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Tsigos C, Chrousos GPHypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 53:865-871
Abstract
The stress system coordinates the adaptive responses of the organism to stressors of any kind.(1). The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-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. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and beta-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5' deiodinase, which converts the relatively inactive tetraiodothyronine (T(4)) to triiodothyronine (T(3)), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing "low turnover" osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.
... The slower response to stress is mediated by the activation of the HPA axis. The HPA axis organizes the body's response to stress, comprising three key endocrine formations: the hypothalamus, pituitary (hypophysis), and adrenal glands (Tsigos & Chrousos, 2002;McCormick et al., 2010). Among these, only the adrenal glands possess a strictly endocrine structure. ...
... Among these, only the adrenal glands possess a strictly endocrine structure. The hypothalamus manages the secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary by releasing corticotrophin-releasing hormone/factor (CRH or CRF) (Vale et al., 1981;Tsigos & Chrousos, 2002). In other words, the process of stress response begins with the release of CRH from the paraventricular nucleus of the hypothalamus into the circulation. ...
... Acting as an enhancer, arginine-vasopressin (AVP) amplifies the stimulatory effect of CRH on ACTH secretion, although its individual impact is modest, suggesting a cooperative regulation with CRH (Tsigos & Chrousos, 2002). CRH and AVP, released from neurons within the parvicellular nuclei of the hypothalamus, cross axons to the median eminence, where they are released into the hypophyseal portal system's first capillary network (Sawchenko, 1987). ...
Stress, an inevitable aspect of human existence, triggers complex physiological and behavioral responses aimed at maintaining internal equilibrium. It requires a multifaceted understanding encompassing its physiological, pathophysiological, and behavioral dimensions to inform effective treatment approaches. This narrative literature review attempts to understand the evolution of research on stress, from its historical roots to current physiological, pathophysiological, and conceptual understandings. Pathophysiological consequences of chronic stress, including cardiovascular disease and immune system dysregulation, highlight the need for comprehensive prevention and intervention strategies. The results demonstrate the importance of adopting a holistic approach to stress management, combining pharmacological interventions with psychological therapies such as cognitive-behavioral therapy and other third-wave approaches. For chronic stress, long-term strategies focusing on lifestyle modifications, social support, and coping skills enhancement are recommended, whereas acute stress may benefit from immediate pharmacological interventions to mitigate physiological arousal and promote relaxation. The review results also indicate the significance of the biopsychosocial framework in understanding stress by acknowledging its multifaceted nature, emphasizing the effectiveness and sustainability of diverse intervention strategies, and highlighting the role of societal factors in shaping stress experiences and treatment outcomes. Further research is warranted to clarify the mechanisms underlying stress responses and refine intervention strategies for optimal efficacy and sustainability.
... CRH stimulates adreno-corticotropic hormone (ACTH) release, which in turn causes cortisol levels to rise. Cortisol exerts negative feedback on the HPA axis, thereby inhibiting the HPA axis activation (Tsigos and Chrousos 2002). ...
... Sustained high cortisol levels result in HPA axis dysfunction, eventually causing cortisol depletion, resistance to GC receptors, or hypersensitivity of the negative feedback system to cortisol (Hannibal and Bishop 2014). Studies in Chronic fatigue syndorme (CFS) have shown that HPA axis dysregulation makes susceptible individuals hypersensitive to life stressors and physical activity, leading to CFS (Tsigos and Chrousos 2002). A similar pathogenesis may exist in LC (Mackay 2021). ...
... We aimed to investigate whether GC treatment during COVID-19 infection would influence the later development of LC. On the one hand, GC treatment during COVID-19 infection may suppress the pathological activation and imbalance of the HPA axis by providing negative feedback on CRH and ACTH release (Tsigos and Chrousos 2002), potentially inhibiting neuroinflammation. On the other hand, steoroid treatment during COVID may contribute to a hypercortisol state, which could later lead to HPA axis dysfunction, cortisol hyporeactivity, and LC (Hannibal and Bishop 2014). ...
Background
Long COVID (LC) is a frequent complication of COVID infection. It usually results in cognitive impairment, myalgia, headache and fatigue. No effective treatment has been found yet. We aimed to explore the effect of glucocorticoid (GC) treatment during COVID-19 infection on the later development of LC.
Methods
We examined electronic health records from Clalit Health Services for documentation of COVID-19, GC treatment, and LC frequency. Background diagnoses, demographic data, hospitalization rates, and the use of anti-COVID drugs were recorded.
Results
1,322,599 cases of COVID-19 infection met the inclusion criteria; 13,530 patients (1.02%) received GC treatment. 149,272 patients, 11.29% of COVID-19 patients were diagnosed with LC. Age and female gender were prognostic risk factors for LC (OR 1.06 for age, OR 1.4 for female gender; p value < 0.0001). Background psychiatric diagnoses, migraine, backache and irritable bowel syndrome were predisposing conditions for LC (OR 2.7, p value < .0001). Higher BMI was associated with a greater probability of LC (OR of 1.25 for obese population).
COVID patients who received GC were diagnosed with LC more frequently: 2294 cases (16.95%) compared to 146,978 cases (11.23%) in the non-GC group; (adjusted OR of 1.28 ± 0.07, 95% CI, p < 0.0001).
Conclusions
GC treatment during COVID-19 is correlated with the development of LC. In vivo and animal models may be used to explore the mechanism of this correlation. Future directions include prospective studies as well.
... Acute and chronic stress affects adult neurogenesis and activates a complex interplay of neural and endocrine mechanisms (Chu et al., 2021;Egeland et al., 2015). Glucocorticoids (GCs), as a key part of the body's stress response system, and brain-derived neurotrophic factor (BDNF), with its multiple roles in the nervous system, influence adult neurogenesis through their dynamic interactions in the context of acute and chronic stress (Miranda et al., 2019;Tsigos and Chrousos, 2002). ...
... The HPA-axis regulates the acute and chronic stress response through the secretion of glucocorticoids, the most important of which is cortisol (Tsigos and Chrousos, 2002). While it is well established that BDNF and cortisol levels increase in response to acute stress (Miranda et al., 2019), how they interact under acute stress is less clear. ...
... Yet, as the stress response concludes, GC signaling could suppress BDNF. One possible explanation might be that this pattern suggests an adaptive mechanism: an initial boost in BDNF could enhance cognitive function and neural plasticity during stress, while its subsequent suppression by GC signaling may help conserve energy and return the system to a baseline state once the stressor has passed (Egeland et al., 2015;Suri and Vaidya, 2013;Tsigos and Chrousos, 2002). By conserving energy and reducing metabolic demands, this mechanism might protect the organism from the harmful effects of prolonged stress, thus balancing the need for immediate cognitive enhancement with long-term homeostasis. ...
... Chronic exposure to stress, including social defeat and immobilization, triggers the release of adrenal hormones like noradrenaline, adrenaline, and glucocorticoids, as well as proinflammatory cytokines like TNF-α and IL-6, leading to depression and anxiety (DA) [1,2]. Stress-induced DA fluctuates the release of serotonin (5-HT) and γ-aminobutyric acid (GABA) from enterochromaffin and neural cells [3,4]. ...
... We found that IS exposure and cFM transplantation increased DA-and sleep disturbancelike behaviors in mice, suppressing GABA and serotonin levels and inducing TNF-α levels and NF-κB-positive cell populations in the brain. Stress-induced DA triggers sleep disturbance, including insomnia and systemic inflammation [1,25,26]. Systemic inflammation including gut inflammation induces DA [27,28]. Depression has been suggested to be closely associated with reduced serotonin and GABA concentrations and increased TNF-α concentrations, which suppresses the release of serotonin and GABA, although there are many conflicting results [29][30][31]. ...
Insomnia (sleeplessness) is a potential symptom of stress-induced depression/anxiety (DA), which induces TNF-α expression. Therefore, this study aimed to examine the effect of Lactobacillus (Lactiplantibacillus) plantarum P72, isolated as a strain suppressing lipopolysaccharide-induced expression of TNF-α in Caco2 cells, on DA and insomnia in immobilization stress (IS)- or cultured fecal microbiota (cFM)-treated mice. Oral administration of live or heat-killed P72 (hP72) reduced IS- or cFM-induced DA-like behaviors. They also reduced sleep latency time (SLT) and enhanced sleep duration (SLD). Additionally, P72 upregulated γ-aminobutyric acid (GABA), GABAA receptor α1, serotonin, and 5-HT1A receptor expression, which were downregulated by IS or cFM. Hempseed oil (HO) alone was ineffective against IS-induced DA- and insomnia-like behaviors, but its combination with P72 (PH) or hP72 (hPH) showed enhanced efficacy, reducing DA- and insomnia-like behaviors more strongly than P72 or HO alone. These also reduced the number of NF-κB-positive cells and the expression of TNF-α in the prefrontal cortex and colon. These results imply that P72 and its combination with HO can alleviate DA and insomnia by upregulating serotonergic and GABAergic systems through the suppression of NF-κB signaling.
... Disturbances in the NE system may impact multiple aspects of fracture healing, including local inflammatory responses, cell proliferation and differentiation, and angiogenesis at the fracture site. For example, NE may interfere with the normal functional coordination between osteoblasts and osteoclasts at the fracture site, impeding the formation and remodeling of bone callus, thereby causing delayed fracture healing [89][90][91]. ...
Parkinson’s disease (PD), as a widespread neurodegenerative disorder, significantly impacts patients’ quality of life. Its primary symptoms include motor disturbances, tremor, muscle stiffness, and balance disorders. In recent years, with the advancement of research, the concept of the bone–brain axis has gradually become a focal point in the field of PD research. The bone–brain axis refers to the interactions and connections between the skeletal system and the central nervous system (CNS), playing a crucial role in the pathogenesis and pathological processes of PD. The purpose of this review is to comprehensively and deeply explore the bone–brain axis in PD, covering various aspects such as the complex relationship between bone metabolism and PD, the key roles of neurotransmitters and hormones in the bone–brain axis, the role of inflammation and immunity, microRNA (miRNA) functional regulation, and potential therapeutic strategies. Through a comprehensive analysis and in-depth discussion of numerous research findings, this review aims to provide a solid theoretical foundation for a deeper understanding of the pathogenesis of PD and to offer strong support for the development of new treatment methods.
... In vertebrates, ACTH plays an important role in stress responses and physiological activities such as steroid hormone biosynthesis and adrenal development [3,4]. Specifically, CRHBP influences the hypothalamus-pituitary-adrenal (HPA) axis, which binds to corticotropin release hormone (CRH) and regulates its bioavailability, including neuroendocrine, autonomous, and behavioral adaptations to stress [5][6][7] . CRHBP may function physiologically or metabolically, such as in the genetic variation in antenatal corticosteroid (ACS) metabolism in cases of small for gestational age (SGA) and in the regulation of biological activities by binding to the corticotropin-releasing hormone (CRH) complex [8,9]. ...
Background
The corticotropin-releasing hormone-binding protein (CRHBP) plays a crucial role in regulating corticotropin release. Little is known about the role of CRHBP, a major regulator of neuroendocrine, autonomic, and stress adaptation, in tumors. In this study, we aimed to investigate the clinical and molecular landscapes of CRHBP in various types of tumors.
