Aschbacher, K.; Rodriguez-Fernandez, M.; Wietmarschen, H. van; Tomiyama, A.; Jain, S.; Epel, E.; Doyle III, F.J.; Greef, J. van der
Glucocorticoids contribute to obesity and metabolic syndrome; however, the mechanisms are unclear, and prognostic measures are unavailable. A systems level understanding of the hypothalamic-pituitary-adrenal (HPA) -leptin axis may reveal novel insights. Eighteen obese premenopausal women provided
Natalie G. Burford
Full Text Available The collective of endocrine organs acting in homeostatic regulation—known as the hypothalamic-pituitary-adrenal (HPA axis—comprises an integration of the central nervous system as well as peripheral tissues. These organs respond to imminent or perceived threats that elicit a stress response, primarily culminating in the release of glucocorticoids into the systemic circulation by the adrenal glands. Although the secretion of glucocorticoids serves to protect and maintain homeostasis in the typical operation at baseline levels, inadequate regulation can lead to physiologic and psychologic pathologies. The cardiovascular system is especially susceptible to prolonged dysregulation of the HPA axis and glucocorticoid production. There is debate about whether cardiovascular health risks arise from the direct detrimental effects of stress axis activation or whether pathologies develop secondary to the accompanying metabolic strain of excess glucocorticoids. In this review, we will explore the emerging research that indicates stress does have direct effects on the cardiovascular system via the HPA axis activation, with emphasis on the latest research on the impact of glucocorticoids signaling in the vasculature and the heart.
Burford, Natalie G; Webster, Natalia A; Cruz-Topete, Diana
The collective of endocrine organs acting in homeostatic regulation-known as the hypothalamic-pituitary-adrenal (HPA) axis-comprises an integration of the central nervous system as well as peripheral tissues. These organs respond to imminent or perceived threats that elicit a stress response, primarily culminating in the release of glucocorticoids into the systemic circulation by the adrenal glands. Although the secretion of glucocorticoids serves to protect and maintain homeostasis in the typical operation at baseline levels, inadequate regulation can lead to physiologic and psychologic pathologies. The cardiovascular system is especially susceptible to prolonged dysregulation of the HPA axis and glucocorticoid production. There is debate about whether cardiovascular health risks arise from the direct detrimental effects of stress axis activation or whether pathologies develop secondary to the accompanying metabolic strain of excess glucocorticoids. In this review, we will explore the emerging research that indicates stress does have direct effects on the cardiovascular system via the HPA axis activation, with emphasis on the latest research on the impact of glucocorticoids signaling in the vasculature and the heart.
Boschloo, Lynn; Vogelzangs, Nicole; Licht, Carmilla M. M.; Vreeburg, Sophie A.; Smit, Johannes H.; van den Brink, Wim; Veltman, Dick J.; de Geus, Eco J. C.; Beekman, Aartjan T. F.; Penninx, Brenda W. J. H.
Heavy alcohol use as well as alcohol dependence (AD) have been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis and the autonomic nervous system (ANS). However, the relative contribution of alcohol use and AD is unclear. Baseline data were derived from 2947 persons of
Duffy, Anne; Lewitzka, Ute; Doucette, Sarah; Andreazza, Ana; Grof, Paul
The study aims to provide a selective review of the literature pertaining to the hypothalamic-pituitary-adrenal (HPA) axis and immune abnormalities as informative biological indicators of vulnerability in bipolar disorder (BD). We summarize key findings relating to HPA axis and immunological abnormalities in bipolar patients and their high-risk offspring. Findings derive from a review of selected original papers published in the literature, and supplemented by papers identified through bibliography review. Neurobiological findings are discussed in the context of emergent BD in those at genetic risk and synthesized into a neurodevelopmental model of illness onset and progression. BD is associated with a number of genetic and possibly epigenetic abnormalities associated with neurotransmitter, hormonal and immunologically mediated neurobiological pathways. Data from clinical and high-risk studies implicate HPA axis and immune system abnormalities, which may represent inherited vulnerabilities important for the transition to illness onset. Post-mortem and clinical studies implicate intracellular signal transduction processes and disturbance in energy metabolism associated with established BD. Specifically, long-standing maladaptive alterations such as changes in neuronal systems may be mediated through changes in intracellular signalling pathways, oxidative stress, cellular energy metabolism and apoptosis associated with substantial burden of illness. Prospective longitudinal studies of endophenotypes and biomarkers such as HPA axis and immune abnormalities in high-risk offspring will be helpful to understand genetically mediated biological pathways associated with illness onset and progression. A clinical staging model describing emergent illness in those at genetic risk should facilitate this line of investigation. © 2011 Blackwell Publishing Asia Pty Ltd.
The function of the hypothalamo-pituitary-adrenal system was studied over time (1986-1993) in 500 liquidators of the Chernobyl accident consequences with external exposure dose of 250 mSv. The concentrations of hydrocortisone, ACTH, and β-endorphine in the peripheral blood were radioimmunoassayed at rest and during functional loading. Glucocorticoids were measured in the urine by thin-layer chromatography. The number of glucocorticoid receptors in peripheral blood lymphocytes was assessed by the radioreceptor method. Stable hypercorticalism in the presence of reduced β-endorphine and increased ACTH levels was observed in the majority of examinees during the first years after the accident. Six years after the accident the above parameters were normal at rest, although during functional loading disorders in the reserve potential of the hypothalamo-pituitary-adrenal system were observed, which deteriorated its adaptation to changes int he environment. It is advisable to single out high risk groups of subjects with disadaptation disorders for regular check-ups among the liquidators. 10 refs.; 3 figs.; 4 tabs
Krause, Eric G; Melhorn, Susan J; Davis, Jon F; Scott, Karen A; Ma, Li Y; de Kloet, Annette D; Benoit, Stephen C; Woods, Stephen C; Sakai, Randall R
Circulating angiotensin II (ANGII) elicits water intake and activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating angiotensin type 1 receptors (AT1Rs) within circumventricular organs. The subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) are circumventricular organs that express AT1Rs that bind blood-borne ANGII and stimulate integrative and effector regions of the brain. The goal of these studies was to determine the contribution of AT1Rs within the SFO and OVLT to the water intake and HPA response to increased circulating ANGII. Antisense oligonucleotides directed against the AT1R [AT1R antisense (AT1R AS)] were administered into the OVLT or SFO. Quantitative receptor autoradiography confirmed that AT1R AS decreased ANGII binding in the SFO and OVLT compared with the scrambled sequence control but did not affect AT1R binding in other nuclei. Subsequently, water intake, ACTH, and corticosterone (CORT) were assessed after administration of isoproterenol, a beta-adrenergic agonist that decreases blood pressure and elevates circulating ANGII. Delivery of AT1R AS into the SFO attenuated water intake, ACTH, and CORT after isoproterenol, whereas similar treatment in the OVLT had no effect. To determine the specificity of this blunted drinking and HPA response, the same parameters were measured after treatment with hypertonic saline, a stimulus that induces drinking independently of ANGII. Delivery of AT1R AS into the SFO or OVLT had no effect on water intake, ACTH, or CORT after hypertonic saline. The results imply that AT1R within the SFO mediate drinking and HPA responses to stimuli that increase circulating ANGII.
Galesi, Fernanda L; Ayanwuyi, Lydia O; Mijares, Miriam Garcia; Cippitelli, Andrea; Cannella, Nazzareno; Ciccocioppo, Roberto; Ubaldi, Massimo
A large body of evidence has shown that the Corticotropin Releasing Factor (CRF) system, which plays a key role in stress modulation, is deeply involved in relapse to alcohol seeking induced by exposure to stressful events such as foot shock or yohimbine injections. Exposure to environmental cues is also known to be a trigger for alcohol relapse, nevertheless, the relationship between the relapse evoked by the cue-induced model and the CRF stress systems remains unclear. The purpose of this study was to evaluate, in male Wistar rats, the involvement of the CRF system and Hypothalamic-Pituitary-Adrenal (HPA) axis in relapse induced by environmental cues. Antalarmin, a selective CRF1 receptor antagonist, Metyrapone, a corticosterone (CORT) synthesis inhibitor and CORT were evaluated for their effects on the reinstatement test in a cue-induced relapse model. Antalarmin (20mg/kg) blocked relapse to alcohol seeking induced by environmental cues. Metyrapone (50 and 100mg/kg) also blocked relapse in Wistar rats but only at the highest dose (100mg/kg). Corticosterone had no effect on relapse at the doses tested. The results obtained from this study suggest that the CRF stress system and the HPA axis are involved in cue-induced alcohol relapse. Copyright © 2016 Elsevier B.V. All rights reserved.
Pivina, S G; Rakitskaya, V V; Akulova, V K; Ordyan, N E
Using the experimental model of post-traumatic stress disorder (stress-restress paradigm), we studied the dynamics of activity of the hypothalamic-pituitary-adrenal system (HPAS) in adult male rats, whose mothers were daily subjected to restraint stress on days 15-19 of pregnancy. Prenatally stressed males that were subjected to combined stress and subsequent restress exhibited not only increased sensitivity of HPAS to negative feedback signals (manifested under restress conditions), but also enhanced stress system reactivity. These changes persisted to the 30th day after restress. Under basal conditions, the number of cells in the hypothalamic paraventricular nucleus of these animals expressing corticotropin-releasing hormone and vasopressin was shown to decrease progressively on days 1-30. By contrast, combined stress and restress in control animals were followed by an increase in the count of CRH-immunopositive cells in the magnocellular and parvocellular parts of the paraventricular nucleus and number of vasopressin-immunopositive cells in the magnocellular part of the nucleus (to the 10th day after restress). Our results indicate a peculiar level of functional activity of HPAS in prenatally stressed males in the stress-restress paradigm: decreased activity under basal conditions and enhanced reactivity during stress.
You Qiumei; Karrow, Niel A.; Cao Honghe; Rodriguez, Alexander; Mallard, Bonnie A.; Boermans, Herman J.
Bi-directional communication between the neuroendocrine and immune systems is designed, in part, to maintain or restore homeostasis during physiological stress. Exposure to endotoxin during Gram-negative bacterial infection for example, elicits the release of pro-inflammatory cytokines that activate the hypothalamic-pituitary-adrenal axis (HPAA). The secretion of adrenal glucocorticoids subsequently down regulates the host inflammatory response, minimizing potential tissue damage. Sequence and epigenetic variants in genes involved in regulating the neuroendocrine and immune systems are likely to contribute to individual differences in the HPAA response, and this may influence the host anti-inflammatory response to toxin exposure and susceptibility to inflammatory disease. In this study, high (HCR) and low (LCR) cortisol responders were selected from a normal population of 110 female sheep challenged iv with Escherichia coli endotoxin (400 ng/kg) to identify potential determinants that contribute to variation in the cortisol response phenotype. This phenotype was stable over several years in the HCR and LCR animals, and did not appear to be attributed to differences in expression of hepatic immune-related genes or systemic pro-inflammatory cytokine concentrations. Mechanistic studies using corticotrophin-releasing factor (0.5 μg/kg body weight), arginine vasopressin (0.5 μg/kg), and adrenocorticotropic hormone (0.5 μg/kg) administered iv demonstrated that variation in this phenotype is largely determined by signalling within the HPAA. Future studies will use this ovine HCR/LCR model to investigate potential genetic and epigenetic variants that may contribute to variation in cortisol responsiveness to bacterial endotoxin
Full Text Available Cytokines are molecules that were initially discovered in the immune system as mediators of communication between various types of immune cells. However, it soon became evident that cytokines exert profound effects on key functions of the central nervous system, such as food intake, fever, neuroendocrine regulation, long-term potentiation, and behavior. In the 80's and 90's our group and others discovered that the genes encoding various cytokines and their receptors are expressed in vascular, glial, and neuronal structures of the adult brain. Most cytokines act through cell surface receptors that have one transmembrane domain and which transduce a signal through the JAK/STAT pathway. Of particular physiological and pathophysiological relevance is the fact that cytokines are potent regulators of hypothalamic neuropeptidergic systems that maintain neuroendocrine homeostasis and which regulate the body's response to stress. The mechanisms by which cytokine signaling affects the function of stress-related neuroendocrine systems are reviewed in this article.
Sorgdrager, F. J. H.; Doornbos, B.; Penninx, B. W. J. H.; de Jonge, P.; Kema, I. P.
Objectives: Persistent changes in serotonergic and hypothalamic pituitary adrenal (HPA) axis functioning are implicated in recurrent types of major depressive disorder (MDD). Systemic tryptophan levels, which influence the rate of serotonin synthesis, are regulated by glucocorticoids produced along
Mikkelsen, Jens D; Hay-Schmidt, Anders; Kiss, Alexander
Acute stimulation of the hypothalamo-pituitary-adrenal (HPA) axis by selective serotonin reuptake inhibitors (SSRIs) is mediated by several postsynaptic 5-HT receptor subtypes. Activation of 5-HT(1A) and 5-HT(2A) receptors increases plasma corticosterone levels, and it is likely that these recept...
Auvinen, H E; Romijn, J A; Biermasz, N R; Havekes, L M; Smit, J W A; Rensen, P C N; Pereira, A M
Hypothalamus-pituitary-adrenal-axis activity is suggested to be involved in the pathophysiology of the metabolic syndrome. In diet-induced obesity mouse models, features of the metabolic syndrome are induced by feeding high fat diet. However, the models reveal conflicting results with respect to the hypothalamus-pituitary-adrenal-axis activation. The aim of this review was to assess the effects of high fat feeding on the activity of the hypothalamus-pituitary-adrenal-axis in mice. PubMed, EMBASE, Web of Science, the Cochrane database, and Science Direct were electronically searched and reviewed by 2 individual researchers. We included only original mouse studies reporting parameters of the hypothalamus-pituitary-adrenal-axis after high fat feeding, and at least 1 basal corticosterone level with a proper control group. Studies with adrenalectomized mice, transgenic animals only, high fat diet for less than 2 weeks, or other interventions besides high fat diet, were excluded. 20 studies were included. The hypothalamus-pituitary-adrenal-axis evaluation was the primary research question in only 5 studies. Plasma corticosterone levels were unchanged in 40%, elevated in 30%, and decreased in 20% of the studies. The effects in the peripheral tissues and the central nervous system were also inconsistent. However, major differences were found between mouse strains, experimental conditions, and the content and duration of the diets. This systematic review demonstrates that the effects of high fat feeding on the basal activity of the hypothalamus-pituitary-adrenal-axis in mice are limited and inconclusive. Differences in experimental conditions hamper comparisons and accentuate the need for standardized evaluations to discern the effects of diet-induced obesity on the hypothalamus-pituitary-adrenal-axis. © Georg Thieme Verlag KG Stuttgart · New York.
Jereme G. Spiers
Full Text Available Glucocorticoids released from the adrenal gland in response to stress-induced activation of the hypothalamic-pituitary-adrenal (HPA axis induce activity in the cellular reduction-oxidation (redox system. The redox system is a ubiquitous chemical mechanism allowing the transfer of electrons between donor/acceptors and target molecules during oxidative phosphorylation while simultaneously maintaining the overall cellular environment in a reduced state. The objective of this review is to present an overview of the current literature discussing the link between HPA axis-derived glucocorticoids and increased oxidative stress, particularly focussing on the redox changes observed in the hippocampus following glucocorticoid exposure.
Handa, Robert J.; Weiser, Michael J.
The hypothalamo-pituitary-adrenal (HPA) axis represents a complex neuroendocrine feedback loop controlling the secretion of adrenal glucocorticoid hormones. Central to its function is the paraventricular nucleus of the hypothalamus (PVN) where neurons expressing corticotropin releasing factor reside. These HPA motor neurons are a primary site of integration leading to graded endocrine responses to physical and psychological stressors. An important regulatory factor that must be considered, pr...
Lucassen, Eliane A.; Cizza, Giovanni
Obesity, exposure to stress and inadequate sleep are prevalent phenomena in modern society. In this review we focus on their relationships and critically evaluate causality. In obese individuals, one of the main stress systems, the hypothalamic-pituitary-adrenal axis, is altered, and concentrations of cortisol are elevated in adipose tissue due to elevated local activity of 11β-hydroxysteroid dehydrogenase (HSD) type 1. Short sleep and decreased sleep quality are also associated with obesity....
It is shown that the model of the hypothalamic-pituitary-adrenal gland axis is a differentially flat one and this permits to transform it to the so-called linear canonical form. For the new description of the system's dynamics the transformed control inputs contain unknown terms which depend on the system's parameters. To identify these terms an adaptive fuzzy approximator is used in the control loop. Thus an adaptive fuzzy control scheme is implemented in which the unknown or unmodeled system dynamics is approximated by neurofuzzy networks and next this information is used by a feedback controller that makes the state variables (CRH - corticotropin releasing hormone, adenocortocotropic hormone - ACTH, cortisol) of the hypothalamic-pituitary-adrenal gland axis model converge to the desirable levels (setpoints). This adaptive control scheme is exclusively implemented with the use of output feedback, while the state vector elements which are not directly measured are estimated with the use of a state observer that operates in the control loop. The learning rate of the adaptive fuzzy system is suitably computed from Lyapunov analysis, so as to assure that both the learning procedure for the unknown system's parameters, the dynamics of the observer and the dynamics of the control loop will remain stable. The performed Lyapunov stability analysis depends on two Riccati equations, one associated with the feedback controller and one associated with the state observer. Finally, it is proven that for the control scheme that comprises the feedback controller, the state observer and the neurofuzzy approximator, an H-infinity tracking performance can be succeeded.
Christensen, M V; Kessing, L V
disorder. The HPA axis is a complex neuroendocrine network with multiple integrated levels of control, and it is likely that the dysregulation involves abnormalities at several sites within the axis. At present, it is not clear whether the abnormalities are related to the affective episodes only......This paper reviews studies of the hypothalamo-pituitary-adrenal (HPA)-axis activity in patients with affective disorders. It is concluded that, despite methodological drawbacks in most studies, dysregulation of the HPA axis seems to be a consistent finding in a proportion of patients with affective...... or to the disorder itself. There is a need for prospective studies of larger samples of patients to be followed during successive affective episodes with a combination of measurements of the HPA-axis activity and brain imaging....
Jansen, Steffy W; Roelfsema, Ferdinand; Akintola, Abimbola A
OBJECTIVE: The hypothalamic-pituitary-adrenal (HPA)-axis is the most important neuro-endocrine stress response system of our body which is of critical importance for survival. Disturbances in HPA-axis activity have been associated with adverse metabolic and cognitive changes. Humans enriched...... for longevity have less metabolic and cognitive disturbances and therefore diminished activity of the HPA axis may be a potential candidate mechanism underlying healthy familial longevity. Here, we compared 24-h plasma ACTH and serum cortisol concentration profiles and different aspects of the regulation...... of the HPA-axis in offspring from long-lived siblings, who are enriched for familial longevity and age-matched controls. DESIGN: Case-control study within the Leiden Longevity study cohort consisting of 20 middle-aged offspring of nonagenarian siblings (offspring) together with 18 partners (controls...
Dinan, Timothy G
Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis characterized by hypercortisolism, adrenal hyperplasia and abnormalities in negative feedback is the most consistently described biological abnormality in melancholic depression. Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are the main secretagogues of the HPA\\/stress system. Produced in the parvicellular division of the hypothalamic paraventricular nucleus the release of these peptides is influenced by inputs from monoaminergic neurones. In depression, anterior pituitary CRH1 receptors are down-regulated and response to CRH infusion is blunted. By contrast, vasopressin V3 receptors on the anterior pituitary show enhanced response to AVP stimulation and this enhancement plays a key role in maintaining HPA overactivity.
Takahashi, L K; Kalin, N H
Previous experiments revealed that 14-day-old prenatally stressed rats have significantly elevated concentrations of plasma adrenocorticotrophic hormone (ACTH) and corticosterone suggesting these animals have an overactive hypothalamic-pituitary-adrenal (HPA) system. In these studies, however, stress-induced hormone levels were determined only immediately after exposure to an acute stressor. Therefore, in the current study, we examined in postnatal days 7, 14 and 21 prenatally stressed rats the stress-induced time course of this pituitary-adrenal hormone elevation. Plasma ACTH and corticosterone were measured in the basal state and at 0.0, 0.5, 1.0, 2.0 and 4.0 h after a 10-min exposure period to foot shocks administered in the context of social isolation. Results indicated that at all 3 ages, plasma ACTH in prenatally stressed rats was significantly elevated. Corticosterone concentrations were also significantly higher in prenatally stressed than in control rats, especially in day 14 rats. Analysis of stress-induced hormone fluctuations over time indicated that by 14 days of age, both prenatally stressed than in control and control rats had significant increases in plasma ACTH and corticosterone after exposure to stress. Furthermore, although prenatally stressed rats had significantly higher pituitary-adrenal hormone concentrations than control animals, the post-stress temporal patterns of decline in ACTH and corticosterone levels were similar between groups. Results suggest that throughout the preweaning period, prenatal stress produces an HPA system that functions in a manner similar to that of controls but at an increased level.
Marković, V. M.; Čupić, Ž.; Ivanović, A.; Kolar-Anić, Lj.
Stoichiometric network analysis (SNA) represents a powerful mathematical tool for stability analysis of complex stoichiometric networks. Recently, the important improvement of the method has been made, according to which instability relations can be entirely expressed via reaction rates, instead of thus far used, in general case undefined, current rates. Such an improved SNA methodology was applied to the determination of exact instability conditions of the extended model of the hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrinological system, whose hormone concentrations exert complex oscillatory evolution. For emergence of oscillations, the Hopf bifurcation condition was utilized. Instability relations predicted by SNA showed good correlation with numerical simulation data of the HPA axis model.
Tyrka, Audrey R.; Wier, Lauren; Price, Lawrence H.; Ross, Nicole; Anderson, George M.; Wilkinson, Charles W.; Carpenter, Linda L.
