ArticleLiterature Review

Tsigos C, Chrousos GPHypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 53:865-871

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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.

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... Psychological stress is often associated with fluctuations of stress hormones, such as cortisol and adrenaline (Tsigos & Chrousos, 2002). Cortisol is the primary stress hormone that is involved in governing the stress response from the moment of stress elicitation to recovery from stressful events. ...
... Commonly known as the "hormonal endpoint" of the HPA axis, cortisol is primarily responsible for the body's reactions to stressors (Tsigos & Chrousos, 2002). Cortisol follows a circadian rhythm which is linked to the sleep/wake pattern in humans; therefore, basal levels of cortisol vary between the daytime and the evening (Tsigos & Chrousos, 2002). ...
... Commonly known as the "hormonal endpoint" of the HPA axis, cortisol is primarily responsible for the body's reactions to stressors (Tsigos & Chrousos, 2002). Cortisol follows a circadian rhythm which is linked to the sleep/wake pattern in humans; therefore, basal levels of cortisol vary between the daytime and the evening (Tsigos & Chrousos, 2002). The rate of its secretion is dependent on the level of circulating corticotrophin, under extreme stimulating conditions, the level of cortisol in the human body can exceed 250 mg a day, approximately an 125% of its typical level of 20 mg (Garrod, 1958). ...
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Psychological stress and its inevitable trajectory toward mental health deteriorations such as clinical and major depression has become an unprecedented global burden. The diagnostic procedures involved in the characterization of mental illnesses commonly follow qualitative and subjective measures of stress, often leading to greater socioeconomic burdens due to misdiagnosis and poor understanding of the severity of such illnesses, further fueled by the stigmatization surrounding mental health. In recent years, the application of cortisol and stress hormone measurements has given rise to an alternative, quantifiable approach for the psychological evaluation of stress and depression. This review comprehensively evaluates the current state-of-the-art technology for measuring cortisol and dehydroepiandrosterone (DHEA) and their applications within stress monitoring in humans. Recent advancements in these fields have shown the importance of measuring stress hormones for the characterization of stress manifestation within the human body, and its relevance in mental health decline. Preliminary results from studies considering multimodal approaches toward stress monitoring have showcased promising developments, emphasizing the need for further technological advancement in this field, which consider both neurochemical and physiological biomarkers of stress, for global benefit.
... The SAM steers the release of the catecholamines epinephrine (adrenalin) and norepinephrine (noradrenaline, NA) from the medullar (O'Connor et al., 2021) into the blood stream, while the HPA axis steers the release of cortisol from the adrenal cortex (O'Connor et al., 2021) into the blood stream. As in the periphery, NA and cortisol play a vital role in the central stress response (Tsigos and Chrousos, 2002). However, while cortisol released by the HPA does cross the blood-brain barrier and influences central processing directly (Pardrige and Mietus, 1979), NA released by the SAM does not permeate the blood-brain barrier and thus cannot directly influence central processing (Weil-Malherbe, 1961). ...
... On the one hand, the central noradrenergic stress response via α1-AR activation in the paraventricular nucleus increases HPA activity, thus leading to increased peripheral and central cortisol (Ma and Morilak, 2005). On the other hand, the glucocorticoidal stress response seems to provide a negative feedback loop for both itself and the LC/NE by inhibiting corticotropin releasing hormone excretion in the paraventricular nucleus (Tsigos and Chrousos, 2002). Secondly, noradrenergic and glucocorticoidal effects on prefrontal processing could potentially enhance each other. ...
... While researchers have already begun to map the role of cortisol regarding changes in human cognition post-stress via correlative analysis or peripheral cortisol application (Shields et al., 2015), evaluating noradrenaline's role in post-stress changes in cognition is uniquely challenging. Other than cortisol (Kirschbaum and Hellhammer, 2000), the structures responsible for releasing cerebral (LC/NE, Tsigos and Chrousos, 2002) and peripheral (adrenal medulla, Wurtman and Axelrod, 1966) noradrenaline are to a great extent independent (but see Lambert et al., 1997). Additionally, noradrenaline does not penetrate the blood-brain barrier (Weil-Malherbe, 1961). ...
Article
Laboratory procedures such as the Trier Social Stress Test or the (Socially Evaluated) Cold Pressor Test have been used to investigate working memory performance under stress. Researchers so far have reported a diverse spectrum of stress effects (including the lack thereof) on working memory tasks. We conducted a systematic review of the effect acute stress on working memory performance in standardized laboratory procedures. An overview of the existing literature suggests that acute stress affects working memory in a time-dependent manner, presumably due to the differing time scales of the main stress-reactive hormones involved. Based on the empirical evidence, we hypothesize that the immediate stress-induced release of noradrenaline decreases working memory performance within the first 10 minutes post stress. In addition, rapid cortisol effects impair working memory at a later time-interval beginning about 25 minutes post stress. We outline future research directions which could further explore the implications of our insights, as for example combined pharmacological and naturalistic stressor interventions.
... The cascade of these catecholamines, hormones, and glucose in the bloodstream from the stress system response stimulates increased heart rate (HR), blood pressure, and respiration (Tsigos and Chrousos, 2002;Chrousos, 2009). The rapid rise in energy, oxygenation, and blood flow is directed in greatest concentration to the heart, brain, and large muscles, while they are inhibited to other areas not required to respond to a threat, such as the digestive system (Tsigos and Chrousos, 2002). ...
... The cascade of these catecholamines, hormones, and glucose in the bloodstream from the stress system response stimulates increased heart rate (HR), blood pressure, and respiration (Tsigos and Chrousos, 2002;Chrousos, 2009). The rapid rise in energy, oxygenation, and blood flow is directed in greatest concentration to the heart, brain, and large muscles, while they are inhibited to other areas not required to respond to a threat, such as the digestive system (Tsigos and Chrousos, 2002). Therefore, activation of this sympatho-adrenal stress response improves chances of survival in the short term, by increasing resistance, strength, and focused attention (Tsigos and Chrousos, 2002;Artwohl, 2008;Fenici et al., 2011). ...
... The rapid rise in energy, oxygenation, and blood flow is directed in greatest concentration to the heart, brain, and large muscles, while they are inhibited to other areas not required to respond to a threat, such as the digestive system (Tsigos and Chrousos, 2002). Therefore, activation of this sympatho-adrenal stress response improves chances of survival in the short term, by increasing resistance, strength, and focused attention (Tsigos and Chrousos, 2002;Artwohl, 2008;Fenici et al., 2011). ...
... Inflammatory mediators, in turn, activate VN fiber endings, which generate postsynaptic excitatory potentials into STN neurons according to a somatotopic pattern [32,153]. Activation of the specific STN subnucleus by the inflammatory process stimulates two different mechanisms via the VN path: (1) the CAP and (2) the hypothalamic-pituitary-adrenal axis (HPA) [154][155][156]. These mechanisms are part of the central-autonomic-network output that could be regulated by the medial prefrontal cortex due to its descending connections to pre-autonomic cell groups in the hypothalamus, periaqueductal gray, and brainstem [157]. ...
... VN inputs to STN modulate the membrane potential of noradrenergic neurons within STN (group A2) that project to the parvicellular neurons of the paraventricular hypothalamic area (PVH) that, in turn, release a specific hormone, the corticotropinstimulating factor (CRF) [174]. CRF binds to specific receptors expressed by cells of the pituitary gland, releasing adrenocorticotropin, a hormone that modulates the cells in the zona fasciculata in the adrenal glands that, in turn, release glucocorticoids, which play a strong anti-inflammatory role [153,155,156]. ...