Methods
We investigated the role of CRHBP in different types of tumors using publicly available databases and performed a comparative expression analysis of CRHBP-related genes in pan-cancer prognosis using methylation profiling, tumor-infiltrating immune cell expression analysis, gene enrichment analysis, and protein-protein interaction analysis, identified common pathways, and in vitro evaluation.
Results
We evaluated CRHBP expression across tumor and corresponding normal tissues using the data from The Cancer Genome Atlas and the Genotype-Tissue Expression database. CRHBP was downregulated in most tumors and was identified as an important factor for predicting the prognosis of patients with cancer. Intracellular metabolic pathways and hormone-related processes were involved in the functional mechanisms of CRHBP. Mechanistically, the downregulation of CRHBP was attributed to the upregulation of four miRNAs in most tumors, and CRHBP expression was related to tumor-infiltrating immune cells in tumors. Overexpression of CRHBP significantly inhibited cell proliferation of LUAD, LIHC, and KIRC cell lines, while inhibition of cell mobility was found only in KIRC and HCC cells.
Conclusions
This study provides a comprehensive summary of the systemic role of CRHBP expression in various types of tumors, highlighting the prognostic importance and clinical significance of tumors. Furthermore, CRHBP decreases cell proliferation and mobility in cancer cell lines associated with OS and DFS, further research is needed to understand the underlying mechanisms and explore clinical applications.
... Many researchers have suggested that the abnormal responses of fish to underwater noise stimulation may be a physiological stress response [26,27]. The main regulatory axes that produce feedback to stress stimuli are the HPA (hypothalamic-pituitary-adrenal) axis and the SNS (sympathetic nervous system) [28,29], both important components of the central nervous system (CNS). ...
The problem of marine noise pollution has a long history. Strong noise (>120 dB re 1 µPa) will affects the growth, development, physiological responses, and behaviors of fish, and also can induce the stress response, posing a mortal threat. Although many studies have reported that underwater noise may affect the survival of fish by disturbing their nervous system and endocrine system, the underlying causes of death due to noise stimulation remain unknown. Therefore, in this study, we used the underwater noise stress models to conduct underwater strong noise (50–125 dB re 1 µPa, 10–22,000 Hz) stress experiments on small yellow croaker for 10 min (short-term noise stress) and 6 days (long-term noise stress). A total of 150 fishes (body weight: 40–60 g; body length: 12–14 cm) were used in this study. Omics (metabolomics and transcriptomics) studies and quantitative analyses of important genes (HPA (hypothalamic–pituitary–adrenal)-axis functional genes) were performed to reveal genetic and metabolic changes in the important tissues associated with the HPA axis (brain, heart, and adrenal gland). Finally, we found that the strong noise pollution can significantly interfere with the expression of HPA-axis functional genes (including corticotropin releasing hormone (CRH), corticotropin releasing hormone receptor 2 (CRHR2), and arginine vasotocin (AVT)), and long-term stimulation can further induce metabolic disorders of the functional tissues (brain, heart, and adrenal gland), posing a lethal threat. Meanwhile, we also found that there were two kinds of death processes, direct death and chronic death, and both were closely related to the duration of stimulation and the regulation of the HPA axis.
... Furthermore, a Y1R agonist showed superior effects in preventing the development of stress-induced depressive-like behaviours compared to NPY (Nwokafor et al. 2019a). The hypothalamic-pituitary-adrenal axis is involved in the stress response with a concomitant increase in plasma corticoids (Tsigos and Chrousos 2002). Significant changes in corticosterone levels have been found following antidepressant treatment after 21 days of chronic stress (Kokras et al. 2021). ...
Depression is responsible for neuropathies such as decreased neurogenesis and increased dendritic atrophy. There is information that antidepressant treatments have an effect by increasing hippocampal neurogenesis and neurotrophic factor expression. The neuropeptide Y1 (NPY1R) receptor agonist has been suggested to have anxiolytic effects. Based on this information, it was aimed to investigate the effect of NPY1R agonist on depression in rats with depression using the CMS model and to determine how depression affects cell proliferation in the hypothalamus and hypothalamic peptide levels. Forty-eight adult, male Wistar albino rats were divided into groups as Control, Depression (D), Depression + NPY1R and NPY1R. Various stressors were applied to D for 30 days. An open field test (OFT) and forced swim test (FST) were performed to check whether the animals were depressed. On the 16th day, an osmotic mini pump was placed under the skin and NPY1R (130 ul/kg/day) was applied for 15 days. Behavioral tests were performed, hypothalamic peptide gene expression levels were analyzed by quantitative RT-PCR and statistical evaluations were made using ANOVA. A decrease in the percentage of movement in the D and control groups were noted in the OFT, an increase in the immobility time in the D group in the FST, and an increase in swimming behavior in the DNPY1R group. The animals did not display any anxiety behavior based on the elevated plus maze test results. It caused a decrease in IGF1R, FGF2, POMC, NPY and GLUT2 gene expression in the hypothalamus of depression group animals, and an increase in NPY gene expression in NPY1R treatment. This study compellingly demonstrated that exposure to chronic mild stress simultaneously downregulates gene expression in the hypothalamus; we observed that NPY receptor NPY1R treatment increased the effect of NPY. Therefore, adjunctive treatments with appropriate molecules such as NPY, Y1 receptor agonists or pharmacological derivatives may have significant potential in the treatment of depression.
... A sufficiently strong and short-lasting negative stimulus activates the HPA axis [17,18], which translates into a release of glucocorticoids and mobilizes the body to the appropriate behavioral and physiological response, which is aimed at restoring the body to a state of complete balance [19][20][21]. The animal's body's response to stress leads to increased attention, cardiac minute capacity, resorption, and catabolism [22]. A commonly used indicator of stress response intensity is cortisol (CORT) [4,5,23]. ...
Roe deer (Capreolus capreolus), as a representative of the Cervidae family, are particularly sensitive to negative environmental stimuli due to their need to maintain increased vigilance during feeding. Intensive hunting seasons are undoubtedly also a stressful factor for this species. The aim of this study was to analyze the cortisol levels in the hair of male roe deer collected at the beginning and the end of the hunting season in eastern Poland. In total, hair samples from 26 individuals collected in May and 31 individuals collected in September were analyzed. The concentration of cortisol in the hair was determined using the EIA kit. It was shown that the concentration of cortisol was significantly higher in samples collected in September compared to those collected in May (Pr. > |t| = 0.0017). Moreover, the age of animals and carcass mass did not significantly affect the concentration of the tested hormone. In summary, the concentration of cortisol in the fur of male roe deer depended on the season and was not influenced by the carcass mass or age of the animals studied.
... First, systemic inflammation activates the hypothalamic-pituitary-adrenal (HPA) axis (Murray et al., 2013) and triggers stress responses, releasing stress hormones like cortisol. These hormones help manage short-term stress, but prolonged HPA activation may lead to anxiety symptoms (Tsigos and Chrousos, 2002;Juruena et al., 2020;Haroon et al., 2012). Second, systemic inflammation may increase the conversion of tryptophan to kynurenine and quinolinic acid through the indoleamine 2,3-dioxygenase pathway, reducing serotonin production. ...
Background
Patients with traumatic brain injury (TBI) often experience post-injury anxiety and depression, which can persist over time. However, the relationships between anxiety and depression in TBI patients and delirium, sleep quality, self-efficacy, and serum inflammatory markers require further investigation.
Objective
This study aims to explore the associations of delirium, sleep quality, self-efficacy, and serum inflammatory markers with anxiety and depression in TBI patients, and to examine potential influencing factors.
Methods
We conducted a cohort study involving 127 patients with TBI. Delirium was assessed using the Confusion Assessment Method (CAM) and CAM-ICU, while anxiety, depression, sleep quality, self-efficacy, and pain were evaluated using the appropriate tools, respectively. Serum inflammatory markers (CRP, TNF-α, IL-6) were collected within 1 day post-injury. Generalized estimating equations (GEE) were used to analyze the relationships between delirium, sleep, self-efficacy, and anxiety/depression.
Results
The study identified 56 patients with delirium. Patients with delirium differed significantly from those without delirium in age, TBI classification, sleep duration, CRP levels, TNF-α levels, pain, self-efficacy, and insomnia (P < 0.05). The GEE analysis revealed that delirium, CRP levels, self-efficacy, underlying diseases, insomnia, TBI classification, age, and sleep duration were associated with anxiety symptoms in TBI patients at 6 months post-discharge (P < 0.05). Depression in TBI patients at 6 months post-discharge was not associated with delirium or insomnia but correlated with CRP levels, TBI classification, and self-efficacy (P < 0.05).
Conclusion
TBI patients who experience delirium, insomnia, and low self-efficacy during the acute phase are likely to exhibit more anxiety at the 6-month follow-up. Depression in TBI patients is not associated with delirium or insomnia but is negatively correlated with self-efficacy. CRP levels post-TBI may serve as a biomarker to identify patients at risk of emotional symptoms and potentially accelerate patient recovery.
... Chronic stress or depression leads to increased levels of CRH in limbic regions of the brain, which are linked with hyperactivity of the HPA axis as well as reduced glucocorticoid (GC) feedback inhibition [44]. The release of CRH, along with the activation of gamma-aminobutyric acid (GABA) signals in the hypothalamus, can inhibit the secretion of GnRH and subsequent LH release [42,45]. GC, the end product of HPA axis activation, can act directly on GnIH neurons via the glucocorticoid receptor, thus mediating the interaction between the HPA axis and HPO axis [46]. ...
This narrative review explores the relationship between psychological stress and ovulatory disorders, focusing on the molecular mechanisms involved. Ovulation is regulated by the hypothalamus-pituitary-ovarian (HPO) axis, and disruptions in this axis can lead to ovulatory dysfunction. Chronic psychological stress affects the HPO axis, resulting in abnormalities in hypothalamus hormone secretion, pituitary hormone release, and ovarian function. These disruptions cause ovulation disorders and menstrual irregularities. The mechanisms by which psychological stress affects ovulation involve alterations in neuropeptides and hormones, activation of the hypothalamic-pituitary-adrenal (HPA) axis, impairment of follicular development, generation of oxidative stress, and the decline in ovarian reserve function. Understanding these mechanisms is crucial for developing interventions to restore reproductive health. Psychological interventions, such as cognitive-behavioral therapy, have shown promise in improving ovulation and pregnancy rates in women with ovulatory disorders. Further research is needed to explore the specific mechanisms of these interventions and optimize treatment strategies. Addressing psychological factors is essential in managing reproductive health and ovulatory disorders.
... Cortisol affects various physiological processes, such as the functioning of the immune system, metabolism, and stress response. Increased activity of the HPA axis and elevated cortisol levels have been associated with various disorders such as anxiety, depression, and metabolic syndrome [1,2]. ...