Background Several decades of research link childhood parental loss with risk for major depression and other forms of psychopathology. A large body of preclinical work on maternal separation and some recent studies of humans with childhood parental loss have demonstrated alterations of hypothalamic-pituitary-adrenal (HPA) axis function which could predispose to the development of psychiatric disorders. Methods Eighty-eight healthy adults with no current Axis I psychiatric disorder participated in this study. Forty-four participants experienced parental loss during childhood, including 19 with a history of parental death and 25 with a history of prolonged parental separation. The loss group was compared to a matched group of individuals who reported no history of childhood parental separation or childhood maltreatment. Participants completed diagnostic interviews and questionnaires and the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Repeated measures general linear models were used to test the effects of parental loss, a measure of parental care, sex, and age on the hormone responses to the Dex/CRH test. Results Parental loss was associated with increased cortisol responses to the test, particularly in males. The effect of loss was moderated by levels of parental care; participants with parental desertion and very low levels of care had attenuated cortisol responses. ACTH responses to the Dex/CRH test did not differ significantly as a function of parental loss. Conclusions These findings are consistent with the hypothesis that early parental loss induces enduring changes in neuroendocrine function. PMID:18339361
Teshima, Takahiro; Matsumoto, Hirotaka; Okusa, Tomoko; Nakamura, Yumi; Koyama, Hidekazu
Cushing's disease caused by pituitary corticotroph adenoma is a common endocrine disease in dogs. A characteristic biochemical feature of corticotroph adenomas is their relative resistance to suppressive negative feedback by glucocorticoids. The abnormal expression of 11beta-hydroxysteroid dehydrogenase (11HSD), which is a cortisol metabolic enzyme, is found in human and murine corticotroph adenomas. Our recent studies demonstrated that canine corticotroph adenomas also have abnormal expression of 11HSD. 11HSD has two isoforms in dogs, 11HSD type1 (HSD11B1), which converts cortisone into active cortisol, and 11HSD type2 (HSD11B2), which converts cortisol into inactive cortisone. It has been suggested that glucocorticoid resistance in corticotroph tumors is related to the overexpression of HSD11B2. Therefore it was our aim to investigate the effects of carbenoxolone (CBX), an 11HSD inhibitor, on the healthy dog's pituitary-adrenal axis. Dogs were administered 50 mg/kg of CBX twice each day for 15 days. During CBX administration, no adverse effects were observed in any dogs. The plasma adrenocorticotropic hormone (ACTH), and serum cortisol and cortisone concentrations were significantly lower at day 7 and 15 following corticotropin releasing hormone stimulation. After completion of CBX administration, the HSD11B1 mRNA expression was higher, and HSD11B2 mRNA expression was significantly lower in the pituitaries. Moreover, proopiomelanocortin mRNA expression was lower, and the ratio of ACTH-positive cells in the anterior pituitary was also significantly lower after CBX treatment. In adrenal glands treated with CBX, HSD11B1 and HSD11B2 mRNA expression were both lower compared to normal canine adrenal glands. The results of this study suggested that CBX inhibits ACTH secretion from pituitary due to altered 11HSD expressions, and is potentially useful for the treatment of canine Cushing's disease.
Full Text Available Dysregulation of the hypothalamic-pituitary-adrenal (HPA axis and inflammatory systems is a consistent finding in patients with Major Depressive Disorder (MDD. Cortisol is often assessed by measurement of the cortisol awakening response (CAR and/or diurnal cortisol levels. Some methods of cortisol measurement overestimate cortisol concentration due to detection of other glucocorticoids including the relatively inert cortisone, therefore this study aimed to assess the presence of both cortisol and cortisone, and the cortisol-cortisone catalyzing enzyme 11β-hydroxysteroiddehydrogenase type 1 (11β-HSD1, in depressed patients and controls. Because the HPA axis is known to regulate the body’s immune system, relationships between measures of cytokines and cortisol were also assessed. Saliva samples were collected from 57 MDD patients and 40 healthy controls at five post-wakening time points (0, +30, +60, +720 and +750 min. Glucocorticoid concentrations were measured by liquid chromatography mass spectrometry. Whole blood mRNA expression of several inflammatory markers was measured by quantitative polymerase chain reaction. This study replicated the common finding of elevated morning cortisol and reduced CAR reactivity in MDD and found no differences in cortisone or 11β-HSD1 mRNA measures. There was a negative association between interleukin 1-β (IL-1β mRNA and morning cortisol reactivity within the depressed group, indicating that dysregulation of the HPA axis and immune system may be interconnected.
Belda, Xavier; Fuentes, Silvia; Daviu, Nuria; Nadal, Roser; Armario, Antonio
Exposure to certain acute and chronic stressors results in an immediate behavioral and physiological response to the situation followed by a period of days when cross-sensitization to further novel stressors is observed. Cross-sensitization affects to different behavioral and physiological systems, more particularly to the hypothalamus-pituitary-adrenal (HPA) axis. It appears that the nature of the initial (triggering) stressor plays a major role, HPA cross-sensitization being more widely observed with systemic or high-intensity emotional stressors. Less important appears to be the nature of the novel (challenging) stressor, although HPA cross-sensitization is better observed with short duration (5-15 min) challenging stressors. In some studies with acute immune stressors, HPA sensitization appears to develop over time (incubation), but most results indicate a strong initial sensitization that progressively declines over the days. Sensitization can affect other physiological system (i.e. plasma catecholamines, brain monoamines), but it is not a general phenomenon. When studied concurrently, behavioral sensitization appears to persist longer than that of the HPA axis, a finding of interest regarding long-term consequences of traumatic stress. In many cases, behavioral and physiological consequences of prior stress can only be observed following imposition of a new stressor, suggesting long-term latent effects of the initial exposure.
Full Text Available Temporal organization is an important feature of biological systems and its main function is to facilitate adaptation of the organism to the environment. The daily variation of biological variables arises from an internal time-keeping system. The major action of the environment is to synchronize the internal clock to a period of exactly 24 h. The light-dark cycle, food ingestion, barometric pressure, acoustic stimuli, scents and social cues have been mentioned as synchronizers or" zeitgebers". The circadian rhythmicity of plasma corticosteroids has been well characterized in man and in rats and evidence has been accumulated showing daily rhythmicity at every level of the hypothalamic-pituitary-adrenal (HPA axis. Studies of restricted feeding in rats are of considerable importance because they reveal feeding as a major synchronizer of rhythms in HPA axis activity. The daily variation of the HPA axis stress response appears to be closely related to food intake as well as to basal activity. In humans, the association of feeding and HPA axis activity has been studied under physiological and pathological conditions such as anorexia nervosa, bulimia, malnutrition, obesity, diabetes mellitus and Cushing's syndrome. Complex neuroanatomical pathways and neurochemical circuitry are involved in feeding-associated HPA axis modulation. In the present review we focus on the interaction among HPA axis rhythmicity, food ingestion, and different nutritional and endocrine states
McCormick, Cheryl M; Mathews, Iva Z
Chronic exposure to stress is known to affect learning and memory in adults through the release of glucocorticoid hormones by the hypothalamic-pituitary-adrenal (HPA) axis. In adults, glucocorticoids alter synaptic structure and function in brain regions that express high levels of glucocorticoid receptors and that mediate goal-directed behaviour and learning and memory. In contrast to relatively transient effects of stress on cognitive function in adulthood, exposure to high levels of glucocorticoids in early life can produce enduring changes through substantial remodeling of the developing nervous system. Adolescence is another time of significant brain development and maturation of the HPA axis, thereby providing another opportunity for glucocorticoids to exert programming effects on neurocircuitry involved in learning and memory. These topics are reviewed, as is the emerging research evidence in rodent models highlighting that adolescence may be a period of increased vulnerability compared to adulthood in which exposure to high levels of glucocorticoids results in enduring changes in adult cognitive function. Copyright 2009 Elsevier Inc. All rights reserved.
Nolten, W E; Goldstein, D; Lindstrom, M; McKenna, M V; Carlson, I H; Trump, D L; Schiller, J; Borden, E C; Ehrlich, E N
Cytokines, which include interferons (IFNs), interleukins (ILs), and tumor necrosis factor (TNF), are immunoregulatory proteins produced by lymphocytes and inflammatory cells. Several cytokines, most noteworthy IFNs and ILs, stimulate glucocorticoid secretion. In this study, the effects of variable doses and repetitive administration of IFNs and TNF on secretion of pituitary hormones and cortisol were measured. Patients were given for a period of 15 days on alternating days injections of IFN-beta (IFN-beta ser), 90 or 450 x 10(6) IU, IFN-gamma, 0.1-100 x 10(6) IU, or TNF 125-275 micrograms/m2. Sixty to 120 min after IFN-beta ser injection median levels of cortisol, adrenocorticotropin (ACTH), prolactin (PRL), and growth hormone (GH) rose two-fold. Urinary free cortisol excretion increased significantly during the day following IFN-beta ser administration. IFN-gamma > or = 30 x 10(6) IU caused a comparable rise in plasma cortisol. TNF induced two- to four-fold increases in ACTH and cortisol. The fact that increased cortisol secretion was associated with a rise in the level of ACTH as well as PRL and GH suggests that the cytokines increased cortisol by stimulating the anterior pituitary. The hormonal response induced by cytokines was unrelated to their pyrogenic effect, undiminished with repetitive treatment, and not dose-dependent above a threshold level. These observations reinforce the concept of a physiologic link between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis.
Reichl, Corinna; Heyer, Anne; Brunner, Romuald; Parzer, Peter; Völker, Julia Madeleine; Resch, Franz; Kaess, Michael
Whereas childhood adversity (CA) and the hypothalamus-pituitary-adrenal (HPA) axis have been suggested to play a major role in the etiology of non-suicidal self-injury (NSSI), no study has thus far investigated both its associations and interactions with adolescent NSSI. We investigated CA (antipathy, neglect, physical, psychological, and sexual abuse) and indices of HPA axis activity (salivary and hair cortisol) in a clinical sample of 26 adolescents engaging in NSSI and 26 age- and gender-matched healthy controls (HC). We used standardized interviews for the assessment of CA (CECA), NSSI (SITBI-G), and axis I diagnoses (MINI-KID). Salivary cortisol sampling was surveyed using a monitoring system and instructed via telephone calls. Adolescents engaging in NSSI exhibited significantly higher cortisol awakening responses compared to HC. No differences were found with respect to the diurnal slope or hair cortisol. In the presence of CA, healthy adolescents showed flatted diurnal cortisol slopes while those engaging in NSSI exhibited significantly steeper ones. Our findings indicate that adolescents engaging in NSSI may exhibit a stronger cortisol awakening response, potentially in expectation of strain. However, elevated cortisol levels may not be maintained throughout the day, especially among adolescents with a history of CA. Copyright © 2016 Elsevier Ltd. All rights reserved.
Addictive drugs (opiates, ethanol, cannabinoids (CBs), nicotine, cocaine, amphetamines) induce activation of the hypothalamic-pituitary-adrenal (HPA) axis, with the subsequent release of adrenocorticotropic hormone and glucocorticoids. The sequence of events leading to HPA activation appears to start within the brain, suggesting that activation is not secondary to peripheral homeostatic alterations. The precise neurochemical mechanisms and brain pathways involved are markedly dependent on the particular drug, although it is assumed that information eventually converges into the hypothalamic paraventricular nucleus (PVN). Whereas some drugs may act on the hypothalamus or directly within PVN neurons (i.e. ethanol), others exert their primary action outside the PVN (i.e. CBs, nicotine, cocaine). Corticotropin-releasing hormone (CRH) has a critical role in most cases, but the changes in c-fos and CRH gene expression in the PVN also reveal differences among drugs. More studies are needed to understand how addictive drugs act on this important neuroendocrine system and their functional consequences. Copyright 2010 Elsevier Ltd. All rights reserved.
Laceulle, O.M.; Nederhof, Esther; van Aken, M.A.G.; Ormel, Johan
The hypothalamic-pituitary-adrenal (HPA) axis has been proposed to be a key mechanism underlying the link between adversity and mental health, but longitudinal studies on adversity and HPA-axis functioning are scarce. Here, we studied adversity-driven changes in HPA-axis functioning during
Pfefferbaum, Betty; Tucker, Phebe; Nitiéma, Pascal
Background: The hypothalamic-pituitary-adrenal (HPA) axis constitutes an important biological component of the stress response commonly studied through the measurement of cortisol. Limited research has examined HPA axis dysregulation in youth exposed to disasters. Objective: This study examined HPA axis activation in adolescent Hurricane Katrina…
Lopez-Duran, Nestor L.; Olson, Sheryl L.; Hajal, Nastassia J.; Felt, Barbara T.; Vazquez, Delia M.
The purpose of this study was to examine the association between hypothalamic-pituitary-adrenal axis (HPA-axis) reactivity and proactive and reactive aggression in pre-pubertal children. After a 30-min controlled base line period, 73 7-year-old children (40 males and 33 females) were randomly assigned to one of two experimental tasks designed to…
Dekkers, J. C.; Geenen, R.; Godaert, G. L.; Glaudemans, K. A.; Lafeber, F. P.; van Doornen, L. J.; Bijlsma, J. W.
There is evidence that the hypothalamic pituitary adrenal (HPA) axis is subresponsive in patients with rheumatoid arthritis (RA). We assessed HPA axis responses to experimental stressors mimicking daily life challenges in patients with RA to determine whether HPA axis activity is associated with Th1
Huizink, Anja C.; Ferdinand, Robert F.; Ormel, Johan; Verhulst, Frank C.
Aims To identify early onset cannabis users by measuring basal hypothalamic-pituitary-adrenal (HPA) axis activity, which may be a risk factor for early onset substance use when showing low activity. Design In a prospective cohort study, adolescents who initiated cannabis use at an early age (9-12
McNeilly, Alison D; Macfarlane, David P; O'Flaherty, Emmett
Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5bet...
Laurent, Heidemarie K.; Duncan, Larissa G.; Lightcap, April; Khan, Faaiza
Mindfulness in the parenting relationship has been proposed to help both parents and children better regulate stress, though this has not yet been shown at the physiological level. In this study, we tested relations between maternal mindfulness in parenting and both mothers' and their infants' hypothalamic-pituitary-adrenal (HPA) axis activity…
Prince van Leeuwen, A.; Creemers, H.E.; Greaves-Lord, K.; Verhulst, F.C.; Ormel, J.; Huizink, A.C.
Aims: To investigate the relationship of life-time and repeated cannabis use with hypothalamic-pituitary-adrenal (HPA) axis reactivity to social stress in a general population sample of adolescents. Design: Adolescents who reported life-time or repeated cannabis use, life-time or repeated tobacco
van Leeuwen, Andrea Prince; Creemers, Hanneke E.; Greaves-Lord, Kirstin; Verhulst, Frank C.; Ormel, Johan; Huizink, Anja C.
Aims To investigate the relationship of life-time and repeated cannabis use with hypothalamic-pituitary-adrenal (HPA) axis reactivity to social stress in a general population sample of adolescents. Design Adolescents who reported life-time or repeated cannabis use, life-time or repeated tobacco use
Meerlo, P; Koehl, M; van der Borght, K; Turek, FW
Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic-pituitary-adrenal (HPA) axis, one of the main neuroendocrine
P.C. Guest (Paul); D. Martins-de-Souza (Daniel); H. Rahmoune (Hassan); S. Bahn (Sabine); P.C. Guest (Paul)
textabstractOver the last few decades, evidence has been emerging that the pathogenesis of psychiatric disorders such as schizophrenia can involve perturbations of the hypothalamic-pituitary-adrenal (HPA) axis. Variations in the manifestation of these effects could be related to the differences in
Huizink, Anja C.; Ferdinand, Robert F.; Ormel, Johan; Verhulst, Frank C.
Aims To identify early onset cannabis users by measuring basal hypothalamic-pituitary-adrenal (HPA) axis activity, which may be a risk factor for early onset substance use when showing low activity. Design In a prospective cohort study, adolescents who initiated cannabis use at an early age (9-12
Full Text Available The hypothalamic-pituitary-adrenal (HPA axis is a major system maintaining body homeostasis by regulating the neuroendocrine and sympathetic nervous systems as well modulating immune function. Recent work has shown that the complex dynamics of this system accommodate several stable steady states, one of which corresponds to the hypocortisol state observed in patients with chronic fatigue syndrome (CFS. At present these dynamics are not formally considered in the development of treatment strategies. Here we use model-based predictive control (MPC methodology to estimate robust treatment courses for displacing the HPA axis from an abnormal hypocortisol steady state back to a healthy cortisol level. This approach was applied to a recent model of HPA axis dynamics incorporating glucocorticoid receptor kinetics. A candidate treatment that displays robust properties in the face of significant biological variability and measurement uncertainty requires that cortisol be further suppressed for a short period until adrenocorticotropic hormone levels exceed 30% of baseline. Treatment may then be discontinued, and the HPA axis will naturally progress to a stable attractor defined by normal hormone levels. Suppression of biologically available cortisol may be achieved through the use of binding proteins such as CBG and certain metabolizing enzymes, thus offering possible avenues for deployment in a clinical setting. Treatment strategies can therefore be designed that maximally exploit system dynamics to provide a robust response to treatment and ensure a positive outcome over a wide range of conditions. Perhaps most importantly, a treatment course involving further reduction in cortisol, even transient, is quite counterintuitive and challenges the conventional strategy of supplementing cortisol levels, an approach based on steady-state reasoning.
Lapp, Hannah E; Ahmed, Sarah; Moore, Celia L; Hunter, Richard G
Histories of early life stress (ELS) or social discrimination can reach levels of severity characterized as toxic to mental and physical health. Such toxic social stress during development has been linked to altered acute hypothalamic-pituitary-adrenal (HPA) response to social stress in adulthood. However, there are important individual differences in the size and direction of these effects. We explored developmental, genetic, epigenetic, and contextual sources of individual differences in the relationship between ELS, discrimination, and adult responses to acute social stress in a standard laboratory test. Additional measures included perceived status, social support, background activity of HPA axis, and genetic variants in aspects of the stress response system. Participants (n = 90) answered questions about historical and ongoing stress, provided a DNA sample to examine genetic polymorphisms and epigenetic marks, and underwent the Trier Social Stress Test (TSST) during which three saliva samples were collected to assess HPA function. Individuals who reported high levels of childhood adversity had a blunted salivary cortisol response to the TSST. Childhood adversity, discrimination experiences, and FKBP5 genotype were found to predict pretest cortisol levels. Following up on recent observations that the glucocorticoid receptor directly interacts with the mitochondrial genome, particularly the NADH dehydrogenase 6 (MT-ND6) gene, individuals who reported high childhood adversity were also found to have higher percent methylation across six CpG sites upstream of MT-ND6. These findings suggest multiple contributions across psychological, genetic, epigenetic, and social domains to vulnerability and resilience in hypothalamic-pituitary-adrenal axis regulation. Further study to examine how these multiple contributors affect developmental endpoints through integrated or independent pathways will be of use. Copyright © 2018 Elsevier Inc. All rights reserved.
Full Text Available Intestinal microbes are an important system in the human body, with significant effects on behavior. An increasing body of research indicates that intestinal microbes affect brain function and neurogenesis, including sensitivity to stress. To investigate the effects of microbial colonization on behavior, we examined behavioral changes associated with hormones and hormone receptors in the hypothalamic-pituitary-adrenal (HPA axis under stress. We tested germ-free (GF mice and specific pathogen-free (SPF mice, divided into four groups. A chronic restraint stress (CRS protocol was utilized to induce external pressure in two stress groups by restraining mice in a conical centrifuge tube for 4 h per day for 21 days. After CRS, Initially, GF restraint-stressed mice explored more time than SPF restraint-stressed mice in the center and total distance of the OFT. Moreover, the CRH, ACTH, CORT, and ALD levels in HPA axis of GF restraint-stressed mice exhibited a significantly greater increase than those of SPF restraint-stressed mice. Finally, the Crhr1 mRNA levels of GF CRS mice were increased compared with SPF CRS mice. However, the Nr3c2 mRNA levels of GF CRS mice were decreased compared with SPF CRS mice. All results revealed that SPF mice exhibited more anxiety-like behavior than GF mice under the same external stress. Moreover, we also found that GF mice exhibited significant differences in, hormones, and hormone receptors compared with SPF mice. In conclusion, Imbalances of the HPA axis caused by intestinal microbes could affect the neuroendocrine system in the brain, resulting in an anxiety-like behavioral phenotype. This study suggested that intervention into intestinal microflora may provide a new approach for treating stress-related diseases.
Martinac, Marko; Pehar, Davor; Karlović, Dalibor; Babić, Dragan; Marcinko, Darko; Jakovljević, Miro
Depression has been associated with various cardiovascular risk factors such as hypertension, obesity, atherogenic dyslipidemia and hyperglycemia. In depressive disorder, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and changes in the immune system have been observed. On the other hand, somatic diseases such as obesity, hyperlipidemia, hypertension and diabetes mellitus type 2 are now perceived as important comorbid conditions in patients with depression. The pathogenesis of the metabolic syndrome and depression is complex and poorly researched; however, it is considered that the interaction of chronic stress, psychotrauma, hypercotisolism and disturbed immune functions contribute to the development of these disorders. The aim of the study was to investigate the relationship between depression and metabolic syndrome regarding the HPA axis dysfunction and altered inflammatory processes. Literature search in Medline and other databases included articles written in English published between 1985 and 2012. Analysis of the literature was conducted using a systematic approach with the search terms such as depression, metabolic syndrome, inflammation, cytokines, glucocorticoids, cortisol, and HPA axis. In conclusion, the relationship between depression and metabolic syndrome is still a subject of controversy. Further prospective studies are required to clarify the possible causal relationship between depression and metabolic syndrome and its components. Furthermore, it is important to explore the possibility of a common biologic mechanism in the pathogenesis of these two disorders, in which special attention should be paid to the immune system function, especially the possible specific mechanisms by which cytokines can induce and maintain depressive symptoms and metabolic disorders. The data presented here emphasize the importance of recognition and treatment of depressive disorders with consequent reduction in the incidence of metabolic syndrome, but
The hypothalamic-pituitary-adrenal (HPA) axis is an extremely sensitive physiological system whose activation, with the consequent release of ACTH and glucocorticoids, is triggered by a wide range of psychological experiences and physiological perturbations (stressors). The HPA axis is also activated by a high number of pharmacological agents that markedly differ in structure and function, although the precise mechanisms remain in most cases unknown. Activation of the HPA axis is the consequence of the convergence of stimulatory inputs from different brain regions into the paraventricular nucleus of the hypothalamus (PVN), where the most important ACTH secretagogues (corticotrophin releasing factor, CRF, and arginin-vasopressin, AVP) are formed. Plasma levels of ACTH and corticosterone (the latter under more restricted conditions), are considered as good markers of stress for three main reasons: (a) their plasma levels are proportional to the intensity of emotional and systemic stressors, (b) daily repeated exposure to a stressor usually resulted in reduced ACTH response to the same stressor, that is termed adaptation or habituation; and (c) chronic exposure to stressful situations results in tonic changes in the HPA axis that can be used as indices of the accumulative impact of these situations. These changes can be evaluated under resting conditions (i.e. adrenal weight, CRF and AVP gene expression in the PVN) or after some challenges (administration of CRF, ACTH or dexamethasone) that are classical endocrinological tests. There is also evidence that the activation of the HPA axis may also reflect subtle changes in the characteristics of the stressful situations (unpredictability, lack of control, omission of expected rewards, presence of conspecifics), although this is a topic that requires further studies.