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Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, are incurable autoimmune diseases characterized by chronic inflammation of the gastrointestinal tract. There is increasing evidence that inappropriate interaction between the enteric nervous system and central nervous system and/or low activity of the vagus nerve, which connects the enteric and central nervous systems, could play a crucial role in their pathogenesis. Therefore, it has been suggested that appropriate neuroprosthetic stimulation of the vagus nerve could lead to the modulation of the inflammation of the gastrointestinal tract and consequent long-term control of these autoimmune diseases. In the present paper, we provide a comprehensive overview of (1) the cellular and molecular bases of the immune system, (2) the way central and enteric nervous systems interact and contribute to the immune responses, (3) the pathogenesis of the inflammatory bowel disease, and (4) the therapeutic use of vagus nerve stimulation, and in particular, the transcutaneous stimulation of the auricular branch of the vagus nerve. Then, we expose the working hypotheses for the modulation of the molecular processes that are responsible for intestinal inflammation in autoimmune diseases and the way we could develop personalized neuroprosthetic therapeutic devices and procedures in favor of the patients.
... It has been reported that prolonged submaximal exercise-induced stress in part by stimulating cortisol secretion (Kanaley et al. 2001;Jacks et al. 2002;Tsigos and Chrousos 2002;Hill et al. 2008;Dergaa et al. 2021). There were significant correlations between the cortisol response and the conscious perception of fatigue during strenuous exercise (Mcguigan et al. 2004;Caetano Junior et al. 2017). ...
... Our results are in agreement with findings reporting that muscular exercise causes an increase in some hormonal responses, such as catecholamines and cortisol (Kanaley et al. 2001;Jacks et al. 2002;Tsigos and Chrousos 2002;Hill et al. 2008;Dergaa et al. 2021;Souissi et al. 2021). We assume that the decrease in glucose responses to exercise was related to more fat burning and glycogen sparing in melatonin conditions (Mazepa et al. 2000). ...
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The regulation of the balance between glucose and lipid use during exercise has gained increasing attention in the last decades. The contribution of fat and glucose to energy expenditure can be modulated by hormones and other endogenous factors. The increase in melatonin during exercise may be linked to an enhancement in lipid utilization, reflected by an increase in triglyceride concentration. The purpose of this study was to explore the effect of daytime melatonin administration on plasma glucose, triglycer-ides, and cortisol responses to submaximal exercise. Eight physical education students were asked to run for 45 minutes at 60% of their maximum aerobic speed after 50 minutes of either melatonin-(6 mg) or placebo consumption. Cortisol, triglycerides, and glucose were measured in plasma samples before and immediately after exercise. Post-exercise cortisol, triglycerides, and glucose levels were corrected for fluid shifts. In both conditions , post-exercise cortisol significantly increased (by ≥20%). Post-exercise glucose levels significantly increased only in the placebo condition. However, post-exercise triglyceride levels significantly increased only in the melatonin condition. To conclude, acute melatonin administration decreases the glucose response while increasing triglycerides' response to exercise. Therefore, it would be possible to suggest that exogenous melatonin administration before endurance exercise could promote fat burning. ARTICLE HISTORY
... Blood pressure and heart rate are involved in the response to acute and chronic psychological stressors. Secretion of salivary cortisol is the final product of the activation of stress-response mechanisms, i.e., the hypothalamic-pituitary-adrenal axis [23]. Changes in the rate of its secretion have been associated with acute stress responses related to disease and cognitive impairment [24,25]. ...
... The decrease in patient stress was measured as a net change in the blood pressure (systolic and diastolic), heart rate, and salivary cortisol level [23][24][25]33]. We expected a significant difference in the biomarkers of stress between the DTI and SI groups. ...
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Background: Doll therapy (DT) is a non-pharmacological intervention for the treatment of the behavioural and psychological symptoms of dementia (BPSD). We designed a single-blind randomized controlled trial of the 30-day efficacy of DT in reducing the BPSD, professional caregivers' distress and patients' biomarkers of stress, and in improving the exploration and caregiving behaviours. Methods: We randomly assigned 134 women with moderate-to-severe dementia living in nursing homes (NHs) to a DT intervention (DTI, 67) or a sham intervention with a cube (SI, 67). Results: From the first to the 30th session, the DTI group showed a significant decrease in the Neuropsychiatric Inventory-NH (NPI-NH) total score and in the NPI-NH-Distress score compared to the SI group (both p < 0.001). We observed a greater interest in the doll than in the cube, a greater acceptance of a separation from the nurse among DTI participants, and caregiving and exploratory behaviours towards the doll. There were no differences between the groups in the stress biomarkers. Conclusions: Consistent with attachment theory, our findings support the 30-day efficacy of DT, as this non-pharmacological intervention promotes perceptions of security by creating a situation in which patients feel confident and engaged in a caregiving relationship with the doll and reduces the challenging behaviours that are stressful for professional caregivers.
... The efferent vagal nerves regulate gastrointestinal secretory and motor function, and also the activity in the endocrine system of the gut, while the vagal afferents allow gutbrain information flow from the gut to the CNS. Vagal afferent signaling has been implicated modulating mood and affect, including distinct forms of anxiety and fear and are involved in the activation/regulation of the Hypothalamic Pituitary Adreno axis, which coordinates the adaptive responses to stressors of any kind (Tsigos and Chrousos, 2002;Howland, 2014). The DMV also has an immunomodulatory role as the cholinergic anti-inflammatory pathway (Goverse et al., 2016;Breit et al., 2018), making the DMV a major component of the neuroendocrine-immune axis. ...
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The gastrointestinal tract communicates with the nervous system through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the enteric nervous system, the vagus nerve, the immune system, endocrine signals, the microbiota, and its metabolites. Alteration of communications in the gut-brain axis is emerging as an overlooked cause of neuroinflammation. Neuroinflammation is a common feature of the pathogenic mechanisms involved in various neurodegenerative diseases (NDs) that are incurable and debilitating conditions resulting in progressive degeneration and death of neurons, such as in Alzheimer and Parkinson diseases. NDs are a leading cause of global death and disability, and the incidences are expected to increase in the following decades if prevention strategies and successful treatment remain elusive. To date, the etiology of NDs is unclear due to the complexity of the mechanisms of diseases involving genetic and environmental factors, including diet and microbiota. Emerging evidence suggests that changes in diet, alteration of the microbiota, and deregulation of metabolism in the intestinal epithelium influence the inflammatory status of the neurons linked to disease insurgence and progression. This review will describe the leading players of the so-called diet-microbiota-gut-brain (DMGB) axis in the context of NDs. We will report recent findings from studies in model organisms such as rodents and fruit flies that support the role of diets, commensals, and intestinal epithelial functions as an overlooked primary regulator of brain health. We will finish discussing the pivotal role of metabolisms of cellular organelles such as mitochondria and peroxisomes in maintaining the DMGB axis and how alteration of the latter can be used as early disease makers and novel therapeutic targets.
... The observed increase in plasma cortisol may be as a result of stimulation of the ACTH secretion by the stress stimuli which stimulated the synthesis of cortisol precursors18. In response to a stressor, neurons with cell bodies in the paraventricular nuclei of the hypothalamus secrete corticotrophin releasing hormone (CRH) and argininevasopressin (AVP) into the hypophyseal portal system 19,20 . The CRH through the HPA then activates the pituitary and adrenal glands which is supported by Burtis C et al, Sabyasachi S et al and Tsigos C et al 18,19 . ...
Article
Background: Stress is an important mental health problem which significantly affects the medical under graduates. Cortisol is known as stress hormone. Medical education is very stressful out of all higher education and medical undergraduates are more affected when compared to other professional students. In that examination has been described as a naturalistic stressor capable of affecting human health. Objectives : To estimate and correlate serum cortisol and lipid profile before & during the examination in medical students. Materials & Methods: A longitudinal follow up study was done on 50 first MBBS students(aged,18-25 years) of Prathima college after taking informed consent. Subjects were assessed for stress parameters with given questionnaire of 42 items(DASS-42) and serum cortisol ,lipid profile at two times. Exactly 5 ml of venous blood was collected from each subject before & during major examination for cortisol & lipid profile. Cortisol was assessed using ELISA techniques, while lipid parameters were assessed using standard enzymaticspectrophotometric methods. Results: There was statistically significant increase in serum cortisol, Total cholesterol, HDL-cholesterol and LDL-cholesterol levels in students during examination stress compared to the before examination period (P = 0.001, 0.001, 0.001, 0.005 and 0.001, respectively). There was also non significant positive correlation between serum cortisol and other lipid profile parameters before examination stress but not during the examination period. Conclusion: Significant increase in cortisol, TC, HDL and LDL but no significant correlation between cortisol and the other parameters were observed during examination stress. This study could be helpful to the students in planning strategies to be adopted to cope up the examination stress to prevent harzards of stress..