Background: Several randomized controlled trials (RCTs) have shown conflicting results on cortisol levels following probiotic administration in healthy and diseased populations. Previous analyses were inconclusive due to limited studies, and evidence is lacking on how these effects vary by health status; region; therapy duration; medications, and use of single or multiple strains. Methods: In this systematic review and meta-analysis (PROSPERO [CRD42024538539]), we searched PubMed, Cochrane Library, Embase, Scopus, Web of Science, CINAHL, ProQuest, and Web of Science Preprints until 13 August 2024, for RCTs on probiotic administration, either alone or combined, across all age groups and without specific medical condition requirements. We applied random-effects meta-analysis, assessed bias using the Cochrane RoB 2 tool, and evaluated evidence certainty with GRADE. Findings: We screened 1739 records and retrieved 46 RCTs (3516 participants). Probiotics supplementation decreased cortisol levels compared to the control arm [46 RCTs; SMD: −0.45; 95% CI: −0.83; −0.07; I²: 92.5%, low certainty]. Among various subgroups; probiotics supplementation decreased the cortisol levels in the subgroups without concomitant medications [37 RCTs; SMD: −0.30; 95% CI [−0.58; −0.03], I²: 88.7%] with a single probiotic strain [30 RCTs; SMD: −0.33; 95% CI: −0.63; −0.028; I²: 88.8%], in a healthy population [35 RCTs; SMD:−0.3; 95% CI: −0.58; −0.03; I²: 88.7] and in the Asia region [21 RCTs; SMD: −0.83; 95% CI: −1.58; −0.07; I²: 95%]. Interpretation: A low level of evidence suggests probiotics might reduce cortisol levels, but more targeted studies are needed to identify variables affecting the response in specific subgroups.
... Stress is accepted as an important risk factor for Alzheimer's disease (AD) (1,2).High levels of cortisol, which is the stress hormone, in the cerebrospinal fluid (CSF), plasma and serum of Alzheimer's patients and the decrease in hippocampus volume and declarative memory disorders in patients with major depression and chronic corticosteroid treatment give rise to thought for a possible relationship between AD and stress (2,3,4). This suggests that the increase in glucocorticoid levels, which occurs as a result of stress, may participate in the formation of pathological mechanisms seen in AD, and raises the question of whether stress triggers the pathways that cause neurodegeneration or not. ...
... Despite the significance of this association, the exact mechanism that drives the link between stress and CVD remains unknown (AbuRuz et al., 2021). Many studies (Dimsdale, 2008;Rozanski, 2014;Richardson et al., 2012;Tsigos and Chrousos, 2002;Fredrikson and Matthews, 1990;Räikkönen et al., 1996;Ramadan et al., 2013) have identified mental stress as the origin of the physiological changes that significantly affect the incidence and development of heart disease. Specifically, psychological stress correlates with altered endothelial function, exaggerated peripheral microvascular tone and vasoconstriction of normal coronary segments. ...
Objectives
Cardiovascular diseases (CVDs) are a leading cause of death worldwide, emerging from a combination of several factors. The aim of this review is to define the psychological factors that are significant in the development and progression of these disorders.
Methods
Studies published through 2023 concerning adults with psychological vulnerability factors and/or cardiovascular disease were selected through searches of PubMed, PsychINFO, Science Direct, and Google Scholar.
Results
Psychological stress may influence CVD, in combination with other risk factors, or it can act independently, as in cases of workplace stress, post-traumatic stress disorder, Takotsubo syndrome and bereavement. Coping strategies, anxiety and depression have also been identified as relevant psychological factors in cardiac patients. Adverse childhood experiences are linked to a reduced quality of life and have been identified as significant risk factors for the development of acquired CVDs.
Conclusion
This review demonstrates that several psychological factors affect cardiovascular function. An in-depth study of the psychological correlates of CVDs would allow healthcare professionals to design more effective prevention and intervention programs.
... However, since circulating cortisol has a short half-life, approximately 1.5 h, and varies considerably with circadian rhythm and brief stressors, these methods provide limited information about longterm cortisol secretion [3,4]. In the last decade, there has been an increased use of hair cortisol concentrations (HCC) as an alternative biomarker for chronic stress, capturing information about cumulative cortisol levels over the course of several months [5][6][7]. ...
Background
Stress is today a common feature of patients seeking medical care and a growing public health issue in society. A method has been developed to measure biological chronic stress by Hair Cortisol Concentrations (HCC). This biomarker, for chronic stress, captures information about cumulative cortisol levels over the course of several months. Long-term stress might be one of the factors contributing to the onset of cardiovascular conditions and also affecting different risk factors. The aim of this study was to analyse the association between Hair Cortisol Concentrations and previous cardiovascular diseases and cardiovascular risk factors.
Methods
The method of measuring chronic stress by Hair Cortisol Concentration was applied in a large Swedish national observational cross-sectional study. A population-based random sample of N = 4,821 Swedish middle-aged men and women was analysed for hair cortisol levels in relation to diagnosed previous cardiovascular diseases and biologically measured cardiovascular risk factors.
Results
Long-term stress, measured by hair cortisol, was significantly associated with the classical cardiovascular risk factors hypertension and high cholesterol, but not smoking. Those with elevated HCC levels also had a significantly increased pre-history of myocardial infarction, type 2 diabetes, atrial fibrillation and by-pass surgery, but not regarding stroke, angina pectoris or sleep apnoea. Higher HCC was significantly associated (p < 0.001) with Body mass index and waist circumference, but only for females. HCC was also associated with the risk markers leukocytes, and high-sensitivity CRP, indicating a possible linkage between HCC and inflammation and hypothetically also the bodily immune defense. No association was found between perceived stress and HCC.
Conclusions
An overall conclusion of our results is that health care should put more emphasis on patients reporting that they have been exposed to long term stress. Altogether, these analyses of Hair cortisol levels in a large middle-aged population show that chronically elevated cortisol levels represent a relevant and significant factor associated with cardiovascular diseases and classical cardiovascular risk factors.
... The non-invasively measurable stress parameters also include HR, which increases due to sympathetic activation during stress [19,20]. Heart rate variability (HRV) has emerged as a promising non-invasive technique for assessing stress and welfare in farm animals, particularly pigs [21]. ...
Pigs (and minipigs) are often restrained with a maxillary sling for blood collection. They mainly produce strong vocalisations and show resistance to the procedure, which subjectively appears to be stressful for the animals. The present study investigated whether minipigs can be trained to tolerate aversive stimuli and whether training can reduce stress during blood collection. Blood was taken from 12 Ellegaard minipigs with fixation; thereafter, the animals were trained for 3 weeks using clicker training. Then, blood was taken again, but without fixation. Before and after each blood sample, saliva samples were taken. The cortisol concentration was determined using ELISAs. Serum cortisol was not significantly different before and after training (paired-sample t-test, t (9) = 2.052, p = 0.07). However, salivary cortisol was significantly lower after training (ANOVA (analysis of variance), p-value < 0.001, F-value 6.181). In addition, trained minipigs showed a significantly lower heart rate after blood sampling (paired-sample t-test, t (11) = 4.678, p = 0.001) as well as significantly lower heart rate variability (t (11) = 3.704, p = 0.003) compared to before training. The minipigs could be trained to tolerate aversive stimuli. This contributed to stress reduction when taking blood samples.
... The experiences mentioned above pose psychological risks including the risk of threat to the integrity of the self [48][49][50]. Many people exposed to such levels of traumatic stress go on to experience stress responses typical to PTSD, including avoidance, sleep disturbances, hyperarousal, and hypervigilance they may also engage in behaviour typical of those who anticipate further risks [51][52][53][54]. Constant activation of the stress response or allostatic load in post-traumatic stress, creates a state of hopelessness, fear, and horror including the risk of suicide [55][56][57]. ...
This study investigates the effectiveness of the TRUST intervention, delivered through Information and Communication Technology (ICT), in addressing trauma and enhancing resilience among Eritrean refugees in impoverished camps. The research aims to explore whether the comprehensive TRUST program, compared to a shorter psycho-education session, can reduce traumatic stress levels and improve social and economic resilience and social capital, indicating a reduction in collective trauma. Ethical approval was obtained, and participants were randomly assigned to intervention groups. Livelihood support availability was assessed, and psychometric tests were administered before and after the intervention. Results indicate a significant decrease in traumatic stress levels and improvements in social and economic resilience among participants receiving the full TRUST intervention. Interestingly, the availability of livelihood support did not significantly impact trauma levels or associated improvements. Challenges in delivering therapy via ICT, such as connectivity issues, were identified. This study underscores the potential of ICT-enabled interventions in addressing mental health challenges in resource-constrained environments but highlights the importance of addressing connectivity issues for effective implementation.
... Despite both immunocastration and surgical castration significantly reducing testosterone levels, only the immunocastrated rats did not exhibit depressive-like behaviors or social deficits. Several hypotheses might explain these differences: Stress response variations: Surgical castration involves pain, trauma, and loss of bodily integrity, possibly triggering a significant psychological stress response, activating the hypothalamic-pituitary-adrenal (HPA) axis, and promoting the release of stress hormones like cortisol, which can negatively impact the brain's reward system and emotional regulation [33][34][35]. In contrast, GnRH immunocastration is achieved by injecting a GnRH vaccine, inducing an autoantibody response against GnRH, blocking the interaction of endogenous GnRH with its receptor, thus suppressing the pituitary-gonadal axis function in a more gradual and non-invasive manner, reducing the acute stress burden, and favoring the maintenance of normal emotional and social behaviors. ...
Castration is often employed in animal management for reproductive control. However, it is important to evaluate its impact on animal welfare. In this study, we developed rat models for both surgical (n = 6) and GnRH immunocastration (n = 6) to assess the effects of these castration methods on physiological and behavioral characteristics. The novel GnRH-based vaccine significantly increased serum GnRH antibody levels and drastically reduced testosterone, with the testes shrinking to one-fifth the size of those in the control group, thereby halting spermatogenesis at the secondary spermatocyte stage. Behavioral evaluations demonstrated that sexual behavior was significantly suppressed in both surgically and immunologically castrated groups compared to the control, confirming the effectiveness of both methods. However, psychological tests revealed significant signs of depression and social deficits in the surgically castrated group, whereas the behavior of the GnRH-immunocastrated group did not significantly differ from the control. Furthermore, no significant differences in learning and memory were observed among the three groups in the water maze test. Compared to surgical castration, GnRH immunocastration offers effective results and better animal welfare, providing a more humane alternative for livestock management.
... The loss of negative feedback on the HPA axis resulting in elevated cortisol contributes to elevated inflammatory markers, oxidative stress, and thyroid and sex hormone dysfunction [68]. Glucocorticoids directly inhibit pituitary gonadotropin, growth hormone (GH), and thyroid-stimulating hormone (TSH), thus decreasing reproductive, growth, and thyroid functions [69]. This cortisol dysfunction results in a decrease in luteinizing hormone (LH) and follicle-stimulating hormone (FSH). ...
