothalamic-pituitary adrenal (HPA) axis, and the immune system. The systematic review has been pre-registered with PROSPERO (CRD42020181415). A total of twenty-five articles were identified as eligible, in which n = 26 studies were reported, with N = 1,142 participants. Our main findings are that SNS activity is significantly higher and PNS activity is significantly lower during MT/DT than during single tasking. Only two studies were found, in which HPA axis (re-)activity was surveyed. No eligible study was identified in which immune system (re-)activity was investigated. This is the first systematic synthesis of the literature base showing that stress system activity is increased during MT/DT in comparison to single-tasking.
... Stress involves nonspecific reactions of organisms to ambient stimuli, and a common stress reaction typically exists for various stress stimuli (e.g., restraint, transportation, blood collection, and hypoglycemia) [6]. Various changes to the endocrine response occur in organisms to maintain homeostasis as a response to these stress stimuli [7]; therefore, chronic stress influences growth and sexual maturation [8]. One of the responses to stress stimuli is increased adrenal gland activity through the activation of the hypothalamicpituitary-adrenocortical axis (HPA axis). ...
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This study investigates whether the measurement of glucocorticoid metabolites (GCMs) in feces is a useful method for the noninvasive evaluation of stress in the endangered Tsushima leopard cats (Prionailurus bengalensis euptilurus). Feces were collected from six seemingly healthy and five diseased (renal dysfunction, adrenal tumor, hernia, feline immunodeficiency virus (FIV), feline leukemia virus (FeLV)) Tsushima leopard cats in captivity. Fecal GCMs were measured by enzyme immunoassay (EIA) for cortisol. Individuals that experienced a physical examination under anesthesia showed increased fecal GCMs 1–2 days after the event. An individual diagnosed with disk herniation showed decreased fecal GCMs after medical administration. The mean fecal GCM concentrations for six healthy animals and five diseased animals were 0.66 ± 0.08 and 2.65 ± 0.76 μg/g, respectively, which was significantly different. Cortisol and corticosterone were not clearly detected in the feces examined by the use of the HPLC-EIA analysis. GCMs may be excreted in the feces; however, the exact identification of these substances is not achieved. The results suggest that the measurement of fecal GCMs is useful for the husbandry and health management of this species.
... Stress is an unavoidable part of human life, and it has been emphasized as a main cause of disease in traditional Oriental medicine. Individual responses to stressors via the activation of the hypothalamic-pituitary-adrenal (HPA) axis lead to the release of key peripheral mediators, such as glucocorticoids and catecholamines (Stratakis and Chrousos, 1995;Bugajski, 1999). However, uncontrolled stress has deleterious effects on the immune, cardiovascular, neuroendocrine, and central nervous systems and even cancer-related pathology (Schneiderman et al., 2005;Moreno-Smith et al., 2010). ...
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Introduction: Stress is a well-known factor for inflammation in diverse organs/tissues. Stress also leads to liver injury, which was supported by clinical observations and animal studies. We herein investigated the hepatoprotective property of an herbal formula (called as CGplus) consisting of Artemisia gmelinii Weber ex Stechm. (syn, Artemisia iwayomogi Kitamura), Wurfbainia villosa var. xanthioides (Wall. ex Baker) Skornick. & A.D.Poulsen (syn, Amomum xanthioides Wallich), and Salvia miltiorrhiza Bunge against stress-induced hepatic damage. Methods: Male BALB/c mice were orally administered water extract of CGplus (0, 50, 100, or 200 mg/kg) daily for 5 days, and then subjected to immobilization stress for 6 h on the 5th day. Results: Acute immobilization stress elevated remarkably serum concentrations of stress hormones (corticosterone and adrenaline) and two hepatic injury parameters (ALT and AST), while these alterations were significantly attenuated by the administration of CGplus. The increases of oxidative parameters (ROS, NO, lipid peroxidation, and protein carbonyl) and deviation of IL-1β and IL-10 in opposite directions in hepatic tissues were significantly normalized by CGplus. Pre-treatment with CGplus also notably ameliorated the abnormal activation of toll-like receptor 4 (TLR4), CD14, and lipopolysaccharide-binding protein (LPB) as well as infiltration of neutrophils in hepatic tissues. Conclusion: These results suggest that an herbal formula (CGplus) derived from traditional pharmaceutical theory has a potent protective effect against stress-induced hepatic injury via regulation of pro- (IL-1β) and anti-inflammatory (IL-10) cytokines.
... Acute stress affects brain function through two interrelated systems: the sympathetic adrenomedullary (SAM) (Frankenhaeuser, 1986) and the HPA (Stratakis & Chrousos, 1995) systems. The SAM system orchestrates the fight/flight response (Cannon, 1953) and is accompanied by the rapid central release of catecholamines such as norepinephrine. ...
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Abundant evidence shows that early‐life stress (ELS) predisposes for the development of stress‐related psychopathology when exposed to stressors later in life, but the underlying mechanisms remain unclear. To study predisposing effects of mild ELS on stress sensitivity, we examined in a healthy human population the impact of a history of ELS on acute stress‐related changes in corticolimbic circuits involved in emotional processing (i.e., amygdala, hippocampus, ventromedial prefrontal cortex; vmPFC). Healthy young male participants (n=120) underwent resting‐state functional magnetic resonance imaging (fMRI) in two separate sessions (stress induction versus control). The Childhood Trauma Questionnaire (CTQ) was administered to index self‐reported ELS, and stress induction was verified using salivary cortisol, blood pressure, heart rate, and subjective affect. Our findings show that self‐reported ELS was negatively associated with baseline cortisol, but not with the acute stress‐induced cortisol response. Critically, individuals with more self‐reported ELS exhibited an exaggerated reduction of functional connectivity in corticolimbic circuits under acute stress. A mediation analysis showed that the association between ELS and stress‐induced changes in amygdala‐hippocampal connectivity became stronger when controlling for basal cortisol. Our findings show, in a healthy sample, that the effects of mild ELS on functioning of corticolimbic circuits only become apparent when exposed to an acute stressor, and may be buffered by adaptations in hypothalamic–pituitary–adrenal axis function. Overall, our findings might reveal a potential mechanism whereby even mild ELS might confer vulnerability to exposure to stressors later in adulthood.
... Stress response is an integral part of organism's life to deal with stressors and to maintain a homeostatic balance [1]. Considering the complex body organization of higher animals including human beings, stress response primarily comes from the interaction of the environment, nervous and endocrine system [2,3]. However, repeated and chronic exposure to adverse stressors not only imbalance the organism's capacity of stress response but also contributes to a number of health effects such as mood dysfunction, obesity, immune dysfunction, cardiovascular disease, post-traumatic stress disorder, etc. [4,5]. ...
Article
Modelling of chronic stress conditions in experimental animals and its neuropsychiatric outcomes has been well documented in literature. Zebrafish (Danio rerio) by exhibiting significant genetic and epidemiological similarities with human beings, has now emerged as a promising animal model of translational research. In this line, risk assessment following exposure to chronic unpredictable stress (CUS) towards neurobehavioral response and neuromorphology of sensitive brain region in zebrafish is the prime objective of the present study. With the existing knowledge on CUS in affecting diverse neurobehavioral aspects, we were primarily interested in whether this neurobehavioral transformation is an outcome of altered glutathione biosynthesis in zebrafish. We were also concerned about whether the precocious neurobehavioral transformation has been linked to altered neuromorphology in the periventricular grey zone (PGZ) of the zebrafish brain. Our basic findings showed that CUS itself represented as a universal factor in altering native bottom-dwelling and scototaxis behaviour of zebrafish. Our findings also backing the argument that CUS itself represented a collective stress regimen by altering the brain glutathione biosynthesis in zebrafish. Correspondingly, a temporal transformation in CUS instigated augmentation in neuronal pyknosis and chromatin condensation were observed in PGZ of the zebrafish brain. Collectively, these findings designate that CUS induced temporal neurobehavioral transformation is an outcome of augmented oxidative stress and neuromorphological alteration in the zebrafish brain. However, the underlying mechanism of such neuropathological manifestation associated with CUS might provide novel insight towards the development of prophylactic/therapeutic intervention to counter such co-morbid behavioral alteration.