... The TSST-C consists of public speaking and a mental arithmetic task in front of an audience (usually the investigators). On the other hand, the ANS is also activated during acute stress [8], with immediate secretion of the catecholamines norepinephrine and epinephrine followed by secretion of interleukin-6, an inflammatory cytokine [9,10]. The latter stimulates the circulating levels of high-sensitivity C-reactive protein (hsCRP) [11,12]. ...
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This pilot repeated measures study aims to evaluate the dynamics of the autonomic nervous system (ANS), the hypothalamic–pituitary–adrenal (HPA) axis, and/or their interplay with low-level inflammation in healthy schoolchildren during consecutive extrinsic stimuli. Twenty healthy schoolchildren and adolescents aged 11–14 years (12.5 ± 1.5) were consecutively exposed to an oral task (#2) and an arithmetic task (#3) (Trier Social Stress Test for Children (TSST-C)), lasting 5 min each, and a three-minute cellular phone call (#4). Salivary cortisol (SC) was sampled at baseline (#1) and immediately after each exposure (#2, 3, and 4). Baseline serum high-sensitivity C-reactive protein (hsCRP) and cortisol levels were also assessed. ANS dynamics and complexity were measured using Sample Entropy (SampEn) at each experimental time period (#1–4). Baseline serum hCRP and cortisol correlated negatively to each other, while the ANS and HPA axis acute reactions to the three consecutive stimuli differed over time. The ANS adaptation to these stimuli included complexity modulation, which was not dependent on baseline hsCRP or cortisol, and weakened during the third stimulation. However, baseline hsCRP and cortisol had a weakening and an increasing effect on the HPA axis over time, respectively. We conclude that low-level inflammation and baseline morning cortisol level have no effect on ANS dynamics but influence the HPA axis response to consecutive external stimuli.
... Additionally, a single traumatic stress exposure can be sufficient to cause depression or anxiety disorders [8][9][10]. Brain stress responses can include neuroinflammation [11][12][13][14] and alterations in key stress-related neuromodulators, such as the corticotropin-releasing hormone (CRH) and dynorphin, as well as mood and emotion regulators, such as dopamine and serotonin, to name a few [15,16]. To further complicate matters, in addition to changing their activity with stress, many stress-responsive neurotransmitters influence each other. ...
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The serotonin and kappa opioid receptor (KOR) systems are strongly implicated in disorders of negative affect, such as anxiety and depression. KORs expressed on axon terminals inhibit the release of neurotransmitters, including serotonin. The substantia nigra pars reticulata (SNr) is involved in regulating affective behaviors. It receives the densest serotonergic innervation in the brain and has high KOR expression; however, the influence of KORs on serotonin transmission in this region is yet to be explored. Here, we used ex vivo fast-scan cyclic voltammetry (FSCV) to investigate the effects of a KOR agonist, U50, 488 (U50), and a selective serotonin reuptake inhibitor, escitalopram, on serotonin release and reuptake in the SNr. U50 alone reduced serotonin release and uptake, and escitalopram alone augmented serotonin release and slowed reuptake, while pretreatment with U50 blunted both the release and uptake effects of escitalopram. Here, we show that the KOR influences serotonin signaling in the SNr in multiple ways and short-term activation of the KOR alters serotonin responses to escitalopram. These interactions between KORs and serotonin may contribute to the complexity in the responses to treatments for disorders of negative affect. Ultimately, the KOR system may prove to be a promising pharmacological target, alongside traditional antidepressant treatments.
... Durante la pubertad se presentan cambios relevantes en el eje hipotalámico pituitario adrenal (HPA), el cual está asociado con la reactividad al estrés (Tsigos y Chrousos, 2002). El desarrollo del eje HPA resulta en respuestas hormonales aumentadas, inducidas por el estrés y que involucran incrementos en los niveles basales de cortisol, hormona principal del eje HPA, lo cual podría llevar a vulnerabilidades y riesgos de psicopatología (Gunnar et al., 2009;Roberts y Lopez-Duran, 2018). ...
... A constant and poorly managed high stress level in people with type 2 diabetes will activate the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis and release stress hormones (e.g. cortisol), while blood glucose levels may also worsen (Tsigos & Chrousos, 2002). Diabetes distress also has an adverse effect on glycaemic control via the dysregulation of stress hormones (Snoek et al., 2015). ...
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Aim: To investigate the relationship between Type D personality and adverse health outcomes [glycated haemoglobin (HbA1c) and health-related quality of life (HRQOL)] directly, and indirectly via diabetes distress and social isolation in people with type 2 diabetes. Design: A secondary analysis of 524 participant's data derived from a cross-sectional, correlational study with people with type 2 diabetes. Methods: Data were analysed using the PROCESS macro of SPSS. Results: Type D personality was present in 31.3% of the participants, and exerted a direct effect on HRQOL but not on HbA1c. Type D personality indirectly affected both HbA1c and HRQOL via the mediators of diabetes distress and social isolation. Nurses need to monitor people with type 2 diabetes to determine whether Type D personality is present. Those with Type D personality should be provided with interventions to reduce diabetes distress and alleviate social isolation in order to improve HbA1c and HRQOL.
... The stress system coordinates the adaptive responses of the organism to stressors of any kind. The main components of the stress system are the corticotropinreleasing hormone (CRH) and locus coeruleus-norepinephrine-autonomic systems (Tsigos & Chrousos 2002). The acute phase response (APR) is part of the early-defense or innate immune system, which is triggered by different stimuli including trauma, infection, stress, neoplasia, and inflammation (Cray et al 2009). ...
... Under chronic stress, the end-hormones of the HPA axis, GCs, have direct as well as insulinmediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) (Tsigos & Chrousos 2002). In metazoa the adaptive reponse to metabolic stress is regulated via the reciprocal glucose-fatty acid cycle (Randle et al. 1963(Randle et al. , 1966Randle 1998;Heininger 2000Heininger , 2001Heininger , 2002a and is characterized by hypometabolism and an altered energy consumption/storage balance. ...
... Vagal efferent transmit messages "down" from the brain to the gut through efferent fibers, which make up 10-20% of all fibers, whereas vagal afferents transmit signals "up" from the intestinal wall to the brain, making up 80-90% of all fibers (Tubbs et al., 2015). The activation and regulation of the HPA axis, which regulates the adaptive responses to stressors, is mediated by the vagal afferent pathways (Tsigos and Chrousos, 2002). EECs, 1% of intestinal epithelial cells, communicate with vagal afferents either directly by releasing serotonin that activates 5-HT3 receptors on these fibers or indirectly through the action of gut hormones that target the brain, such as cholecystokinin (CCK), glucagon-like peptide-1, and peptide YY, via vagal afferents that express receptors for these anorexigenic or orexigenic (ghrelin, orexin) hormone (Strader and Woods, 2005). ...
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Gut-brain axis is a dynamic, complex, and bidirectional communication network between the gut and brain. Changes in the microbiota-gut-brain axis are responsible for developing various metabolic, neurodegenerative, and neuropsychiatric disorders. According to clinical and preclinical findings, the gut microbiota is a significant regulator of the gut-brain axis. In addition to interacting with intestinal cells and the enteric nervous system, it has been discovered that microbes in the gut can modify the central nervous system through metabolic and neuroendocrine pathways. The metabolites of the gut microbiome can modulate a number of diseases by inducing epigenetic alteration through DNA methylation, histone modification, and non-coding RNA-associated gene silencing. Short-chain fatty acids, especially butyrate, are well-known histone deacetylases inhibitors. Similarly, other microbial metabolites such as folate, choline, and trimethylamine-N-oxide also regulate epigenetics mechanisms. Furthermore, various studies have revealed the potential role of microbiome dysbiosis and epigenetics in the pathophysiology of depression. Hence, in this review, we have highlighted the role of gut dysbiosis in epigenetic regulation, causal interaction between host epigenetic modification and the gut microbiome in depression and suggest microbiome and epigenome as a possible target for diagnosis, prevention, and treatment of depression.