Naert, G; Zussy, C; Tran Van Ba, C; Chevallier, N; Tang, Y-P; Maurice, T; Givalois, L
Brain-derived neurotrophic factor (BDNF) appears to be highly involved in hypothalamic-pituitary-adrenal (HPA) axis regulation during adulthood, playing an important role in homeostasis maintenance. The present study aimed to determine the involvement of BDNF in HPA axis activity under basal and stress conditions via partial inhibition of this endogenous neurotrophin. Experiments were conducted in rats and mice with two complementary approaches: (i) BDNF knockdown with stereotaxic delivery of BDNF-specific small interfering RNA (siRNA) into the lateral ventricle of adult male rats and (ii) genetically induced knockdown (KD) of BDNF expression specifically in the central nervous system during the first ontogenesis in mice (KD mice). Delivery of siRNA in the rat brain decreased BDNF levels in the hippocampus (-31%) and hypothalamus (-35%) but not in the amygdala, frontal cortex and pituitary. In addition, siRNA induced no change of the basal HPA axis activity. BDNF siRNA rats exhibited decreased BDNF levels and concomitant altered adrenocortoctrophic hormone (ACTH) and corticosterone responses to restraint stress, suggesting the involvement of BDNF in the HPA axis adaptive response to stress. In KD mice, BDNF levels in the hippocampus and hypothalamus were decreased by 20% in heterozygous and by 60% in homozygous animals compared to wild-type littermates. Although, in heterozygous KD mice, no significant change was observed in the basal levels of plasma ACTH and corticosterone, both hormones were significantly increased in homozygous KD mice, demonstrating that robust cerebral BDNF inhibition (60%) is necessary to affect basal HPA axis activity. All of these results in both rats and mice demonstrate the involvement and importance of a robust endogenous pool of BDNF in basal HPA axis regulation and the pivotal function of de novo BDNF synthesis in the establishment of an adapted response to stress. © 2015 British Society for Neuroendocrinology.
Meerlo, P.; Koehl, M.; van der Borght, K.; Turek, F. W.
Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic-pituitary-adrenal (HPA) axis, one of the main neuroendocrine stress systems. However, few attempts have been made to examine how sleep loss affects the HPA axis response to subsequent stressors. Furthermore, most studies applied short-lasting total sleep deprivation and not restriction of sleep over a longer period of time, as often occurs in human society. Using the rat as our model species, we investigated: (i) the HPA axis activity during and after sleep deprivation and (ii) the effect of sleep loss on the subsequent HPA response to a novel stressor. In one experiment, rats were subjected to 48 h of sleep deprivation by placing them in slowly rotating wheels. Control rats were placed in nonrotating wheels. In a second experiment, rats were subjected to an 8-day sleep restriction protocol allowing 4 h of sleep each day. To test the effects of sleep loss on subsequent stress reactivity, rats were subjected to a 30-min restraint stress. Blood samples were taken at several time points and analysed for adrenocorticotropic hormone (ACTH) and corticosterone. The results show that ACTH and corticosterone concentrations were elevated during sleep deprivation but returned to baseline within 4 h of recovery. After 1 day of sleep restriction, the ACTH and corticosterone response to restraint stress did not differ between control and sleep deprived rats. However, after 48 h of total sleep deprivation and after 8 days of restricted sleep, the ACTH response to restraint was significantly reduced whereas the corticosterone response was unaffected. These results show that sleep loss not only is a mild activator of the HPA axis itself, but also affects the subsequent response to stress. Alterations in HPA axis regulation may gradually appear under
Elias, E; Benrick, A; Behre, C J; Ekman, R; Zetterberg, H; Stenlöf, K; Wallenius, V
Lipocalin-type prostaglandin D2-synthase (L-PGDS) is the main producer of prostaglandin D2 (PGD2) in the central nervous system (CNS). Animal data suggest effects of central nervous L-PGDS in the regulation of food intake and obesity. No human data are available. We hypothesised that a role for CNS L-PGDS in metabolic function in humans would be reflected by correlations with known orexigenic neuropeptides. Cerebrospinal fluid (CSF) and serum samples were retrieved from 26 subjects in a weight loss study, comprising a 3-week dietary lead-in followed by 12-weeks of leptin or placebo treatment. At baseline, CSF L-PGDS was positively correlated with neuropeptide Y (NPY) (ρ = 0.695, P fat distribution and central HPA axis mediators. The importance of these findings is unclear but could suggest a role for CSF L-PGDS in the regulation of visceral obesity by interaction with the neuroendocrine circuits regulating appetite and fat distribution. Further interventional studies will be needed to characterise these interactions in more detail. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.
Lee, Richard; Sawa, Akira
In this review, we provide a brief summary of several key studies that broaden our understanding of stress and its epigenetic control of the hypothalamic-pituitary-adrenal axis (HPA)-axis function and behavior. Clinical and animal studies suggest a link among exposure to stress, dysregulation of the HPA-axis, and susceptibility to neuropsychiatric illnesses. Recent studies have supported the notion that exposure to glucocorticoids and stress in various forms, duration, and intensity during di...
Góth, Miklós; Hubina, Erika; Korbonits, Márta
The metabolic syndrome has several similarities with Cushing's syndrome (impaired glucose tolerance, hypertension, dyslipidemia, central obesity) suggesting that abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis may have a link with the metabolic syndrome. Several studies suggested an association between the clinical signs of the metabolic syndrome and the increased hypothalamic-pituitary-adrenal axis activity based on increased cortisol concentration at 09.00 a.m. and increased cortisol response to corticotropin. According to the Barker hypothesis the fetal malnutrition could determine adult cardiovascular diseases (coronary heart disease, hypertension), some endocrine and metabolic disorders (obesity, type 2 diabetes and hyperlipidemia). The suggested mechanism of the phenomenon is that the suboptimal fetal nutrition results in glucocorticoid overproduction. The 11beta-hydroxysteroid dehydrogenase (converts biological inactive cortisone to cortisol and vice versa) is an important enzyme in cortisol metabolism. The increased expression of 11beta-hydroxysteroid dehydrogenase type 1 in fat tissue could lead to central obesity and impaired glucose tolerance. The hypothesis that increased corticotropin-releasing hormone production drives the overactive hypothalamo-pituitary-adrenal axis was not proven. Further investigations are needed to identify additional pathogenetic factors and to find new therapeutic possibilities.
van Bodegom, Miranda; Homberg, Judith R.; Henckens, Marloes J. A. G.
Exposure to stress during critical periods in development can have severe long-term consequences, increasing overall risk on psychopathology. One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis; a cascade of central and peripheral events resulting in the release of corticosteroids from the adrenal glands. Activation of the HPA-axis affects brain functioning to ensure a proper behavioral response to the stressor, but stress-induced (mal)adaptation of the HPA-axis' functional maturation may provide a mechanistic basis for the altered stress susceptibility later in life. Development of the HPA-axis and the brain regions involved in its regulation starts prenatally and continues after birth, and is protected by several mechanisms preventing corticosteroid over-exposure to the maturing brain. Nevertheless, early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood, affecting both its basal and stress-induced activity. According to the match/mismatch theory, encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context. Here, we review studies investigating the mechanistic underpinnings of the ELS-induced alterations in the structural and functional development of the HPA-axis and its key external regulators (amygdala, hippocampus, and prefrontal cortex). The effects of ELS appear highly dependent on the developmental time window affected, the sex of the offspring, and the developmental stage at which effects are assessed. Albeit by distinct mechanisms, ELS induced by prenatal stressors, maternal separation, or the limited nesting model inducing fragmented maternal care, typically results in HPA
Belda, Xavier; Nadal, Roser; Armario, Antonio
Stress-induced sensitization represents a process whereby prior exposure to severe stressors leaves animals or humans in a hyper-responsive state to further stressors. Indeed, this phenomenon is assumed to be the basis of certain stress-associated pathologies, including post-traumatic stress disorder and psychosis. One biological system particularly prone to sensitization is the hypothalamic-pituitary-adrenal (HPA) axis, the prototypic stress system. It is well established that under certain conditions, prior exposure of animals to acute and chronic (triggering) stressors enhances HPA responses to novel (heterotypic) stressors on subsequent days (e.g. raised plasma ACTH and corticosterone levels). However, such changes remain somewhat controversial and thus, the present study aimed to identify the critical characteristics of the triggering and challenging stressors that affect acute stress-induced HPA cross-sensitization in adult rats. We found that HPA cross-sensitization is markedly influenced by the intensity of the triggering stressor, whereas the length of exposure mainly affects its persistence. Importantly, HPA sensitization is more evident with mild than strong challenging stressors, and it may remain unnoticed if exposure to the challenging stressor is prolonged beyond 15 min. We speculate that heterotypic HPA sensitization might have developed to optimize biologically adaptive responses to further brief stressors.
Kalsbeek, A.; van der Spek, R.; Lei, J.; Endert, E.; Buijs, R. M.; Fliers, E.
The pronounced daily variation in the release of adrenal hormones has been at the heart of the deciphering and understanding of the circadian timing system. Indeed, the first demonstration of an endocrine day/night rhythm was provided by Pincus (1943), by showing a daily pattern of 17-keto-steroid
The main purpose of the studies described in this thesis was to gain more insight in the regulation of the hypothalamic-pituitary-adrenocorticaI (HPA) system and the mechanisms underlying adaptation to chronic stress in female pigs. The function of the HPA axis, which
Vinther, Frank; Andersen, Morten; Ottesen, Johnny T.
-physiological values of the parameters are needed in order to achieve local instability of the fixed point. Small changes inphysiologically relevant parameters cause the system to be globally stable using the analytical criteria. All simulations show a globally stable fixed point, ruling out periodic solutions even...... are modeled as a system of three coupled, nonlinear differential equations. Experimental data shows the circadian as well as the ultradian rhythm. This paper focuses on the ultradian rhythm. The ultradian rhythm can mathematically be explained by oscillating solutions. Oscillating solutions to an ODE emerges...... from an unstable fixed point with complex eigenvalues with a positive real parts and a non-zero imaginary parts. The first part of the paper describes the general considerations to be obeyed for a mathematical model of the HPA axis. In this paper we only include the most widely accepted mechanisms...
Keltikangas-Järvinen, L; Ravaja, N; Räikkönen, K; Hautanen, A; Adlercreutz, H
We examined whether the relationships between the pituitary-adrenal hormones (corticotropin [ACTH) and cortisol), insulin, and glucose differ as a function of psychosocial stress defined in terms of vital exhaustion (VE) and depressive behavior (DB). The participants were 69 normotensive and 21 unmedicated borderline hypertensive (BH) middle-aged men whose work is stressful. Hormonal and metabolic variables were measured during an oral glucose tolerance test (OGTT), and the cortisol response to dexamethasone (DXM) suppression and intravenous ACTH stimulation was also measured. We found that the basal ACTH level during the OGTT was positively associated with the cortisol response to ACTH at 60 minutes, the fasting insulin level, and the insulin to glucose ratio among exhausted and high DB men, while the reverse was true for nonexhausted and low DB men. Also, a high cortisol response to ACTH, a low cortisol level during the OGTT, and a high ratio of these cortisol determinations (cortisol ratio) were associated with high fasting insulin and glucose levels, the summed insulin values, and the insulin to glucose ratio only among nonexhausted and low DB men; among exhausted and high DB men, these associations were less pronounced, absent, or in the opposite direction. The findings suggest that VE and DB have a moderating influence on the relationships among the hormonal and metabolic parameters studied. Psychosocial stress may affect the pituitary-adrenocortical system in complex ways, contributing thereby to insulin resistance, hyperinsulinemia, and coronary heart disease (CHD) risk.
Calhoun, Casey D; Helms, Sarah W; Heilbron, Nicole; Rudolph, Karen D; Hastings, Paul D; Prinstein, Mitchell J
Adolescents' peer experiences may have significant associations with biological stress-response systems, adding to or reducing allostatic load. This study examined relational victimization as a unique contributor to reactive hypothalamic-pituitary-adrenal (HPA) axis responses as well as friendship quality and behavior as factors that may promote HPA recovery following a stressor. A total of 62 adolescents (ages 12-16; 73% female) presenting with a wide range of life stressors and adjustment difficulties completed survey measures of peer victimization and friendship quality. Cortisol samples were collected before and after a lab-based interpersonally themed social stressor task to provide measures of HPA baseline, reactivity, and recovery. Following the stressor task, adolescents discussed their performance with a close friend; observational coding yielded measures of friends' responsiveness. Adolescents also reported positive and negative friendship qualities. Results suggested that higher levels of adolescents' relational victimization were associated with blunted cortisol reactivity, even after controlling for physical forms of victimization and other known predictors of HPA functioning (i.e., life stress or depressive symptoms). Friendship qualities (i.e., low negative qualities) and specific friendship behaviors (i.e., high levels of responsiveness) contributed to greater HPA regulation; however, consistent with theories of rumination, high friend responsiveness in the context of high levels of positive friendship quality contributed to less cortisol recovery. Findings extend prior work on the importance of relational victimization and dyadic peer relations as unique and salient correlates of adaptation in adolescence.
Armario, Antonio; Daviu, Núria; Muñoz-Abellán, Cristina; Rabasa, Cristina; Fuentes, Silvia; Belda, Xavier; Gagliano, Humberto; Nadal, Roser
Exposure to stress induces profound physiological and behavioral changes in the organisms and some of these changes may be important regarding stress-induced pathologies and animal models of psychiatric diseases. Consequences of stress are dependent on the duration of exposure to stressors (acute, chronic), but also of certain characteristics such as intensity, controllability, and predictability. If some biological variables were able to reflect these characteristics, they could be used to predict negative consequences of stress. Among the myriad of physiological changes caused by stress, only a restricted number of variables appears to reflect the intensity of the situation, mainly plasma levels of ACTH and adrenaline. Peripheral hypothalamic-pituitary-adrenal (HPA) hormones (ACTH and corticosterone) are also able to reflect fear conditioning. In contrast, the activation of the HPA axis is not consistently related to anxiety as evaluated by classical tests such as the elevated plus-maze. Similarly, there is no consistent evidence about the sensitivity of the HPA axis to psychological variables such as controllability and predictability, despite the fact that: (a) lack of control over aversive stimuli can induce behavioral alterations not seen in animals which exert control, and (b) animals showed clear preference for predictable versus unpredictable stressful situations. New studies are needed to re-evaluate the relationship between the HPA axis and psychological stress characteristics using ACTH instead of corticosterone and taking advantages of our current knowledge about the regulation of this important stress system.
Laurent, Heidemarie K.; Leve, Leslie D.; Neiderhiser, Jenae M.; Natsuaki, Misaki N.; Shaw, Daniel S.; Fisher, Philip A.; Marceau, Kristine; Harold, Gordon T.; Reiss, David
Child hypothalamic pituitary adrenal (HPA) activity was investigated as a moderator of parental depressive symptom effects on child behavior in an adoption sample ("n" = 210 families). Adoptive parents' depressive symptoms and child internalizing and externalizing were assessed at 18, 27, and 54 months, and child morning and evening HPA…
Gordijn, Maartje S.; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.
Background Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress
Gordijn, Maartje S.; Rensen, Niki; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.
Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate
Rensen, Niki; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.
Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate
Gardner, M.P.; Lightman, S.; Sayer, A.A.; Cooper, C.; Cooper, R.; Deeg, D.J.H.; Ebrahim, S.; Gallacher, J.; Kivimaki, M.; Kumari, M.; Kuh, D; Martin, R.M.; Peeters, G.; Ben-Shlomoa, Y.
The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is
Carter, R. N.; Paterson, J. M.; Tworowska, U.; Stenvers, D. J.; Mullins, J. J.; Seckl, J. R.; Holmes, M. C.
Inter-individual differences in hypothalamic-pituitary-adrenal (HPA) axis activity underlie differential vulnerability to neuropsychiatric and metabolic disorders, although the basis of this variation is poorly understood. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has previously been
Evans, B.E.; Greaves-Lord, K.; Euser, A.S.; Franken, I.H.A.; Huizink, A.C.
Aims: Hypothalamic-pituitary-adrenal (HPA) axis activity may prove a viable biomarker for identifying those susceptible to alcohol use disorders. The purpose of this study was to examine the relation of the age at which adolescents begin drinking with diurnal and stress cortisol. Design:
Stanojević, A.; Marković, V. M.; Čupić, Ž.; Vukojević, V.; Kolar-Anić, L.
A model was developed that can be used to study the effect of gradual cholesterol intake by food on the HPA axis dynamics. Namely, well defined oscillatory dynamics of vital neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis has proven to be necessary for maintaining regular basal physiology and formulating appropriate stress response to various types of perturbations. Cholesterol, as a precursor of all steroid HPA axis hormones, can alter the dynamics of HPA axis. To analyse its particular influence on the HPA axis dynamics we used stoichiometric model of HPA axis activity, and simulate cholesterol perturbations in the form of finite duration pulses, with asymmetrically distributed concentration profile. Our numerical simulations showed that there is a complex, nonlinear dependence between the HPA axis responsiveness and different forms of applied cholesterol concentration pulses, indicating the significance of kinetic modelling, and dynamical systems theory for the understanding of large-scale self-regulatory, and homeostatic processes within this neuroendocrine system.
Buttenschøn, Henriette Nørmølle; Krogh, Jesper; Nielsen, Marit Nyholm
OBJECTIVE: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in depression. The aim was to investigate the potential association between depression and seven genes regulating or interfering with the HPA axis, including the gene encoding angiotensin converting enzyme......) was investigated. RESULTS: After quality control, 68 genetic variants were left for analyses. Four of nine variants within ACE were nominally associated with depression and a gene-wise association was likewise observed. However, none of the SNPs located within AVP, CRH, CRHR1, CRHR2, FKBP5 or NC3C1 were associated...... with depression. One nominally significant interaction, most likely due to chance, was identified. CONCLUSION: The results indicate that ACE could be a potential candidate gene for depression....
Jehn, Christian Friedrich; Kühnhardt, Dagmar; Bartholomae, Andrea; Pfeiffer, Sebastian; Schmid, Peter; Possinger, Kurt; Flath, Bernd Christian; Lüftner, Diana
Evidence suggests that cytokines (IL-6) and alteration of the hypothalamic-pituitary-adrenal (HPA) axis play a crucial role in the etiology of depression. Patients with cancer show elevated prevalence rates for depression. The objective of this cross-sectional study was to investigate the associations between these abnormalities and depression. Plasma concentrations of IL-6 and cortisol were measured in cancer patients with (N = 31) and without depression (N = 83). The relative diurnal variation of cortisol (cortisol VAR), expressed in percentage, was calculated. There was a significant difference in median plasma concentration of IL-6 between the patients with depression and those without (18.7 vs 2.7 pg/mL; P cancer is associated with increased plasma IL-6 concentrations and dysfunction of the HPA axis.
Mello Andrea de Abreu Feijó de
Full Text Available Over the past 50 years, relationships between stress and the neurobiological changes seen in psychiatric disorders have been well-documented. A major focus of investigations in this area has been the role of the hypothalamic-pituitary-adrenal (HPA axis, both as a marker of stress response and as a mediator of additional downstream pathophysiologic changes. This review examines the emerging literature concerning the relationship between stress, HPA axis function, and depression, as well as the role of early life stress as an important risk factor for HPA axis dysregulation. The more recent studies reviewed suggest that the prominence of HPA axis hyperactivity in adults with depressive and anxiety disorders may constitute a link between the occurrence of adversity in childhood and the development of adult psychopathology
Xiong, Fuxia; Zhang, Lubo
Adverse environments during the fetal and neonatal development period may permanently program physiology and metabolism, and lead to increased risk of diseases in later life. Programming of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key mechanisms that contribute to altered metabolism and response to stress. Programming of the HPA axis often involves epigenetic modification of the glucocorticoid receptor (GR) gene promoter, which influences tissue-specific GR expression patterns and response to stimuli. This review summarizes the current state of research on the HPA axis and programming of health and disease in the adult, focusing on the epigenetic regulation of GR gene expression patterns in response to fetal and neonatal stress. Aberrant GR gene expression patterns in the developing brain may have a significant negative impact on protection of the immature brain against hypoxic-ischemic encephalopathy in the critical period of development during and immediately after birth. PMID:23200813
Beta-endorphin and adrenocorticotropic hormone (ACTH) were determined simultaneously in the plasma using a radioimmunological procedure. It was found that in patients showing imbalances within the hypothalamus-pituitary-adrenal system (Addison's disease, Cushing's Syndrome, Nelson's Syndrome) as well as elevated levels of beta-endorphin the values of ACHT invariably were also increased. The behaviour of the plasma levels of beta-endorphin and ACTH before, during and subsequent to hypophyseal surgery gives evidence to prove the close link between the two hormones. Tests performed to examine the function of the corticotropin releasing factor (CRF) both in healthy volunteers and patients suffering from endocrinological disorders likewise pointed to a parallel behaviour pattern of the two hormones in their responding or failure to respond to stimulation. The fact that a significant correlation was established between all measured values of beta-endorphin and ACTH is further evidence in confirmation of a parallel release of these two hormones in man. (TRV) [de
Nadezhda Dmitrievna Goncharova
Full Text Available The hypothalamic-pituitary-adrenal (HPA axis plays a key role in adaptation to environmental stresses. Parvicellular neurons of the hypothalamic paraventricular nucleus secrete corticotrophin releasing hormone (CRH and arginine vasopressin (AVP into pituitary portal system; CRH and AVP stimulate ACTH release through specific G protein-coupled membrane receptors on pituitary corticotrophs, CRH1 for CRH and V1b for AVP; the adrenal gland cortex secretes glucocorticoids in response ACTH. The glucocorticoids activate specific receptors in brain and peripheral tissues thereby triggering the necessary metabolic, immune, neuromodulatory and behavioral changes to resist stress. While importance of CRH, as a key hypothalamic factor of HPA axis regulation in basal and stress conditions in most species, is generally recognized, role of AVP remains to be clarified. This review focuses on the role of AVP in the regulation of stress responsiveness of the HPA axis with emphasis on the effects of aging on vasopressinergic regulation of HPA axis stress responsiveness. Under most of the known stressors, AVP is necessary for acute ACTH secretion but in a context-specific manner. The current data on the AVP role in regulation of HPA responsiveness to chronic stress in adulthood are rather contradictory. The importance of the vasopressinergic regulation of the HPA stress responsiveness is greatest during fetal development, in neonatal period, and in the lactating adult. Aging associated with increased variability in several parameters of HPA function including basal state, responsiveness to stressors, and special testing. Reports on the possible role of the AVP/V1b receptor system in the increase of HPA axis hyperactivity with aging are contradictory and requires further research. Many contradictory results may be due to age and species differences in the HPA function of rodents and primates.