Chronic stress is a significant factor affecting modern society, with profound implications for both physical and mental health. Central to the stress response is cortisol, a glucocorticoid hormone produced by the adrenal glands. While cortisol release is adaptive in acute stress, prolonged exposure to elevated levels can result in adverse effects. This manuscript explores the neurobiological implications of chronic stress and its impact on metabolic dysregulation, particularly in the context of inflammatory bowel diseases (IBDs). The hypothalamic-pituitary-adrenal (HPA) axis regulates cortisol production, which influences metabolism, immune response, and neurobiology. Elevated cortisol levels are associated with the development and exacerbation of metabolic disorders like IBD and contribute to neurodegenerative processes, including cognitive impairments and increased susceptibility to psychiatric conditions. The interaction between cortisol and its receptors, particularly glucocorticoid receptors, underscores the complexity of these effects. This review aims to elucidate the mechanisms through which chronic stress and cortisol dysregulation impact metabolic health and neurobiological function, providing insights into potential therapeutic strategies for mitigating these effects.
... Research has shown that those undergoing stressful situations tend to show an increase in food intake, particularly for highly palatable food. At a physiological level, the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis following exposure to a stressor can increase the release of cortisol, stimulating appetite, and increasing food intake (Tsigos & Chrousos, 2002). The activation of the HPA can also affect the dopaminergic neuronal activity in the mesolimbic reward pathways (Trainor, 2011) and motivate approach responses toward rewards such as food (Baldo & Kelley, 2007; but see Lemos et al., 2012). ...
Objetivo: Comer en respuesta al estrés puede volverse habitual y tener consecuencias a largo plazo en el aumento de peso, pero poca investigación ha explorado qué puede ayudar a romper los ciclos de alimentación por estrés. Examinamos los recursos sociales diarios como posibles factores protectores contra la alimentación diaria por estrés y el eventual aumento de peso. Métodos: En el estudio 1 (N = 1,264), evaluamos las tendencias a comer por estrés, el índice de masa corporal (BMI, por sus siglas en inglés) y la relación cintura-cadera (WHR, por sus siglas en inglés) al inicio del estudio, la recepción de apoyo emocional durante ocho días (9,649 informes) y realizamos un seguimiento de BMI/WHR después de unos diez años. Examinamos la probabilidad promedio de recibir apoyo emocional como moderador del vínculo entre comer por estrés y el BMI/WHR en el seguimiento. En el Estudio 2 (N = 536; 10,288 informes), evaluamos el estado de alimentación por estrés y el BMI al inicio del estudio, la capacidad de respuesta social (sentir que los demás se preocupan) y el comportamiento de alimentación por estrés durante 24 días y realizamos un seguimiento del BMI un año después. Examinamos si la capacidad de respuesta social modera las conductas diarias de alimentación estresada de los consumidores y los cambios en el BMI. Resultados: En el Estudio 1, comer por estrés predijo aumentos en el BMI y el WHR en el seguimiento de 10 años, pero no entre las personas que tenían más (frente a menos) probabilidades de recibir apoyo emocional en la vida diaria. En el Estudio 2, los consumidores que comían por estrés tendían a informar más conductas diarias de alimentación estresada en comparación con los que no comían por estrés, pero esa tendencia se atenuaba en los días en que percibían niveles altos (frente a bajos) de capacidad de respuesta social. Comer bajo estrés no predijo el BMI al año de seguimiento. Conclusiones: Estos hallazgos observacionales sugieren que los recursos sociales en la vida diaria pueden tener beneficios a largo plazo para quienes comen por estrés, potencialmente al reducir su alimentación diaria por estrés.
... In addition to the HPA, the hypothalamus is closely interconnected with the sympathetic nervous system (SNS), another important system involved in the physiological components of stress response, through the activation of endocrine and autonomic responses such as cardiovascular activation. Together, the HPA axis and the SNS manage psychophysical activities with the aim of ensuring the maintenance of homeostasis in the human body [63]. The experience of emotional distress, also termed psychological distress, triggers various endocrine responses. ...
Music and sounds evoke a wide range of emotions and activate numerous psychological and physiological effects. Since emotions involve the autonomic nervous system (ANS) associated with the maintenance of homeostasis, they play an important role in supporting human wellbeing. The aim of the present study is to further validate the mechanisms underlying the relationship between sound, emotions and homeostasis. To this end, the effects of spatial sound projection of two different singing bowls with fundamental frequencies at 73 Hz and 110 Hz were investigated by monitoring behavioural and emotional response in healthy subjects. Overall, we find that the spatial projection of singing bowl sounds elicits a highly significant increase in positive emotions. Exposure to both frequencies resulted in a significant improvement in emotional wellbeing and a significant reduction in negative emotions. We demonstrate frequency-dependent effects indicating a shift in arousal, where 73 Hz elicits feeling more wide awake while 110 Hz elicits sleepiness. These results indicate that non-invasive interventions, such as sound immersion with singing bowls, are effective means in restoring and maintaining homeostasis and underline the need for further research on the effect of discrete frequencies on human psychology and physiology, opening new perspectives on potential treatment of various disorders and conditions.
... They often co-occur: approximately 90% of individuals with anxiety disorders also exhibit symptoms of depression, and 85% of those with depression exhibit symptoms of anxiety [2,3]. Excessive exposure to stressors, such as social defeat and pathogens, triggers the adrenal release of glucocorticoids, which can lead to anxiety and/or depression and subsequently induce systemic inflammation, including neuroinflammation [4,5]. Stresses also cause gut inflammation-mediated gut dysbiosis including bacterial lipopolysaccharide (LPS) overproduction [6,7]. ...
Background
Gut microbiota dysbiosis is closely associated with psychiatric disorders such as depression and anxiety (DA). In our preliminary study, fecal microbiota transplantation from volunteers with psychological stress and subclinical symptoms of depression (Vsd) induced DA-like behaviors in mice. Escherichia fergusonii (Esf) was found to be more abundant in the feces of Vsd compared to healthy volunteers. Therefore, we investigated the effect of Esf on DA-like behavior and neuroinflammation in mice with and without celiac vagotomy.
Methods and results
Orally gavaged Esf increased DA-like behaviors, tumor necrosis factor (TNF)-α, and toll-like receptor-4 (TLR4) expression, and NF-κB⁺Iba1⁺ and lipopolysaccharide (LPS)⁺Iba1⁺ cell populations, while decreasing serotonin, 5-HT1A receptor, and brain-derived neurotrophic factor (BDNF) expression in the hippocampus and prefrontal cortex. However, celiac vagotomy attenuated Esf-induced DA-like behavior and neuroinflammation. Orally gavaged extracellular vesicle (EV) from Vsd feces (vfEV) or Esf culture (esEV) induced DA-like behavior and inflammation in hippocampus, prefrontal cortex and colon. However, celiac vagotomy attenuated vfEV- or esEV-induced DA-like behaviors and inflammation in the brain alone, while vfEV- or esEV-induced blood LPS and TNF-α levels, colonic TNF-α expression and NF-κB-positive cell number, and fecal LPS level were not. Although orally gavaged fluorescence isothiocyanate-labeled esEV was translocated into the blood and hippocampus, celiac vagotomy decreased its translocation into the hippocampus alone.
Conclusions
esEVs may be translocated into the brain via the vagus nerve and bloodstream, subsequently inducing TNF-α expression and suppressing serotonin, its receptor, and BDNF expression through the activation of TLR4-mediated NF-κB signaling, thereby contributing to DA pathogenesis.
... Another major regulatory mechanism found to be disrupted in MDD is the hypothalamic pituitary adrenal (HPA) axis [20,21]. This system is crucial for stress adaptation and is normally activated in response to emotional or physical stressors [22]. The HPA axis is involved in the regulation of blood pressure, metabolism, and the fightflight response, which in turn may increase heart rate, body temperature, and perspiration when activated [23][24][25]. ...
The rising popularity of wearable devices allows for extensive and unobtrusive collection of personal health data for extended periods of time. Recent studies have used machine learning to create predictive algorithms to assess symptoms of major depressive disorder (MDD) based on these data. This review evaluates the clinical relevance of these models. Studies were selected to represent the range of methodologies and applications of wearables for MDD algorithms, with a focus on wrist-worn devices. The reviewed studies demonstrated that wearable-based algorithms were able to predict symptoms of MDD with considerable accuracy. These models may be used in the clinic to complement the monitoring of treatments or to facilitate early intervention in high-risk populations. In a preventative context, they could prompt users to seek help for earlier intervention and better clinical outcomes. However, the lack of standardized methodologies and variation in which performance metrics are reported complicates direct comparisons between studies. Issues with reproducibility, overfitting, small sample sizes, and limited population demographics also limit the generalizability of findings. As such, wearable-based algorithms show considerable promise for predicting and monitoring MDD, but there is significant room for improvement before this promise can be fulfilled.
... However, we did not expect to observe an opposite effect with respect to alpha-amylase change scores. Potentially, this could be explained by the fact that cortisol changes reflect an increase in HPA activity (Tsigos & Chrousos, 2002) and alphaamylase indicates reactivity of the SAM axis (Rohleder et al., 2004), while both stress axes differ in their timing and, most importantly, potentially also in which direction higher . CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. ...
Stress threatens physical and mental health. Reactions to acute stress comprise multiple levels, including negative thoughts, bodily symptoms and behaviors. Individuals differ in their reaction to acute stress, and importantly, also in the extent to which these levels align, with a closer correspondence between psychological and physiological stress indicators being beneficial for mental health and well-being. This preregistered study investigates such individual differences systematically by inducing psychological (social-evaluative) and physiological (cold water) stress with the Maastricht Acute Stress Test (MAST) in 149 healthy adults. Participants indicated the extent to which they perceived to be stressed and four physiological stress indicators (blood pressure, heart rate, salivary cortisol, alpha-amylase) were measured. Finally, multiple personality traits were assessed as potential moderators, including the Big Five, trait anxiety, and general cognitive ability. In line with previous research, psychological and physiological stress indicators were only weakly correlated. However, considering individual differences in personality, revealed especially conscientiousness and openness as potential moderators of the correspondence between psychological and physiological stress indicators. We propose individual differences in interoceptive abilities as another critical moderator, which deserves further investigation, and discuss how future research on individual differences in psycho-physiological correspondence can contribute to further our understanding of mental and physical diseases.
... Studies have shown All data are shown as mean ± SEM, n = 4-6 in each group, * p < 0.05, ** p < 0.01, ***p < 0.001 elevated central CRH levels in stress-related anxiety and depressive patients, with normalization observed after treatment [40]. Corticotropin releasing hormone receptor 1 (CRHR1) antagonists such as antalarmin [41] and miR-34b, which targets CRHR1 and negatively regulates its mRNA [30], have been reported to alleviate anxiety. Additionally, anxiety patients exhibit evident HPA axis hyperactivity, and chronic activation of the HPA axis has been linked to the development and exacerbation of anxiety [42]. ...
Background
Hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis constitutes a pivotal response by surgical trauma, manifesting as a critical aspect of the acute stress reaction. This hyperactivity resulted in adverse surgical outcomes and is often associated with increased postoperative anxiety. Increased evidence suggests that Nesfatin-1 plays a crucial role in stress responses and stress-related psychiatric disorders. Electroacupuncture (EA) is widely used to alleviate stress responses and anxiety, although its mechanism of action remains unclear. This study aimed to assess the mechanisms by which hypothalamic Nesfatin-1 contribute to the alleviation of HPA axis hyperactivity and anxiety by EA.