... Almost any type of physical or mental stress can lead within minutes to greatly enhanced secretion of cortisol due to increased activity in the limbic system, especially the amygdala and hippocampus, both transmit signals to the posterior medial hypothalamus. Cortisol has direct negative [9] feedback effects on. The increase stress hormones may be as a result of stimulation of the ACTH secretion by the stress stimuli which stimulated the synthesis of adrenaline and [10] cortisol precursors. ...
Article
Stress is described as a state of anxiety, strain, nervousness, tension, constant worry or pressure, to produce hypertension and other cardiovascular disorders and can greatly enhanced secretion of cortisol due to increased activity in the limbic system, especially in the region of the amygdala and hippocampus,The aims of this study was to investigate whether regular practice of yoga for sixty minutes twice a day for six months can improve the cardiovascular status and decrease serum cortisol in hyper-reactors to cold pressor test in young healthy medical students. SummaryThe regular practice of yoga for six months acts as stress buster, to reduce the hyerrectivity to cold pressor test by inducing parasympathetic predominance and cortico- hypothalamo-medullary inhibition.
... Almost any type of physical or mental stress can lead within minutes to greatly enhanced secretion of cortisol due to increased activity in the limbic system, especially the amygdala and hippocampus, both transmit signals to the posterior medial hypothalamus. Cortisol has direct negative [7] feedback effects on. The increase stress hormones may be as a result of stimulation of the ACTH secretion by the stress stimuli which stimulated the synthesis of adrenaline and [8] cortisol precursors. ...
Article
Stress is a complex,dynamic process of interaction between a person and his or her life Stress is described as a state of anxiety, strain, nervousness, tension, constant worry or pressure, to produce hypertension and other cardiovascular disorders due to greatly enhanced secretion of cortisol and adrenaline due to increased activity in the limbic system, amygdala and hippocampus and parasympathetic predominance The aims of this study was to investigate whether regular practice of yoga for sixty minutes twice a day for six months can improve the cardiovascular parameters in hyper-reactors to cold pressor test in young healthy medical students. Summary- The regular practice of yoga for six months acts as stress buster,to reduce the hyerrectivity to cold pressor test by inducing parasympathetic predominance and cortico- hypothalamo-medullary inhibition.
... One potential physiological cause of abnormal vaginal bleeding, irregular menstruation and oligomenorrhea in students with perceived stress, is the extended activation of the hypothalamicpituitary adrenal axis by stress, which may change hormonal pro les and cause the disruption of normal ovulation and menstrual cycles. [53] Study limitations: While using a validated stress questionnaire, this study enrolled a sizable sample size to examine the relationship between psychological stress and menstruation problems. Nevertheless, the current study does have a number of limitations, such as the fact that it was cross-sectional and hence unable to draw a causal link between psychological stress and menstruation disorders. ...
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Background: Menstrual disorders are of the most prevalent health issues in young female students studying in health science faculties. The purpose of this study was to provide an insight on the menstrual patterns among medical faculties students, and to determine whether stress can be an identified factor for its various disorders. Methods: This was a cross-sectional study conducted in the Faculties of Medicine, Dentistry and pharmacy in the Syrian Private University, Damascus, Syria, between October and November of 2022. Nine hundred and eighty female students anonymously completed the identification of menstrual problems and Perceived Stress Scale (PSS) questionnaire. The date was analyzed with Social Science Statistics Package. Results: The mean age of the students was 21.52 ± 2.06 years. The most common menstrual disorders in this study were dysmenorrhea (88%), premenstrual syndrome (87%), and irregular menstrual cycle (21%). We found a statistically significant relationship between the occurrence of irregular menstrual cycle and amenorrhea, polymenorrhea, and oligomenorrhea. 82% had mild to moderate stress, 10% had high stress, while 8% had low stress. There was a statistically significant relationship between stress and abnormal vaginal bleeding, oligomenorrhea, and menstrual irregularity. Conclusion: There was a really high prevalence of stress among these students, which was also associated with the occurrence of various menstrual disorders, both of which can not only have an impact on a student's ability to function academically, but also may potentially have detrimental impacts on their reproductive and mental health. It is for that reason we advise that all students of medical faculties get brief courses on stress management strategies as part of their curriculum. Additionally, all medical faculties universities should set up procedures for the early detection of individuals with stress and menstruation disorders. The identified students with high stress levels should also get prompt gynaecological and psychiatric counselling.
... [8][9][10][11] Stress and anxiety lead to similar brain activity, such as an increase in amygdala activity. [12,13] High levels of stress have been linked to several physical and mental health issues, such as cardiovascular disease, persistent pain, anxiety disorders, depression, burnout, and addictions. [14][15][16] There has been evidence that listening to or making music reduces physiological arousal, as evidenced by lower cortisol levels, or a reduction in blood pressure and heart rate. ...
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Background: The effectiveness of educational music training in lowering stress and performance anxiety among first-year undergraduate music education students is an understudied area. The goal of this study was to determine if educational music training affects first-year undergraduate music education students' stress and anxiety associated with musical performance. Methods: A randomized controlled trial design was used in this study. A waiting list group of 35 students and an educational music training intervention group of 35 first-year undergraduate music education students were randomized for the study to commence. The Kenny music performance anxiety (MPA) scale and perceived stress scale (PSS) were used as outcome measures. Results: The findings show that, among first-year undergraduate music education students, educational music training decreased their stress level associated with music performance [F(1, 68) = 390.751; P = .001, ηp2 = 0.270]. It was also found that after the educational music training, the students reported decreased anxiety level associated with music performance [F(1, 68) = 1375.495; P = .001, ηp2 = 0.344]. Significant interaction effects of educational music training and time on students' stress [F(2, 68) = 127.301; P = .001] and anxiety levels [F(2, 68) = 260.535; P = .001] were also found. Conclusion: Educational music intervention can be successful as a means of reducing anxiety and stress in undergraduate music education students during the first year of study.
... One potential physiological cause of abnormal vaginal bleeding, irregular menstruation and oligomenorrhea in students with perceived stress, is the extended activation of the hypothalamicpituitary adrenal axis by stress, which may change hormonal pro les and cause the disruption of normal ovulation and menstrual cycles. [53] Study limitations: While using a validated stress questionnaire, this study enrolled a sizable sample size to examine the relationship between psychological stress and menstruation problems. Nevertheless, the current study does have a number of limitations, such as the fact that it was cross-sectional and hence unable to draw a causal link between psychological stress and menstruation disorders. ...
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Background: Menstrual disorders are of the most prevalent health issues in young female students studying in health science faculties. The purpose of this study was to provide an insight on the menstrual patterns among medical faculties students, and to determine whether stress can be an identified factor for its various disorders. Methods: This was a cross-sectional study conducted in the Faculties of Medicine, Dentistry and pharmacy in the Syrian Private University, Damascus, Syria, between October and November of 2022. Nine hundred and eighty female students anonymously completed the identification of menstrual problems and Perceived Stress Scale (PSS) questionnaire. The date was analyzed with Social Science Statistics Package. Results: The mean age of the students was 21.52 ± 2.06 years. The most common menstrual disorders in this study were dysmenorrhea (88%), premenstrual syndrome (87%), and irregular menstrual cycle (21%). We found a statistically significant relationship between the occurrence of irregular menstrual cycle and amenorrhea, polymenorrhea, and oligomenorrhea. 82% had mild to moderate stress, 10% had high stress, while 8% had low stress. There was a statistically significant relationship between stress and abnormal vaginal bleeding, oligomenorrhea, and menstrual irregularity. Conclusion: There was a really high prevalence of stress among these students, which was also associated with the occurrence of various menstrual disorders, both of which can not only have an impact on a student's ability to function academically, but also may potentially have detrimental impacts on their reproductive and mental health. It is for that reason we advise that all students of medical faculties get brief courses on stress management strategies as part of their curriculum. Additionally, all medical faculties universities should set up procedures for the early detection of individuals with stress and menstruation disorders. The identified students with high stress levels should also get prompt gynaecological and psychiatric counselling.