Full Text Available response to endotoxin (LPS). Derijk RH, van Rooijen N, Berkenbosch F. Res Immunol. 1992 Feb;143(2):224-9. (....e hypothalamic-pituitary-adrenal activation inresponse to endotoxin (LPS). Authors Derijk RH, van Rooijen N, Berk
Kempke, Stefan; Luyten, Patrick; De Coninck, Sarah; Van Houdenhove, Boudewijn; Mayes, Linda C; Claes, Stephan
There is a paucity of studies that have investigated the assumption that early childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction in Chronic Fatigue Syndrome (CFS). The current study is the first to simultaneously investigate relationships among early childhood trauma, cortisol activity, and cortisol stress reactivity to psychosocial stress in a sample of well-screened CFS patients. We also examined whether self-critical perfectionism (SCP) plays a mediating role in the potential relationship between early trauma and neurobiological stress responses. A total of 40 female patients diagnosed with CFS were asked to provide morning saliva cortisol samples (after awakening, 30min later, and 1h later) for seven consecutive days as a measure of cortisol activity. In addition, patients were exposed to the Trier Social Stress Test, a well-validated stress test, to investigate the relationship between early childhood trauma and cortisol stress reactivity. Before the start of the study, patients completed the Childhood Trauma Questionnaire-Short form (CTQ-SF) as a measure of early childhood trauma (i.e. sexual, physical and emotional traumatic experiences). SCP was measured with the Depressive Experiences Questionnaire (DEQ). Data were analyzed by calculating several indices of cortisol secretion (i.e. Cortisol Awakening Response and Area Under the Curve). There was no association between early childhood trauma and cortisol as measured over the 7-day period. However, emotional neglect was significantly negatively related to cortisol reactivity in the TSST. SCP did not significantly mediate this association. Findings of this study suggest that emotional neglect is associated with blunted HPA axis reactivity, congruent with the assumption that CFS may reflect loss of adaptability of the neuroendocrine stress response system in at least a subgroup of patients. Copyright © 2014 Elsevier Ltd. All rights reserved.
Carrasco, Javier; Márquez, Cristina; Nadal, Roser; Tobeña, Adolfo; Fernández-Teruel, Albert; Armario, Antonio
Several studies performed in outbred Roman high- and low-avoidance lines (RHA and RLA, respectively) have demonstrated that the more anxious line (RLA) is characterized by a higher hypothalamic-pituitary-adrenal (HPA) response to certain stressors than the less anxious one (RHA). However, inconsistent results have also been reported. Taking advantage of the generation of an inbred colony of RLA and RHA rats (RHA-I and RLA-I, respectively), we have characterized in the two strains not only resting and stress levels of peripheral HPA hormones but also central components of the HPA axis, including CRF gene expression in extra-hypothalamic areas. Whereas resting levels of ACTH and corticosterone did not differ between the strains, a greater response to a novel environment was found in RLA-I as compared to RHA-I rats. RLA-I rats showed enhanced CRF gene expression in the paraventricular nucleus (PVN) of the hypothalamus, with normal arginin-vasopressin gene expression in both parvocellular and magnocellular regions of the PVN. This enhanced CRF gene expression is not apparently related to altered negative corticosteroid feedback as similar levels of expression of brain glucorticoid and mineralocorticoid receptors were found in the two rat strains. CRF gene expression tended to be higher in the central amygdala and it was significantly higher in the dorsal region of the bed nucleus of stria terminalis (BNST) of RLA-I rats, while no differences appeared in the ventral region of BNST. Considering the involvement of CRF and the BNST in anxiety and stress-related behavioral alterations, the present data suggest that the CRF system may be a critical neurobiological substrate underlying differences between the two rat strains.
Xu, Tao-Tao; Jin, Hong-Ting; Tong, Pei-Jian
As a traditional concept of Chinese medicine (CM), the theory of "Shen (Kidney) controlling bones" has been gradually proven. And in modern allopathic medicine, the multiple mechanisms of bone growth, development and regeneration align with the theory. Shen defifi ciency as a pathological condition has a negative effect on the skeleton of body, specififi cally the disorder of bone homeostasis. Present studies indicate that Shen defifi ciency shares a common disorder characterized by dysfunction of hypothalamic-pituitary-adrenal (HPA) axis. HPA axis may be an important regulator of bone diseases with abnormal homeostasis. Therefore, we posit the existence of hypothalamic-pituitary-adrenal-osteo-related cells axis: cells that comprise bone tissue (osteo-related cells) are targets under the regulation of HPA axis in disorder of bone homeostasis. Chinese herbs for nourishing Shen have potential in the development of treatments for disorder of bone homeostasis.
Hypothalamic-Pituitary-Adrenal Function in Posttraumatic Stress PRINCIPAL INVESTIGATOR: Sabra Inslicht, Ph.D. RECIPIENT: Northern California Institute...Posttraumatic Stress 5b. GRANT NUMBER W81XWH-16-1-0313 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Sabra Inslicht, PhD 5d. PROJECT NUMBER 5e. TASK NUMBER...ABSTRACT Post-traumatic stress (PTS) is a common psychiatric condition that may result after combat exposure and can have a profound effect on sleep
Cheryl M. McCormick
Full Text Available Elevations in glucocorticoids that result from environmental stressors can have programming effects on brain structure and function when the exposure occurs during sensitive periods that involve heightened neural development. In recent years, adolescence has gained increasing attention as another sensitive period of development, a period in which pubertal transitions may increase the vulnerability to stressors. There are similarities in physical and behavioural development between humans and rats, and rats have been used effectively as an animal model of adolescence and the unique plasticity of this period of ontogeny. This review focuses on benefits and challenges of rats as a model for translational research on hypothalamic-pituitary-adrenal (HPA function and stressors in adolescence, highlighting important parallels and contrasts between adolescent rats and humans, and we review the main stress procedures that are used in investigating HPA stress responses and their consequences in adolescence in rats. We conclude that a greater focus on timing of puberty as a factor in research in adolescent rats may increase the translational relevance of the findings.
Hillman, Jennifer B; Dorn, Lorah D; Loucks, Tammy L; Berga, Sarah L
Stress and stress-related concomitants, including hypothalamic-pituitary-adrenal (HPA) axis activation, are implicated in obesity and its attendant comorbidities. Little is known about this relationship in adolescents. To begin to address this important knowledge gap, we studied HPA axis activity in 262 healthy adolescent girls aged 11, 13, 15, and 17 years. We hypothesized that obesity would be correlated with increased HPA axis activity and reactivity. Measures of HPA axis activity included 3 blood samples obtained midday (between 1:00 and 2:00 pm) over the course of 40 minutes; overnight urine free cortisol; and cortisol levels 0, 20, and 40 minutes after venipuncture (cortisol reactivity). Measures of adiposity included body mass index (BMI), BMI z score (BMI-Z), percentage body fat, and fat distribution (central adiposity) assessed by dual-energy x-ray absorptiometry. Daytime levels of serum cortisol were inversely associated with BMI-Z and central adiposity (P cortisol excretion rate was positively correlated with BMI, BMI-Z, and central adiposity. There was blunting of cortisol response to venipuncture with increasing adiposity. Our results suggest that there may be reduced cortisol levels during the day and increased levels at night with increasing degree of adiposity. This study provides preliminary findings indicating an alteration of the circadian rhythm of cortisol with obesity. We conclude that obesity is associated with altered HPA activity in adolescent girls. The clinical implications of our findings require further investigation. Copyright Â© 2012 Elsevier Inc. All rights reserved.
Moch, Shirra L; Panz, Vanessa R; Joffe, Barry I; Havlik, Ivan; Moch, Jonathan D
The authors' goal was to document baseline pituitary-adrenal hormonal and related metabolic variables in 16 female patients with burnout. Then, following stress management intervention, to compare the changes with an equal number of untreated control subjects. At monthly intervals for 4 mo, 24-h urine samples were obtained for determination of free cortisol excretion. In addition, fasting blood samples were analyzed for levels of cortisol, dehydroepiandrosterone sulfate (DHEAS), ACTH, aldosterone, and catecholamines. Other biochemical measurements included growth hormone, prolactin, insulin, glucose, and lipid components. The Maslach Burnout Inventory, General Health Questionnaire- 28, and Zung depression rating scale were completed on each consecutive visit. The most striking finding was the reduction of urine free-cortisol excretion in the patients compared with controls. Initial urinary free cortisol was significantly lower in the patients (mean +/- SEM = 47.2 +/- 11.0 vs 79.0 +/- 6.8 nmol/L, p = 0.02) and remained significantly reduced at 4 mo (mean +/- SEM = 44.0 +/- 6.1 vs 91.1 +/- 8.8 nmol/L, p = 0.0001). There were no significant changes in the other hormonal and biochemical data. We conclude that there is functional hypocortisolism in burnout, which is not immediately restored on stress management intervention despite clinical and psychological improvement.
Warren, W B; Gurewitsch, E D; Goland, R S
We hypothesized that maternal plasma corticotropin-releasing hormone levels are elevated in chronic hypertension and that elevations modulate maternal and fetal pituitary-adrenal function. Venous blood samples and 24-hour urine specimens were obtained in normal and hypertensive pregnancies at 21 to 40 weeks of gestation. Corticotropin-releasing hormone, corticotropin, cortisol, dehydroepiandrosterone sulfate, and total estriol levels were measured by radioimmunoassay. Mean hormone levels were compared by unpaired t test or two-way analysis of variance. Plasma corticotropin-releasing hormone levels were elevated early in hypertensive pregnancies but did not increase after 36 weeks. Levels of pituitary and adrenal hormones were not different in normal and hypertensive women. However, maternal plasma estriol levels were lower in hypertensive pregnancies compared with normal pregnancies. Fetal 16-hydroxy dehydroepiandrosterone sulfate, the major precursor to placental estriol production, has been reported to be lower than normal in hypertensive pregnancies, possibly explaining the decreased plasma estriol levels reported here. Early stimulation of placental corticotropin-releasing hormone production or secretion may be related to accelerated maturation of placental endocrine function in pregnancies complicated by chronic hypertension.
Aloisi, A M; Steenbergen, H L; van de Poll, N E; Farabollini, F
The sex-dependent effects of acute restraint (RT) on nociceptive and pituitary-adrenal responses were investigated in the rat. In a first experiment, the effect of 30 min RT on pain sensitivity was evaluated through repeated use of the tail withdrawal test during and after treatment. RT induced an increase in the nociceptive threshold, i.e., analgesia, in males and females, but the duration and time-course of this effect varied between sexes. The latencies returned to approximately control values in females in the second half of RT, but in males they remained higher for the whole period of RT and immediately afterwards. Twenty-four hours later, males displayed longer latencies than controls in response to simple reexposure to the environment. In a second experiment, ACTH and corticosterone plasma levels were measured immediately after 15 or 30 min of RT. ACTH and corticosterone were higher in restrained animals than in controls after both periods of treatment, and in both sexes; however, females showed higher basal and stress corticosterone levels than males. The role played by corticosteroids in the nociceptive responses of the two sexes is discussed.
Čupić, Željko; Marković, Vladimir M.; Maćešić, Stevan; Stanojević, Ana; Damjanović, Svetozar; Vukojević, Vladana; Kolar-Anić, Ljiljana
Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamic-pituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations.
Kunugi, Hiroshi; Hori, Hiroaki; Numakawa, Tadahiro; Ota, Miho
Depression is a stress-induced disorder and there is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in the disease. Chronic hyperactivity of the HPA axis and resultant excessive glucocorticoid (hypercortisolism) may be causal to depression. We demonstrated that the dexamethasone (DEX)/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities. Restoration from HPA axis abnormalities occurs with clinical responses to treatment. Brain-derived neurotrophic factor (BDNF) has also been implicated in depression. We found that glucocorticoid (DEX) suppresses BDNF-induced dendrite outgrowth and synaptic formation via blocking the MAPK pathway in early-developing cultured hippocampal neurons. Furthermore, we demonstrated that glucocorticoid receptor (GR) and TrkB (a specific receptor of BDNF) interact and that DEX acutely suppresses BDNF-induced glutamate release by affecting the PLC-gamma pathway in cultured cortical neurons, indicating a mechanism underlying the effect of excessive glucocorticoid on BDNF function and resultant damage in cortical neurons. In a macroscopic view using magnetic resonance imaging (MRI), we found that individuals with hypercortisolism detected by the DEX/CRH test demonstrated volume loss in gray matter and reduced neural network assessed with diffusion tensor imaging in several brain regions. Finally, we observed that individuals with hypocortisolism detected by the DEX/CRH test tend to present more distress symptoms, maladaptive coping styles, and schizotypal personality traits than their counterparts, which points to the important role of hypocortisolism as well as hypercortisolism in depression spectrum disorders.
Kunugi, Hiroshi; Hori, Hiroaki; Adachi, Naoki; Numakawa, Tadahiro
Although the pathophysiology of depressive disorder remains elusive, two hypothetical frameworks seem to be promising: the involvement of hypothalamic pituitary-adrenal (HPA) axis abnormalities and brain-derived neurotrophic factor (BDNF) in the pathogenesis and in the mechanism of action of antidepressant treatments. In this review, we focused on research based on these two frameworks in relation to depression and related conditions and tried to formulate an integrated theory of the disorder. Hormonal challenge tests, such as the dexamethasone/corticotropin-releasing hormone test, have revealed elevated HPA activity (hypercortisolism) in at least a portion of patients with depression, although growing evidence has suggested that abnormally low HPA axis (hypocortisolism) has also been implicated in a variety of stress-related conditions. Several lines of evidence from postmortem studies, animal studies, blood levels, and genetic studies have suggested that BDNF is involved in the pathogenesis of depression and in the mechanism of action of biological treatments for depression. Considerable evidence has suggested that stress reduces the expression of BDNF and that antidepressant treatments increase it. Moreover, the glucocorticoid receptor interacts with the specific receptor of BDNF, TrkB, and excessive glucocorticoid interferes with BDNF signaling. Altered BDNF function is involved in the structural changes and possibly impaired neurogenesis in the brain of depressed patients. Based on these findings, an integrated schema of the pathological and recovery processes of depression is illustrated. © 2010 The Authors. Psychiatry and Clinical Neurosciences © 2010 Japanese Society of Psychiatry and Neurology.
Geisel, Olga; Panneck, Patricia; Hellweg, Rainer; Wiedemann, Klaus; Müller, Christian A
Alterations in secretion of stress hormones within the hypothalamic-pituitary-adrenal (HPA) axis have repeatedly been found in substance-related addictive disorders. It has been suggested that glucocorticoids might contribute to the development and maintenance of substance use disorders by facilitatory effects on behavioral responses to substances of abuse. The objective of this pilot study was to investigate HPA axis activity in patients with non-substance-related addictive disorders, i.e. pathological gambling and internet use disorder. We measured plasma levels of copeptin, a vasopressin surrogate marker, adrenocorticotropic hormone (ACTH) and cortisol in male patients with pathological gambling (n=14), internet use disorder (n=11) and matched healthy controls for pathological gambling (n=13) and internet use disorder (n=10). Plasma levels of copeptin, ACTH and cortisol in patients with pathological gambling or internet use disorder did not differ among groups. However, cortisol plasma levels correlated negatively with the severity of pathological gambling as measured by the PG-YBOCS. Together with our findings of increased serum levels of brain-derived neurotrophic factor (BDNF) in pathological gambling but not internet use disorder, these results suggest that the pathophysiology of pathological gambling shares some characteristics with substance-related addictive disorders on a neuroendocrinological level, whereas those similarities could not be observed in internet use disorder. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Full Text Available The daily rhythm of cortisol secretion is relatively stable and primarily under the influence of the circadian clock. Nevertheless, several other factors affect hypothalamo-pituitary-adrenal (HPA axis activity. Sleep has modest but clearly detectable modulatory effects on HPA axis activity. Sleep onset exerts an inhibitory effect on cortisol secretion while awakenings and sleep offset are accompanied by cortisol stimulation. During waking, an association between cortisol secretory bursts and indices of central arousal has also been detected. Abrupt shifts of the sleep period induce a profound disruption in the daily cortisol rhythm, while sleep deprivation and/or reduced sleep quality seem to result in a modest but functionally important activation of the axis. HPA hyperactivity is clearly associated with metabolic, cognitive and psychiatric disorders and could be involved in the well-documented associations between sleep disturbances and the risk of obesity, diabetes and cognitive dysfunction. Several clinical syndromes, such as insomnia, depression, Cushing's syndrome, sleep disordered breathing (SDB display HPA hyperactivity, disturbed sleep, psychiatric and metabolic impairments. Further research to delineate the functional links between sleep and HPA axis activity is needed to fully understand the pathophysiology of these syndromes and to develop adequate strategies of prevention and treatment.
van Haalen, Femke M; van Dijk, Elon H C; Dekkers, Olaf M; Bizino, Maurice B; Dijkman, Greet; Biermasz, Nienke R; Boon, Camiel J F; Pereira, Alberto M
Central serous chorioretinopathy (CSC), a specific form of macular degeneration, has been reported as presenting manifestation of Cushing's syndrome. Furthermore, CSC has been associated with both exogenous hypercortisolism and endogenous Cushing's syndrome. It is important to know whether CSC patients should be screened for Cushing's syndrome. Although hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in CSC has been suggested, no detailed evaluation of the HPA axis has been performed in a large cohort of CSC patients. This study aimed to investigate whether Cushing's syndrome prevalence is increased among chronic CSC (cCSC) patients and whether detailed endocrinological phenotyping indicates hyperactivity of the HPA axis. Cross-sectional study. 86 cCSC patients and 24 controls. Prevalence of Cushing's syndrome, HPA axis activity. None of the cCSC patients met the clinical or biochemical criteria of Cushing's syndrome. However, compared to controls, HPA axis activity was increased in cCSC patients, reflected by higher 24 h urinary free cortisol, and accompanying higher waist circumference and diastolic blood pressure, whereas circadian cortisol rhythm and feedback were not different. Chronic CSC patients did not report more stress or stress-related problems on questionnaires. No case of Cushing's syndrome was revealed in a large cohort of cCSC patients. Therefore, we advise against screening for Cushing's syndrome in CSC patients, unless additional clinical features are present. However, our results indicate that cCSC is associated with hyperactivity of the HPA axis, albeit not accompanied with perception of more psychosocial stress.
Demiraslan, Hayati; Şimşek, Yasin; Tanriverdi, Fatih; Doğanay, Mehmet; Keleştemur, Hasan Fahrettin
To investigate prospectively the hypothalamo-pituitary-adrenal (HPA) axis by adrenocorticotropic hormone (ACTH) stimulation test. Tularemia was diagnosed according to guidelines. An ACTH stimulation test (1 µg) and a dexamethasone suppression test (DST; 1 mg) were performed in patients in the acute phase of tularemia before antibiotic treatment and in the chronic phase. Nineteen patients (mean age: 41.0 ± 13.2 years; 57.9% female) with tularemia were enrolled in the study in 2011 and 2012. Cortisol response to ACTH stimulation test was sufficient in all patients during the acute phase. After the DST, the cortisol was not suppressed during the acute phase in only one patient. The median control time of 11 patients after acute tularemia was 13 months. During the chronic phase, cortisol response to ACTH stimulation was normal in all patients, and after DST cortisol was suppressed in all patients. The peak cortisol level after the ACTH stimulation test in the acute phase was higher than that in the chronic phase, but the difference was not statistically significant. The HPA axis of patients with tularemia was not significantly affected in the acute and chronic phases.
Laceulle, Odilia M; Nederhof, Esther; van Aken, Marcel A G; Ormel, Johan
The hypothalamic-pituitary-adrenal (HPA) axis has been proposed to be a key mechanism underlying the link between adversity and mental health, but longitudinal studies on adversity and HPA-axis functioning are scarce. Here, we studied adversity-driven changes in HPA-axis functioning during adolescence (N=141). HPA-axis functioning (basal cortisol, cortisol awakening response, anticipation of, reaction to and recovery after a stress task) was measured twice, at age 16 and 19. Adversity (i.e., social defeat and loss/illness) since age 16 was measured extensively with the Life Stress Interview at age 19. Adolescents who reported being exposed to social defeat showed increases in basal cortisol (ɳ 2 =0.029) and decreases in reaction to the stress task (ɳ 2 =0.030) from age 16-19, compared to their peers in the loss/illness and no stress group. The current study provides unique longitudinal data on the role of adversity in HPA-axis functioning. Evidence is provided that adversity can affect the body's neuroendocrine response to stress, dependent on the nature of both the HPA-measures and adverse events under study. Copyright © 2017 Elsevier Ltd. All rights reserved.