... The most prominent is the activation of the hypothalamus-pituitary adrenal (HPA) axis which leads to secretion of the stress hormone cortisol from the adrenal cortex [1,2]. Furthermore, the sympathetic nervous system (SNS) becomes activated in response to acute stressors which leads to the release of epinephrine and norepinephrine from the adrenal medulla, as well as to a variety of secondary reactions such as an increase in blood pressure and heart rate, and a decrease in heart rate variability [3][4][5]. Both stress systems can interact with the brain via direct and indirect pathways and can, therefore, alter brain chemistry which can consecutively alter cognitive functioning [6][7][8]. ...
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Speech fluency can be impaired in stressful situations. In this study, it was investigated whether a verbal fluency task by itself, i.e. without the presence of any further stressors, induces responses of the hypothalamic-pituitary adrenal (HPA) axis and of the sympathetic nervous system (SNS). The sample consisted of n = 85 participants (68.2% female; 33.3 ± 15.2 years) who performed two consecutive verbal fluency tasks for two minutes each. The categories were either 'stress' or 'disease' and 'animals' or 'foods' which were presented in a randomized order. Three saliva samples were collected, prior to the task (t 0), immediately after (t 1), and ten minutes after it (t 2). Salivary α-amylase and cortisol were assessed. Furthermore , blood pressure, heart rate, and ratings of actual stress perception, level of effort, and tiredness were measured. The verbal fluency task induced a HPA axis response with a maximum cortisol level at t 2 which was independent of task performance. Furthermore, perceived stress and effort, as well as tiredness increased after the task. Moreover, tiredness immediately after the task was negatively correlated with task performance. No α-amylase, blood pressure, or heart rate, and therefore SNS, responses were found. Implications for the integrated specificity model are discussed. We conclude that a verbal fluency task acts like an acute stressor that induces a cortisol and a perceived stress response without the need for further (e.g., social-evaluative) stress components. Therefore, it is a less time-consuming alternative to other stress tasks that can be used in field studies with little effort.
... Psychological health indicators are important for monitoring and evaluating the health status of communities. Because psychological health problems contribute heavily to the total burden of disability in the population, especially within the younger age groups [Stratakis & Chrousos, 1995].Perceived stress is a dynamic multidimensional concept, with a wide spectrum of causative and conducive factors. The perceptions comprise medical, physical, psychological, and psychosocial aspects and are both culturally and socially context dependent [Moore & Cooper, 1996].Over the lifespan, parents face many challenges associated with raising children. ...
... Adrenal glucocorticoid interacts with the brain receptors to keep a circulation motion action. During the circulation adrenal glucocorticoid provides the negative feedback to the hypothalamicpituitary-adrenal to turn it off to maintaining physiological processes and this affects the person's health (Stratakis & Chrousos, 1995). Figure 6 shows the Circadian rhythm system in mammals across the gene, cell and system levels. ...
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This paper examines the development of sedentary work practices for railway network control room workers. The railway control room is used to illustrate how subtle changes to this unique work environment have covertly led to health risks more commonly found in traditional office settings. Advancements in railway technology have been introduced to primarily increase safety, however, they have gradually led to higher levels of sedentary work in the control room and have unwittingly introduced new health risks. The complicating factor for the railways is that network controllers are faced with the added burden of extended shifts and working with safety-critical systems. To date, Human Factors / Ergonomic (HF/E) research within network control rooms has traditionally focussed on the cognitive issues that arise at the human-automation interface; therefore, few studies have focused on the new, less obvious sedentary physical risks and their emerging resultant health issues. In looking for workplace solutions, interventions are needed to reduce, or interrupt, bouts of sedentary time, rather than to focus on increasing physical activity alone. This paper discusses the increased risks associated with sedentary work and sedentary time and a number of practical solutions have been offered to support risk reduction in the railway control room.
... The most prominent is the activation of the hypothalamus-pituitary adrenal (HPA) axis which leads to secretion of the stress hormone cortisol from the adrenal cortex [1,2]. Furthermore, the sympathetic nervous system (SNS) becomes activated in response to acute stressors which leads to the release of epinephrine and norepinephrine from the adrenal medulla, as well as to a variety of secondary reactions such as an increase in blood pressure and heart rate, and a decrease in heart rate variability [3][4][5]. Both stress systems can interact with the brain via direct and indirect pathways and can, therefore, alter brain chemistry which can consecutively alter cognitive functioning [6][7][8]. ...
Article
The conceptualization of stress‐responsive physiological systems as operating in an integrated manner is evident in several theoretical models of cross‐system functioning. However, limited empirical research has modeled the complexity of multisystem activity. Moreover, few studies have explored developmentally‐regulated changes in multisystem activity during early childhood when plasticity is particularly pronounced. The current study used latent profile analysis (LPA) to evaluate multisystem activity during fall and spring of children’s transition to kindergarten in three biological systems: the parasympathetic nervous system (PNS), sympathetic nervous system (SNS), and hypothalamic pituitary adrenal (HPA) axis. Latent transition analysis (LTA) was then used to examine the stability of profile classification across time. Across both timepoints, three distinct profiles of multisystem activity emerged. One profile was characterized by heightened HPA axis activity (HPA Axis Responders), a second profile was characterized by moderate, typically adaptive patterns across the PNS, SNS, and HPA axis (Active Copers/Mobilizers), and a third profile was characterized by heightened baseline activity, particularly in the PNS and SNS (Anticipatory Arousal/ANS Responders). LTA of fall‐to‐spring profile classifications indicated higher probabilities that children remained in the same profile over time compared to probabilities of profile changes, suggesting stability in certain patterns of cross‐system responsivity. Patterns of profile stability and change were associated with socioemotional outcomes at the end of the school year. Findings highlight the utility of LPA and LTA to detect meaningful patterns of complex multisystem physiological activity across three systems and their associations with early adjustment during an important developmental transition.
Chapter
Preclinical, clinical, and population research demonstrates that stress and early life adversity (ELA) increase vulnerability to initiate, maintain, and relapse in addiction. Individuals with addiction problems have higher prevalence of trauma exposure than nondrug users; and this association extends to young populations (e.g., adolescents). Mechanisms for these associations likely involve multiple systems, including changes in the mesolimbic reward functions, HPA axis stress response, and other stress- and reward-related pathways. Other brain morphological and functional changes are also likely involved and directly contribute to the neurohormonal and behavioral alterations observed during adulthood in those exposed to ELA. Stress-related risk is influenced by sex, genetic factors, and resilience, among other factors. Our heuristic model proposes that long-term effects of stress and ELA on the brain contribute to dysregulation of the stress response, emotional reactivity, reward systems, cognitive dysregulation, and delay discounting that lead to impulsive and high-risk behaviors, such as drug use and relapse.
Article
Cenpj is a centrosomal protein located at the centrosomes and the base of cilia, it plays essential roles in regulating neurogenesis and cerebral cortex development. Although centrosomal and cilium dysfunction are one of the causes of obesity, insulin resistance, and type 2 diabetes, the role that Cenpj plays in the regulation of body weight remains unclear. Here, we deleted Cenpj by crossing Cenpjflox/flox mice with Nkx2.1-Cre mice. Loss of the centrosomal protein Cenpj in Nkx2.1-expressing cells causes morbid obesity in mice at approximately 4 months of age with expended brain ventricles but no change of brain size. We found that hypothalamic cells exhibited reduced proliferation and increased apoptosis upon Cenpj depletion at the embryonic stages, resulting in a dramatic decrease in the number of Proopiomelanocortin (POMC) neurons and electrophysiological dysfunction of NPY neurons in the arcuate nucleus (ARC) in adults. Furthermore, depletion of Cenpj also reduced the neuronal projection from the ARC to the paraventricular nucleus (PVN), with decreased melanocortin-4 receptors (MC4R) expression in PVN neurons. The study defines the roles that Cenpj plays in regulating hypothalamus development and body weight, providing a foundation for further understanding of the pathological mechanisms of related diseases.