... Vagal efferent transmit messages "down" from the brain to the gut through efferent fibers, which make up 10-20% of all fibers, whereas vagal afferents transmit signals "up" from the intestinal wall to the brain, making up 80-90% of all fibers (Tubbs et al., 2015). The activation and regulation of the HPA axis, which regulates the adaptive responses to stressors, is mediated by the vagal afferent pathways (Tsigos and Chrousos, 2002). EECs, 1% of intestinal epithelial cells, communicate with vagal afferents either directly by releasing serotonin that activates 5-HT3 receptors on these fibers or indirectly through the action of gut hormones that target the brain, such as cholecystokinin (CCK), glucagon-like peptide-1, and peptide YY, via vagal afferents that express receptors for these anorexigenic or orexigenic (ghrelin, orexin) hormone (Strader and Woods, 2005). ...
... 22 In our study as per IDRS score high risk was found in 68 (34%) for developing diabetes whereas high-risk category percentage was lower in the studies done by Arun 39,40 The IDRS has a sensitivity of 72.5% and specificity of 60.1% according to CURES by Mohan et al. 41 As per Dudeja et al study, the IDRS has a sensitivity of 72.5% and specificity of 60.1% and is derived based on the largest population-based study on diabetes in India CURES. 42 This risk score has moderate sensitivity of 75.4% and specificity of 70% in detecting undiagnosed DM. 43 Psychological stress is involved in the progression of multiple diseases. Severe types of psychological stress affect both the nervous and peripheral systems. ...
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Background: Diabetes mellitus is a major public health problem in Andhra Pradesh and Indian diabetes risk score (IDRS) is a cost-effective tool for screening of undiagnosed diabetic individuals in the community. The objectives of this study were to assess the sensitivity and specificity of IDRS method as a screening tool in community as well as to determine the importance of stress scale in relation with diabetes. Methods: This cross-sectional study was conducted from April 2022 to May 2022 among 18 years and above residing in select areas of Prakasam and Visakhapatnam districts. House to house survey was done for collecting data on IDRS with pretested questionnaire. Cohen's perceived stress scale was used to assess the level of stress. Results: Out of 200 study subjects, 53.5% were males, mean age was 40.13±15 years and 23% were illiterate. The overall prevalence of diabetes was 21.0%, as per IRDS, 20.5% were in low-risk category. 44.5% and 31.5% were in moderate and high-risk category respectively. No physical exercise- 45 (71.7%), consumption of non-vegetarian food43 (65%), low consumption of fruits- 47 (74.6%) among high-risk category. Sensitivity of IDRS was 50.6%, specificity 71.6%, positive predictive value 33.8% and negative predictive value 86.3%. Mean perceived stress score was found to be 19.5±4.03. Conclusions: This study estimated the usefulness of Indian diabetes risk score for identifying high risk diabetic subjects in Indian urban population so that proper intervention can be done to reduce the burden of disease. Stress may be included in the IDRS. Keywords: Diabetes mellitus, IDRS, Perceived stress scale, Physical activity, BMI
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The hypothalamic paraventricular nucleus (PVN) expresses multiple neuropeptides and plays an essential role in several physiological processes. Among the brain areas directly projecting to the PVN are deep brain structures closely related to instinctive behavior. Moreover, the PVN neurons can project abundant axons to multiple downstream brain regions and are key components of the stress response. Accordingly, PVN malfunction is implicated in stress-related psychiatric diseases. When facing stressors, the PVN releases neuropeptides into the pituitary, activating the hypothalamic–pituitary–adrenocortical axis to regulate blood pressure, energy metabolism, and electrolyte balance. This review summarizes the physiological functions of PVN-related neural circuits and neuropeptides, as well as their role in anxiety, which may provide insights into the mechanism of stress-related psychiatric disorders assisting in the development of new treatments.
... The HPA axis comprises the paraventricular nucleus (PVN) of the hypothalamus, the anterior pituitary, and the adrenal cortex [29]. When stressed, PVN of the hypothalamus releases corticotropin-releasing factor (CRF), which then engages the release of the adrenocorticotropic hormone (ACTH) from the anterior pituitary, and ACTH travels through the circulation and stimulates the adrenal gland to synthesize and release glucocorticoids (cortisol in humans, or corticosterone in rats) [30]. As an acute stress, IS can activate HPA axis output in a time-specific manner. ...
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Ischemic stroke (IS) remains a leading cause of death and long-term disability globally. Several mechanisms including glutamate excitotoxicity, calcium overload, neuroinflammation, oxidative stress, mitochondrial damage, and apoptosis are known to be involved in the pathogenesis of IS, but the underlying pathophysiology mechanisms of IS are not fully clarified. During the past decade, gut microbiota were recognized as a key regulator to affect the health of the host either directly or via their metabolites. Recent studies indicate that gut bacterial dysbiosis is closely related to hypertension, diabetes, obesity, dyslipidemia, and metabolic syndrome, which are the main risk factors for cardiovascular diseases. Increasing evidence indicates that IS can lead to perturbation in gut microbiota and increased permeability of the gut mucosa, known as “leaky gut,” resulting in endotoxemia and bacterial translocation. In turn, gut dysbiosis and impaired intestinal permeability can alter gut bacterial metabolite signaling profile from the gut to the brain. Microbiota-derived products and metabolites, such as short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine N-oxide (TMAO), lipopolysaccharides (LPS), and phenylacetylglutamine (PAGln) can exert beneficial or detrimental effects on various extraintestinal organs, including the brain, liver, and heart. These metabolites have been increasingly acknowledged as biomarkers and mediators of IS. However, the specific role of the gut bacterial metabolites in the context of stroke remains incompletely understood. In-depth studies on these products and metabolites may provide new insight for the development of novel therapeutics for IS.
Chapter
The hypothalamic-pituitary-adrenal (HPA) axis is the main component of the endogenous stress response system which regulates the bodily response to real or perceived environmental stressors threatening homeostasis. Several theoretical models have been developed to conceptualize the link between stress and eating behavior, so the HPA axis activity has been widely investigated in people with eating disorders. In patients with eating disorders, both increased and decreased HPA axis activity has been reported. The contradictory findings can be due in part to the heterogeneity of methodologies used across studies. Reduced caloric intake and weight loss, as well as binge-purging behaviors, are associated with an increased activity of HPA axis. However, when considering the occurrence of early adverse experiences, which are associated with impairment of HPA axis functioning, the findings are less clear-cut. Thus, it is important to remember that the mechanisms connecting stress and eating disorders are complex and multi-layered. It is important to recognize the variables that can contribute to these results in order to build formulations and develop precise and targeted treatments.
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Stress is a biological phenomenon that can be described in biological terms, even at a cellular level. Poverty is a social (and societal) challenge that can be examined using both the descriptive language of the social sciences and the normative language of moral philosophy and ethics. Poverty is experienced as stressful, and many studies discuss the link between poverty and stress. A book about stress and poverty connects a biological phenomenon with a social and societal challenge. This book is about poverty “and” stress, not in the sense of an addition—we talk about stress, and then we talk about poverty—but in the sense of a connection in which we talk about poverty insofar as it is related to stress, and we talk about stress insofar as it is related to poverty. By exploring this link, we are exploring an intersection, the intersection between stress and poverty. How can stress research help us to reach a deeper understanding of poverty, and how can poverty research contribute to a richer discourse on stress?