Methods
Partial hepatectomy (HT) was performed to simulate surgical trauma, and EA was applied at Zusanli (ST36) and Sanyinjiao (SP6). The levels of hypothalamic Nesfatin-1, c-Fos, and corticotropin-releasing hormone (CRH) were detected, and serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were regarded as indicators of HPA axis activity. Anxiety levels were assessed through open field tests (OFT), elevated plus maze (EPM), and light–dark box tests (LDBT). To investigate the role of Nesfatin-1, its expression was modulated using stereotactic viral injections or plasmid transfections. Transcriptome sequencing was employed to explore the downstream signaling pathways of Nesfatin-1. Additionally, brain cannula implantation was performed to facilitate targeted drug administration.
Results
Our findings demonstrated that EA reduced the hypothalamic overexpression of CRH and Nesfatin-1, as well as serum levels of ACTH and CORT. Additionally, it alleviated anxiety-like behaviors resulting from surgical trauma. We observed that overexpression of Nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) triggered hyperactivity of the HPA axis and anxiety. Conversely, knocking down Nesfatin-1 in the PVN reversed these effects caused by surgical trauma. Transcriptome sequencing identified the extracellular regulated protein kinases (ERK)/cAMP-response element binding protein (CREB) pathway as a key mediator in the impacts of surgical trauma and EA on the hypothalamus. Both in vivo and in vitro studies showed that overexpression of Nesfatin-1 activated the ERK/CREB pathway. Furthermore, administering ERK or CREB inhibitors into the PVN mitigated HPA axis hyperactivity and anxiety-like behaviors induced by surgical trauma. Finally, EA was observed to decrease the phosphorylation levels of ERK and CREB in the PVN.
Conclusion
EA alleviates HPA axis hyperactivity and anxiety-like behaviors caused by surgical trauma through inhibition of Nesfatin-1/ERK/CREB pathway in the hypothalamus.
... In a more recent study, Cucunubo Santos et al. (2022) observed that lame cows had a lower BUN level compared with their non-lame peers (Cucunubo Santos et al. 2022). Under initial stress events, the release of cortisol binds to the glucocorticoid receptors and acts as an antiinflammatory, stimulating the hepatic gluconeogenesis and muscle protein catabolism, which may result in an increase of BUN (Tsigos and Chrousos 2002;Pineda and Dooley 2003). In our study, we found a significantly lower BUN level (p ¼ 0.042) for EG, in the samples taken on day 0, with this difference being eliminated by the end of the experiment. ...
Dairy cows lameness represents a significant welfare issue for the dairy industry. The aim of this study was to investigate metabolic and hormonal parameters associated with lameness in cows. The study included two treatment groups of 10 multiparous Holstein–Friesian dairy cows each. The control group consisted of cows with locomotion score 1 and in the experimental group cows with locomotion scores 3 and 4 were included. Milk, urine and blood samples were collected to determine the fat, protein, urea, creatinine, electrolytes and copeptin vasopressin (AVP) content. The milk fat, protein and energy-corrected milk (ECM) levels were higher in lame animals compared with non-lame cows. The blood urea nitrogen (BUN) and BUN/serum creatinine ratio were lower at the start of the trial in lame animals suggesting a metabolic acidosis state. There were significantly lower serum Na levels in the lame cows, from the start until the end of the trial (p<0.011), as well as between lame and non-lame groups at the end of the trial (p<0.041). A lower copeptin AVP was detected in lame compared with non-lame cows at the end of the trial (p<0.004). The decrease of serum Na levels as the comfort improves indicates
that the animals started to recover from the effect of cortisol on mineralocorticoid receptors. Our data also indicates that the BUN and BUN/serum creatinine ratios are associated with lameness. Further investigations involving a larger number of cows would be recommended to confirm these results and to evaluate these parameters in the early stages of lameness.
The regulation of growth hormone (GH) synthesis and secretion by somatotroph cells of the anterior pituitary is a highly complex process, mediated by a variety of neuroendocrine and peripheral influences. In particular, a key role is played by the hypothalamic peptides growth hormone-releasing hormone (GHRH) and somatostatin, which regulate the somatotroph axis with opposite actions, stimulating and inhibiting GH release, respectively. Since the discovery of GHRH about 50 years ago, many pathophysiological studies have explored the underlying intricate hormonal balance that regulates GHRH secretion and its interplay with the somatotroph axis. Various molecules and pathophysiological states have been shown to modulate the release of GH, GHRH, somatostatin and GH secretagogues. Collectively, the available evidence demonstrates how a vast number of neural and peripheral signals are conveyed and integrated to orchestrate a finely tuned response of the somatotroph axis that adapts to the body’s varying needs for growth, metabolism, and repair. The present review aims to summarize the available evidence regarding the key regulators involved in the modulation of the somatotroph axis in humans, presenting detailed molecular insights on the signaling cascades at play. The interplay between different mechanisms governing somatotroph secretion is highlighted, underscoring the nuanced interdependence that maintains homeostasis and facilitates the body’s ability to respond to internal and external stimuli.
Mood disorders affect around 1 in 5 people, but the diagnosis and management of these conditions can be challenging. This practical handbook presents a comprehensive overview of these disorders, as well as detailed guidelines for their treatment. The handbook takes a transdisciplinary approach to mood disorders, focusing not only on the biological aspects but also on psychosocial features of importance for optimal diagnosis and management. Content covers nosological considerations, historical aspects, peculiarities along the lifespan, and the associations between mood disorders and other conditions, with a focus on their implications for the optimal management of patients. Practical and evidence-based information is discussed on the role of guidelines related to treatment in selected population groups, including youth, the elderly, and women. With a practical, reader-friendly approach, this book will be invaluable for mental health professionals involved in the treatment of patients with mood disorders, including trainees from different mental health areas.
The article analyzes contemporary studies of family, dyadic and financial stress, the influence of family stressors on marital relations and family functioning. The importance of analyzing stress with social consequences is emphasized, which made it possible to consider stress between partners, or spouses, as a dyadic phenomenon. A review of scientific publications has shown that financial stress has a more negative impact on family relationships, including family stability. The analysis of various studies of the influence of dyadic coping showed that the choice of adequate dyadic strategies plays an important role in maintaining long-term relationships between partners. The study of the impact of the structural characteristics of the family on the choice of dyadic strategies showed that the functionality of the family is an indicator of productive coping with difficulties.
Experiencing major life stressors is associated with negative health outcomes, yet the mechanisms are not fully understood. Major stressors are threatening, discrete events that can have lingering consequences on emotional and cognitive processes. This can lead to maladaptive coping strategies, such as rumination, that compromise the ability to handle subsequent stressors and disrupt the hypothalamic-pituitary-adrenal (HPA) axis response. Based on the Perseverative Cognition Hypothesis, it was hypothesized that greater exposure to major stressors would be associated with greater rumination during a laboratory stressor, which, in turn, would predict higher cortisol reactivity and peak and delayed recovery. Participants were 211 healthy adults (Mage = 30.2, SD = 10.9, range = 18 – 55) who underwent the Trier Social Stress Test and self-reported rates of major stressors in the past 12 months and stress-related state rumination. Two-piece growth curve modeling with landmark registration was used to calculate peak salivary cortisol levels along with cortisol reactivity and recovery slopes to capture individual differences in the trajectory of cortisol response. Results showed that state rumination significantly mediated the link between more major stressors and elevated peak cortisol levels as well as steeper reactivity and recovery slopes. Interpersonal stressors and non-interpersonal stressors showed similar associations to cortisol response via state rumination. This study enhances our understanding of how stress contributes to HPA axis dysregulation by connecting major stressors with acute stressors, pointing at stress-induced rumination as a plausible mechanism.
Recent advancements in neurodegenerative research have embraced a multisystemic approach, emphasizing the role of the gut microbiota and its interactions with various systems, including the central nervous system. This review explores the interactions between the gut-brain axis and neurological illnesses associated with ageing, with a particular focus on the potential influence of sex. Despite increased life expectancy, the chronological ceiling of human well-being remains unchanged, implying that conditions such as dementia and Parkinson's disease will continue to affect individuals for extended periods as lifespans increase. Understanding the microbiota-gut-brain axis in relation to neurodegenerative diseases may pave the way for novel therapeutic approaches. Additionally, emerging research suggests that sex-related variations in gut microbiota and the influence of sex hormones may impact the manifestation of several neurodegenerative conditions, including those related to mental health. This review updates the current knowledge on age-related neurodegenerative diseases, such as dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and dementia with Lewy bodies. Future research should focus on exploring microbial therapeutics for the treatment and prevention of age-related neurodegenerative disorders, as well as gender-specific variations in gut microbiota. In this context, the EU-funded project MEMOIR will investigate the impact of a healthy diet on gut microbiota and the progression of Mild Cognitive Impairment.
The symbiotic relationship between the human gastrointestinal tract and microbial communities plays a vital role in maintaining overall bodily homeostasis and defending against diseases. This link to the brain emphasizes the significant influence of the gut microbiota on mental well-being. The significance of microbial dysbiosis in the genesis of disease, particularly in mental health problems, has been clarified by research on the gut microbiome. This chapter investigates how the gut-brain axis affects behavior and brain function in relation to the gut microbiota. It looks into microbiome-based treatments for mental health, such as dietary changes, fecal microbiota transplantation, probiotics, and prebiotics. An overview of the available data on the effectiveness, security, and processes of various interventions is given in this chapter. The difficulties and possibilities of using microbiome-based treatments in clinical settings are also covered. Ultimately, the chapter concludes by considering the potential impact of these emerging therapies on the treatment of mental health disorders. By offering a comprehensive review of microbiome-based therapies for mental health, this chapter provides valuable insights into this rapidly evolving field.
Glucose, a primary energy source derived from animals’ feed ration, is crucial for their growth, production performance, and health. However, challenges such as metabolic stress, oxidative stress, inflammation, and gut microbiota disruption during animal production practices can potentially impair animal glucose metabolism pathways. Phytochemicals, probiotics, prebiotics, and trace minerals are known to change the molecular pathway of insulin-dependent glucose metabolism and improve glucose uptake in rodent and cell models. These compounds, commonly used as animal feed additives, have been well studied for their ability to promote various aspects of growth and health. However, their specific effects on glucose uptake modulation have not been thoroughly explored. This article focuses on glucose metabolism is on discovering alternative non-pharmacological treatments for diabetes in humans, which could have significant implications for developing feed additives that enhance animal performance by promoting insulin-dependent glucose metabolism. This article also aims to provide information about natural materials that impact glucose uptake and to explore their potential use as non-antibiotic feed additives to promote animal health and production. Further exploration of this topic and the materials involved could provide a basis for new product development and innovation in animal nutrition.