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Understanding the function of non-coding genomic sequence variants represents a major challenge for biomedicine. Many diseases are products of gene × environment interactions with complex mechanisms. My thesis addresses these themes by mechanistic characterization of environment-responsive non-coding variants that influence gene expression only after drug or hormone exposure. Using glucocorticoid signaling as a model system, I integrated genomic, transcriptomic, and epigenomic approaches to unravel mechanisms by which variant function could be revealed by hormones or drugs. Specifically, I identified cis-regulatory elements and 3-dimensional interactions underlying ligand-dependent associations between variants and gene expression. One-quarter of the glucocorticoid-modulated variants identified had already been associated with clinical phenotypes. However, their affected genes were “unmasked” only after glucocorticoid exposure and those genes often displayed function relevant to the disease phenotypes. These diseases involved glucocorticoids as risk factors or as therapeutic agents and included autoimmunity, metabolic and mood disorders, osteoporosis and cancer, demonstrating an interaction between environmental and genetic risk factors in disease predisposition. My subsequent functional studies of genes discovered via this mechanism in bipolar disorder with metabolic comorbidity yielded novel insights into disease pathophysiology. The team then moved beyond the traditional role of the glucocorticoid receptor (GR) as a ligand-activated transcription factor to interrogate its role in post-transcriptional regulation. We discovered that glucocorticoids could also regulate alternative polyadenylation of mRNA for a variety of genes involved in immunity. We also observed evidence that genetic risk variants for certain immune-related diseases could modulate glucocorticoid-dependent alternative polyadenylation. Together, these results provide a mechanistic framework for understanding the function of non-coding genetic variants across chemical environments.
Introduction Animal-based studies are essential for assessing toxicity to environmental pollutants, especially when the potential targets are specific developmental time points, teratogenic, or multi-organ systems that cannot be modeled in vitro. Orogastric gavage is a widely used technique for exposure because of its increased accuracy of dose administration over free feeding. However, repeated use of this method has been reported to cause physiological stress on the exposed animals that could interfere with interpretation of results. Previous studies have shown that genetic background also contributes to the level of stress and can affect individual response. Methods To evaluate the impact of stress on repeated orogastric gavage, we exposed C67BL/6J and 129S1/SvImJ inbred mouse strains to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), a potent xenobiotic that has been extensively studied in vivo. Pregnant females were dosed for ten days after mating using orogastric gavage with olive oil as vehicle or through diet using peanut butter as vehicle. Serum corticosterone levels, body weight, and reproduction endpoints were measured to evaluate levels of stress induced by the dosing technique. Results The levels of stress caused by orogastric gavage was strongly dependent on strain background and on the phenotypic endpoint. Orogastric gavage-induced stress was more detrimental in 129S1/SvlmJ pregnant female mice than in C57BL/6J. Conclusion These results show that administration of xenobiotics via controlled diet can improve the reproducibility and rigor of exposure studies requiring orogastric delivery.
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Background. Endogenous opioids regulate pain, drug reward, and stress responses. We have previously shown reduced hypothalamic-pituitary-adrenal (HPA) responses to psychological stress and to opioid blockade among dependent smokers. In this study, we examined the extent to which biologically confirmed nicotine withdrawal alters endogenous opioid regulation of HPA axis functioning during rest and in response to acute stress.Design and Methods. Smokers were randomly assigned to one of two conditions; 24 hr withdrawal from all nicotine-containing products (n = 62) or smoking ad libitum (n = 44). A non-smoking comparison group (n = 43) was also included. Participants (85 males and 64 females) completed two acute stress sessions during which a placebo or 50 mg of naltrexone (opioid antagonist) were administered using a double-blind design. Blood and saliva samples (assayed for cortisol and adrenocorticotropic hormone, i.e., ACTH) and mood measures were obtained during a resting absorption period, after acute stress (public speaking, mental arithmetic, and cold pressor tasks), and during an extended recovery period.Results. Opioid blockade (naltrexone) was associated with increased ACTH and cortisol responses to stress, and tobacco withdrawal was associated with blunted hormonal responses. A pattern of sex differences also emerged, with women exhibiting reduced ACTH responses to stress and higher ACTH and plasma cortisol response to opioid blockade.Conclusions. Compared to ad libitum smoking, nicotine withdrawal is associated with blunted opioid modulation of the HPA axis. Sex may modulate these effects. Blunted endogenous opioid regulation may underlie an incentive process that reinforces smoking behavior and may warrant therapeutic attention.
Chapter
Steroid hormones, like sex hormones and corticosteroids, are involved in normal brain function. They can influence behavior and higher functions via binding to the corresponding hormone receptors. Steroid hormones also play a crucial role in psychiatric disorders by interacting with different neurotransmitter systems in the brain. Most of the studies in this field have been performed on postmortem tissue of animals and humans. However, noninvasive techniques could provide new insight into the role that steroid hormones play in normal and pathological brain function. PET and SPECT are techniques that allow noninvasive quantitative analysis of the expression of steroid hormone receptors. This chapter will briefly explain the role of steroid hormones in physiological and pathological conditions and provide an overview of the available PET and SPECT imaging methods that could be used to study the role steroid hormones and their receptors in the brain.
Chapter
This chapter focuses on neuropeptides of central nervous system (CNS) origin, but predominantly on those that have known clinical relevance. Consequently, neuropeptides secreted by the lower or more primitive parts of the brain, in particular, the hypothalamus, are somewhat more of a focus than those elaborated by higher-level organizations, such as the cerebral cortex. In fact, not only is more known about the neuroendocrinology of the hypothalamus than of the higher centers, but the position of the hypothalamus at the base of the brain is an intrinsic source of its power to influence all brain signals that flow out into the periphery of the corpus. Thus, although evolutionarily "lower or more primitive" than cortical neurons, the hypothalamus elaborates products, such as pituitary releasing hormones, that are of exceptional importance in regulating all mass-sustained organismic functions.
Chapter
Parental gene expression and even changes in the epigenome have been reported to influence the offspring. Parental lifestyle and exposure to environmental factors have been shown to cause alterations of the epigenome of the individual as well as the offspring. Epidemiological and laboratory based experimental studies have shown that parental exposure to stress and environmental factors lead to variation in the methylation profiles of DNA obtained from offsprings and in some cases grand-offsprings. Strong association has been reported between maternal, prenatal stress and altered DNA methylation profiles of several genes in the offsprings. Upon stress exposure, many outcomes, such as low birth weight, immune system anomalies or HPA axis aberrations, has been correlated with the epigenetic profiles of many genes in the offspring. Furthermore, paternal lifestyle and exposure to chemicals have been associated with aberrant methylation profiles in the sperm DNA as well as in the offsprings’ DNA. All these investigations on the parental exposure to stress and lifestyle choices have proven to have a direct role in the methylation profiles of the offsprings.
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Lay Summary Thyroid hormone reference intervals—used to determine normal thyroid function —currently don’t take into account many significant factors that can cause variation in thyroid hormone levels. These factors include age, sex, ethnicity, season, time of day, iodine content in the diet, socioeconomic status, stress levels, body composition, immune status, menstrual cycle phase, and overall health status. This paper shows how early life experiences as well as short term stressors may affect variation in thyroid function. These are energetic challenges to which the thyroid physiology can respond to. Our investigation shows that much variation in thyroid function is natural. It may result from a complex interplay of evolutionary, genetic, developmental, and physiological factors in response to energetic challenges in the environment, beyond what is currently considered in biomedicine. A new research agenda for thyroid health should explore the way that diversity in thyroid function has evolved as a response to different contexts people live in—like focusing on how people’s metabolisms adapt to the energetic requirements of their environments.