Chapter
Stress research started with a seminal paper in Nature (Selye. Nature 138:32, 1936). Although the concept existed in medicine before that time, it was not called “stress,” and Hans Selye was the first to give it a firm footing as a basic endocrinological and medical concept. His idea, based on the case histories of his patients and later on animal experiments, was that a rather large variety of cases could lead to very similar ailments, among them ulcers, heart disease, thymic regression, adrenal hyperplasia, and depression, all accompanied by activation of the hormonal hypothalamic–pituitary–adrenal axis (HPA axis) (Tsigos and Chrousos. J Psychosom Res 53:865–871, 2002). In this chapter, we offer a brief portrayal of Hans Selye and an introduction to the groundbreaking early developments of stress research that he sparked, thereby strongly inspiring subsequent generations of researchers.
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While we have seen in Chap. 3 that stress is an ambivalent phenomenon that is at the same time unavoidable and necessary for life and—if exceeding an organism’s capacities to respond to stress—life threatening. In this chapter, we turn to the often-destructive effects and detrimental consequences of chronic stress. Focusing on different regions of the brain, we will describe manifestations of chronic stress in terms of “typical” stress-related syndromes and diseases, such as major depression, psychosomatic heart diseases, and the impact of stress on the immune system. The findings from research we draw on in this chapter concerning such adverse outcomes of stress exposure clearly touch not solely on the physiology of stress but also on stress’s psychological side. This is a crucial aspect when we address the stress of poverty. Before going into a deeper conversation between stress research and poverty studies in later chapters of this book, here we will present some anchor points on the relationship of chronic stress and the experience of poverty, and provide a working hypothesis for the generation of psychological stress.
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Background:The number of student nurses leaving the training in the first year is increasing, and one of the reasons could be the fear of facing reality like death and dying. This study aimed to explore first-year African indigenous student nurses' experiences with death and a patient dying in the clinical area. Method:Qualitative research method was employed, and data were collected using semi-structured interviews. Data were collected from African indigenous student nurses during their first year of study. Thematic analysis of the responses provided by nine participants revealed four themes and nine sub-themes. Themes included knowledge, emotional trauma, low self-esteem, and nutritional disorder. Results:Results revealed lack of experience, emotional trauma, low self-esteem, and nutritional disorder as the main effects among these nurses. Negative attitudes of clinical professionals, shortage of staff, and congested block programs were identified as some courses of attrition. Conclusions:Findings suggest the need to review the curriculum for first-year student nurses. In addition, professional clinical nurses who serve as preceptors are trained as mentors of these student nurses. Students felt overwhelmed by this experience which can be attributed to indigenous belief systems about death and dying. Most of these nurses come to nursing without seeing a dead or dying person because they believe that the evil spirit surrounds a dead person until they have reached a certain age.
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The current narrative review summarizes and examines several theories of panic disorder (PD) including biological theories, encompassing neurochemical factors, metabolic and genetic theories, respiratory and hyperventilation theories and cognitive theory. Biological theories have informed the development of psychopharmacological treatments; however, they may be limited in their utility given the efficacy of psychological treatments. In particular, behavioral and, more recently, cognitive models have garnered support due to the efficacy of cognitive-behavior therapy (CBT) in treating PD. The role of combination treatments has been found to be superior in the treatment of PD in particular cases, lending support for the need for an integrated approach and model for PD given that the etiology of PD is complex and multifactorial.
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The symposium discussed mechanisms of interleukin (IL)-6 blockade for the treatment and management of patients with rheumatoid arthritis (RA). Prof Smolen provided a clinical update of the latest efficacy and safety data on various anti-IL-6 drugs, including sirukumab. He noted that all anti-IL-6 drugs were efficacious in treating physical and mental symptoms of RA. When the efficacy of anti-IL-6 antibodies was compared between drugs, targeting the IL-6 ligand was similar to targeting its receptor. Prof Pitzalis described the pathophysiology of IL-6 in RA and the reason for targeting IL-6. Lastly, Prof Choy outlined the importance of measuring patient-reported outcomes to monitor symptom improvement and evaluate the impact of IL-6 on mental functioning. Because IL-6 modulates the hypothalamic pituitary axis, fatigue and depression are common in patients with RA. Evidence suggests that the inhibition of IL-6 activity reduces symptoms of fatigue and depression in patients with RA, and that improvement in mental health occurs independently, rather than as a consequence of improvement in physical functioning.
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Background: The hypothalamic-pituitary-adrenocortical axis (HPAA) response to sepsis can be impaired in critical illness. Corticotropin-releasing hormone (CRH) stimulation test might assess HPAA function in foals. Objective: To evaluate plasma cortisol, ACTH, arginine vasopressin (AVP), and endogenous CRH (eCRH) response to different doses of ovine CRH (oCRH). Animals: Healthy (n = 14) and hospitalized (n = 15) foals <7 days of age. Methods: In this prospective randomized study, oCRH (0.1, 0.3, and 1 μg/kg) was administered intravenously and blood samples were collected before, 15, 30, 60, and 90 minutes after administration of oCRH to determine plasma hormone concentrations. The hormonal response was evaluated as the difference (Delta; μg/dL or pg/mL) or percent change between baseline hormone concentration and each time point after oCRH stimulation. Results: Cortisol concentrations increased from baseline at 15 minutes with 0.1 and 0.3 μg/kg and at 30 and 60 minutes from baseline with 1 μg/kg oCRH (P < .05) in healthy and hospitalized foals. ACTH concentrations increased from baseline at 15 minutes with 0.1 μg/kg and at 30 minutes with 1 μg/kg oCRH (P < .05) in hospitalized foals. Delta cortisol 0 - 30, ACTH 0 - 30, and eCRH 0 - 30 was higher for the 1 μg/kg compared with 0.1 μg/kg oCRH in healthy foals (P < .05). Delta ACTH 0 - 15 and eCRH 0 - 30 was higher for the 1 μg/kg compared with the lower doses of oCRH in hospitalized foals (P < .05). Conclusions and clinical importance: Cortisol, ACTH, and eCRH concentrations increased in response to administration of all doses of oCRH. One microgram per kilogram of oCRH appears to be optimal for the assessment of HPAA in healthy and hospitalized foals.
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All humans deal with acute psychological stress periodically. Some individuals are affected by needle phobia in which a heightened sense of arousal is precipitated by venepuncture. Acute psychological stress invokes a range of physiological changes including activation of the sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal axes. In this review article, we first examine the human response to acute stress. We then provide an overview of how psychological stress in a subject is likely to be a source of pre-analytical variability for certain measurands, and the major biochemical markers that have been studied in research aiming to quantify stress. As such, we highlight how stress can be a hindrance to the accurate interpretation of certain laboratory results (particularly cortisol, prolactin, metanephrines and growth hormone), and point out the role that biochemical analysis might play in future studies looking at the effects of stress on human behaviour.
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The objective was to evaluate the effects of a stress management cognitive behavioural therapy (CBT) followed during pregnancy on subsequent childhood on hair cortisol at birth and on neurodevelopment and hair cortisol concentrations at 6 months of age. The study sample included 48 pregnant women, divided into two groups: 24 women in the Therapy Group (TG) and 24 women who received standard pregnancy care (Control Group; CG). To test the therapy efficacy, an evaluation of the hair cortisol concentrations and psychological stress, psychopathological symptomatology and resilience was conducted before and after the treatment. The level of cortisol in their hair was obtained during pregnancy and that of their babies at birth. Six months after birth, a cortisol sample was taken from the hair and the babies' neurodevelopment was evaluated based on a Bayley-III test. The TG presented reductions in psychological stress and psychopathological symptomatology after treatment. On the other hand, the CG increased their cortisol concentrations between the pre and post intervention, remaining stable in the TG. Moreover, results showed that TG babies had lower cortisol concentrations at birth and obtained significantly higher cognitive and motor development scores at 6 months. These findings support that providing psychological care to pregnant women may not only have a benefit on these women's mental state, but may also benefit the neurodevelopment of their offspring. This article is protected by copyright. All rights reserved.