Vasconcelos-Moreno, Mirela Paiva; Gubert, Carolina; dos Santos, Bárbara Tietböhl Martins Quadros; Sartori, Juliana; Eisele, Bárbara; Ferrari, Pamela; Fijtman, Adam; Rüegg, Joëlle; Gassen, Nils Christian; Kapczinski, Flávio; Rein, Theo; Kauer-Sant’Anna, Márcia
Background: Impaired stress resilience and a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis are suggested to play key roles in the pathophysiology of illness progression in bipolar disorder (BD), but the mechanisms leading to this dysfunction have never been elucidated. This study aimed to examine HPA axis activity and underlying molecular mechanisms in patients with BD and unaffected siblings of BD patients. Methods: Twenty-four euthymic patients with BD, 18 siblings of BD patients, and 26 healthy controls were recruited for this study. All subjects underwent a dexamethasone suppression test followed by analyses associated with the HPA axis and the glucocorticoid receptor (GR). Results: Patients with BD, particularly those at a late stage of illness, presented increased salivary post-dexamethasone cortisol levels when compared to controls (p = 0.015). Accordingly, these patients presented reduced ex vivo GR responsiveness (p = 0.008) and increased basal protein levels of FK506-binding protein 51 (FKBP51, p = 0.012), a co-chaperone known to desensitize GR, in peripheral blood mononuclear cells. Moreover, BD patients presented increased methylation at the FK506-binding protein 5 (FKBP5) gene. BD siblings presented significantly lower FKBP51 protein levels than BD patients, even though no differences were found in FKBP5 basal mRNA levels. Conclusions: Our data suggest that the epigenetic modulation of the FKBP5 gene, along with increased FKBP51 levels, is associated with the GR hyporesponsiveness seen in BD patients. Our findings are consistent with the notion that unaffected first-degree relatives of BD patients share biological factors that influence the disorder, and that such changes are more pronounced in the late stages of the illness. PMID:25522387
Kennedy, P J; Cryan, J F; Quigley, E M M; Dinan, T G; Clarke, G
Despite stress being considered a key factor in the pathophysiology of the functional gastrointestinal (GI) disorder irritable bowel syndrome (IBS), there is a paucity of information regarding the ability of IBS patients to respond to acute experimental stress. Insights into the stress response in IBS could open the way to novel therapeutic interventions. To this end, we assessed the response of a range of physiological and psychological parameters to the Trier Social Stress Test (TSST) in IBS. Thirteen female patients with IBS and 15 healthy female age-matched control participants underwent a single exposure to the TSST. Salivary cortisol, salivary C-reactive protein (CRP), skin conductance level (SCL), GI symptoms, mood and self-reported stress were measured pre- and post-exposure to the TSST. The hypothalamic-pituitary-adrenal (HPA) axis response to the TSST was sustained in IBS, as shown by a greater total cortisol output throughout (p = 0.035) and higher cortisol levels measured by an area under the curve with respect to ground (AUCG) analysis (p = 0.044). In IBS patients, GI symptoms increased significantly during the recovery period following exposure to the TSST (p = 0.045). Salivary CRP and SCL activity showed significant changes in relation to stress but with no differential effect between experimental groups. Patients with IBS exhibit sustained HPA axis activity, and an increase in problematic GI symptoms in response to acute experimental psychosocial stress. These data pave the way for future interventional studies aimed at identifying novel therapeutic approaches to modulate the HPA axis and GI symptom response to acute psychosocial stress in IBS.
Martín-Blanco, Ana; Ferrer, Marc; Soler, Joaquim; Arranz, Maria Jesús; Vega, Daniel; Calvo, Natalia; Elices, Matilde; Sanchez-Mora, Cristina; García-Martinez, Iris; Salazar, Juliana; Carmona, Cristina; Bauzà, Joana; Prat, Mónica; Pérez, Víctor; Pascual, Juan C
Current knowledge suggests that borderline personality disorder (BPD) results from the interaction between genetic and environmental factors. Research has mainly focused on monoaminergic genetic variants and their modulation by traumatic events, especially those occurring during childhood. However, to the best of our knowledge, there are no studies on the genetics of hypothalamus-pituitary-adrenal (HPA) axis, despite its vulnerability to early stress and its involvement in BPD pathogenesis. The aim of this study was to investigate the contribution of genetic variants in the HPA axis and to explore the modulating effect of childhood trauma in a large sample of BPD patients and controls. DNA was obtained from a sample of 481 subjects with BPD and 442 controls. Case-control differences in allelic frequencies of 47 polymorphisms in 10 HPA axis genes were analysed. Modulation of genetic associations by the presence of childhood trauma was also investigated by dividing the sample into three groups: BPD with trauma, BPD without trauma and controls. Two FKBP5 polymorphisms (rs4713902-C and rs9470079-A) showed significant associations with BPD. There were also associations between BPD and haplotype combinations of the genes FKBP5 and CRHR1. Two FKBP5 alleles (rs3798347-T and rs10947563-A) were more frequent in BPD subjects with history of physical abuse and emotional neglect and two CRHR2 variants (rs4722999-C and rs12701020-C) in BPD subjects with sexual and physical abuse. Our findings suggest a contribution of HPA axis genetic variants to BPD pathogenesis and reinforce the hypothesis of the modulating effect of childhood trauma in the development of this disorder.
Di Iorio, Christina R; Carey, Caitlin E; Michalski, Lindsay J; Corral-Frias, Nadia S; Conley, Emily Drabant; Hariri, Ahmad R; Bogdan, Ryan
Early life stress may precipitate psychopathology, at least in part, by influencing amygdala function. Converging evidence across species suggests that links between childhood stress and amygdala function may be dependent upon hypothalamic-pituitary-adrenal (HPA) axis function. Using data from college-attending non-Hispanic European-Americans (n=308) who completed the Duke Neurogenetics Study, we examined whether early life stress (ELS) and HPA axis genetic variation interact to predict threat-related amygdala function as well as psychopathology symptoms. A biologically-informed multilocus profile score (BIMPS) captured HPA axis genetic variation (FKBP5 rs1360780, CRHR1 rs110402; NR3C2 rs5522/rs4635799) previously associated with its function (higher BIMPS are reflective of higher HPA axis activity). BOLD fMRI data were acquired while participants completed an emotional face matching task. ELS and depression and anxiety symptoms were measured using the childhood trauma questionnaire and the mood and anxiety symptom questionnaire, respectively. The interaction between HPA axis BIMPS and ELS was associated with right amygdala reactivity to threat-related stimuli, after accounting for multiple testing (empirical-p=0.016). Among individuals with higher BIMPS (i.e., the upper 21.4%), ELS was positively coupled with threat-related amygdala reactivity, which was absent among those with average or low BIMPS. Further, higher BIMPS were associated with greater self-reported anxious arousal, though there was no evidence that amygdala function mediated this relationship. Polygenic variation linked to HPA axis function may moderate the effects of early life stress on threat-related amygdala function and confer risk for anxiety symptomatology. However, what, if any, neural mechanisms may mediate the relationship between HPA axis BIMPS and anxiety symptomatology remains unclear. Copyright © 2017 Elsevier Ltd. All rights reserved.
Whitaker, Annie M; Gilpin, Nicholas W
Individuals with trauma- and stress-related disorders exhibit increases in avoidance of trauma-related stimuli, heightened anxiety and altered neuroendocrine stress responses. Our laboratory uses a rodent model of stress that mimics the avoidance symptom cluster associated with stress-related disorders. Animals are classified as 'Avoiders' or 'Non-Avoiders' post-stress based on avoidance of predator-odor paired context. Utilizing this model, we are able to examine subpopulation differences in stress reactivity. Here, we used this predator odor model of stress to examine differences in anxiety-like behavior and hypothalamo-pituitary adrenal (HPA) axis function in animals that avoid a predator-paired context relative to those that do not. Rats were exposed to predator odor stress paired with a context and tested for avoidance (24h and 11days), anxiety-like behavior (48h and 5days) and HPA activation following stress. Control animals were exposed to room air. Predator odor stress produced avoidance in approximately 65% of the animals at 24h that persisted 11days post-stress. Both Avoiders and Non-Avoiders exhibited a heightened anxiety-like behavior at 48h and 5days post-stress when compared to unstressed Controls. Non-Avoiders exhibited significant increases in circulating adrenocorticotropin hormone (ACTH) and corticosterone (CORT) concentrations immediately following predator odor stress compared to Controls and this response was significantly attenuated in Avoiders. There was an inverse correlation between circulating ACTH/CORT concentrations and avoidance, indicating that lower levels of ACTH/CORT predicted higher levels of avoidance. These results suggest that stress effects on HPA stress axis activation predict long-term avoidance of stress-paired stimuli, and build on previous data showing the utility of this model for exploring the neurobiological mechanisms of trauma- and stress-related disorders. Copyright © 2015. Published by Elsevier Inc.
Full Text Available Abstract Background Lung maturation is modulated by several factors, including glucocorticoids. Expression of hypothalamic-pituitary-adrenal (HPA axis-related components, with proposed or described local regulatory systems analogous to the HPA axis, was reported in peripheral tissues. Here, HPA axis-related genes were studied in the mouse developing lung during a period overlapping the surge of surfactant production. Methods Expression of genes encoding for corticotropin-releasing hormone (CRH, CRH receptors (CRHR 1 and 2beta, CRH-binding protein, proopiomelanocortin (POMC, melanocortin receptor 2 (MC2R, and glucocorticoid receptor was quantified by real-time PCR and localized by in situ hydridization in fetal lungs at gestational days (GD 15.5, 16.5, and 17.5, and was also quantified in primary mesenchymal- and epithelial cell-enriched cultures. In addition, the capability of CRH and adrenocorticotropic hormone (ACTH to stimulate pulmonary expression of enzymes involved in the adrenal pathway of glucocorticoid synthesis was addressed, as well as the glucocorticoid production by fetal lung explants. Results We report that all the studied genes are expressed in fetal lungs according to different patterns. On GD 15.5, Mc2r showed peaks in expression in samples that have previously presented high mRNA levels for glucocorticoid synthesizing enzymes, including 11beta-hydroxylase (Cyp11b1. Crhr1 mRNA co-localized with Pomc mRNA in cells surrounding the proximal epithelium on GD 15.5 and 16.5. A transition in expression sites toward distal epithelial cells was observed between GD 15.5 and 17.5 for all the studied genes. CRH or ACTH stimulation of genes involved in the adrenal pathway of glucocorticoid synthesis was not observed in lung explants on GD 15.5, whereas CRH significantly increased expression of 21-hydroxylase (Cyp21a1 on GD 17.5. A deoxycorticosterone production by fetal lung explants was observed. Conclusions Temporal and spatial
Kovács, L; Kézér, F L; Kulcsár-Huszenicza, M; Ruff, F; Szenci, O; Jurkovich, V
Behavior, hypothalamic-pituitary-adrenal axis, and cardiac autonomic nervous system (ANS) activity were evaluated in response to transrectal examination in nonlactating Holstein-Friesian cows with different behavioral reactivity. According to behavioral reactions shown to the procedure of fixing the heart rate (HR) monitors, the 20 cows with the highest and the 20 cows with the lowest behavioral reactivity were involved in the study (high responder, n=20; and low responder, n=20, respectively). Activity of the ANS was assessed by HR and HR variability parameters. Blood and saliva were collected at 5 min before (baseline) and 0, 5 10, 15, 20, 30, 40, 60, and 120 min after the examination to determine cortisol concentrations. The examination lasted for 5 min. Cardiac parameters included HR, the root mean square of successive differences between the consecutive interbeat intervals, the high frequency (HF) component of heart rate variability, and the ratio between the low frequency (LF) and HF parameter (LF/HF). Following the examination, peak plasma and saliva cortisol levels and the amplitude of the plasma and saliva cortisol response were higher in high responder cows than in low responders. Areas under the plasma and saliva cortisol response curves were greater in high responder cows. Plasma and salivary cortisol levels correlated significantly at baseline (r=0.91), right after examination (r=0.98), and at peak levels (r=0.96). Area under the HR response curve was higher in low responder cows; however, maximum HR and the amplitude of the HR response showed no differences between groups. Minimum values of both parameters calculated for the examination were higher in high responders. Following the examination, response parameters of root mean square of successive differences and HF did not differ between groups. The maximum and the amplitude of LF/HF response and area under the LF/HF response curve were lower in low responder cows, suggesting a lower sympathetic
Kaslik, Eva; Navolan, Dan Bogdan; NeamÅ£u, Mihaela
This paper analyzes a four-dimensional model of the hypothalamic-pituitary-adrenal (HPA) axis that includes the influence of the glucocorticoid receptor in the pituitary. Due to the spatial separation between the hypothalamus, pituitary and adrenal glands, distributed time delays are introduced in the mathematical model. The existence of the positive equilibrium point is proved and a local stability and bifurcation analysis is provided, considering several types of delay kernels. The fractional-order model with discrete time delays is also taken into account. Numerical simulations are provided to illustrate the effectiveness of the theoretical findings.
Luan, Huiqin; Huang, Yunfei; Li, Jian; Sun, Lianwen; Fan, Yubo
Astronauts are severely affected by spaceflight-induced bone loss. Mechanical stimulation through exercise inhibits bone resorption and improves bone formation. Exercise and vibration can prevent the degeneration of the musculoskeletal system in tail-suspended rats, and long-term exercise stress will affect endocrine and immune systems that are prone to fatigue. However, the mechanisms through which exercise and vibration affect the endocrine system remain unknown. This study mainly aimed to investigate the changes in the contents of endocrine axis-related hormones and the effects of local vibration and passive exercise on hypothalamic-pituitary-adrenal (HPA) axis-related hormones in tail-suspended rats. A total of 32 Sprague-Dawley rats were randomly distributed into four groups (n = 8 per group): tail suspension (TS), TS + 35Hz vibration, TS + passive exercise, and control. The rats were placed on a passive exercise and local vibration regimen for 21 days. On day 22 of the experiment, the contents of corticotrophin-releasing hormone, adrenocorticotropic hormone, cortisol, and 5-hydroxytryptamine in the rats were quantified with kits in accordance with the manufacturer's instructions. Histomorphometry was applied to evaluate histological changes in the hypothalamus. Results showed that 35Hz local vibration cannot cause rats to remain in a stressed state and that it might not inhibit the function of the HPA axis. Therefore, we speculate that this local vibration intensity can protect the function of the HPA axis and helps tail-suspended rats to transition from stressed to adaptive state.
Incollingo Rodriguez, Angela C; Epel, Elissa S; White, Megan L; Standen, Erin C; Seckl, Jonathan R; Tomiyama, A Janet
Although there is substantial evidence of differential hypothalamic-pituitary-adrenal (HPA) axis activity in both generalized and abdominal obesity, consistent trends in obesity-related HPA axis perturbations have yet to be identified. To systematically review the existing literature on HPA activity in obesity, identify possible explanations for inconsistencies in the literature, and suggest methodological improvements for future study. Included papers used Pubmed, Google Scholar, and the University of California Library search engines with search terms body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, sagittal diameter, abdominal versus peripheral body fat distribution, body fat percentage, DEXA, abdominal obesity, and cortisol with terms awakening response, slope, total daily output, reactivity, feedback sensitivity, long-term output, and 11β-HSD expression. Empirical research papers were eligible provided that they included at least one type of obesity (general or abdominal), measured at least one relevant cortisol parameter, and a priori tested for a relationship between obesity and cortisol. A general pattern of findings emerged where greater abdominal fat is associated with greater responsivity of the HPA axis, reflected in morning awakening and acute stress reactivity, but some studies did show underresponsiveness. When examined in adipocytes, there is a clear upregulation of cortisol output (due to greater expression of 11β-HSD1), but in hepatic tissue this cortisol is downregulated. Overall obesity (BMI) appears to also be related to a hyperresponsive HPA axis in many but not all studies, such as when acute reactivity is examined. The reviewed literature contains numerous inconsistencies and contradictions in research methodologies, sample characteristics, and results, which partially precluded the development of clear and reliable patterns of dysregulation in each investigated cortisol parameter. The literature to date is
Li-Tempel, Ting; Larra, Mauro F; Winnikes, Ulrike; Tempel, Tobias; DeRijk, Roel H; Schulz, André; Schächinger, Hartmut; Meyer, Jobst; Schote, Andrea B
The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects. We found that polymorphisms of GR influenced both, the basal state of the HPA axis as well as self-perceived stress. MR only associated with self-perceived stress and 5-HTT only with CAR. BDNF did not affected any of the investigated indices. In summary, we suggest that GR variants together with the CAR and supplemented with self reports on perceived stress might be useful indicators for the basal HPA axis activity. Copyright © 2016 Elsevier B.V. All rights reserved.
Li, Hong-mian; Liang, Zi-qian; Luo, Zuo-jie
To investigate the postburn dynamic changes in the hypothalamus-pituitary-adrenal hormones in severely burned patients. Fifty burn patients were enrolled in the study. The plasma contents of total GC (cortisol), ACTH and aldosterone (ALDO) and urinary contents of 17-OHO and 17-KS were determined with radio-immunological assay (RIA) method after burn injury to compare with the normal values which were well established clinically. The postburn plasma and urinary contents of the above indices were increased evidently with two peak values in shock and infectious stages, whilst the majority of he indices were lower than the normal values after 6 postburn weeks (PBWs). The values of these hormones were the lowest in dying patients. On the other hand, the values approached normal levels in those patients whose burn wounds were healing. Increases of the plasma and urinary levels of hypothalamus-pituitary -adrenal hormones in severely burned patients were constantly seen. Burn shock and infection seemed to be the two major factors in inducing postburn stress reaction in burn victims. Abrupt decrease of the hormone levels in plasma and or urine indicated adrenal failure predicting a poor prognosis of the burn patients.
van Norren, Klaske; Dwarkasing, Jvalini T; Witkamp, Renger F
In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia-cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. The anorexia-cachexia syndrome is directly associated with higher mortality in cancer patients. Recent reports confirm its severe impact on the quality of life of patients and their families.Hypothalamic inflammation has been shown to contribute to muscle and adipose tissue loss in cancer via central hypothalamic interleukine (IL)1β-induced activation of the hypothalamic-pituitary-adrenal axis. The resulting release of glucocorticoids directly stimulates catabolic processes in these tissues via activation of the ubiquitin-proteosome pathway. Next to this, hypothalamic inflammation has been shown to reduce food intake in cancer by triggering changes in orexigenic and anorexigenic responses via upregulation of serotonin availability and stimulation of its signalling pathways in hypothalamic tissues. This combination of reduced food intake and stimulation of tissue catabolism represents a dual mechanism by which hypothalamic inflammation contributes to the development and maintenance of anorexia and cachexia in cancer. Hypothalamic inflammation is a driving force in the development of the anorexia-cachexia syndrome via hypothalamic-pituitary-adrenal axis and serotonin pathway activation.
Mariappan, Subramanian; Bogdanowicz, Wieslaw; Marimuthu, Ganapathy; Rajan, Koilmani Emmanuvel
In a stressful situation, greater short-nosed fruit bats (Cynopterus sphinx) emit audible vocalization either to warn or to inform conspecifics. We examined the effect of distress calls on bats emitting the call as well as the bats receiving the distress signal through analysis of the hypothalamic-pituitary-adrenal axis and catacholaminargic systems. We measured the levels of neurotransmitters [serotonin (5-HT), dopamine (DA), norepinephrine (NE)] and stress hormones [(adrenocorticotropic hormone (ACTH) and corticosterone (CORT)]. Our results showed that distress call emission elevated the level of ACTH and CORT, as well as 5-HT, DA and NE in the amygdala, for both the call emitting bat and the responding bat. Subsequently, we observed increased activity of glucocorticoid receptor and its steroid receptor co-activator (SRC-1). An expression of SRC-1 was up-regulated in the distress call emitter only, whereas it was at a similar level in both the call responder and silent bats. These findings suggest that bats emitting distress calls and also bats responding to such calls have similar neurotransmitter expression patterns, and may react similarly in response to stress.
Terence Y Pang
Full Text Available Depression is a commonly reported co-morbidity during rehabilitation from alcohol use disorders and its presence is associated with an increased likelihood of relapse. Interventions which impede the development of depression could be of potential benefit if incorporated into treatment programs. We previously demonstrated an ameliorative effect of physical exercise on depressive behaviours in a mouse model of alcohol abstinence. Here, we show that environmental enrichment (cognitive and social stimulation has a similar beneficial effect. The hypothalamic-pituitary-adrenal (HPA axis is a key physiological system regulating stress responses and its dysregulation has been separably implicated in the pathophysiology of depression and addiction disorders. We performed a series of dexamethasone challenges and found that mice undergoing 2 weeks of alcohol abstinence had significantly greater corticosterone and ACTH levels following a DEX-CRH challenge compared to water controls. Environmental enrichment during alcohol abstinence corrected the abnormal DEX-CRH corticosterone response despite a further elevation of ACTH levels. Examination of gene expression revealed abstinence-associated alterations in glucocorticoid receptor (Gr, corticotrophin releasing hormone (Crh and pro-opiomelanocortin (Pomc1 mRNA levels which were differentially modulated by environmental enrichment. Overall, our study demonstrates a benefit of environmental enrichment on alcohol abstinence-associated depressive behaviours and HPA axis dysregulation.
Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse
Rinne, Thomas; de Kloet, E. Ronald; Wouters, Luuk; Goekoop, Jaap G.; DeRijk, Roel H.; van den Brink, Wim
Background: High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis
Auvinen, H.E.; Romijn, J.A.; Biermasz, N.R.; Havekes, L.M.; Smit, J.W.A.; Rensen, P.C.N.; Pereira, A.M.
Hypothalamus-pituitary-adrenal-axis activity is suggested to be involved in the pathophysiology of the metabolic syndrome. In diet-induced obesity mouse models, features of the metabolic syndrome are induced by feeding high fat diet. However, the models reveal conflicting results with respect to the
Gispen, W.H.; Frijtag, J.C. von; Croiset, G.; Adan, R.A.H.; Wiegant, V.M.
In accord with previous studies intracerebroventricular (i.c.v.) injections of ACTH1-24 (1 g) induced a display of excessive grooming, and increased the plasma concentrations of ACTH and corticosterone. Pituitary-adrenal activation was blocked by pretreatment with dexamethasone, indicating that the
Giletta, M.; Calhoun, C.D.; Hastings, P.D.; Rudolph, K.D.; Nock, M.K.; Prinstein, M.J.
Adopting a multi-level approach, this study examined risk factors for adolescent suicidal ideation, with specific attention to (a) hypothalamic-pituitary-adrenal (HPA) axis stress responses and (b) the interplay between HPA-axis and other risk factors from multiple domains (i.e., psychological,
Lamberts, S.W.J.; Klijn, J.G.M.; Jong, F.H. de; Birkenhager, J.C.