Article
Background: Subarachnoid hemorrhage (SAH) is a potential cause of hypopituitarism. Most of the studies regarding the relationship between SAH and anterior pituitary function were retrospective and hormonal assessment was performed several months after SAH. Aim: To prospectively evaluate the prevalence of anterior pituitary hormone deficiencies in the acute phase after spontaneous SAH and their possible correlation with clinical and radiological parameters. Methods: Pituitary function was tested in 60 patients within 72 h after spontaneous SAH. Results: 56.9% of the patients showed at least one anterior pituitary hormone deficiency: gonadotropin and GH secretion failure represented the most prevalent hormonal deficiencies (33.3 and 22.0%, respectively), whereas ACTH and TSH deficiency was less frequent (7.1 and 1.8%, respectively). With the exception of secondary hypogonadism, the prevalence of other pituitary hormone deficiencies is in agreement with previous studies, which evaluated pituitary function on longterm follow up after SAH. No correlation was found between hypopituitarism and clinical status, as assessed with Hunt-Hess and Glascow Coma Scales. Moreover, no correlation was found between hypopituitarism and bleeding severity evaluated with Fisher's scale. Conclusions: We demonstrated a high prevalence of anterior pituitary hormone deficiencies acutely after SAH. Although part of GH and gonadotropin deficiencies might be a consequence of functional alteration due to SAH itself, the finding of low cortisol levels in this stressful condition strongly suggests the presence of true hypocortisolism. Therefore, an evaluation of pituitary function shortly after SAH might be useful to identify a subset of patients who deserve a more accurate follow-up.
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High-volume breeders often produce purebred or “designer breeds” to supply the pet industry. Some high-volume commercial breeding facilities (CBEs) include extreme conditions such as overcrowding, little human contact, exposure to harsh weather conditions, inadequate food and water, and untreated medical conditions. Previous research with puppies born in these extreme conditions reports that this early life history of deprivation is associated with multiple behavioral and psychological abnormalities once adopted. Still, few studies to date have examined whether impoverished conditions affect the physiological systems of domestic dogs. The following study examined hormonal and behavioral differences in dogs from adverse early-life environments (i.e., puppy mills, unlicensed commercial breeders, hoarding situations) and a control group of dogs during social interactions with an unfamiliar human while in the shelter environment. Dogs from known early adverse backgrounds displayed significantly higher salivary cortisol levels than other dogs found at the shelter, F(1, 23) = 4.51, p = 0.045. Neither time spent in adverse living conditions nor time spent in the shelter correlated with cortisol output. During social interactions with an unfamiliar human, dogs from adverse backgrounds exhibited more fear behavior (p = 0.022) and displayed lower levels of affiliative behavior (p = 0.039). Dogs from adverse backgrounds spent more time in stationary positions (i.e., sitting, standing, freezing) than other shelter dogs (p = 0.043), and we were unable to complete a food-based social-cognitive task because of this. Using a moderated multiple regression model, we found dogs’ background was a significant moderator of the relationship between total cortisol output and panting during interactions with an unfamiliar human, R² = 0.39, F(1, 11) = 6.94, p = 0.023. In contrast, no relationship between these variables was seen in other shelter dogs. The findings of this study demonstrate that even when residing in the same shelter environment, a history of living in extreme conditions may lead to higher cortisol levels and altered behavior in a novel social context. While studies have examined dogs while still in the CBEs or once they have been adopted, this study examines their behavior and cortisol levels once removed and placed in a shelter environment where the public might interact with them and consider them for adoption. Gaining a better understanding of the behavioral and hormonal outcomes of dogs that have experienced extreme early life deficiencies may assist in the development of effective interventions that will facilitate rehabilitation and enhance the welfare of these dogs as pets.
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Developmental researchers studying how stress affects health have often focused on specific, individual, physiological parameters such as cortisol. Yet, recent theories of stress biology emphasize that the stress response is multi‐faceted and engages distinct yet interconnected physiological systems, including metabolic, immune, and cardiovascular systems that respond to one another. Moreover, advocates of a systems approach also argue that the confluence of changes across several physiological systems presents a health risk, even when one indicator alone is not predictive of health outcomes. Allostatic load is one potential multi‐system indicator of stress, capturing the cumulative, physiological burden of chronic stress exposure on the body. At the same time, studying allostatic load during early development raises several issues, including how allostatic load is operationalized, the clinical importance of commonly used biomarkers during distinct periods of development, and the fundamental role of timing. In this review paper, we discuss the potential of allostatic load in the context of studies of stress in developmental science, review developmental studies that have assessed allostatic load, and articulate critical conceptual questions regarding the study of allostatic load during the childhood years.
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Background First described in 1955, night eating syndrome refers to an abnormal eating behavior clinically defined by the presence of evening hyperphagia (>25% of daily caloric intake) and/or nocturnal awaking with food ingestion occurring ⩾ 2 times per week. Aims Although the syndrome is frequently comorbid with obesity, metabolic and psychiatric disorders, its etiopathogenesis, diagnosis, assessment and treatment still remain not fully understood. Methods This review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines; PubMed database was searched until 31 October 2020, using the key terms: ‘Night Eating Syndrome’ AND ‘complications’ OR ‘diagnosis’ OR ‘drug therapy’ OR ‘epidemiology’ OR ‘etiology’ OR ‘physiology’ OR ‘physiopathology’ OR ‘psychology’ OR ‘therapy’. Results From a total of 239 citations, 120 studies assessing night eating syndrome met the inclusion criteria to be included in the review. Conclusion The inclusion of night eating syndrome into the Diagnostic and Statistical Manual of Mental Disorders-5 ‘Other Specified Feeding or Eating Disorders’ category should drive the attention of clinician and researchers toward this syndrome that is still defined by evolving diagnostic criteria. The correct identification and assessment of NES could facilitate the detection and the diagnosis of this disorder, whose bio-psycho-social roots support its multifactorial nature. The significant rates of comorbid illnesses associated with NES and the overlapping symptoms with other eating disorders require a focused clinical attention. Treatment options for night eating syndrome include both pharmacological (selective serotonin reuptake inhibitors, topiramate and melatonergic drugs) and non-pharmachological approaches; the combination of such strategies within a multidisciplinary approach should be addressed in future, well-sized and long-term studies.
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Major depression represents a complex and prevalent psychological disease that is characterized by persistent depressed mood, impaired cognitive function and complicated pathophysiological and neuroendocrine alterations. Despite the multifactorial etiology of depression, one of the most recent factors to be identified as playing a critical role in the development of depression is blood–brain barrier (BBB) disruption. The occurrence of BBB integrity disruption contributes to the disturbance of brain homeostasis and leads to complications of neurological diseases, such as stroke, chronic neurodegenerative disorders, neuroinflammatory disorders. Recently, BBB associated tight junction disruption has been shown to implicate in the pathophysiology of depression and contribute to increased susceptibility to depression. However, the underlying mechanisms and importance of BBB damage in depression remains largely unknown. This review highlights how BBB disruption regulates the depression process and the possible molecular mechanisms involved in development of depression-induced BBB dysfunction. Moreover, insight on promising therapeutic targets for treatment of depression with associated BBB dysfunctions are also discussed.
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Psychological distress, such as chronic depression and anxiety, is a topical problem. In the context of cancer patients, prevalence rates of psychological distress are four-times higher than in the general population and often confer worse outcomes. In addition to evidence from epidemiological studies confirming the links between psychological distress and cancer progression, a growing body of cellular and molecular studies have also revealed the complex signaling networks which are modulated by psychological distress-derived chronic stress during cancer progression. In this review, aiming to uncover the intertwined networks of chronic stress-driven oncogenesis and progression, we summarize physiological stress response pathways, like the HPA, SNS, and MGB axes, that modulate the release of stress hormones with potential carcinogenic properties. Furthermore, we discuss in detail the mechanisms behind these chronic stimulations contributing to the initiation and progression of cancer through direct regulation of cancer hallmarks-related signaling or indirect promotion of cancer risk factors (including obesity, disordered circadian rhythms, and premature senescence), suggesting a novel research direction into cancer prevention and therapy on the basis of psychological interventions.