Clinical mental health researchers may understandably struggle with how to incorporate biological assessments in clinical research. The options are numerous and are described in a vast and complex body of literature. Here we provide guidelines to assist mental health researchers seeking to include biological measures in their studies. Apart from a focus on behavioral outcomes as measured via interviews or questionnaires, we advocate for a focus on biological pathways in clinical trials and epidemiological studies that may help clarify pathophysiology and mechanisms of action, delineate biological subgroups of participants, mediate treatment effects, and inform personalized treatment strategies. With this paper we aim to bridge the gap between clinical and biological mental health research by (1) discussing the clinical relevance, measurement reliability, and feasibility of relevant peripheral biomarkers; (2) addressing five types of biological tissues, namely blood, saliva, urine, stool and hair; and (3) providing information on how to control sources of measurement variability.
Background
Stress is one of the most common precipitating factors in migraine and is identified as a trigger in nearly 70% of patients. Responses to stress include release of glucocorticoids as an adaptive mechanism, but this may also contribute to migraine attacks. Here, we investigated the role of glucocorticoids on stress-induced migraine-like behaviors.
Methods
We have shown previously that repeated stress in mice evokes migraine-like behavioral responses and priming to a nitric oxide donor. Metyrapone, mifepristone, and corticosterone (CORT) were used to investigate whether CORT contributes to the stress-induced effects. Facial mechanical hypersensitivity was evaluated by von Frey testing and grimace scoring assessed the presence of non-evoked pain. We also measured serum CORT levels in control, stress, and daily CORT injected groups of both male and female mice.
Results
Metyrapone blocked stress-induced responses and priming in male and female mice. However, repeated CORT injections in the absence of stress only led to migraine-like behaviors in females. Both female and male mice showed similar patterns of serum CORT in response to stress or exogenous administration. Finally, administration of mifepristone, the glucocorticoid receptor antagonist, prior to each stress session blocked stress-induced behavioral responses in male and female mice.
Conclusions
These findings demonstrate that while CORT synthesis and receptor activation is necessary for the behavioral responses triggered by repeated stress, it is only sufficient in females. Better understanding of how glucocorticoids contribute to migraine may lead to new therapeutic opportunities.
To determine whether an officer’s use of force is reasonable, courts consider the totality of the circumstances known at the time of the incident by the officer and consider whether other reasonably prudent officers would have responded in a similar way. The results of the source article suggest it is unreasonable to expect officers to perform perfectly in high-stress situations. Regardless of their training and experience, officers often make errors in such situations and experience a range of performance problems. Training standards need to be set in an attempt to minimize poor officer performance. Realistic scenario-based training should be used, which elicits stress responses and focuses on the development of skills that have been shown to improve performance under stress.
Intensification of swine production can predispose pigs to chronic stress, with adverse effects on the neuroendocrine and immune systems that can lead to health problems, poor welfare, and reduced production performance. Consequently, there is an interest in developing tools to prevent or eliminate chronic stress. Music is widely used as a therapeutic strategy for stress management in humans and may have similar benefits in non-human animals. This study evaluated the effects of a music-based auditory enrichment program in pigs from a multidimensional perspective by assessing psychophysiological responses. Two experimental groups of 20 pigs each were selected for the study: one enriched, exposed to a program of functional veterinary music designed for pigs, and a control group without auditory stimulation. Qualitative behavior assessment (QBA) and skin lesions indicative of agonistic behavior were used to evaluate the psychological determinants underlying the observed behaviors. Physiological assessment included hemograms, with the determination of the neutrophil:lymphocyte ratio and daily measurements of cortisol and salivary alpha-amylase levels. The results demonstrated a positive effect of a music-based auditory program on psychophysiological responses. Therefore, this strategy developed for environmental enrichment may be beneficial in reducing stress and contributing to the welfare and health of pigs under production conditions.
Aim
This study aimed to explore the relationships between serum cortisol levels, personality traits, and the development of Post‐Traumatic Stress Disorder (PTSD) over 2 years among individuals with physical injuries.
Methods
Participants were consecutively recruited from a trauma center and followed prospectively for 2 years. At baseline, serum cortisol levels were measured, and personality traits were categorized into five dimensions (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness), using the Big Five Inventory‐10. The diagnosis of PTSD during follow‐up (at 3, 6, 12, and 24 months post‐injury) was determined using the Clinician‐Administered PTSD Scale for DSM‐5. Binary and multinomial logistic regression analyses were conducted to examine the interactions between cortisol levels, personality traits, and PTSD development.
Results
Among 923 patients analyzed, 112 (12.1%) were diagnosed with PTSD at some point during the study period, with prevalence rates decreasing from 8.8% at 3 months to 3.7% at 24 months post‐injury. Direct associations between cortisol levels or personality traits and PTSD were not observed. However, a significant interaction between lower cortisol levels and higher Neuroticism in relation to PTSD risk was identified, especially during the early follow‐up periods (3 to 6 months), but this association waned from the 12‐month follow‐up onward.
Conclusion
Our findings reveal Neuroticism‐dependent associations between serum cortisol levels and PTSD development, exhibiting temporal variations. These results suggest that PTSD development may be influenced by a complex, time‐sensitive interplay of biological and psychosocial factors, underscoring the importance of considering individual differences in stress reactivity and personality in PTSD research and treatment.
Objective.
—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.
We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin
on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral
administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid
by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response
studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this
dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of
two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited
a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and
defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress.
Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic,
and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological
stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive,
and cardiovascular disorders associated with CRH system hyperactivity.
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.
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.
Celsus described four of the five cardinal signs of inflammation 2000 years ago, and Eustachio discovered the adrenal glands almost 500 years ago, but not until 1936 did Selye note that in rats exposed to stressors, the adrenal glands were enlarged, and the thymus and lymph nodes shrunken.1–3 Cortisone, the active principle of the adrenal glands, was isolated by Kendall and Reichstein in the late 1940s and shown to suppress immune organs. These scientists, along with Hench, received the Nobel Prize in Physiology and Medicine, after Hench and colleagues showed that cortisone could ameliorate rheumatoid arthritis.4,5 In recent . . .
Glucocorticoids are potent immunosuppressants which work in part by inhibiting cytokine gene transcription. We show here that NF-kappa B, an important regulator of numerous cytokine genes, is functionally inhibited by the synthetic glucocorticoid dexamethasone (DEX). In transfection experiments, DEX treatment in the presence of cotransfected glucocorticoid receptor (GR) inhibits NF-kappa B p65-mediated gene expression and p65 inhibits GR activation of a glucocorticoid response element. Evidence is presented for a direct interaction between GR and the NF-kappa B subunits p65 and p50. In addition, we demonstrate that the ability of p65, p50, and c-rel subunits to bind DNA is inhibited by DEX and GR. In HeLa cells, DEX activation of endogenous GR is sufficient to block tumor necrosis factor alpha or interleukin 1 activation of NF-kappa B at the levels of both DNA binding and transcriptional activation. DEX treatment of HeLa cells also results in a significant loss of nuclear p65 and a slight increase in cytoplasmic p65. These data reveal a second mechanism by which NF-kappa B activity may be regulated by DEX. We also report that RU486 treatment of wild-type GR and DEX treatment of a transactivation mutant of GR each can significantly inhibit p65 activity. In addition, we found that the zinc finger domain of GR is necessary for the inhibition of p65. This domain is also required for GR repression of AP-1. Surprisingly, while both AP-1 and NF-kappa B can be inhibited by activated GR, synergistic NF-kappa B/AP-1 activity is largely unaffected. These data suggest that NF-kappa B, AP-1, and GR interact in a complex regulatory network to modulate gene expression and that cross-coupling of NF-kappa B and GR plays an important role in glucocorticoid-mediated repression of cytokine transcription.
Corticotropin-releasing hormone (CRH) plays major roles in coordination of the stress response and regulation of the immune/inflammatory reaction, two important functions associated with sexual dimorphism. Two overlapping segments of the 5' flanking region of the human (h) CRH gene, the proximal 0.9 kb (containing two perfect half-palindromic estrogen-responsive elements [EREs]) and the 2.4 kb (including the former and containing two additional perfect half-palindromic EREs), were examined for their ability to confer estrogen-mediated transcriptional enhancement to a homologous or heterologous promoter. The level of estrogen-induced transactivation by the 0.9- and 2.4-kb segments was determined by chloramphenicol acetyltransferase analysis in CV-1 cells cotransfected with estrogen receptor (ER) cDNA expression plasmids, and found to be respectively approximately 10% and 20% of that of the strongly estrogen-responsive Xenopus vitellogenin A2 enhancer. Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. These findings may constitute the basis of sexual dimorphism in the expression of the CRH gene in the central nervous system and periphery, and might shed light in existing gender differences in stress response and immune regulation.
Inflammatory cytokines have metabolic actions that probably contribute to the general adaptation of the organism during infectious or inflammatory stress. To examine the effects of interleukin 6 (IL-6), the main circulating cytokine, on glucose metabolism in man, we performed dose-response studies of recombinant human IL-6 in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/Kg BW) were injected sc in 15 healthy male volunteers (3 in each dose) after a 12-h fast. All IL-6 doses were tolerated well and produced no significant adverse effects. We measured the circulating levels of glucose, insulin, C-peptide, and glucagon at baseline and half-hourly over 4 h after the IL-6 injection. Mean peak plasma levels of IL-6 were achieved between 120 and 240 min and were 8, 22, 65, 290, and 4050 pg/mL, respectively, for the 5 doses. After administration of the 2 smaller IL-6 doses, we observed no significant changes in plasma glucose levels, which, because of continued fasting, decreased slightly over time. By 60 min after the 3 higher IL-6 doses, however, the decline in fasting blood glucose was arrested, and glucose levels increased in a dose-dependent fashion. The concurrent levels of plasma insulin and C-peptide were not affected by any IL-6 dose. In contrast, IL-6 caused significant increases in plasma glucagon levels, which peaked between 120 and 150 min after the IL-6 injection. In conclusion, sc IL-6 administration induced dose-dependent increases in fasting blood glucose, probably by stimulating glucagon release and other counteregulatory hormones and/or by inducing peripheral resistance to insulin action.
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.
A peptide with high potency and intrinsic activity for stimulating the
secretion of corticotropin-like and β -endorphin-like
immunoactivities by cultured anterior pituitary cells has been purified
from ovine hypothalamic extracts. The primary structure of this
41-residue corticotropin- and β -endorphin-releasing factor has
been determined to be:
H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-
Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-
Lys-Leu-Leu-Asp-Ile-Ala-NH2 The synthetic peptide is active
in vitro and in vivo.