The recovery of the hypothalamo-pituitary-adrenal axis after selective transsphenoidal adenomectomy was studied in 3 patients with Cushing's disease by measuring basal plasma ACTH and cortisol concentrations, cortisol secretion rate, the diurnal rhythm of cortisol, and the reaction of cortisol to lysine vasopressin (LVP), of compound S to metyrapone and of cortisol and growth hormone to an insulin-induced hypoglycaemia. The third patient had been treated previously by external pituitary irradiation. In 2 patients basal plasma ACTH levels returned within normal values before plasma cortisol, but no supra-physiological plasma concentrations of ACTH were seen as has been observed after withdrawal of exogenous glucocorticoids. With regard to the different stimulation tests: at first the normal reaction of plasma cortisol to LVP returned after 3 months, at the same time as the restoration of growth hormone secretion in response to hypoglycaemia. A normalization of the reaction to metyrapone was seen thereafter while finally the reaction of cortisol to an insulin-induced hypoglycaemia and the diurnal rhythm of plasma cortisol returned 15 to 18 months after operation in the first patient and after 12 months in the second patient. Selective adenomectomy had also been carried out in the third patient, as evidenced by normal TSH, LH and FSH secretion. Hypocortisolism, and a deficient ACTH and growth hormone secretion in response to the stimuli mentioned, however, did not normalize up till 22 months after operation. The restoration of the hypothalamo-pituitary-adrenal axis after selective pituitary adenomectomy in Cushing's disease was prevented in this patient by prior external pituitary irradiation. (author)
Belda, Xavier; Rotllant, David; Fuentes, Silvia; Delgado, Raúl; Nadal, Roser; Armario, Antonio
Exposure to some predominantly emotional (electric shock) and systemic (interleukin-1beta) stressors has been found to induce long-term sensitization of the hypothalamic-pituitary-adrenal (HPA) responsiveness to further superimposed stressors. Since exposure to immobilization on wooden boards (IMO) is a severe stressor and may have interest regarding putative animal models of post-traumatic stress disorders (PTSD), we have characterized long-lasting effects of a single exposure to IMO and other stressors on the HPA response to the same (homotypic) and to novel (heterotypic) stressors and the putative mechanisms involved. A single exposure to IMO caused a long-lasting reduction of peripheral and central responses of the HPA axis, likely to be mediated by some brain areas, such as the lateral septum and the medial amygdala. This desensitization is not explained by changes in negative glucocorticoid feedback, and, surprisingly, it is positively related to the intensity of the stressors. In contrast, the HPA response to heterotypic stressors (novel environments) was enhanced, with maximal sensitization on the day after IMO. Sensitization progressively vanished over the course of 1-2 weeks and was not modulated by IMO-induced corticosterone release. Moreover, it could not be explained by changes in the sensitivity of the HPA axis to fast or intermediate/delayed negative feedback, as evaluated 1 week after exposure to IMO, using shock as the heterotypic stressor. Long-lasting stress-induced behavioral changes reminiscent of enhanced anxiety and HPA sensitization are likely to be parallel but partially independent phenomena, the former being apparently not related to the intensity of stressors.
Calis, M; Gökçe, C; Ates, F; Ulker, S; Izgi, H B; Demir, H; Kirnap, M; Sofuoglu, S; Durak, A C; Tutus, A; Kelestimur, F
Primary fibromyalgia syndrome (PFS) is characterized by widespread chronic pain that affects the musculoskeletal system, fatigue, anxiety, sleep disturbance, headache and postural hypotension. The pathophysiology of PFS is unknown. The hypothalamic-pituitary-adrenal (HPA) axis seems to play an important role in PFS. Both hyperactivity and hypoactivity of the HPA axis have been reported in patients with PFS. In this study we assessed the HPA axis by 1 microg ACTH stimulation test and metyrapone test in 22 patients with PFS and in 15 age-, sex-, and body mass index (BMI)- matched controls. Metyrapone (30 mg/kg) was administered orally at 23:00 h and blood was sampled at 08:30 h the following morning for 11-deoxycortisol. ACTH stimulation test was carried out by using 1 microg (iv) ACTH as a bolus injection after an overnight fast, and blood samples were drawn at 0, 30 and 60 min. Peak cortisol level (659.4 +/- 207.2 nmol/l) was lower in the patients with PFS than peak cortisol level (838.7 +/- 129.6 nmol/l) in the control subjects (p < 0.05). Ten patients (45%) with PFS had peak cortisol responses to 1 microg ACTH test lower than the lowest peak cortisol detected in healthy controls. After metyrapone test 11-deoxycortisol level was 123.7 +/- 26 nmol/l in patients with PFS and 184.2 +/- 17.3 nmol/l in the controls (p < 0.05). Ninety five percent of the patients with PFS had lower 11-deoxycortisol level after metyrapone than the lowest 11-deoxycortisol level after metyrapone detected in healthy controls. We also compared the adrenal size of the patients with that of the healthy subjects and we found that the adrenal size between the groups was similar. This study clearly shows that HPA axis is underactivated in PFS, rather than overactivated.
Finn, David P; Hudson, Alan L; Kinoshita, Hiroshi; Coventry, Toni L; Jessop, David S; Nutt, David J; Harbuz, Michael S
Central noradrenaline regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the neuroendocrine response to stress. alpha2-adrenoceptors and imidazoline2 (I2) receptors modulate the activity of the central noradrenergic system. The present set of experiments investigated the role of alpha2-adrenoceptors and I2 receptors in the regulation of HPA axis activity under basal conditions and during exposure to the acute psychological stress of restraint. Three separate experiments were carried out in which rats were given an i.p. injection of either saline vehicle, the combined alpha2-adrenoceptor antagonist and I2 receptor ligand idazoxan (10 mg/kg), the selective I2 receptor ligand BU224 (2.5 or 10 mg/kg) or the selective alpha2-adrenoceptor antagonist RX821002 (2.5 mg/kg) with or without restraint stress. Drugs were administered immediately prior to restraint of 60 min duration. Blood was sampled pre-injection, 30, 60 and 240 min post-injection and plasma corticosterone was measured by radioimmunoassay. In experiment 1, idazoxan increased plasma corticosterone levels in naive animals and potentiated the corticosterone response to acute restraint stress. In experiment 2, BU224 administration increased plasma corticosterone levels in a dose-related manner in naive rats. The results of experiment 3 indicated that RX821002 also elevated plasma corticosterone levels in naive rats, however, only BU224 potentiated the corticosterone response to restraint stress. These studies suggest that both alpha2-adrenoceptors and I2 receptors play a role in modulating basal HPA axis activity and that I2 receptors may play a more important role than alpha2-adrenoceptors in modulating the HPA axis response to the acute psychological stress of restraint.
Lingis, Melissa; Richards, Elaine M.
During pregnancy, plasma ACTH and cortisol are chronically increased; this appears to occur through a reset of hypothalamo-pituitary-adrenal (HPA) activity. We have hypothesized that differences in mineralocorticoid receptor activity in pregnancy may alter feedback inhibition of the HPA axis. We tested the effect of MR antagonism in pregnant and nonpregnant ewes infused for 4 h with saline or the MR antagonist canrenoate. Pregnancy significantly increased plasma ACTH, cortisol, angiotensin II, and aldosterone. Infusion of canrenoate increased plasma ACTH, cortisol, and aldosterone in both pregnant and nonpregnant ewes; however, the temporal pattern of these responses differed between these two reproductive states. In nonpregnant ewes, plasma ACTH and cortisol transiently increased at 1 h of infusion, whereas in pregnant ewes the levels gradually increased and were significantly elevated from 2 to 4 h of infusion. MR blockade increased plasma aldosterone from 2 to 4 h in the pregnant ewes but only at 4 h in the nonpregnant ewes. In both pregnant and nonpregnant ewes, the increase in plasma aldosterone was significantly related to the timing and magnitude of the increase in plasma potassium. The results indicate a differential effect of MR activity in pregnant and nonpregnant ewes and suggest that the slow changes in ACTH, cortisol, and aldosterone are likely to be related to blockade of MR effects in the kidney rather than to effects of MR blockade in hippocampus or hypothalamus. PMID:21205934
Houser, Dorian S; Champagne, Cory D; Jensen, Eric D; Smith, Cynthia R; Cotte, Lara S; Meegan, Jenny M; Booth, Rebecca K; Wasser, Samuel K
OBJECTIVE To evaluate the impact of oral megestrol acetate (MA) administration on adrenal function in male bottlenose dolphins (Tursiops truncatus). DESIGN Serial cross-sectional study. ANIMALS 8 adult male dolphins, all of which were receiving MA at various daily doses (range, 0 to 60 mg, PO) for the control of reproductive behavior. PROCEDURES Blood samples were collected every 2 weeks for 1 year from dolphins trained to voluntarily provide them. Cortisol, ACTH, and other hormone concentrations were measured in serum or plasma via radioimmunoassay or ELISA. Fecal samples, also provided by dolphins voluntarily, were assayed for glucocorticoid metabolite concentrations. Effects of daily MA dose on hormone concentrations were evaluated. RESULTS Daily MA doses as low as 10 mg strongly suppressed cortisol secretion in nearly all dolphins, and except for a single measurement, no dolphin had measurable serum concentrations at doses ≥ 20 mg. Variations in serum cortisol concentration were unrelated to season but were directly related to ACTH concentrations, suggesting primary effects upstream of the adrenal gland. Cessation of MA administration resulted in almost immediate restoration of measurable serum cortisol concentrations, although concentrations continued to rise in a few dolphins over the following weeks to months. CONCLUSIONS AND CLINICAL RELEVANCE Caution should be exercised when administering MA to control reproductive behavior in male dolphins. Because the hypothalamic-pituitary-adrenal axis appeared to be sensitive to even small doses of MA in dolphins, duration of treatment may be the most critical consideration.
Merlo, Eduardo; Podratz, Priscila L; Sena, Gabriela C; de Araújo, Julia F P; Lima, Leandro C F; Alves, Izabela S S; Gama-de-Souza, Letícia N; Pelição, Renan; Rodrigues, Lívia C M; Brandão, Poliane A A; Carneiro, Maria T W D; Pires, Rita G W; Martins-Silva, Cristina; Alarcon, Tamara A; Miranda-Alves, Leandro; Silva, Ian V; Graceli, Jones B
Tributyltin chloride (TBT) is an environmental contaminant that is used as a biocide in antifouling paints. TBT has been shown to induce endocrine-disrupting effects. However, studies evaluating the effects of TBT on the hypothalamus-pituitary-adrenal (HPA) axis are especially rare. The current study demonstrates that exposure to TBT is critically responsible for the improper function of the mammalian HPA axis as well as the development of abnormal morphophysiology in the pituitary and adrenal glands. Female rats were treated with TBT, and their HPA axis morphophysiology was assessed. High CRH and low ACTH expression and high plasma corticosterone levels were detected in TBT rats. In addition, TBT leads to an increased in the inducible nitric oxide synthase protein expression in the hypothalamus of TBT rats. Morphophysiological abnormalities, including increases in inflammation, a disrupted cellular redox balance, apoptosis, and collagen deposition in the pituitary and adrenal glands, were observed in TBT rats. Increases in adiposity and peroxisome proliferator-activated receptor-γ protein expression in the adrenal gland were observed in TBT rats. Together, these data provide in vivo evidence that TBT leads to functional dissociation between CRH, ACTH, and costicosterone, which could be associated an inflammation and increased of inducible nitric oxide synthase expression in hypothalamus. Thus, TBT exerts toxic effects at different levels on the HPA axis function.
Eman A. Hasan
Full Text Available Objectives. Hypothalamic-Pituitary-Adrenal axis function may be abnormal in rheumatoid arthritis (RA. A pilot study in 7 patients suggested impaired glucocorticoid feedback in some patients after the dexamethasone-corticotrophin releasing hormone (CRH test. This study aimed to investigate the dexamethasone-corticotrophin releasing factor test in a larger group of patients and relate the results to characteristics of the disease. Methods. Outpatients with active RA (≥3 swollen and tender joints and C-reactive protein > 10 mg/L took dexamethasone (1.5 mg at 23:00 hour in the evening. Next day, baseline saliva and plasma samples were collected, CRH was infused at 11:00 hour, and 4 serial blood and saliva samples were collected. Plasma samples were stored at −80∘C and a radioimmunoassay performed for saliva and plasma cortisol. Results. All 20 participants showed normal dexamethasone suppression and mounted no response to the CRH challenge. In samples with measurable cortisol, there was a strong correlation between saliva and plasma values (r = 0.876, n = 26, P<.01. Conclusion. No abnormalities were found in the Dexamethasone-CRH test in RA patients in contrast to a previous pilot study. Salivary cortisol measurement may offer an alternative noninvasive technique to plasma cortisol in RA patients in future studies.
Obasi, Ezemenari M; Shirtcliff, Elizabeth A; Cavanagh, Lucia; Ratliff, Kristen L; Pittman, Delishia M; Brooks, Jessica J
Rurally situated African Americans suffer from chronic exposure to stress that may have a deleterious effect on health outcomes. Unfortunately, research on potential mechanisms that underlie health disparities affecting the African American community has received limited focus in the scientific literature. This study investigated the relationship between perceived stress, family resources, and cortisol reactivity to acute stress. A rural sample of African American emerging adults (N = 60) completed a battery of assessments, the Trier Social Stress Test (TSST), and provided four samples of salivary cortisol: prior to receiving TSST instructions, prior to conducting the speech task, immediately following the TSST, and 15-20 min following the TSST. As predicted, cortisol levels increased in response to a controlled laboratory inducement of acute stress. Moreover, diminished levels of family resources were associated with blunted cortisol reactivity to acute stress. Of note, higher levels of perceived stress over the past month and being male were independently associated with lower levels of cortisol at baseline. Lack of family resources had a blunting relationship on the hypothalamic-pituitary-adrenal axis reactivity. These findings provide biomarker support for the relationship between family resources-an indicator associated with social determinants of health-and stress physiology within a controlled laboratory experiment. Identifying mechanisms that work toward explanation of within-group differences in African American health disparities is both needed and informative for culturally informed prevention and intervention efforts.
Gunnar, Megan R; Wewerka, Sandi; Frenn, Kristin; Long, Jeffrey D; Griggs, Christopher
Home baseline and laboratory stressor (Trier Social Stress Test for Children) measures of salivary cortisol were obtained from 82 participants (40 girls) aged 9, 11, 13, and 15 years. Measures of pubertal development, self-reported stress, parent reports of child depressive symptoms and fearful temperament, and cardiac measures of sympathetic and parasympathetic activity were also obtained. Significant increases in the home cortisol baselines were found with age and pubertal development. Cortisol stress reactivity differed by age group with 11-year-olds and 13-year-old boys showing blunted reactivity and 9-year-olds, 13-year-old girls, and 15-year-olds showing significant cortisol reactions. Cortisol reactivity correlated marginally with sexual maturation. Measures of sympathetic activity revealed increased sympathetic modulation with age. Higher sympathetic tone was associated with more fearful temperament, whereas greater cortisol reactivity was associated with more anxious and depressed symptoms for girls. The importance of these findings for the hypothesis that puberty-associated increases in hypothalamic-pituitary-adrenal axis activity heightens the risk of psychopathology is discussed.
Bonfiglio, Juan José; Inda, Carolina; Refojo, Damián; Holsboer, Florian; Arzt, Eduardo; Silberstein, Susana
Corticotropin-releasing hormone (CRH) plays a key role in adjusting the basal and stress-activated hypothalamic-pituitary-adrenal axis (HPA). CRH is also widely distributed in extrahypothalamic circuits, where it acts as a neuroregulator to integrate the complex neuroendocrine, autonomic, and behavioral adaptive response to stress. Hyperactive and/or dysregulated CRH circuits are involved in neuroendocrinological disturbances and stress-related mood disorders such as anxiety and depression. This review describes the main physiological features of the CRH network and summarizes recent relevant information concerning the molecular mechanism of CRH action obtained from signal transduction studies using cells and wild-type and transgenic mice lines. Special focus is placed on the MAPK signaling pathways triggered by CRH through the CRH receptor 1 that plays an essential role in CRH action in pituitary corticotrophs and in specific brain structures. Recent findings underpin the concept of specific CRH-signaling pathways restricted to specific anatomical areas. Understanding CRH action at molecular levels will not only provide insight into the precise CRH mechanism of action, but will also be instrumental in identifying novel targets for pharmacological intervention in neuroendocrine tissues and specific brain areas involved in CRH-related disorders. Copyright © 2011 S. Karger AG, Basel.
Roh, Hee-Tae; So, Wi-Young
Cranial electrotherapy stimulation (CES) is reported to aid in relieving symptoms of depression and anxiety, though the mechanism underlying this effect remains unclear. Therefore, the present study aimed to evaluate changes in the hypothalamic-pituitary-adrenal (HPA) axis response and levels of neurotrophic factors, as well as changes in mood state, in patients undergoing CES therapy. Fifty healthy postmenopausal women were randomly assigned to either a Sham CES group (n = 25) or an Active CES group (n = 25). CES treatment was conducted in 20-minute sessions, three times per week for 8 weeks, using a micro current cranial electrotherapy stimulator. Blood samples were collected prior to and following the 8-week treatment period for measurement of cortisol, adrenocorticotropic hormone (ACTH), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) levels. Changes in mood state were also examined at the time of blood collection using the Profile of Mood States (POMS). No significant differences in cortisol, ACTH, BDNF, or NGF were observed between the two participant groups (p > 0.05) following the treatment period. However, those in the Active CES group exhibited significantly decreased Tension-Anxiety and Depression-Dejection scores on the POMS relative to pre-treatment scores (p 0.05). These results suggest that 8 weeks of CES treatment does not induce changes in blood levels of neurotrophic factors or HPA-axis-related hormones, though such treatment may be effective in treating symptoms of anxiety and depression.
Souza Queiroz, Julia; Marín Blasco, Ignacio; Gagliano, Humberto; Daviu, Nuria; Gómez Román, Almudena; Belda, Xavier; Carrasco, Javier; Rocha, Michelle C; Palermo Neto, João; Armario, Antonio
Predominantly emotional stressors activate a wide range of brain areas, as revealed by the expression of immediate early genes, such as c-fos. Chlorella vulgaris (CV) is considered a biological response modifier, as demonstrated by its protective activities against infections, tumors and stress. We evaluated the effect of acute pretreatment with CV on the peripheral and central responses to forced swimming stress in adult male rats. Pretreatment with CV produced a significant reduction of stress-related hypothalamic-pituitary-adrenal activation, demonstrated by decreased corticotrophin releasing factor gene expression in the hypothalamic paraventricular nucleus (PVN) and lower ACTH response. Hyperglycemia induced by the stressor was similarly reduced. This attenuated neuroendocrine response to stress occurred in parallel with a diminished c-fos expression in most evaluated areas, including the PVN. The data presented in this study reinforce the usefulness of CV to diminish the impact of stressors, by reducing the HPA response. Although our results suggest a central effect of CV, further studies are necessary to understand the precise mechanisms underpinning this effect. Copyright © 2015 Elsevier Ltd. All rights reserved.
Sanchís-Ollé, Maria; Ortega-Sánchez, Juan A; Belda, Xavier; Gagliano, Humberto; Nadal, Roser; Armario, Antonio
We have recently demonstrated that adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to repeated exposure to a stressor does not follow the rules of habituation and can be fully expressed after a single experience with severe stressors. In the present work we tested the hypothesis that adaptation could be impaired if animals experience malaise during initial exposure to the stressor. To this end, animals were allowed to drink saccharin for 30min before being exposed for 3h to immobilization on boards (IMO), a severe stressor; then they were given either saline or lithium ip after the first hour of IMO. Stress-naïve rats followed exactly the same procedure except IMO. Exposure to IMO caused a strong activation of the HPA axis whereas the effect of lithium was modest. Both IMO and lithium administration resulted in conditioned taste aversion to saccharin when evaluated 4days later. When all animals were exposed to IMO 6days later, reduced HPA response and less impact on body weight was observed in the two groups previously exposed to IMO as compared with stress-naïve rats. Therefore, lithium administration during the first IMO exposure did not affect adaptation of the HPA axis and weight gain. These results indicate that malaise per se only weakly activated the HPA axis and argue against the hypothesis that signs of physical malaise during exposure to the stressor could impair HPA adaptation. Copyright © 2017 Elsevier Inc. All rights reserved.
Pochigaeva, Ksenia; Druzhkova, Tatiana; Yakovlev, Alexander; Onufriev, Mikhail; Grishkina, Maria; Chepelev, Aleksey; Guekht, Alla; Gulyaeva, Natalia
Hair cortisol is regarded as a promising marker of hypothalamic-pituitary-adrenal axis (HPAA) activity alterations due to stress, somatic and mental health conditions. Hair cortisol was previously reported to be elevated in patients with depression, however the data related to remission and recurrent depressive episodes are different. In this study, levels of hair cortisol were assessed in female patients with major depressive disorder (MDD) and the validity of hair cortisol as a marker of HPAA activity in this condition was evaluated. Hair cortisol was measured in 1 cm hair segments of 21 female patients with MDD and 22 female age-matched controls using enzyme-immunoassay analysis. Concurrently, serum cortisol was assessed and psychological status was evaluated using 17-item Hamilton Depression Rating Scale (HAMD-17), Beck Depression Inventory (BDI) and the Spielberger state trait anxiety inventory (STAI). The levels of hair cortisol were significantly lower in the MDD group, while serum cortisol levels were significantly higher in patients, as compared with controls. A significant negative correlation was found between HAMD-17 scores and hair cortisol. Decreased hair cortisol found in female patients with MDD as compared to controls suggests downregulation of HPAA activity during the preceding month. Further studies are needed to investigate the profiles of hair cortisol at different stages of depressive disorder to establish this parameter as a handy clinical tool.