Chapter
This chapter focuses on salivary bioscience applications in Human–Animal Interaction (HAI) research, an expanding field of interdisciplinary inquiry examining the mutual, dynamic relationships between people and animals and the ways in which these interactions may affect health and well-being in both species. Using a social neuroscience perspective, this chapter provides a snapshot of research on the physiological impacts of animal companionship, pet ownership, and the intentional inclusion of animals as part of a therapeutic or ameliorative process or milieu, Animal Assisted Interventions (AAIs), in both humans and animals. While considering a wide range of contexts, populations, species, interactions, and therapeutic outcomes, this chapter will explore empirical evidence aiming to capture the bidirectional links between HAI and the activity of biological systems through examining a variety of salivary analytes. Given the focus of existing empirical work in the field, we will emphasize activity of the Hypothalamic–Pituitary–Adrenal (HPA) axis and its main marker, cortisol, although other analytes including salivary alpha amylase (sAA), secretory immunoglobulin A (SIgA), salivary Oxytocin (sOT), and Nerve Growth Factor (sNGF) will be discussed. After an overview of relevant theoretical perspectives and the introduction of a model describing links between HAI and HPA axis activity, we provide an empirical review organized by intervention approach, population, and species, including dyadic approaches. Methodological challenges, implications for practice, and future research are discussed.
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To study the effects of physical conditioning on the hypothalamic-pituitary-adrenal axis, we examined the plasma ACTH, cortisol, and lactate responses in sedentary subjects, moderately trained runners, and highly trained runners to graded levels of treadmill exercise (50, 70, and 90 percent of maximal oxygen uptake) and to intravenous ovine corticotropin-releasing hormone (1 microgram per kilogram of body weight). Basal evening concentrations of ACTH and cortisol, but not of lactate, were elevated in highly trained runners as compared with sedentary subjects and moderately trained runners. Exercise-stimulated ACTH, cortisol, and lactate responses were similar in all groups and were proportional to the exercise intensity employed. These responses, however, were attenuated in the trained subjects when plotted against applied absolute workload. Only the highly trained group had diminished responses of ACTH and cortisol to ovine corticotropin-releasing hormone, consistent with sustained hypercortisolism. We conclude that physical conditioning is associated with a reduction in pituitary-adrenal activation in response to a given workload. Alterations of the hypothalamic-pituitary-adrenal axis consistent with mild hypercortisolism and similar to findings in depression and anorexia nervosa were found only in highly trained runners. Whether these alterations represent an adaptive change to the daily stress of strenuous exercise or a marker of a specific personality profile in highly trained athletes is unknown.
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During the past several decades many investigators have devoted their efforts to determining whether psychosocial factors, such as stress or depression, are associated with the onset, course, or outcome of physical illness. Considerable evidence suggests that both stressful life events and depressive disorders are associated with increased morbidity and mortality.1 A large body of research in the last few years has considered the possibility that immunologic alterations may be associated with depressive disorders and depressive symptoms accompanying stressful life events. The related immunologic alterations have been viewed as a link between depression and stress and increased risk for immune-related disease states, such as cancer, autoimmune disorders, and infections, including human immunodeficiency virus (HIV). However, there has been a lack of substantial evidence supporting the association between depression or stress and increased morbidity or mortality due to disorders involving the immune system. In a series of articles recently published in
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This article defines stress and related concepts and reviews their historical development. The notion of a stress system as the effector of the stress syndrome is suggested, and its physiologic and pathophysiologic manifestations are described. A new perspective on human disease states associated with dysregulation of the stress system is provided. Published original articles from human and animal studies and selected reviews. Literature was surveyed utilizing MEDLINE and the Index Medicus. Original articles from the basic science and human literature consisted entirely of controlled studies based on verified methodologies and, with the exception of the most recent studies, replicated by more than one laboratory. Many of the basic science and clinical studies had been conducted in our own laboratories and clinical research units. Reviews cited were written by acknowledged leaders in the fields of neurobiology, endocrinology, and behavior. Independent extraction and cross-referencing by the authors. Stress and related concepts can be traced as far back as written science and medicine. The stress system coordinates the generalized stress response, which takes place when a stressor of any kind exceeds a threshold. The main components of the stress system are the corticotropin-releasing hormone and locus ceruleus-norepinephrine/autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. There has been an exponential increase in knowledge regarding the interactions among the components of the stress system and between the stress system and other brain elements involved in the regulation of emotion, cognitive function, and behavior, as well as with the axes responsible for reproduction, growth, and immunity. This new knowledge has allowed association of stress system dysfunction, characterized by sustained hyperactivity and/or hypoactivity, to various pathophysiologic states that cut across the traditional boundaries of medical disciplines. These include a range of psychiatric, endocrine, and inflammatory disorders and/or susceptibility to such disorders. We hope that knowledge from apparently disparate fields of science and medicine integrated into a working theoretical framework will allow generation and testing of new hypotheses on the pathophysiology and diagnosis of, and therapy for, a variety of human illnesses reflecting systematic alterations in the principal effectors of the generalized stress response. We predict that pharmacologic agents capable of altering the central apparatus that governs the stress response will be useful in the treatment of many of these illnesses.
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To examine whether the hypothalamic corticotropin-releasing hormone (CRH) neuron is regulated by CRH, by products of the proopiomelanocortin (POMC) gene, and/or by glucocorticoids, we used a rat hypothalamic organ culture system in which rat CRH secretion from single explanted hypothalami was evaluated by an RIA (iCRH) specific for rat CRH. The effects of graded concentrations of ovine CRH (oCRH), adrenocorticotropin hormone (ACTH), beta-endorphin (beta-EP), alpha-melanocyte-stimulating hormone (alpha-MSH), corticotropin-like intermediate lobe peptide (CLIP), ovine beta-lipotropin (ovine beta-LPH), and dexamethasone (DEX) upon unstimulated and serotonin- (5HT), acetylcholine- (ACh), and norepinephrine-(NE) stimulated CRH secretion were determined. oCRH and DEX inhibited unstimulated iCRH secretion with ID50 at the 10(-8) M range. ACTH had no detectable suppressive effect at 10(-8) M. oCRH, ACTH, and DEX inhibited 5HT-, ACh-, and NE-stimulated iCRH secretion in a dose-dependent fashion. beta-EP, alpha-MSH, and CLIP also inhibited 5HT-induced iCRH secretion. Of the latter peptides, the strongest inhibitor was beta-EP and the weakest was CLIP. Ovine beta-LPH had only a weak inhibitory effect on 5HT-induced iCRH secretion. Generally, the concentrations required for 50% suppression of neurotransmitter-stimulated iCRH secretion were significantly lower than those required for a similar suppression of unstimulated iCRH secretion. In conclusion, these data suggest the presence of multiple negative feedback loops involved in the regulation of the hypothalamic CRH neuron: an ultrashort CRH-mediated loop, a short, hypothalamic POMC-derived peptide loop, and a long, glucocorticoid-mediated negative feedback loop. The potency of these negative feedback loops may be determined by the state of activation of the CRH neuron.
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To further our understanding of the functional role of catecholaminergic systems in regulating hypothalamic corticotropin-releasing hormone (CRH) secretion, we assessed the direct effects of a multiplicity of catecholamine agonists and antagonists on hypothalamic CRH secretion. To accomplish this, we used an in vitro rat hypothalamic organ culture system in which CRH secretion from single explants was evaluated by a specific RIA (IR-rCRH). Norepinephrine (NE) stimulated IR-rCRH secretion dose dependently, with peak effects in the nanomolar range. The effect of NE was antagonized by the mixed alpha antagonist phentolamine, the alpha 1 antagonist prazosin, and the alpha 2 antagonist yohimbine, but not by the beta blocker, L-propanolol. Compatible with these data were the findings that the alpha 1 agonist phenylephrine and the alpha 2 agonist clonidine both stimulated IR-rCRH secretion in a dose-dependent fashion. On the other hand, whereas the beta agonist, isoproterenol, caused a weak, non-dose-dependent increase in IR-rCRH secretion, this effect could not be antagonized by L-propanolol. Despite pretreatment with serotonin and acetylcholine antagonists, the effect of NE upon IR-rCRH secretion was undiminished, suggesting that NE-induced CRH secretion is not mediated by either neurotransmitter. On the other hand, pretreatment with gamma-aminobutyric acid (GABA) attenuated NE-induced IR-rCRH secretion. Whereas epinephrine (E) stimulated IR-rCRH secretion, this occurred only at higher concentrations, and was antagonized by phentolamine, but not by L-propanolol. Dopamine (DA) had a weak stimulatory effect that could be antagonized by the DA1 receptor antagonist, SCH 23390, but not by phentolamine. We conclude that NE and E stimulate hypothalamic IR-rCRH secretion via alpha 1 and alpha 2 receptors. The effect of NE upon IR-rCRH secretion is not apparently mediated by serotonergic or cholinergic interneurons, but is modulated by the inhibitory neurotransmitter, GABA. These data support the idea that the central catecholaminergic systems are excitatory rather than inhibitory upon CRH secretion when acting directly at the hypothalamic level.