Interleukin-6 (IL-6), the main circulating cytokine, is putatively a major mediator of the effects of the immune system on several endocrine axes and intermediate metabolism. We performed dose-response studies of recombinant human IL·6 on pituitary hormone secretion in 15 healthy male volunteers, using 5 single, escalating subcutaneous doses of IL-6 (0.1, 0.3, 1.0, 3.0 and 10.0 μg/kg body weight), each in 3 volunteers. We measured resting metabolic rate (RMR) with indirect calorimetry and plasma anterior pituitary hormones and vasopressin (AVP) at baseline and half-hourly over 4 h after the injection. All doses examined were tolerated well and produced no significant adverse effects. Dose-dependent RMR increases were observed in response to the 3.0- and 10.0-μg/kg doses of IL-6, beginning at 60 min and slowly peaking between 180 and 240 min. Plasma adrenocorticotropic-hormone concentrations increased dramatically and dose-dependently in all the patients who received the 3.0- and 10.0-μg/kg doses of IL-6, respectively, peaking to 150 and 255 pg/ml at 60 min, and slowly returning to normal by 4 h. Corresponding plasma cortisol levels peaked dose-dependently between 90 and 150 min, but remained elevated throughout the sampling period. In contrast, the growth hormone (GH) dose-response was bell-shaped, with maximum (approximately 100-fold) stimulation achieved by 3.0 μg/kg IL-6. Prolactin (PRL) showed a similar but less pronounced response pattern. Thyroid-stimulating hormone (TSH) dose-dependently and progressively decreased over the 240 min, while gonadotropins showed no clear-cut changes. In conclusion, subcutaneous IL-6 administration induced synchronized dose-dependent increases in the RMR and hypothalamic-pituitary-adrenal axis activity, suggesting that hypothalamic corticotropin-releasing hormone may mediate both of these functions in humans. IL-6 also acutely stimulated GH and PRL secretion and suppressed TSH secretion. The dose of 3.0 μg/kg could be used safely in the study of patients with disturbances of the hypothalamic-pituitary unit or of thermogenesis.
Studies were undertaken to characterize the secretion of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) into the hypophysial-portal circulation of the conscious sheep. In addition, we examined the temporal relationship between the secretion of these two hypothalamic peptides and the secretion of three pro-opiomelanocortin peptides – adrenocorticotropic hormone (ACTH), ir-β-endorphin, and ir-α-melanocyte-stimulating hormone – and cortisol and determined the effects of an audiovisual emotional stimulus and insulin-induced hypoglycemia on the entire hypothalamic-pituitary-adrenal axis. In the basal state, the secretion of CRF, AVP, the three pro-opiomelanocortin peptides, and cortisol was pulsatile in nature, and three CRF and AVP pulse patterns were observed: a concordant increase in CRF and AVP, an isolated rise in CRF, and an isolated increase in AVP. In 4 of the 5 animals, a 3-min audiovisual stress (barking dog) rapidly increased the plasma levels of all the measured substances, although the magnitude and duration of the effect differed markedly between the animals. Insulin-induced hypoglycemia markedly increased AVP and, to a lesser extent, CRF concentrations in portal plasma and thereby altered the CRF:AVP molar ratio. Although pituitary-adrenal activation was closely correlated with the increased hypothalamic activity, a strict 1:1 concordance between CRF/AVP secretion and ACTH secretion was not seen. The anesthetic ketamine selectively increased portal AVP concentrations to levels which exceeded those attained during hypoglycemia and rapidly activated the pituitary-adrenal axis. We conclude the following: (1) CRF and AVP are secreted by the hypothalamus in a pulsatile fashion; (2) ACTH secretion can be stimulated by increases in either CRF or AVP; (3) the absence of a strict 1:1 concordance between hypothalamic CRF/AVP release and pituitary ACTH secretion during stress may be partly due to the release of additional hypothalamic ACTH secretagogues; (4) the ability of both audiovisual stimuli and insulin-induced hypoglycemia to augment CRF and AVP secretion indicates that the paraventricular hypothalamus may be activated by a variety of neural inputs, and (5) the marked alteration of the CRF:AVP molar ratio during stress suggests that AVP may be an important ACTH secretagogue in vivo in the sheep.
Corticotropin-releasing hormone (CRH) influences the immune system indirectly, through activation of the hypothalamic-pituitary-adrenal axis and sympathetic system, and directly, through local modulatory actions of peripheral (immune) CRH. We recently demonstrated that catecholamines and histamine potently inhibited interleukin (IL)-12 and stimulated IL-10, whereas glucocorticoids suppressed IL-12, but did not affect IL-10 production ex vivo. Thus, both glucocorticoids and catecholamines, the end products of the stress system, and histamine, a product of activated mast cells, may selectively suppress cellular immunity and favor humoral immune responses. We localized immunoreactive CRH in experimental carrageenin-induced aseptic inflammation and, in humans, in inflamed tissues from patients with several autoimmune diseases. In addition, we demonstrated that CRH activated mast cells via a CRH receptor type 1-dependent mechanism, leading to release of histamine and hence vasodilatation and increased vascular permeability. Thus, activation of the stress system, through direct and indirect effects of CRH, may influence the susceptibility of an individual to certain autoimmune, allergic, infectious or neoplastic diseases. Antalarmin, a novel nonpeptide CRH antagonist, prevented several proinflammatory effects of CRH, thus revealing its therapeutic potential in some forms of inflammation.
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.
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.
This article reviews the mechanisms believed to mediate stress-induced inhibition of reproductive functions and the anatomical sites at which these effects take place. Particular emphasis is placed on the potential modulating role of hormones or neurotransmitters released during stress. At the level of the gonads, adrenal corticoids, pro-opiomelanocortin (POMC)-like peptides, and corticotropin-releasing factor (CRF) are reported to interfere with the stimulatory action of gonadotropins on sex steroid-producing cells. Increased circulating corticosteroid levels may also decrease pituitary responsiveness to GnRH. There is, however, increasing evidence that these mechanisms are primarily involved in mediating the effects of prolonged stress, but not those of an acute stimulus. In contrast, a variety of hormones or neurotransmitters, including CRF, POMC peptides, and biogenic amines act within the brain to mediate the inhibitory influence of both acute and prolonged stresses on reproductive function.
It is widely accepted that chronic administration of corticoids in man inhibits the GH response to all of the stimuli tested so far. To study the action of corticoids administered acutely, several dexamethasone challenge tests were performed, after which GH levels were measured for 7 h. In eight volunteers, administration of 4 mg dexamethasone (Dex), iv, induced a clear-cut GH release compared with saline administration. The secretion followed an unusual pattern; basal GH levels (1.5 +/- 0.1 micrograms/L) started rising 2 h after Dex injection, reaching a peak of 17.5 +/- 4.4 micrograms/L after 3 or 3.5 h. Peak levels were maintained until 5 h post-Dex and decreased thereafter. Similar data were obtained when Dex was administered to five volunteers at the dose of 8 mg, orally, with a 30-min delay of the GH peak (19.6 +/- 7.9 micrograms/L). To study whether there was a cholinergic input responsible for the Dex action, another group of eight volunteers underwent three Dex tests (4 mg, iv) on three occasions, followed 90 min later by the administration of placebo (control), atropine (0.5 mg, iv), or pyridostigmine (120 mg, orally). The Dex-induced GH peak (20.8 +/- 5.2 micrograms/L) was not significantly increased by pyridostigmine (cholinergic agonist) treatment (24.2 +/- 4.0 micrograms/L). The blockade of muscarinic receptors by atropine induced a delay in the Dex-induced secretory peak, which appeared at 5 h. However, the Dex-atropine GH peak (14.9 +/- 4.1 micrograms/L) was not different from the Dex-placebo one. In conclusion, Dex alone is able to induce a clear-cut GH secretion in man. The stimulus followed a peculiar time pattern, with peaks levels attained 3 h after either iv or oral administration.
In humans, corticoids suppress growth and growth hormone (GH) secretion elicited by a variety of stimuli, while in the rat they potentiate both in vivo and in vitro GH release. To further study this problem, growth-hormone-releasing hormone (GHRH) tests were performed in 6 nonobese Cushing's syndrome patients and 6 controls. The normal GHRH-induced GH secretion was completely abolished in the Cushing's syndrome group. To study the action of shorter corticoid exposures, 34 volunteers were subjected to four tests each: placebo treatment (control); dexamethasone (Dex) administration 4 mg i.v., 3 h before; Dex 8 mg p.o., 12 h before, and Dex 22 mg p.o. over the 2 days before the pituitary challenge that was always administered at 0 min (12.00 h). In the first test (n = 9), GHRH (1 microgram/kg i.v.) induced a GH peak of 14.5 +/- 3.8 ng/ml (control) that was potentiated by Dex 4 mg i.v. administered 3 h before (26.4 +/- 6.8 ng/ml). On the contrary, longer Dex treatments suppress GHRH-induced GH values (6.0 +/- 1.1 ng/ml after Dex 8 mg and 1.8 +/- 0.3 ng/ml after Dex 22 mg). Clonidine administration 300 micrograms p.o. (n = 7) increased GH secretion with an area under the secretory curve (AUC) of 1,274 +/- 236 that was potentiated by Dex 4 mg i.v. given 3 h before clonidine (2,380 +/- 489) and reduced by Dex 8 mg, the reduction being significant only after 22 mg Dex (595 +/- 47).(ABSTRACT TRUNCATED AT 250 WORDS)
Thyrotrophin (TSH) secretion was studied in 63 patients with Cushing's syndrome (53 patients with pituitary dependent Cushing's disease, eight with adrenocortical tumours, and two with the ectopic ACTH syndrome). Prior to treatment, TSH response to 200 micrograms of TRH intravenously was significantly decreased compared to controls; TSH response was 'flat' (increment less than 2 mU/l) in 34 patients (54%). Patients with a flat response to TRH had significantly higher morning and midnight cortisol levels than patients with a TSH response of 2 mU/l and more; this was not due to differences in serum thyroid hormone levels. Basal TSH, TSH increment after TRH, and stimulated TSH value, but not serum triiodothyronine, were correlated with cortisol measurements (0800 h serum cortisol, midnight cortisol, and urinary free corticoid excretion). After exclusion of 40 patients with additional disease (severe systemic disease, diabetes mellitus, or goitre), cortisol-TSH correlations were even more pronounced (r = -0.73 for midnight cortisol and stimulated TSH levels), while in the patients with additional complications, these correlations were slight or absent. Successful treatment in 20 patients was associated with a rise in thyroid hormone levels and the TSH response to TRH. These results indicate that (1) the corticoid excess but not serum T3 is the principal factor regulating TSH secretion in Cushing's syndrome, (2) a totally flat response to TRH is rare, and (3) TSH suppression and lower than normal serum thyroid hormone levels are reversible after treatment. Since factors like severe systemic disease, diabetes mellitus and goitre also affect TSH secretion, they tend to obscure the statistically significant correlations between cortisol excess and TSH secretion.
Patterns of plasma ACTH and cortisol concentrations were studied in 10 healthy subjects (five male, five female in the early follicular phase, overall age range 21-32 years) by sampling through an indwelling cannula every 15 min for 24 h. The subjects were in hospital, ambulant, and taking normal meals. Plasma ACTH was measured by a two-site immunoradiometric assay with a detection limit of 3.9 ng/l (0.9 pmol/l). Pulses were identified by the method of Clayton et al. (1987) using stringent criteria to minimize false positive peaks. All subjects showed a circadian rhythm of ACTH, the acrophase occurring between 0615 and 0920 h in all but one subject and the mesor value was between 9.2 and 18.6 ng/l (2.0 and 4.1 pmol/l). There were significantly fewer pulses between 1800 and 2400 h compared with the other three 6-h periods. The pattern of ACTH differed between males and females in several respects: more pulses (18 vs 10), greater mean peak amplitude (16.8 vs 10.3 ng/l), greater area under the 24-h profile (350.9 vs 206.6 ng/l h) and higher mean level (14.7 vs 8.6 ng/l) in the males. In contrast, the cortisol pattern did not show statistically different sex differences. The sex differences suggest greater sensitivity to, or availability of, ACTH to the female adrenal cortex, or different set points in cortisol feedback.