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Background: Major depressive disorder (MDD) with comorbid anxiety is very common and is associated with worse clinical outcomes. MDD patients at different ages of onset may have different clinical features and associated factors. The aim of this study was to investigate the prevalence of anxiety and related factors in MDD patients at different ages of onset. Methods: A total of 1718 first-episode and drug-naïve (FEDN) MDD patients were recruited. The cutoff point for early-adulthood onset (EAO) and mid-adulthood onset (MAO) was the first depressive episode before or after age 45 years. Clinical features (depressive, anxiety and psychiatric symptoms) and some metabolic parameters were collected. Results: There was no significant difference in the prevalence of anxiety between EAO patients (50.7 %) and MAO patients (55.7 %). For EAO patients, regression analysis showed that TSH levels, TgAb levels, and TC levels were significantly associated with anxiety. For MAO patients, regression analysis showed that anxiety was associated with HDL-c levels and impaired glucose metabolism. Furthermore, suicide attempts, psychotic symptoms, and depression severity were correlated with anxiety in both groups. Limitations: Our cross-sectional study cannot explain the causal relationship between anxiety and related factors in MDD patients at different ages of onset. Conclusions: This study revealed that the clinical characteristics and factors associated with anxiety in MDD patients differed according to age of onset, and therefore age of onset needs to be considered while treating anxiety.
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Type 2 diabetes (T2D) is associated with severe mental illnesses (SMIs), such as schizophrenia, bipolar disorder, and depression. However, causal relationships between SMIs and T2D remain unclear owing to potential bias in observational studies. We aimed to characterize the causal effect of SMI liability on T2D using two-sample Mendelian randomization (MR). The causality between liability to SMI and T2D was investigated using the inverse-variance weighted (IVW), MR-Egger, MR-Egger with a simulation extrapolation, weighted median, and the MR pleiotropy residual sum and outlier method. Similarly, we performed additional MR which can detect the reverse causation effect by switching exposure and outcome for T2D liability for SMI. To further consider pleiotropic effects between SMIs, multivariable MR analysis was performed after accounting for the other traits. In the univariable IVW method, depression showed a causal effect on T2D (odds ratio [OR]: 1.128, 95% confidence interval [CI]: 1.024–1.245, P = 0.014). Multinomial MR more strongly supported these results (IVW OR: 1.197, 95% CI: 1.069, 1.340, P = 0.002; MR-Egger OR: 1.198, 95% CI: 1.062, 1.349, P = 0.003). Bidirectional MR showed reverse-causality absence between depression and T2D. However, causal relationship of bipolar and schizophrenia on T2D was not detected. Careful attention is needed for patients with depression regarding T2D prevention and treatment.
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Background Tuberculosis (TB) patients commonly suffer from sleep issues owing to various adverse drug reactions (ADRs), disease symptoms, and the contagious nature of their disease. These sleep issues negatively affect the treatment outcome and quality of life. However, the prevalence of sleep disturbance and its associated factors among TB patients have rarely been reported. Methods A total of 497 inpatients with TB from three hospitals in China were enrolled in this cross-sectional study to investigate their sleep quality using the Pittsburgh sleep quality index (PSQI). Clinical data, including demographic information, TB-related stigma, perceived stress, and nutrition- and immunity-related indicators, were also collected to explore the factors associated with sleep disturbance among the recruited patients. Results Approximately 70% of the recruited patients reported a sleep disturbance to varying degrees, presenting poorer global and subjective sleep qualities, longer sleep latency, shorter sleep duration, lower sleep efficiency, more frequent sleep disturbances, greater use of sleeping medication, and more severe daytime dysfunction. Furthermore, the body mass index (BMI), hemoglobin levels, albumin levels, and T lymphocyte count of the patients in the poor sleep quality group were significantly lower than those in the good sleep quality group ( p < 0.05). Increasing age, higher income, drug resistance, higher stigma or stress perception, lower albumin levels, and lower CD4 levels were significantly associated with sleep disturbance among TB patients ( p < 0.05). Conclusion Three-quarters of the participants were found to suffer from a probable sleep disturbance. And sleep problems are linked to biological traits that interact with psychological, cultural, and social factors in complex ways. It is therefore important to pay attention to the sleep quality of TB patients, especially those with the identified risk factors. Besides, taking care of these risk factors may prove to be an effective sleep management strategy.
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This meta‐analysis examined the relationship between prenatal maternal stress and/or anxiety and the outcomes of children aged 3 months to 9 years. Of the 8754 studies published before June 2021 that were synthesized, 17 conducted in Western countries were included in the meta‐analysis (Ntotal = 23,307; Mmales 54%; Methnicity White 77%, Pacific 15%, African American/Black 10%, Middle Eastern 7%, Eastern 8%). Effect sizes ranged from −0.41 to 0.15. A weak negative association was found between prenatal stress and/or anxiety exposure and children's general intellectual development. Associations varied based on the type of exposure. Findings are limited to developed counties and cannot be generalized to low‐ and middle‐income countries. Directions for maternal prenatal intervention and future studies are discussed.
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Background The past two years of the COVID-19 pandemic were stressful to most children and adolescents, and some of the children may have experienced a high level of stress and trauma. To date, no study has examined differences in self-reported stress and trauma levels due to COVID-19 in children. This study aimed to assess the differences between perceived threat, exposure and trauma symptoms in children aged 7–13 years. In addition, we explored whether parent-reported factors could predict a higher risk of COVID-19 vulnerability in their children. Method Cross-sectional data from 752 children were assessed with regard to COVID-19 threat and exposure and trauma symptoms using the self- and parent-reported CATS Trauma questionnaire. We used exploratory data analysis methods (factor analysis of mixed data and hierarchical clustering) to identify subgroups (i.e. clusters) of children sharing similar characteristics in the data set. Linear regression modelling was applied to determine the likelihood of higher threat and vulnerability in children with parent-reported COVID-19 threat, exposure, CATS trauma symptoms and behaviour using the child behaviour checklist (CBCL). Results We identified a high-risk group of children reporting clinically relevant trauma symptoms and COVID-19 related fears. Parents’ reports of trauma could identify these. Conclusions In about 25% of children clinical relevant trauma symptoms and threat are present. It is especially important to offer adequate support to ease the trauma and prevent development into further psychopathology.
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Depression, a mental illness that is receiving increasing attention, is caused by multiple factors and genes and adversely affects social life and health. Several hypotheses have been proposed to clarify the pathogenesis of depression, and various synthetic antidepressants have been introduced to treat patients with depression. However, these drugs are effective only in a proportion of patients and fail to achieve complete remission. Recently, herbal medicines have received much attention as alternative treatments for depression because of their fewer side effects and lower costs. In this review, we have mainly focused on the herbal medicines that have been proven in clinical studies (especially randomized controlled trials and preclinical studies) to have antidepressant effects; we also describe the potential mechanisms of the antidepressant effects of those herbal medicines; the cellular and animal model of depression; and the development of novel drug delivery systems for herbal antidepressants. Finally, we objectively elaborate on the challenges of using herbal medicines as antidepressants and describe the benefits, adverse effects, and toxicity of these medicines.
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Stress is an important trigger for brain plasticity: Acute stress can rapidly affect brain activity and functional connectivity, and chronic or pathological stress has been associated with structural brain changes. Measures of structural magnetic resonance imaging (MRI) can be modified by short-term motor learning or visual stimulation, suggesting that they also capture rapid brain changes. Here, we investigated volumetric brain changes (together with changes in T1 relaxation rate and cerebral blood flow) after acute stress in humans as well as their relation to psychophysiological stress measures. Sixty-seven healthy men (25.8±2.7 years) completed a standardized psychosocial laboratory stressor (Trier Social Stress Test) or a control version while blood, saliva, heart rate, and psychometrics were sampled. Structural MRI (T1 mapping / MP2RAGE sequence) at 3T was acquired 45 min before and 90 min after intervention onset. Grey matter volume (GMV) changes were analysed using voxel-based morphometry. Associations with endocrine, autonomic, and subjective stress measures were tested with linear models. We found significant group-by-time interactions in several brain clusters including anterior/mid-cingulate cortices and bilateral insula: GMV was increased in the stress group relative to the control group, in which several clusters showed a GMV decrease. We found a significant group-by-time interaction for cerebral blood flow, and a main effect of time for T1 values (longitudinal relaxation time). In addition, GMV changes were significantly associated with state anxiety and heart rate variability changes. Such rapid GMV changes assessed with VBM may be induced by local tissue adaptations to changes in energy demand following neural activity. Our findings suggest that endogenous brain changes are counteracted by acute psychosocial stress, which emphasizes the importance of considering homeodynamic processes and generally highlights the influence of stress on the brain.