Book
It has been over 50 years since Hans Selye formulated his concept of stress. This came after the isolation of epinephrine and norepinephrine and after the sympathetic system was associated with Walter Cannon's "fight or flight" response. The intervening years have witnessed a number of dis­ coveries that have furthered our understanding of the mechanisms of the stress response. The isolation, identification and manufacture of gluco­ corticoids, the identification and synthesis of ACTH and vasopressin, and the demonstration of hypothalamic regulation of ACTH secretion were pivotal discoveries. The recent identification and synthesis of CRR by Willie Vale and his colleagues gave new impetus to stress research. Several new concepts of stress have developed as a result of advances in bench research. These include the concept of an integrated "stress sys­ tem", the realization that there are bi-directional effects between stress and the immune system, the suggestion that a number of common psychiatric disorders represent dysregulation of systems responding to stress, and the epidemiologic association of stress with the major scourges of humanity.
Article
Administration of lipopolysaccharide (LPS) results in activation of the hypothalamic-pituitary-adrenal axis. LPS induces the release of a number of proinflammatory cytokines, i.e. interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF), which activate the hypothalamic-pituitary-adrenal axis as well and may mediate the effects of LPS. Variations in the kinetics of appearance of IL-1, TNF, and IL-6 after LPS challenge suggested that these cytokines may play different roles at different times. To elucidate the mutual dependence and contribution of individual cytokines in the course of LPS-induced ACTH release, we used blocking antibodies to IL-6, TNF, and the IL-1 receptor. Our results demonstrate that anti-IL-6 antibody abrogated ACTH induction throughout the course of the response both 2 and 4 h after LPS challenge. In contrast, anti-IL-1 receptor and anti-TNF antibody, given individually, blocked ACTH production at 4 h, but not at 2 h. Only combined administration of these two antibodies diminished, but did not eliminate, ACTH release at 2 h. This is the first demonstration that all three inflammatory cytokines are obligatory for LPS-induced elevation of plasma ACTH. In addition, these results suggest that IL-1, IL-6, and TNF play different roles in LPS-induced ACTH release.
Article
This review examines the central actions exerted by corticosteroids that are mediated by mineralocorticoid receptors (MRs or Type 1) and glucocorticoid receptocs (GRs or Type 2) in the brain. The leitmotiv is that these MR- and GR-mediated effects of the steroid hormones are of critical importance for homeostatic control. MRs have aldosterone (ALDO)-selective properties in some nerve cells and apparent corticosterone (B)-selective properties in others, notably the limbic neurons. Compartmentalization of the MR subtypes hinges on activity of 11β-hydroxysteroid dehydrogenase and corticosteroid-binding globulin. B also binds to GRs, but with 10-fold lower affinity. GR density is high in brain regions involved in organization of the stress response. GR-mediated corticosteroid effects inhibit stress-induced pituitary proopiomelanocortin and hypothalamic corticotropin-releasing hormone and vasopressin synthesis, but facilitate activation and sensitization of ascending aminergic neurons. In hippocampal CA1 neurons, co-localized MRs and GRs coordinately and differentially mediate corticosteroid control of ion regulation and transmitter responsiveness. MRs are involved in maintenance of excitability, while GRs suppress excitability, which is transiently raised by excitatory transmitters. At the neuroendocrine level, B sets the threshold for the stress response system via binding to MRs. Blockade of MRs enhances basal and stress-induced hypothalamo-pituitary-adrenal (HPA) activity. Stress- and circadian-induced episodic occupancy by B of GRs in hippocampus attenuates MR-mediated limbic inhibition. In hypothalamus, B blocks via binding to GRs the communication of the HPA axis. At the behavioral level, the ALDO-selective MRs mediate specific effects on salt hunger and functions associated with sodium homeostasis such as central cardiovascular control. Limbic MRs seem primarily concerned with B effects on information handling and the organization of behavioral strategies. GRs mediate steroid effects on fear- and food-motivated behavior and information storage. GR-mediated effects on behavior may persist for weeks in adulthood and appear permanent during development. High glucocorticoids decrease hippocampal GR and increase MR capacity, while mineralocorticoids down-regulate both receptor types. Animals with an increased relative amount of limbic MRs over GRs show reduced emotional and adrenocortical reactivity and a decreased ability to organize behavior with the help of external stimuli. Deviations of an idiosyncratic MR/GR balance are proposed to alter individual-specific susceptibility to stress and © 1991 Raven Press perhaps to stress-related brain diseases. The findings place Selye's "pendulum hypothesis" on mineralocorticoid and glucocorticoid action in the perspective of co-localized MRs and GRs mediating coordinate and differential effects of B on regulation of cellular homeostasis and behavioral adaptation.
Article
The molecular and biochemical bases for interactions between the immune and central nervous systems are described. Immune cytokines not only activate immune function but also recruit central stress-responsive neurotransmitter systems in the modulation of the immune response and in the activation of behaviors that may be adaptive during injury or inflammation. Peripherally generated cytokines, such as interleukin-1, signal hypothalamic corticotropin-releasing hormone (CRH) neurons to activate pituitary-adrenal counter-regulation of inflammation through the potent antiinflammatory effects of glucocorticoids. Corticotropin-releasing hormone not only activates the pituitary-adrenal axis but also sets in motion a coordinated series of behavioral and physiologic responses, suggesting that the central nervous system may coordinate both behavioral and immunologic adaptation during stressful situations. The pathophysiologic perturbation of this feedback loop, through various mechanisms, results in the development of inflammatory syndromes, such as rheumatoid arthritis, and behavioral syndromes, such as depression. Thus, diseases characterized by both inflammatory and emotional disturbances may derive from common alterations in specific central nervous system pathways (for example, the CRH system). In addition, disruptions of this communication by genetic, infectious, toxic, or pharmacologic means can influence the susceptibility to disorders associated with both behavioral and inflammatory components and potentially alter their natural history. These concepts suggest that neuropharmacologic agents that stimulate hypothalamic CRH might potentially be adjunctive therapy for illnesses traditionally viewed as inflammatory or autoimmune.
Article
The premise that effects of maturational timing are mediated by social context is explored by comparing adolescent girls in dance and nondance schools. Because the dance student must maintain a relatively low body weight, being a late maturer (who is often leaner than an on-time maturer) is expected to be more advantageous to the dancer than to the student not required to meet a weight standard. Girls aged 14 to 18 were seen; 276 attended private schools and 69 attended national ballet company schools. AllSs were weighed and measured and asked questions about their secondary sexual development, weight-related concerns, eating concerns, adult sex-role expectancies, body image, emotional functioning, and family relationships. Menarcheal age was used to classify girls as early (before 11.5 years of age), on time (between 11.5 and 14 years), and late maturers (after 14 years). More dance than non-dance school students were late maturers (55% versus 29%). The dance students weighed less and were leaner, had higher eating scores, and had lower family relationship and impulse control scores than the comparison sample. Across groups, late maturing students weighed less, were leaner, and had lower diet and higher oral control scores than on-time maturers, with the differences more pronounced in the dance than nondance students. In addition, the on-time dancers had higher psychopathology, perfection, and bulimia scores and lower body image scores than the late maturing dancers. The findings are discussed in terms of a goodness of fit between the requirements of a social context and a person's physical and behavioral characteristics.