Vargas, Ivan; Lopez-Duran, Nestor
The hypothalamic-pituitary-adrenal (HPA) axis has been previously identified as one potential mechanism that may explain the link between sleep deprivation and negative health outcomes. However, few studies have examined the direct association between sleep deprivation and HPA-axis functioning, particularly in the context of stress. Therefore, the aim of the current study was to investigate the relationship between acute sleep deprivation and HPA-axis reactivity to a psychosocial stressor. Participants included 40 healthy, young adults between the ages of 18-29. The current protocol included spending two nights in the laboratory. After an adaptation night (night 1), participants were randomized into either a sleep deprivation condition (29 consecutive hours awake) or a control condition (night 2). Following the second night, all participants completed the Trier Social Stress Test (TSST). Salivary cortisol was collected before, during, and after the TSST. Results indicated that there were significant group differences in cortisol stress reactivity. Specifically, compared to participants in the control condition, participants in the sleep deprivation condition had greater baseline (i.e., pre-stress) cortisol, yet a blunted cortisol response to the TSST. Taken together, a combination of elevated baseline cortisol (and its subsequent effect on HPA-axis regulatory processes) and a relative 'ceiling' on the amount of cortisol a laboratory stressor can produce may explain why participants in the sleep deprivation condition demonstrated blunted cortisol responses. Copyright © 2017 Elsevier Ltd. All rights reserved.
Full Text Available Imidacloprid (IMI is known to target the nicotinic acetylcholine receptors (nAChRs in insects, and potentially in mammals. However, IMI toxicity on mammalian tissues has not been adequately evaluated. The aim of the present study was to examine whether IMI induced functional impairment in hypthalamic-pituitary-adrenal (HPA axis tissues. An oral exposure of 40 mg IMI/kg for 28 days in male rats caused a significant increase in malondialdehyde (MDA level. The antioxidant catalase, superoxide dismutase, and glutathione S-transferase showed various alterations following administration, but a significantly depleted thiol (SH groups was only recorded in hypothalamic tissues. The increase in the relative weight of adrenal glands and the increased adrenal cholesterol and plasma adrenocorticotropic hormone (ACTH levels are indicative of general adaptation syndrome. The hypothalamic and pituitary acetylcholinesterase activity and calcium level were significantly increased, highlighting the alteration of cholinergic transmission. In conclusion, the findings obtained show that chronic exposure to IMI may alter biochemical processes of HPA axis.
Nederhof, E; van Oort, F V A; Bouma, E M C; Laceulle, O M; Oldehinkel, A J; Ormel, J
Hypothalamic-pituitary-adrenal axis functioning, with cortisol as its major output hormone, has been presumed to play a key role in the development of psychopathology. Predicting affective disorders from diurnal cortisol levels has been inconclusive, whereas the predictive value of stress-induced cortisol concentrations has not been studied before. The aim of this study was to predict mental disorders over a 3-year follow-up from awakening and stress-induced cortisol concentrations. Data were used from 561 TRAILS (TRacking Adolescents' Individual Lives Survey) participants, a prospective cohort study of Dutch adolescents. Saliva samples were collected at awakening and half an hour later and during a social stress test at age 16. Mental disorders were assessed 3 years later with the Composite International Diagnostic Interview (CIDI). A lower cortisol awakening response (CAR) marginally significantly predicted new disorders [odds ratio (OR) 0.77, p = 0.06]. A flat recovery slope predicted disorders with a first onset after the experimental session (OR 1.27, p = 0.04). Recovery revealed smaller, non-significant ORs when predicting new onset affective or anxiety disorders, major depressive disorder, or dependence disorders in three separate models, corrected for all other new onsets. Our results suggest that delayed recovery and possibly reduced CAR are indicators of a more general risk status and may be part of a common pathway to psychopathology. Delayed recovery suggests that individuals at risk for mental disorders perceived the social stress test as less controllable and less predictable.
Lisonbee, Jared A.; Pendry, Patricia; Mize, Jacquelyn; Gwynn, Eugenia Parrett
Self-regulation ability is an important component of children's academic success. Physiological reactivity may relate to brain activity governing attention and behavioral regulation. Saliva samples collected from 186 preschool children (101 boys, mean age = 53 months, 34% minority) before and after a series of mildly challenging games and again 30…
Giesbrecht, Gerald F; Ejaredar, Maede; Liu, Jiaying; Thomas, Jenna; Letourneau, Nicole; Campbell, Tavis; Martin, Jonathan W; Dewey, Deborah
Animal models show that prenatal bisphenol A (BPA) exposure leads to sexually dimorphic disruption of the neuroendocrine system in offspring, including the hypothalamic-pituitary-adrenal (HPA) neuroendocrine system, but human data are lacking. In humans, prenatal BPA exposure is associated with sex-specific behavioural problems in children, and HPA axis dysregulation may be a biological mechanism. The objective of the current study was to examine sex differences in associations between prenatal maternal urinary BPA concentration and HPA axis function in 3 month old infants. Mother-infant pairs (n = 132) were part of the Alberta Pregnancy Outcomes and Nutrition study, a longitudinal birth cohort recruited (2010-2012) during pregnancy. Maternal spot urine samples collected during the 2nd trimester were analyzed for total BPA and creatinine. Infant saliva samples collected prior to and after a blood draw were analyzed for cortisol. Linear growth curve models were used to characterize changes in infant cortisol as a function of prenatal BPA exposure. Higher maternal BPA was associated with increases in baseline cortisol among females (β = 0.13 log μg/dL; 95% CI: 0.01, 0.26), but decreases among males (β = -0.22 log μg/dL; 95% CI: -0.39, -0.05). In contrast, higher BPA was associated with increased reactivity in males (β = .30 log μg/dL; 95% CI: 0.04, 0.56) but decreased reactivity in females (β = -0.15 log μg/dL; 95% CI: -0.35, 0.05). Models adjusting for creatinine yielded similar results. Prenatal BPA exposure is associated with sex-specific changes in infant HPA axis function. The biological plausibility of these findings is supported by their consistency with evidence in rodent models. Furthermore, these data support the hypotheses that sexually dimorphic changes in children's behaviour following prenatal BPA exposure are mediated by sexually dimorphic changes in HPA axis function.
Oyola, Mario G; Handa, Robert J
Gonadal hormones play a key role in the establishment, activation, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. By influencing the response and sensitivity to releasing factors, neurotransmitters, and hormones, gonadal steroids help orchestrate the gain of the HPA axis to fine-tune the levels of stress hormones in the general circulation. From early life to adulthood, gonadal steroids can differentially affect the HPA axis, resulting in sex differences in the responsivity of this axis. The HPA axis influences many physiological functions making an organism's response to changes in the environment appropriate for its reproductive status. Although the acute HPA response to stressors is a beneficial response, constant activation of this circuitry by chronic or traumatic stressful episodes may lead to a dysregulation of the HPA axis and cause pathology. Compared to males, female mice and rats show a more robust HPA axis response, as a result of circulating estradiol levels which elevate stress hormone levels during non-threatening situations, and during and after stressors. Fluctuating levels of gonadal steroids in females across the estrous cycle are a major factor contributing to sex differences in the robustness of HPA activity in females compared to males. Moreover, gonadal steroids may also contribute to epigenetic and organizational influences on the HPA axis even before puberty. Correspondingly, crosstalk between the hypothalamic-pituitary-gonadal (HPG) and HPA axes could lead to abnormalities of stress responses. In humans, a dysregulated stress response is one of the most common symptoms seen across many neuropsychiatric disorders, and as a result, such interactions may exacerbate peripheral pathologies. In this review, we discuss the HPA and HPG axes and review how gonadal steroids interact with the HPA axis to regulate the stress circuitry during all stages in life.
Joseph, S P; Ho, J T; Doogue, M P; Burt, M G
There is limited consensus regarding optimal glucocorticoid administration for pituitary surgery to prevent a potential adrenal crisis. To assess the investigation and management of the hypothalamic-pituitary-adrenal (HPA) axis in patients undergoing trans-sphenoidal hypophysectomy in Australasia. A questionnaire was sent to one endocrinologist at each of 18 centres performing pituitary surgery in Australasia. Using hypothetical case vignettes, respondents were asked to describe their investigation and management of the HPA axis for a patient with a: non-functioning macroadenoma and intact HPA axis, non-functioning macroadenoma and HPA deficiency and growth hormone secreting microadenoma undergoing trans-sphenoidal hypophysectomy. Responses were received from all 18 centres. Seventeen centres assess the HPA axis preoperatively by measuring early morning cortisol or a short synacthen test. Preoperative evaluation of the HPA status influenced glucocorticoid prescription by 10 centres, including 2/18 who would not prescribe perioperative glucocorticoids for a patient with a macroadenoma and an intact HPA axis. Tumour size influenced glucocorticoid prescribing patterns at 7/18 centres who prescribe a lower dose or no glucocorticoids for a patient with a microadenoma. Choice of investigations for definitive postoperative assessment of the HPA axis varied with eight centres requesting an insulin tolerance test, four centres a 250 µg short synacthen test and six centres requesting other tests. There is wide variability in the investigation and management of perioperative glucocorticoid requirements for patients undergoing pituitary surgery in Australasia. This may reflect limited evidence to define optimal management and that further well-designed studies are needed. © 2011 The Authors; Internal Medicine Journal © 2011 Royal Australasian College of Physicians.
Bauer, Carolyn M; Needham, Katie B; Le, Chuong N; Stewart, Emily C; Graham, Jessica L; Ketterson, Ellen D; Greives, Timothy J
During spring, increasing daylengths stimulate gonadal development in migratory birds. However, late-stage reproductive development is typically postponed until migration has been completed. The hypothalamic-pituitary-adrenal (HPA) axis regulates the secretion of glucocorticoids, which have been associated with pre-migratory hyperphagia and fattening. The HPA-axis is also known to suppress the hypothalamic-pituitary-gonadal (HPG) axis, suggesting the possibility that final transition into the breeding life history stage may be slowed by glucocorticoids. We hypothesized that greater HPA-axis activity in individuals preparing for migration may foster preparation for migration while simultaneously acting as a "brake" on the development of the HPG-axis. To test this hypothesis, we sampled baseline corticosterone (CORT), stress-induced CORT, and negative feedback efficacy of Dark-eyed Juncos (Junco hyemalis) in an overwintering population that included both migratory (J.h. hyemalis) and resident (J.h. carolinensis) individuals. We predicted that compared to residents, migrants would have higher baseline CORT, higher stress-induced CORT, and weaker negative feedback. Juncos were sampled in western Virginia in early March, which was about 2-4wk before migratory departure for migrants and 4-5wk before first clutch initiation for residents. Contrary to our predictions, we found that migrants had lower baseline and stress-induced CORT and similar negative feedback efficacy compared with residents, which suggests that delayed breeding in migrants is influenced by other physiological mechanisms. Our findings also suggest that baseline CORT is not elevated during pre-migratory fattening, as migrants had lower baseline CORT and were fatter than residents. Copyright © 2015 Elsevier Inc. All rights reserved.
Jeremy D Coplan
Full Text Available Background: Chronic stress may conceivably require plasticity of maternal physiology and behavior to cope with the conflicting primary demands of infant rearing and foraging for food. In addition, social rank may play a pivotal role in mandating divergent homeostatic adaptations in cohesive social groups. We examined cerebrospinal fluid (CSF oxytocin (OT levels and hypothalamic pituitary adrenal (HPA axis regulation in the context of maternal social stress and assessed the contribution of social rank to dyadic-distance as reflective of distraction from normative maternal-infant interaction. Methods: Twelve socially-housed mother-infant bonnet macaque dyads were studied after variable foraging demand (VFD exposure compared to 11 unstressed dyads. Dyadic-distance was determined by behavioral observation. Social ranking was performed blindly by two observers. Post-VFD maternal plasma cortisol and CSF OT were compared to corresponding measures in non-VFD exposed mothers. Results: High social rank was associated with increased dyadic-distance only in VFD-exposed dyads and not in control dyads. In mothers unexposed to VFD, social rank was not related to maternal cortisol levels whereas VFD-exposed dominant versus subordinate mothers exhibited increased plasma cortisol. Maternal CSF OT directly predicted maternal cortisol only in VFD-exposed mothers. CSF OT was higher in dominant versus subordinate mothers. VFD-exposed mothers with high cortisol specifically exhibited CSF OT elevations in comparison to control groups. Conclusions: Pairing of maternal social rank to dyadic-distance in VFD presumably reduces maternal contingent responsivity, with ensuing long-term sequelae. VFD-exposure dichotomizes maternal HPA axis response as a function of social rank with relatively reduced cortisol in subordinates. OT may serve as a homeostatic buffer during maternal stress exposure.
Ambrus, Livia; Lindqvist, Daniel; Träskman-Bendz, Lil; Westrin, Åsa
Both decreased levels of brain-derived neurotrophic factor (BDNF) and hypothalamic-pituitary-adrenal (HPA) axis dysregulation may be involved in the pathophysiology of suicidal behaviour, as well as cognitive symptoms of depression. Pre-clinical and clinical studies have shown interactions between HPA-axis activity and BDNF, but this has not been studied in a clinical cohort of suicidal subjects. The purpose of this study was, therefore, to investigate associations between HPA-axis activity and BDNF in suicide attempters. Furthermore, this study examined the relationship between the HPA-axis, BDNF, and cognitive symptoms in suicidal patients. Since previous data indicate gender-related differences in BDNF and the HPA axis, males and females were examined separately. Seventy-five recent suicide attempters (n = 41 females; n = 34 males) were enrolled in the study. The Dexamethasone Suppression Test (DST) was performed and BDNF in plasma were analysed. Patients were evaluated with the Comprehensive Psychopathological Rating Scale (CPRS) from which items 'Concentration difficulties' and 'Failing memory' were extracted. Only among females, DST non-suppressors had significantly lower BDNF compared to DST suppressors (p = 0.022), and there was a significant correlation between post-DST serum cortisol at 8 a.m. and BDNF (rs = -0.437, p = 0.003). Concentration difficulties correlated significantly with post-DST cortisol in all patients (rs = 0.256, p = 0.035), in females (rs = 0.396, p = 0.015), and with BDNF in females (rs = -0.372, p = 0.020). The findings suggest an inverse relationship between the HPA-axis and BDNF in female suicide attempters. Moreover, concentration difficulties may be associated with low BDNF and DST non-suppression in female suicide attempters.
Smy, Laura; Shaw, Kaitlyn; Amstutz, Ursula; Smith, Anne; Berger, Howard; Carleton, Bruce; Koren, Gideon
Cortisol is a hormone involved in many physiological functions including fetal maturation and epigenetic programming during pregnancy. This study aimed to use hair cortisol as a biomarker of chronic inhaled corticosteroid (ICS) exposure and assess the potential effects of asthma on the hypothalamic-pituitary-adrenal (HPA) axis in pregnant women. We hypothesized that pregnant women with asthma treated with ICS would exhibit lower hair cortisol concentrations, indicative of adrenal suppression, compared to women with asthma not using ICS and women who do not have asthma. We performed an observational retrospective cohort study. Hair samples were analyzed from pregnant women with asthma, with (n = 56) and without (n = 31) ICS treatment, and pregnant women without asthma (n = 31). Hair samples were segmented based on the growth rate of 1 cm/month and analyzed by enzyme immunoassay to provide cortisol concentrations corresponding to preconception, trimesters 1-3, and postpartum. Hair cortisol concentrations were compared within and among the groups using non-parametric statistical tests. Hair cortisol concentrations increased across trimesters for all three groups, but this increase was dampened in women with asthma (P = 0.03 for Controls vs. ICS Treated and Controls vs. No ICS). ICS Treated women taking more than five doses per week had hair cortisol concentrations 47 % lower in third trimester than Controls. Linear regression of the third trimester hair cortisol results identified asthma as a significant factor when comparing consistent ICS use or asthma as the predictor (F(1, 25) = 9.7, P = 0.005, R(2) adj = 0.257). Hair cortisol successfully showed the expected change in cortisol over the course of pregnancy and may be a useful biomarker of HPA axis function in pregnant women with asthma. The potential impact of decreased maternal cortisol in women with asthma on perinatal outcomes remains to be determined.
Muñoz-Abellán, Cristina; Daviu, Nuria; Rabasa, Cristina; Nadal, Roser; Armario, Antonio
A single exposure to a cat or cat odors has been reported by some groups to induce contextual and auditory fear conditioning and long-lasting changes in anxiety-like behaviour, but there is no evidence for parallel changes in biological stress markers. In the present study we demonstrated in male rats that exposure to a novel environment containing a cloth impregnated with cat fur odor resulted in avoidance of the odor, lower levels of activity and higher pituitary-adrenal (PA) response as compared to those exposed to the novel environment containing a clean cloth, suggesting increased levels of stress in the former animals. When re-exposed 9 days later to the same environment with a clean cloth, previously cat fur exposed rats again showed avoidance of the cloth area and lower levels of activity, suggesting development of contextual fear conditioning, which again was associated with a higher PA activation. In contrast, unaltered both anxiety-like behaviour and PA responsiveness to an elevated plus-maze were found 7 days after cat odor exposure. It is concluded that: (i) PA activation is able to reflect both the stressful properties of cat fur odor and odor-induced contextual fear conditioning; (ii) development of cat odor-induced contextual fear conditioning is independent of the induction of long-lasting changes in anxiety-like behaviour; and (iii) greater PA activation during exposure to the odor context is not explained by non-specific sensitization of the PA axis caused by previous exposure to cat fur odor.
Belda, Xavier; Fuentes, Silvia; Nadal, Roser; Armario, Antonio
We have previously reported that a single exposure to immobilization (IMO) in rats causes a long-term desensitization of the hypothalamic-pituitary-adrenal (HPA) response to the same (homotypic) stressor. Since there are reports showing that a single exposure to other stressors causes sensitization of the HPA response to heterotypic stressors and increases anxiety-like behavior, we studied in the present work the long-term effects of IMO on behavioral and HPA response to mild superimposed stressors. In Experiments 1 and 2, adult male Sprague-Dawley rats were subjected to 2 h of IMO and then exposed for 5 min to the elevated plus-maze (EPM) at 1, 3 or 7 days after IMO. Blood samples were taken at 15 min after initial exposure to the EPM. Increases in anxiety-like behavior and HPA responsiveness to the EPM were found at all times post-IMO. Changes in the resting levels of HPA hormones did not explain the enhanced HPA responsiveness to the EPM (Experiment 3). In Experiments 4 and 5, we studied the effects of a single exposure to a shorter session of IMO (1 h) on behavioral and HPA responses to a brief and mild session of foot-shocks done 10 days after IMO. Neither previous IMO nor exposure to shocks in control rats modified behavior in the EPM. However, a brief session of shocks in previously IMO-exposed rats dramatically increased anxiety in the EPM. HPA and freezing responses to shocks were similar in control and previous IMO groups. Therefore, a single exposure to IMO appears to induce long-lasting HPA and behavioral sensitization to mild superimposed stressors, although the two responses are likely to be at least partially independent. Long-term effects of IMO on the susceptibility to stress-induced endocrine and emotional disturbances may be relevant to the characterization of animal models of post-traumatic stress.
Belda, Xavier; Ons, Sheila; Carrasco, Javier; Armario, Antonio
Partial food restriction (FR) protocols have been used not only to study behavioral and physiological consequences of decrease food intake, but as a necessary treatment of the animals in some operant learning tasks. It is well-established in rodents that restricting food availability to a few hours in the morning causes an alteration of the daily rhythm of corticosterone, thus making it difficult to evaluate whether or not such treatments are stressful. In the present experiment adult male Sprague-Dawley rats were subjected to two different FR schedules: food availability after 1100 h (LFR) or after 1900 h (DFR). After 14 days, animals from both groups, together with corresponding controls, were killed under resting conditions, either in the morning or in the evening, just before daily access to food in FR rats. Both FR schedules reduced body weight gain to the same extent, but their impact on the hypothalamic-pituitary-adrenal (HPA) axis was different: DFR increased relative, but not absolute, adrenal weight and morning and evening levels of corticosterone, whereas LFR increased both absolute and relative adrenal weights and increased morning corticosterone levels to a greater extent than DFR rats. Neither serum ACTH nor corticotropin-releasing factor (CRF) mRNA levels in the paraventricular nucleus of the hypothalamus were altered by DFR or LFR protocols, suggesting that factors other than CRF and ACTH are involved in the control of adrenocortical secretion under FR. It appears that LFR caused more alterations in the HPA axis than DFR and, therefore, the latter FR schedule should be used in those protocols necessarily involving partial FR.
Daviu, Núria; Andero, Raül; Armario, Antonio; Nadal, Roser
In recent years, special attention is being paid to sex differences in susceptibility to disease. In this regard, there is evidence that male rats present higher levels of both cued and contextual fear conditioning than females. However, little is known about the concomitant hypothalamic-pituitary-adrenal (HPA) axis response to those situations which are critical in emotional memories. Here, we studied the behavioural and HPA responses of male and female Wistar rats to context fear conditioning using electric footshock as the aversive stimulus. Fear-conditioned rats showed a much greater ACTH and corticosterone response than those merely exposed to the fear conditioning chamber without receiving shocks. Moreover, males presented higher levels of freezing whereas HPA axis response was greater in females. Accordingly, during the fear extinction tests, female rats consistently showed less freezing and higher extinction rate, but greater HPA activation than males. Exposure to an open-field resulted in lower activity/exploration in fear-conditioned males, but not in females, suggesting greater conditioned cognitive generalization in males than females. It can be concluded that important sex differences in fear conditioning are observed in both freezing and HPA activation, but the two sets of variables are affected in the opposite direction: enhanced behavioural impact in males, but enhanced HPA responsiveness in females. Thus, the role of sex differences on fear-related stimuli may depend on the variables chosen to evaluate it, the greater responsiveness of the HPA axis in females perhaps being an important factor to be further explored. Copyright © 2014 Elsevier Inc. All rights reserved.