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Chronic Urticaria (CU) is a chronic inflammatory, predominantly mast cell-driven disease, characterized by the development of wheals and/or angioedema for more than 6 weeks. It affects approximately 1%–5% of the total population worldwide and imposes a substantial burden on health-related quality of life, significantly affecting patients' daily life. The economic impact on the health system is also not negligible, with an estimated cost per patient per year of approximately 2.000 $ in the United States. Although the underlying pathophysiology is not fully explored, autoimmune mechanisms have been proposed, including type I (“autoallergy” by means of autoantibodies to self-antigens) and type IIb (autoimmunity). Atopic, autoimmune, and psychiatric disorders are prevalent comorbidities in both children and adults with Chronic Spontaneous Urticaria (CSU). Although malignancies, cardiovascular diseases and other comorbidities have also been reported as associated diseases in patients with CSU, data remain scarce. It is still unknown whether the aforementioned comorbidities share common pathophysiological mechanisms with specific endotypes of CSU. The current review aims to overview current data on comorbidities of CU, and furthermore to comment on the potential linked pathways underlying these diseases.
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Background: Military service members are at increased risk for mental health issues and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations between white matter microstructure, psychological functioning, and serum neuroactive steroids that are part of the stress-response system. Methods: Diffusion-weighted brain imaging was acquired from 163 participants (with and without military affiliation) and free-water-corrected fractional anisotropy (FAT) was extracted. Associations between serum neurosteroid levels of allopregnanolone (ALLO) and pregnenolone (PREGNE), psychological functioning, and whole-brain white matter microstructure were assessed using regression models. Moderation models tested the effect of mTBI and comorbid post-traumatic stress disorder (PTSD) and mTBI on these associations. Results: ALLO is associated with whole-brain white matter FAT (β=.24, t=3.00, p= .006). This association is significantly modulated by PTSD+mTBI comorbidity (β=.01, t=3.07, p=.003) while an mTBI diagnosis alone did not significantly impact this association (p=.183). There was no significant association between PREGNE and FAT (p=.380). Importantly, lower FAT is associated with poor psychological functioning (β=-.19, t=-2.35, p=.020). Conclusion: This study provides novel insight into a potential common pathophysiological mechanism of neurosteroid dysregulation underlying the high risk for mental health issues in military service members. Further, comorbidity of PTSD and mTBI may bring the compensatory effects of the brain's stress response to their limit. Future research is needed to investigate whether neurosteroid regulation may be a promising tool for restoring brain health and improving psychological functioning.
Chapter
Approximately two-thirds of individuals diagnosed with Alzheimer’s disease are women. Although women tend to have longer life expectancy than men, this does not entirely explain the differences in the prevalence of dementia and Alzheimer’s disease. Some evidence suggests that men and women have different patterns of risk and protective factors across the lifespan. The goal of this chapter is to summarize the current evidence on sex differences in genetic and modifiable lifestyle factors that are associated with dementia risk. These include demographic factors such education, vascular, metabolic, lifestyle, and psychosocial factors, and sex-specific factors such as menopause and andropause. Potential mechanisms such as neural reserve and resilience are also summarized. The chapter also summarizes the evidence from recent multidomain lifestyle intervention trials, and the intervention response observed in men and women. While there have been insightful advancements in the field, many important questions still remain. Considerations for future research and risk reduction initiatives are also highlighted.
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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.
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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.
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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.
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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.
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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.
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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.
Article
To determine the integrity of the hypothalamic-pituitary-adrenal (HPA) axis responses to immune/inflammatory stimuli in patients with rheumatoid arthritis (RA). Diurnal secretion of cortisol and the cytokine and cortisol responses to surgery were studied in subjects with active RA, in subjects with chronic osteomyelitis (OM), and in subjects with noninflammatory arthritis, who served as controls. Patients with RA had a defective HPA response, as evidenced by a diurnal cortisol rhythm of secretion which was at the lower limit of normal in contrast to those with OM, and a failure to increase cortisol secretion following surgery, despite high levels of interleukin-1 beta (IL-1 beta) and IL-6. The corticotropin-releasing hormone stimulation test in the RA patients showed normal results, thus suggesting a hypothalamic defect, but normal pituitary and adrenal function. These findings suggest that RA patients have an abnormality of the HPA axis response to immune/inflammatory stimuli which may reside in the hypothalamus. This hypothalamic abnormality may be an additional, and hitherto unrecognized, factor in the pathogenesis of RA.
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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.
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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.
Article
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.
Article
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)
Article
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.
Article
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.
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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
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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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
The sympathetic nervous system consists of efferent neurones supplying the viscera. The cell bodies of preganglionic neurones are located in four areas in the thoracolumbar cord; however, the majority are found in the IML. Various tracing techniques have provided information concerning the location of the cell bodies of sympathetic preganglionic neurones projecting into various nerves and ganglia and regulating the adrenal gland, the kidney and the sympathetic supply to skeletal muscle. Numerous supraspinal neurones project to the neuropil surrounding sympathetic preganglionic neurones and may form synaptic contacts with these neurones. The areas of the brain that project to the IML appear to be part of a network of reciprocally connected supraspinal cell groups. Although much emphasis has been placed on the importance of the RVLM in the mediation of tonic and phasic inputs to sympathetic preganglionic neurones, it appears that other areas are of significant import; the RVLM should not be considered to be 'the vasomotor centre'. Spinal and cranial afferents influence the sympathetic nervous system. Baroreceptor afferents terminate in the NTS and may utilize an excitatory amino acid as their neurotransmitter. However, a number of neuropeptides are also associated with these afferents. Neurones within the NTS project to a number of brain stem areas thought to be involved in the regulation of sympathetic activity; consequently the baroreceptor reflex may be mediated over a number of parallel pathways involving both supraspinal and spinal sites of inhibition. Many neurotransmitters are thought to regulate the activity of sympathetic preganglionic neurons: monoamines, peptides and amino acids. Matching the chemical content of the cell bodies of neurones within a particular cell group with physiological characteristics is a challenging task; some barosensitive neurones of the RVLM do not appear to be adrenergic although they are in the midst of the C1 adrenergic cell group. Besides acetylcholine and noradrenaline, neurotransmission in the periphery appears to involve numerous peptides and ATP.
Article
This study has sought to investigate whether diabetic neuropathy is a major determinant of the basal tone of the hypothalamic-pituitary-adrenal axis in diabetes mellitus. We have analyzed the changes in ACTH and cortisol by measuring hourly samples from 0800-1900 h in diabetic patients carefully characterized for the presence of neuropathy. The circadian variation for ACTH and cortisol was normal in these patients. However, integrated secretion (area under the curve) of both ACTH and cortisol was increased specifically in the 25 diabetic patients with symptomatic polyneuropathy (43 +/- 20 pmol/L and 3609 +/- 169 nmol/L, respectively) compared to 19 diabetic patients without neuropathy (30 +/- 10 pmol/L and 2800 +/- 690 nmol/L, respectively) (P < 0.02) and to 11 normal controls (26 +/- 10 pmol/L and 2694 +/- 476 nmol/L, respectively) (P < 0.007). These differences occurred independently of the type of diabetes and were significant for most individual time points. ACTH and cortisol concentrations correlated with most clinical and neurophysiological parameters of neuropathy (P < 0.05-0.001), but not with glycemic control, retinopathy, or proteinuria. Overall, these results suggest that diabetic neuropathy is associated with a specific and persistent increase in the activity of the hypothalamic-pituitary-adrenal axis.