Article
This paper presents data suggesting that insights regarding adolescent depressive phenomena in humans can be provided through systematic studies of nonhuman primates such as rhesus monkeys. First, species-normative patterns of social changes that emerge as rhesus monkeys pass through puberty are described. Next, developmental changes in depressive-like behavioral and physiological response to separation shown by monkeys as they become adolescents are outlined. Issues of developmental continuity and risk factors for depressive symptomology are then discussed. Finally, the issue of sex differences that emerge in adolescence will be considered.
Article
To study the pathophysiology of hypercortisolism in patients with anorexia nervosa, we examined plasma ACTH and cortisol responses to ovine corticotropin-releasing hormone before and after correction of weight loss. We also studied patients with bulimia whose weight was normal, since this disorder has been suspected to be a variant of anorexia nervosa. Before their weight loss was corrected, the anorexic patients had marked hypercortisolism but normal basal plasma ACTH. The hypercortisolism was associated with a marked reduction in the plasma ACTH response to corticotropin-releasing hormone. When these patients were studied three to four weeks after their body weight had been restored to normal, the hypercortisolism had resolved but the abnormal response to corticotropin-releasing hormone remained unchanged. On the other hand, at least six months after correction of weight loss their responses were normal. The bulimic patients whose weight was normal also had a normal response to corticotropin-releasing hormone. We conclude that in underweight anorexics, the pituitary responds appropriately to corticotropin-releasing hormone, being restrained in its response by the elevated levels of cortisol. This suggests that hypercortisolism in anorexics reflects a defect at or above the hypothalamus. The return to eucortisolism soon after correction of the weight loss indicates resolution of this central defect despite persistence of abnormalities in adrenal function.
Article
Rats were reared during the first 3 weeks of life in a group or singly, with the mother rat or in an incubator with no maternal contact. Variations in early experience were assessed in terms of adrenal steroid functioning when the animals were 1-yr old. Whether they were reared in a group or individually, incubator-reared animals were found to have significantly higher basal and stress levels of plasma corticosterone. In addition, their corticosterone response to stress was greater regardless of initial levels.
Article
Corticotropin-releasing hormone (CRH) has been considered a major coordinator of the overall physical and behavioral response to stress. Moreover, prolonged hypersecretion of CRH has been implicated in the pathogenesis of disorders characterized by anxiety and/or depression. Drugs acting through the gamma-aminobutyric acid/benzodiazepine (GABA/BZD) receptor system have anxiolytic and/or antidepressant properties whereas benzodiazepine inverse agonists cause anxiety and stimulate the pituitary-adrenal axis in vivo. To examine the involvement of the GABA/BZD system in the regulation of hypothalamic CRH secretion, we studied the effects of various agonists and antagonists of GABAA and GABAB receptors using a sensitive rat hypothalamic organ culture with radioimmunoassayable CRH (IR-rCRH) as endpoint. The GABAA and GABAB receptor agonist GABA inhibited serotonin (5-HT)-induced IR-rCRH secretion from 10(-9) to 10(-6) M, but failed to do so at 10(-5) M. The GABAA receptor agonist muscimol was a weak inhibitor of 5-HT-induced IR-rCRH secretion, being effective only at the concentration of 10(-6) M. In contrast, the specific GABAB receptor agonist baclofen was able to inhibit 5-HT-induced IR-rCRH secretion from 10(-7) to 10(-5) M. The rank of potency was thus, GABA much greater than baclofen greater than muscimol. Bicuculline, a GABAA receptor antagonist, partially reversed the inhibitory effects of GABA. Diazepam, a classic benzodiazepine which interacts with the benzodiazepine-site of the GABAA receptor complex, inhibited 5-HT-induced IR-rCRH secretion from 3.3 X 10(-9) to 10(-5) M, an effect that could be reversed by the BZD inactive ligand Ro15-1788.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
We compared the baseline cortisol secretory pattern and ACTH and cortisol responses to hCRH (100 μg) in eight patients acutely withdrawn from ethanol and 12 patients who abstained from ethanol for two to six weeks. Acute withdrawal from ethanol was characterized by elevated baseline cortisol and blunted ACTH release after hCRH, while medium-term abstention was associated with normalized cortisol secretion but persistence of decreased ACTH output following stimulation. These findings support an altered corticotrophic CRH receptor function in detoxified sober alcoholics. The pathophysiology underlying the blunted ACTH response to hCRH in medium-term ethanol abstention appears to be different from that in acute alcohol withdrawal and hypercortisolemic depression.
Article
Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
Article
We investigated the neurotransmitter regulation of corticotropin-releasing hormone (CRH). Among 21 depressed patients cerebrospinal fluid (CSF) levels of CRH significantly correlated with urinary outputs of norepinephrine and its major metabolites, and there were trends for significant correlations with both CSF and plasma levels of norepinephrine. These results suggest that CRH may be associated with the dysregulation of the norepinephrine system that is found in desperation.
Article
Thirty-two dwarfed children and adolescents were studied clinically, by laboratory assessment, by a battery of psychological tests and a structured interview. Growth hormone deficiency was present in 16 cases, but in the remaining 16 cases there was no endocrine disease. Dwarfed children differed from nornal controls in perception, and a specific personality pattern emerged in the dwarfed children. The effects of age, sex, and socioeconomic status on personality traits were similar for dwarfs as for controls. Intelligence and personality variable were similar in dwarfs with and without endocrine disease. However, symptoms of the psychoendocrine syndrome, namely appetite and thirst disturbances, hypersensitivities, and impulse reduction, were more frequently seen among hypopituitary dwarfs. Social and coping behaviour was impaired in the majority of dwarfs. It is concluded that psychological disturbance occuring inchildren of small stature is a response to being small and is not attributable to any endocrine effect.
Article
We now have substantial evidence demonstrating noradrenergic sympathetic and peptidergic innervation of both primary and secondary lymphoid organs. We have established criteria for norepinephrine, and some of the neuropeptides, as neurotransmitters, and have found changes in immune responsiveness following pharmacological manipulation of noradrenergic sympathetic or peptidergic nerves. Classic receptor binding studies have demonstrated a wide variety of target cells that possess beta-adrenoceptors and receptors for neuropeptides on cells of the immune system, including lymphocyte subsets, macrophages, accessory cells, or stromal elements. In this chapter we describe noradrenergic and peptidergic innervation of primary and secondary lymphoid organs in development, at maturation and during the normal aging process, and discuss possible functional implications of direct neural signals onto cells of the immune system at critical time points in the lifespan of an animal. Further, we examine for involvement of noradrenergic sympathetic and peptidergic innervation in the development and progression of several autoimmune disorders, including adjuvant-induced arthritis, New Zealand mice strains as a model for hemolytic anemia and lupus-like syndrome, and the experimental allergic encephalomyelitis model for multiple sclerosis.
Article
The molecular and biochemical bases for interactions between the immune and central nervous systems are described. Immune cytokines not only activate immune function but also recruit central stress-responsive neurotransmitter systems in the modulation of the immune response and in the activation of behaviors that may be adaptive during injury or inflammation. Peripherally generated cytokines, such as interleukin-1, signal hypothalamic corticotropin-releasing hormone (CRH) neurons to activate pituitary-adrenal counter-regulation of inflammation through the potent antiinflammatory effects of glucocorticoids. Corticotropin-releasing hormone not only activates the pituitary-adrenal axis but also sets in motion a coordinated series of behavioral and physiologic responses, suggesting that the central nervous system may coordinate both behavioral and immunologic adaptation during stressful situations. The pathophysiologic perturbation of this feedback loop, through various mechanisms, results in the development of inflammatory syndromes, such as rheumatoid arthritis, and behavioral syndromes, such as depression. Thus, diseases characterized by both inflammatory and emotional disturbances may derive from common alterations in specific central nervous system pathways (for example, the CRH system). In addition, disruptions of this communication by genetic, infectious, toxic, or pharmacologic means can influence the susceptibility to disorders associated with both behavioral and inflammatory components and potentially alter their natural history. These concepts suggest that neuropharmacologic agents that stimulate hypothalamic CRH might potentially be adjunctive therapy for illnesses traditionally viewed as inflammatory or autoimmune.