Excerpt
The classical perspective of the adrenal gland has, in general, treated the cortex and medulla as functionally independent tissues which, by chance, are located together. Recent data challenge this outlook, and there is now evidence of regulatory mechanisms which are common to both the cortex and the medulla. There is, additionally, more evidence that the products of each of these tissues may influence the function of the other.
In mammals the arrangement of the adrenal gland is such that the adrenal cortex forms the outer part of the gland and totally encloses the medulla. Indeed, a close anatomical relationship, between the morphologically and functionally distinct steroid-secreting tissue and chromaffin tissue in the adrenal gland, is seen in most vertebrate groups. Why should these embryologically unrelated tissues be located together, and what is their functional link?
There is a wealth of experimental evidence to support the contention that these tissues have
Corticotropin-releasing factor (CRF) at doses of 10(-12)-10(-8) M significantly stimulated the release of beta-endorphin and dynorphin from superfused rat hypothalamic slices. These effects were shown to be mediated by the CRF receptor since they were antagonized by the CRF receptor antagonist alpha-helical CRF9-41 (10(-6) M). The two opioid peptides showed different time courses of response and in the case of beta-endorphin, an attenuation of the response upon continued exposure to CRF was observed.
Vasopressin (arginine vasopressin, AVP) is present in two types of nerve fibres in the median eminence (ME). First, it is found in nerve terminals that originate in the parvicellular neurones of the hypothalamic paraventricular nucleus (PVN) and abut on the pericapillary space surrounding the fenestrated capillaries of the primary pituitary portal plexus in the external zone (EZ) of the ME. These neurones also synthesize corticotropin-releasing factor (CRF), which acts synergetically with vasopressin to stimulate release of adrenocorticotropin (ACTH) from the pituitary gland (see ref. 7). Second, vasopressinergic axons of the magnocellular neurosecretory system pass through the internal zone (IZ) of the ME to terminate in the neurohaemal contact zone of the neurohypophysis. The involvement of vasopressinergic magnocellular neurones in the control of ACTH secretion is much debated. Of particular interest in this context is the origin of the vasopressin found in pituitary portal blood. Although it has been demonstrated that vasopressin and CRF are present in the same neurosecretory granules of EZ fibres, parallel determinations of vasopressin and CRF in pituitary portal blood have shown alterations of the concentration of vasopressin without a concomitant change in that of CRF. Such a dissociation suggests that either differential release of vasopressin and CRF can occur from a single population of nerve endings, or there are fibres in the pituitary-stalk ME which release vasopressin but not CRF. Here we present evidence for the latter. Our results indicate that stimuli causing depolarization of the axonal membrane in vitro elicit release of vasopressin from nerve fibres in the external and internal zones of the ME.
Thousands of studies have been conducted of the functioning of the many neurotransmitter systems in order to explore the biologic basis of major depressive disorder. Instead of reviewing this literature exhaustively, we have attempted to propose a model that accommodates the clinical observation that chronic stress early in life in vulnerable persons predisposes them to major depression with contemporary observations of the potential consequences of repeated central nervous system exposure to effectors of the stress response. This model accords with current clinical judgment that major depression is best treated with a combination of psychopharmacologic agents and psychotherapy. Accordingly, whereas psychopharmacologic intervention may be required to resolve an active episode of major depression and to prevent recurrences, psychotherapy may be equally important to lessen the burden of stress imposed by intense inner conflict and counterproductive defenses.
In this review, the emerging functional roles of the brain angiotensin system have been considered. The major effects of Ang II can be classified into three groups, which imply three possible functions: The first, and largest, group is actions associated with the regulation of body fluid volume in response to hypovolemia. These include thirst, blood pressure increase, vasopressin release, sodium appetite and excretion, and ACTH and aldosterone release. This function alone has important implications for the control of blood pressure and the disease of hypertension. Another possible function is a role for angiotensin in the activity of gonadotropic hormone releasing hormones and pituitary hormones during the reproductive cycle and pregnancy. A third group of functions is the synaptic, neurotransmitter interactions of Ang II with catecholamines, serotonin, prostaglandins, and other peptides, not all of which could be reviewed here due to space limitations. This interaction is significant for all functions mentioned and leads to alterations in motivation (thirst, pain), memory (and possibly learning), and motor control. The amount of data available, however, is so limited that to claim angiotensin plays any major role in the latter functions would be premature. Throughout this review, we compared the central and peripheral effects of Ang II. We suggest that normally, a blood-CVO barrier prevents diffusion of peripheral Ang II to brain receptors inside the BBB. Because of this mechanism, the responses to the two routes of administration are distinctly different. When systemic peptide levels are low, Ang II activates only receptors in the CVOs; however, when these levels are high, the peptide diffuses to receptors that are normally activated only by brain Ang II.
A peptide with high potency and intrinsic activity for stimulating the secretion of corticotropin-like and beta -endorphin-like immunoactivities by cultured anterior pituitary cells has been purified from ovine hypothalamic extracts. The primary structure of this 41-residue corticotropin- and beta -endorphin-releasing factor has been determined to be: H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu- Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg- Lys-Leu-Leu-Asp-Ile-Ala-NH2 The synthetic peptide is active in vitro and in vivo.
The daily rhythm of plasma corticosteroid concentration was studied in nonhypophysectomized rats and in hypophysectomized rats implanted with beeswax pellets containing ACTH and T4. In the first experiment, male hypophysectomized rats were placed on a 12-h light, 12-h dark cycle (onset of light, 0600 h) with food and water available ad libitum. Beeswax pellets containing 1.5 mg ACTH and 150 micrograms T4 were implanted sc in these rats. Beginning 4 days after the implantation of ACTH and T4, daily rhythms of plasma corticosteroid concentration were detected in these rats on 3 successive days. The injection of sodium pentobarbital (40 mg/kg BW) or atropine sulfate (10 mg/kg BW) ip at 1200 h blocked the expected rise in plasma corticosteroid concentration at 1800 h in both these rats and a group of intact rats. In the second experiment, adrenal innervation was disrupted by spinal cord transection at the T-7 level. L-1-transected rats served as operated controls, and a third group was maintained as unoperated controls. One week after surgery, daily rhythms of plasma corticosteroid concentration were present in both unoperated and L-1 controls (P less than 0.01) but not in the T-7-transected rats. Inasmuch as an extrapituitary mechanism was capable of maintaining adrenocortical rhythmicity in hypophysectomized rats and disruption of adrenal innervation suppressed adrenocortical rhythmicity, it was hypothesized that adrenal innervation may be an extrapituitary mechanism which has a role in adrenocortical rhythmicity.
The effects of ovine CRF, lysine vasopressin (LVP), and their interrelationships, and rat hypothalamic extract (HME), on ACTH and beta-endorphin release by human pituitary tumor cells from two patients with Nelson's syndrome and one with Cushing's disease and on ACTH and cortisol secretion in vivo were studied. In cultured pituitary tumor cells, both LVP and CRF greatly stimulated ACTH and beta-endorphin release at maximally active concentrations of 0.1 microM and 10 nM, respectively. At these concentrations, the combination of the two substances had an additive or synergistic effect on hormone release. Low concentrations of HME potentiated and/or were synergistic with CRF-mediated ACTH release. In vivo, the combination of CRF (1 microgram/kg) and LVP (10 pressor units) induced greater ACTH release than the sum of the responses to CRF and LVP alone. This synergistic effect of CRF plus LVP concerned only ACTH release, while cortisol release after CRF plus LVP was equivalent to the sum of the maximal increments in this hormone after CRF and LVP alone. The peak levels of cortisol after a combination of CRF and LVP probably reflect the maximum stimulatory capacity of the adrenal cortex. These data support the concept that in man, both ovine CRF and vasopressin are corticotropin-releasing factors which act synergistically. Both substances might well regulate, at the pituitary level, the responsiveness of the pituitary-adrenal axis to stimuli reaching the hypothalamus. A test using ovine CRF and LVP together might provide a better index of total pituitary ACTH reserve than one using the two compounds separately.
The HPA axis is the principal effector of the generalized stress response and crucial for maintaining basal and stress-related homeostasis. There has been an exponential increase in knowledge regarding the interactions among the elements of the HPA axis (CRH, AVP, ACTH, glucocorticoids) and between the HPA axis and the other components of the stress system (locus ceruleus/norepinephrine-sympathetic systems), as well as with the axes responsible for reproduction, growth, and immunity. This new knowledge has allowed association of HPA axis dysfunction, characterized by sustained hyperactivity 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 or susceptibility to such disorders.
Even though functional CRH receptors have been identified in several brain regions by ligand binding, the identity of brain areas expressing the CRH receptor gene has not been described. The recent cloning of the rat CRH receptor gene has permitted us to conduct an in situ hybridization histochemistry study to localize CRH receptor mRNA in brain, using an antisense 35S-labeled riboprobe and autoradiography. In virus- and pathogen-free, unstressed, adult male Sprague-Dawley rats we observed CRH receptor gene expression in several brain regions, most of which had been previously shown to bind radiolabeled CRH. Those regions include the pituitary, olfactory bulb, hippocampal formation, cerebral and cerebellar cortexes, hypothalamus, median eminence, amygdala, olfactory tubercle, choroid plexus, thalamus, and inferior colliculus. Further studies are needed to determine the cell types expressing both CRH receptor mRNA and the CRH receptor peptide in nervous system as well as in peripheral tissues.
Neuropeptides are ubiquitous in the sympathetic system and modulate transmission at the levels of the intermediolateral cell column, sympathetic ganglia, and neuroeffector junctions. Several neuropeptide-containing pathways from the hypothalamus and medulla modulate excitability of preganglionic neurons. Neuropeptides coexist with norepinephrine or acetylcholine in subpopulations of chemically coded, target-specific sympathetic ganglion neurons. Neuropeptide Y is colocalized in adrenergic vasoconstrictor neurons, whereas vasoactive intestinal polypeptide is colocalized in cholinergic sudomotor neurons. Neuropeptide expression is plastic; during development, neurons that switch from a noradrenergic to a cholinergic phenotype increase expression of vasoactive intestinal polypeptide, somatostatin, and substance P. Preganglionic inputs increase neuropeptide Y and inhibit substance P expression. Sympathetic denervation produces sprouting of sensory fibers containing substance P and calcitonin gene-related peptide in target tissues. Neuropeptides from preganglionic fibers (e.g., enkephalin) and primary afferents (e.g., substance P, vasoactive intestinal polypeptide) modulate transmission in sympathetic ganglia. Neuropeptide Y produces vasoconstriction, prejunctional inhibition of norepinephrine release, and postjunctional potentiation of norepinephrine effects. Plasma neuropeptide Y increases during intense sympathoexcitation, hypertension, and pheochromocytoma. Dystrophic neurites containing neuropeptide Y occur in human sympathetic ganglia during aging, diabetes, and dysautonomia. Sympathetic neuropeptides may thus have important clinical implications.