Article
To determine the integrity of the hypothalamic-pituitary-adrenal (HPA) axis responses to immune/inflammatory stimuli in patients with rheumatoid arthritis (RA). Diurnal secretion of cortisol and the cytokine and cortisol responses to surgery were studied in subjects with active RA, in subjects with chronic osteomyelitis (OM), and in subjects with noninflammatory arthritis, who served as controls. Patients with RA had a defective HPA response, as evidenced by a diurnal cortisol rhythm of secretion which was at the lower limit of normal in contrast to those with OM, and a failure to increase cortisol secretion following surgery, despite high levels of interleukin-1 beta (IL-1 beta) and IL-6. The corticotropin-releasing hormone stimulation test in the RA patients showed normal results, thus suggesting a hypothalamic defect, but normal pituitary and adrenal function. These findings suggest that RA patients have an abnormality of the HPA axis response to immune/inflammatory stimuli which may reside in the hypothalamus. This hypothalamic abnormality may be an additional, and hitherto unrecognized, factor in the pathogenesis of RA.
Article
This article is an up-to-date review of the impact that the discovery of corticotropin-releasing hormone (CRH) has had on basic science and clinical medicine. It discusses hypothalamic CRH, placental CRH, immune CRH, and hypothalamic and immune CRH. Clinical studies in normal and disease states and synthesis and future directions also are presented.
Article
Both endogenous and exogenous glucocorticoid excess are well established as causes of osteoporosis. However, there are few data describing bone mineral density in these subjects following the restoration of normal steroid levels. The present study addresses this issue. A cross-sectional assessment of bone mineral density in patients cured of Cushing's syndrome, and comparison of each with four normal subjects matched by age, sex, weight, menopausal status and race, was used. Seventeen adults cured of Cushing's syndrome 8.6 +/- 1.6 years (mean +/- SEM) took part. The bone mineral density of the lumbar spine and proximal femur was measured by dual energy X-ray absorptiometry. Bone mineral densities, relative to control, were 100 +/- 16, 98 +/- 14, 97 +/- 19 and 98 +/- 16% (mean +/- SD), in the lumbar spine, femoral neck, Ward's triangle and trochanteric regions, respectively. There was a positive relationship between bone density and time since cure (r = 0.24-0.59, in the four regions). In contrast, bone density was significantly reduced in five subjects with active Cushing's disease when similarly matched (BMD = 87 +/- 4, 83 +/- 4, 75 +/- 6 and 82 +/- 6%, in the respective regions; 0.01 less than P less than 0.05). Bone density is reduced in subjects with Cushing's syndrome but not in those having undergone cure some years previously. This implies that steroid-induced osteoporosis is substantially reversible, though long-term prospective studies will be necessary to establish this definitively.
Article
Urinary cortisol output and serum cortisol concentrations were measured in the steady state, under "field" conditions, and during standardized inhibitory and stimulatory tests in premenopausal, obese women, and were analyzed in relation to adipose tissue distribution. Urinary cortisol output was increased under field conditions in women with an elevated waist to hip circumference ratio (WHR) and, in particular, in women with a large abdominal sagittal diameter, indicating visceral fat accumulation. However, dexamethasone inhibition of cortisol secretion was normal. Stimulation with corticotropin analogue and with physical (cold-pressor test) or mental (color-word or mathematic) stress tests also showed elevated responses of serum cortisol, but not of prolactin or growth hormone concentrations. It is suggested that women with visceral fat accumulation have elevated cortisol secretion due to an increased sensitivity along the hypothalamic-pituitary-adrenal axis, and that this may be causing their abnormal fat depot distribution.
Article
CRH has been shown to produce increased locomotion, arousal, and anorexia in experimental animals. A deficiency of CRH in patients with seasonal affective disorder could contribute to the characteristic lethargy, hypersomnia, and hyperphagia characteristic of this illness. To test this hypothesis, we studied basal plasma ACTH and cortisol levels and their responses to ovine CRH in controls and depressed patients with seasonal affective disorder before and after light treatment. Untreated seasonal affective disorder patients showed normal basal plasma cortisol and ACTH levels, but their responses to CRH tended to be delayed and were significantly reduced. When patients were studied after 9 days of light treatment, a significant increase in plasma ACTH and cortisol responses to CRH was observed. Our findings in untreated patients with seasonal affective disorder are similar to those in patients with Cushing's disease 2 weeks after transsphenoidal hypophysectomy, who uniformly show sustained suppression of their CRH neuron because of long-standing hypercortisolism. This findings suggest that the CRH neuron of patients with seasonal affective disorder is hypofunctional. We postulate that the clinical symptomatology in patients with seasonal affective disorder could reflect deficient activity of this important arousal-producing system.
Article
It was hypothesized that symptoms in functional dyspepsia are originated by an altered mechanism at the brain-gut axis (one or several) in the process of gastric accommodation to a meal. To test the key mechanisms potentially involved in symptomatic gastric accommodation, the sensorial responses (on a 0-10 perception score) and the gastric tone responses (by electronic barostat) to either gastric accommodation (n = 10) or to cold stress (n = 10) were measured in 20 patients with functional dyspepsia and 20 healthy controls. The mechanical accommodation of the stomach to gastric distention (compliance) was similar in patients (52 +/- 8 mL/mm Hg) and controls (57 +/- 6 mL/mm Hg). However, isobaric gastric distention elicited more upper abdominal discomfort in dyspeptics than in controls (perception scores, 4.7 +/- 0.9 vs. 1.1 +/- 0.5, respectively; mean +/- SE; P less than 0.005). Cold stress induced a similar gastric relaxatory response in dyspeptics and controls (delta vol, 145 mL +/- 40 mL vs. 141 mL +/- 42 mL, respectively); hand perception (scores, 8.3 +/- 0.4 vs. 7.9 +/- 0.4, respectively) and autonomic responses were also similar. It is concluded that an abnormal afferent sensorial pathway (altered gastric perception) may be a major mechanism of symptom production in functional dyspepsia.
Article
The impact of chronic alcohol abuse on the hypothalamic-pituitary-adrenal (HPA) axis was investigated in actively drinking, nondepressed alcoholics with no evidence of liver disease. Fourteen male alcoholics and 13 matched nonalcoholics were studied. Although alcoholics and controls had similar decrements in cortisol levels after metyrapone blockade, plasma ACTH and 11-deoxycortisol levels in alcoholics were 60% (P < 0.05) and 40% (P < 0.05), respectively, of control values. To further clarify defects in the HPA axis of the alcoholic group, each subject underwent a CRH stimulation test. Compared to control subjects, alcoholics had a significantly blunted plasma ACTH response to CRH stimulation (P < 0.05). Timing of the peak plasma ACTH response was altered in alcoholics. Whereas all control subjects had a peak plasma ACTH response 30 min after CRH administration, 50% of alcoholics demonstrated a peak plasma ACTH response 60 min after CRH administration, and 50% demonstrated a peak plasma ACTH response 30 min after CRH. To determine if adrenal function was also impaired, alcoholics and controls underwent a standard (250 μg) and a submaximal (0.250 μg) Cortrosyn stimulation test. Controls demonstrated a significant cortisol response to both standard and low dose Cortrosyn. Although alcoholics had a cortisol response similar to that of controls after the standard dose of Cortrosyn, they did not have a statistically significant rise in cortisol after the submaximal dose of Cortrosyn. Twentyfour-hour urinary free cortisol levels were 2-fold higher in alcoholics compared to controls. In summary, although a subset of alcoholics demonstrated enhanced basal production of cortisol, most alcoholics had a blunted response to acute intervening stress, including CRH, low dose ACTH-(1-24), and metyrapone blockade. These data suggest that alcoholics have ethanol-induced HPA axis injury, resulting in an inappropriately reduced response to nonethanol-induced stress.