Rabasa, Cristina; Muñoz-Abellán, Cristina; Daviu, Núria; Nadal, Roser; Armario, Antonio
Factors involved in adaptation to repeated stress are not well-characterized. For instance, acute footshock (FS) of high intensity appears to be less severe than immobilization (IMO) in light of the speed of post-stress recovery of the hypothalamic-pituitary-adrenal (HPA) axis and other physiological variables. However, repeated exposure to IMO consistently resulted in reduction of the HPA response to the same stressor (adaptation), whereas failure to adapt has been usually reported after FS. Thus, in the present work we directly compared the activation of HPA axis and other physiological changes in response to both acute and repeated exposure to IMO and two intensities of FS (medium and high) in adult male rats. Control rats were exposed to the FS boxes but they did not receive shocks. Daily repeated exposure to IMO resulted in significant adaptation of the overall ACTH and corticosterone responses to the stressor. Such a reduction was also observed with repeated exposure to FS boxes and FS-medium, whereas repeated exposure to FS-high only resulted in a small reduction of the corticosterone response during the post-stress period. This suggests that some properties of FS-high make adaptation to it difficult. Interestingly, overall changes in food intake and body weight gain throughout the week of exposure to the stressors reveal a greater impact of IMO than FS-high, indicating that factors other than the intensity of a stressor, at least when evaluated in function of the above physiological variables, can influence HPA adaptation. Since FS exposure is likely to cause more pain than IMO, activation of nociceptive signals above a certain level may negatively affect HPA adaptation to repeated stressors. Copyright © 2011 Elsevier Inc. All rights reserved.
Harris, Breanna N; Carr, James A
Maintaining energy balance and reproducing are important for fitness, yet animals have evolved mechanisms by which the hypothalamus-pituitary-adrenal/interrenal (HPA/HPI) axis can shut these activities off. While HPA/HPI axis inhibition of feeding and reproduction may have evolved as a predator defense, to date there has been no review across taxa of the causal evidence for such a relationship. Here we review the literature on this topic by addressing evidence for three predictions: that exposure to predators decreases reproduction and feeding, that exposure to predators activates the HPA/HPI axis, and that predator-induced activation of the HPA/HPI axis inhibits foraging and reproduction. Weight of evidence indicates that exposure to predator cues inhibits several aspects of foraging and reproduction. While the evidence from fish and mammals supports the hypothesis that predator cues activate the HPA/HPI axis, the existing data in other vertebrate taxa are equivocal. A causal role for the HPA axis in predator-induced suppression of feeding and reproduction has not been demonstrated to date, although many studies report correlative relationships between HPA activity and reproduction and/or feeding. Manipulation of HPA/HPI axis signaling will be required in future studies to demonstrate direct mediation of predator-induced inhibition of feeding and reproduction. Understanding the circuitry linking sensory pathways to their control of the HPA/HPI axis also is needed. Finally, the role that fear and anxiety pathways play in the response of the HPA axis to predator cues is needed to better understand the role that predators have played in shaping anxiety related behaviors in all species, including humans. Copyright © 2016 Elsevier Inc. All rights reserved.
Previous studies have demonstrated that exposure to the pulmonary irritant ozone causes myriad systemic metabolic and pulmonary effects attributed to sympathetic and hypothalamus-pituitary-adrenal (HPA) axis activation, which are exacerbated in metabolically impaired models. We...
Previous studies have demonstrated that exposure to ozone, a pulmonary irritant, causes myriad systemic metabolic and pulmonary effects that are attributed to neuronal and hypothalamus-pituitary-adrenal (HPA) axis activation, which are exacerbated in metabolically-impaired models...
Stephens, Mary Ann C; Mahon, Pamela B; McCaul, Mary E; Wand, Gary S
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N=282) completed the Trier Social Stress Test (TSST), a widely used and well-validated stress-induction laboratory procedure. All women (n=135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to the
Chadio, S E; Kotsampasi, B; Papadomichelakis, G; Deligeorgis, S; Kalogiannis, D; Menegatos, I; Zervas, G
Epidemiological and experimental data support the hypothesis of 'fetal programming', which proposes that alterations in fetal nutrition and endocrine status lead to permanent adaptations in fetal homeostatic mechanisms, producing long-term changes in physiology and determine susceptibility to later disease. Altered hypothalamic-pituitary-adrenal (HPA) axis function has been proposed to play an important role in programming of disease risk. The aim of the present study was to examine the effects of maternal nutrient restriction imposed during different periods of gestation on the HPA axis function in sheep, at different ages postnatal. Pregnant ewes were fed a 50% nutrient-restricted diet from days 0-30 (group R1, n = 7), or from days 31-100 of gestation (group R2, n = 7) or a control 100% diet throughout pregnancy, (Control, n = 8). Blood samples were collected at 10-day intervals from day 40 of gestation to term. Lambs were born naturally and fed to appetite throughout the study period. At 2, 5.5, and 10 months of age lambs were given an i.v. injection of corticotrophin-releasing hormone (CRH) and blood samples were collected at -15, 0, 15, 30, 60, 120, and 180 min postinjection. Maternal cortisol levels were significantly higher (P < 0.05) in group R1 compared with the other two groups, whereas maternal insulin levels were lower (P < 0.05) in group R2 compared with control. Birth weight of lambs was not affected by the maternal nutritional manipulation. The area under the curve for ACTH and cortisol response to CRH challenge was greater (P < 0.05) in lambs of group R1 at two months of age, whereas no difference was detected at the ages of 5.5 and 10 months. However, significantly higher (P < 0.01) basal cortisol levels were observed in lambs of R1 group at 5.5 months of age. There was no interaction between treatment and sex for both pituitary and adrenal responses to the challenge. A significant sex effect was evident with females responding with higher ACTH and
O'Connor, T M
Organisms survive by maintaining equilibrium with their environment. The stress system is critical to this homeostasis. Glucocorticoids modulate the stress response at a molecular level by altering gene expression, transcription, and translation, among other pathways. The effect is the inhibition of the functions of inflammatory cells, predominantly mediated through inhibition of cytokines, such as IL-1, IL-6, and TNF-alpha. The central effectors of the stress response are the corticotrophin-releasing hormone (CRH) and locus coeruleus-norepinephrine (LC-NE)\\/sympathetic systems. The CRH system activates the stress response and is subject to modulation by cytokines, hormones, and neurotransmitters. Glucocorticoids also modulate the growth, reproductive and thyroid axes. Abnormalities of stress system activation have been shown in inflammatory diseases such as rheumatoid arthritis, as well as behavioural syndromes such as melancholic depression. These disorders are comparable to those seen in rats whose CRH system is genetically abnormal. Thus, the stress response is central to resistance to inflammatory and behavioural syndromes. In this review, we describe the response to stress at molecular, cellular, neuroendocrine and behavioural levels, and discuss the disease processes that result from a dysregulation of this response, as well as recent developments in their treatment.
Guan Shaoxia; Chen Jianfei; Ma Yaling
Objective: To find the relationship between FENG syndrome and pituitary-adrenal axis hormones (adrenocorticotropic hormone ACTH, corticosteroid CS) at the onset of acute cerebral infarction (ACI). Methods: Using the table of syndrome quantitative diagnosis formulated according to the experiences of apoplectic experts to score the patient at the onset for 151 cases, the patients were divided into two groups: those of FENG syndrome (score ≥ 7 n=77) and NON-FENG syndrome (score<7 n=74). Levels of plasma ACTH and CS in there two groups and 60 healthy subject were determined with RIA. Results: 1) The levels of plasma ACTH and CS in the FENG group were very significantly higher than those in the NON-FENG group (p<0.001); the same result existed between patients and healthy subjects (p<0.001). 2) Highly positive cor-relationship existed between the scores of 77 FENG syndrome cases and the levels of plasma ACTH (r=0.89, t=14.61); moderately positive cor-relationship existed between the scores of FENG syndrome cases and the levels of plasma CS (r=0.53, t=4.83). Conclusion: There is a positive cor-relationship between FENG syndrome and pituitary adrenal axis hormones (ACTH, CS), the levels of plasma ACTH and CS can be regarded as index to differentiate FENG syndrome from NON-FENG syndrome
Suppression Test (DST) The dexamethasone suppression test (DST) is a pharmacological challenge test typically used to identify the cause of abnormal ...suppres- sion is in effect. One way to further probe the system is to combine a nonpharmacological, psychological stressor with the DST. The ensuing...second stage of our proposed test, we assume Iext(t) to be a positive constant when the external ( psychological ) stressor is on, and zero while off. In
Full Text Available Epidural steroid injections are well accepted as a treatment for radicular back pain in appropriate candidates. While overall incidence of systemic side effects has not been well established, at least five biochemically proven cases of iatrogenic Cushing's Syndrome have been reported as complications of epidural steroid treatment. We present an additional case of iatrogenic Cushing's Syndrome and adrenal suppression in a middle-aged woman who received three epidural steroid injections over a four-month period. We review this case in the context of previous cases and discuss diagnostic and management issues.
David M. Walton
Full Text Available The mechanisms underlying the development of persistent posttraumatic pain and disability remain elusive. Recent evidence suggests that disordered stress-system pathway (hypothalamic-pituitary-adrenal axis activity may be responsible for the genesis and maintenance of long-term sensory and emotional problems. However, confidence in current evidence is limited by the necessarily retrospective collection of data. Hair cortisol can serve as a calendar of HPA axis activity going back several months prior to injury. The purposes of this pilot study were to determine the feasibility of using hair cortisol and hair-normalized salivary cortisol as biomarkers of distress following traumatic injuries of whiplash or distal radius fracture. Ten subjects provided complete data within 3 weeks of injury. Hair cortisol, cortisol waking response (CWR, and mean daily cortisol (MDC were captured at inception, as were self-report indicators of pain, disability, and pain catastrophizing. Pain and disability were also captured 3 months after injury. Results indicate that cortisol waking response may be a useful biomarker of current distress as measured using the pain catastrophizing scale, especially when normalized to 3-month hair cortisol (r=0.77 raw, 0.93 normalized. Hair-normalized CWR may also have predictive capacity, correlating with 3-month self-reported disability at r=0.70. While promising, the results must be viewed in light of the small sample.
Garcia-Leal, C; Del-Ben, C M; Leal, F M; Graeff, F G; Guimarães, F S
Simulated public speaking (SPS) test is sensitive to drugs that interfere with serotonin-mediated neurotransmission and is supposed to recruit neural systems involved in panic disorder. The study was aimed at evaluating the effects of escitalopram, the most selective serotonin-selective reuptake inhibitor available, in SPS. Healthy males received, in a double-blind, randomized design, placebo (n = 12), 10 (n = 17) or 20 (n = 14) mg of escitalopram 2 hours before the test. Behavioural, autonomic and neuroendocrine measures were assessed. Both doses of escitalopram did not produce any effect before or during the speech but prolonged the fear induced by SPS. The test itself did not significantly change cortisol and prolactin levels but under the higher dose of escitalopram, cortisol and prolactin increased immediately after SPS. This fear-enhancing effect of escitalopram agrees with previously reported results with less selective serotonin reuptake inhibitors and the receptor antagonist ritanserin, indicating that serotonin inhibits the fear of speaking in public.
Haller, J; Barna, I; Kovács, J L
The effects of adrenergic activation on aggressiveness and the aggression induced endocrine changes were tested in rats. Alpha 2 adrenoceptor blockers were used for enhancing activation of the adrenergic system, and changes in aggressiveness were tested in resident-intruder contests. Three experiments were conducted. In experiment 1, saline injected rats responded to the presence of an opponent by aggression and the increase in plasma ACTH and corticosterone. Intraperitoneal administration of 1 mg/kg CH-38083 (an alpha 2 adrenoceptor antagonist) produced a several fold increase in clinch fighting and mutual upright scores, and also further enhanced the plasma ACTH and corticosterone response. In experiment 2, the effect of three doses (0.5, 1 and 2 mg/kg) of three different alpha 2 adrenoceptor blockers CH-38083, idazoxan and yohimbine were tested. All the substances increased aggression at 0.5 and 1 mg/kg; at 2 mg/kg the effect of idazoxan and yohimbine disappeared, while with CH-38083 an additional increase was obtained. In yohimbine treated animals the enhancement of aggression was reduced already at 1 mg/kg. In experiment 3, indomethacin, a potent inhibitor of the catecholamine-induced ACTH release completely abolished the effects of the alpha 2 adrenoceptor antagonist CH-38083: the intensity of agonistic interactions, as well as ACTH and corticosterone plasma concentrations, returned to control levels. The possible role of catecholamines and the stress hormones in the activation of aggression is discussed.
Rabasa, Cristina; Gagliano, Humberto; Pastor-Ciurana, Jordi; Fuentes, Silvia; Belda, Xavier; Nadal, Roser; Armario, Antonio
Repeated exposure to a wide range of stressors differing in nature and intensity results in a reduced response of prototypical stress markers (i.e. plasma levels of ACTH and adrenaline) after an acute challenge with the same (homotypic) stressor. This reduction has been considered to be a habituation-like phenomenon. However, direct experimental evidence for this assumption is scarce. In the present work we demonstrate in adult male rats that adaptation of the hypothalamus-pituitary-adrenal (HPA) axis to repeated stress does not follow some of the critical rules of habituation. Briefly, adaptation was stronger and faster with more severe stressors, maximally observed even with a single exposure to severe stressors, extremely long-lasting, negatively related to the interval between the exposures and positively related to the length of daily exposure. We offer a new theoretical view to explain adaptation to daily repeated stress. Copyright © 2015 Elsevier Ltd. All rights reserved.
Lithium attenuated the depressant and anxiogenic effect of juvenile social stress through mitigating the negative impact of interlukin-1β and nitric oxide on hypothalamic-pituitary-adrenal axis function.
Haj-Mirzaian, A; Amiri, S; Kordjazy, N; Momeny, M; Razmi, A; Rahimi-Balaei, M; Amini-Khoei, H; Haj-Mirzaian, A; Marzban, H; Mehr, S E; Ghaffari, S H; Dehpour, A R
The neuroimmune-endocrine dysfunction has been accepted as one of fundamental mechanisms contributing to the pathophysiology of psychiatric disorders including depression and anxiety. In this study, we aimed to evaluate the involvement of hypothalamic-pituitary-adrenal (HPA) axis, interleukin-1β, and nitrergic system in mediating the negative behavioral impacts of juvenile social isolation stress (SIS) in male mice. We also investigated the possible protective effects of lithium on behavioral and neurochemical changes in socially isolated animals. Results showed that experiencing 4-weeks of juvenile SIS provoked depressive and anxiety-like behaviors that were associated with hyper responsiveness of HPA axis, upregulation of interleukin-1β, and nitric oxide (NO) overproduction in the pre-frontal cortex and hippocampus. Administration of lithium (10 mg/kg) significantly attenuated the depressant and anxiogenic effects of SIS in behavioral tests. Lithium also restored the negative effects of SIS on cortical and hippocampal interleukin-1β and NO as well as HPA axis deregulation. Unlike the neutralizing effects of l-arginine (NO precursor), administration of l-NAME (3 mg/kg) and aminoguanidine (20 mg/kg) potentiated the positive effects of lithium on the behavioral and neurochemical profile of isolated mice. In conclusion, our results revealed that juvenile SIS-induced behavioral deficits are associated with abnormalities in HPA-immune function. Also, we suggest that alleviating effects of lithium on behavioral profile of isolated mice may be partly mediated by mitigating the negative impact of NO on HPA-immune function. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
Mohammadi, Ali Akbar; Jazayeri, Shima; Khosravi-Darani, Kianoush; Solati, Zahra; Mohammadpour, Nakisa; Asemi, Zatollah; Adab, Zohre; Djalali, Mahmoud; Tehrani-Doost, Mehdi; Hosseini, Mostafa; Eghtesadi, Shahryar
The aim of this study was to determine effects of probiotic yogurt and multispecies probiotic capsule supplementation on mental health and hypothalamic-pituitary-adrenal axis in petrochemical workers. The present randomized double-blind, placebo-controlled trial was conducted on 70 petrochemical workers. Subjects were randomly divided into three groups to receive 100 g/day probiotic yogurt + one placebo capsule (n = 25) or one probiotic capsule daily + 100 g/day conventional yogurt (n = 25) or 100 g/day conventional yogurt + one placebo capsule (n = 20) for 6 weeks. Mental health parameters including general health questionnaire (GHQ) and depression anxiety and stress scale (DASS) scores were measured. Fasting blood samples were obtained at the beginning and 6 weeks after the intervention to quantify hypothalamic-pituitary-adrenal axis. After 6 weeks of intervention, a significant improvement of GHQ was observed in the probiotic yogurt (18.0 ± 1.5 vs. 13.5 ± 1.9, P = 0.007) and in the probiotic capsule group (16.9 ± 1.8 vs. 9.8 ± 1.9, P = 0.001), as well as a significant improvement in DASS scores in the probiotic yogurt (23.3 ± 3.7 vs. 13.0 ± 3.7, P = 0.02) and the probiotic capsule group (18.9 ± 3.2 vs. 9.4 ± 4.0, P = 0.006). However, there was no significant improvement in the conventional yogurt group (P = 0.05 for GHQ and P = 0.08 for DASS). The consumption of probiotic yogurt or a multispecies probiotic capsule had beneficial effects on mental health parameters in petrochemical workers.
Full Text Available It is a difficult task to improve animal production by means of genetic selection, if the environment does not allow full expression of the animal’s genetic potential. This concept may well be the future for animal welfare, because it highlights the need to incorporate traits related to production and robustness, simultaneously, to reach sustainable breeding goals. This review explores the identification of potential genetic markers for robustness within the hypothalamic-pituitary-adrenal axis (HPAA, since this axis plays a vital role in the stress response. If genetic selection for superior HPAA responses to stress is possible, then it ought to be possible to breed robust and easily managed genotypes that might be able to adapt to a wide range of environmental conditions whilst expressing a high production potential. This approach is explored in this review by means of lessons learnt from research on Merino sheep, which were divergently selected for their multiple rearing ability. These two selection lines have shown marked differences in reproduction, production and welfare, which makes this breeding programme ideal to investigate potential genetic markers of robustness. The HPAA function is explored in detail to elucidate where such genetic markers are likely to be found.
Marieke J van der Werf-Eldering
Full Text Available Dysregulation of the hypothalamic-pituitary-adrenal (HPA axis is thought to be associated with more mood symptoms and worse cognitive functioning. This study examined whether variation in HPA axis activity underlies the association between mood symptoms and cognitive functioning.In 65 bipolar patients cognitive functioning was measured in domains of psychomotor speed, speed of information processing, attentional switching, verbal memory, visual memory, executive functioning and an overall mean score. Severity of depression was assessed by the Inventory of Depressive Symptomatology-self rating version. Saliva cortisol measurements were performed to calculate HPA axis indicators: cortisol awakening response, diurnal slope, the evening cortisol level and the cortisol suppression on the dexamethasone suppression test. Regression analyses of depressive symptoms and cognitive functioning on each HPA axis indicator were performed. In addition we calculated percentages explanation of the association between depressive symptoms and cognition by HPA axis indicators. Depressive symptoms were associated with dysfunction in psychomotor speed, attentional switching and the mean score, as well as with attenuation in diurnal slope value. No association was found between HPA axis activity and cognitive functioning and HPA axis activity did not explain the associations between depressive symptoms and cognition.As our study is the first one in this field specific for bipolar patients and changes in HPA-axis activity did not seem to explain the association between severity of depressive symptoms and cognitive functioning in bipolar patients, future studies are needed to evaluate other factors that might explain this relationship.
Annabi, Alya; Dhouib, Ines Bini; Lamine, Aicha Jrad; El Golli, Nargès; Gharbi, Najoua; El Fazâa, Saloua; Lasram, Mohamed Montassar
Imidacloprid is the most important example of the neonicotinoid insecticides known to target the nicotinic acetylcholine receptor in insects, and potentially in mammals. N-Acetyl-l-cysteine (NAC) has been shown to possess curative effects in experimental and clinical investigations. The present study was designed to evaluate the recovery effect of NAC against Imidacloprid-induced oxidative stress and cholinergic transmission alteration in hypothalamic-pituitary-adrenal (HPA) axis of male rats following subchronic exposure. About 40 mg/kg of Imidacloprid was administered daily by intragastric intubation and 28 days later, the rats were sacrificed and HPA axis tissues were removed for different analyses. Imidacloprid increased adrenal relative weight and cholesterol level indicating an adaptive stage of the general alarm reaction to stress. Moreover, Imidacloprid caused a significant increase in malondialdehyde level, the antioxidants catalase, superoxide dismutase and glutathione-S-transferase showed various alterations following administration and significant depleted thiols content was only recorded in hypothalamic tissue. Furthermore, the hypothalamic and pituitary acetylcholinesterase activity and calcium level were significantly increased highlighting the alteration of cholinergic activity. The present findings revealed that HPA axis is a sensitive target to Imidacloprid (IMI). Interestingly, the use of NAC for only 7 days post-exposure to IMI showed a partial therapeutic effect against Imidacloprid toxicity.
Scorrano, Fabrizio; Carrasco, Javier; Pastor-Ciurana, Jordi; Belda, Xavier; Rami-Bastante, Alicia; Bacci, Maria Laura; Armario, Antonio
The evaluation of chronic activity of the hypothalamic-pituitary-adrenal (HPA) axis is critical for determining the impact of chronic stressful situations. However, current methods have important limitations. The potential use of hair glucocorticoids as a noninvasive retrospective biomarker of long-term HPA activity is gaining acceptance in humans and wild animals. However, there is no study examining hair corticosterone (HC) in laboratory animals. The present study validates a method for measuring HC in rats and demonstrates that it properly reflects chronic HPA activity. The HC concentration was similar in male and female rats, despite higher total plasma corticosterone levels in females, tentatively suggesting that it reflects free rather than total plasma corticosterone. Exposure of male rats to 2 different chronic stress protocols (chronic immobilization and chronic unpredictable stress) resulted in similarly higher HC levels compared to controls (1.8-fold). HC also increased after a mild chronic stressor (30 min daily restraint). Chronic administration of 2 different doses of a long-acting ACTH preparation dramatically increased HC (3.1- and 21.5-fold, respectively), demonstrating that a ceiling effect in HC accumulation is unlikely under other more natural conditions. Finally, adrenalectomy significantly reduced HC. In conclusion, HC measurement in rats appears appropriate to evaluate integrated chronic changes in circulating corticosterone. © FASEB.
Daviu, Núria; Rabasa, Cristina; Nadal, Roser; Armario, Antonio
Acute exposure to severe stressors causes marked activation of the hypothalamic-pituitary-adrenal (HPA) axis that is reflected on the day after higher resting levels of HPA hormones and sensitization of the HPA response to novel (heterotypic) stressors. However, whether a single exposure to a severe stressor or daily repeated exposure to the same (homotypic) stressor modifies these responses to the same extent has not been studied. In this experiment, we studied this issue in adult male Sprague-Dawley rats daily exposed for seven days to a severe stressor such as immobilization on boards (IMO). A first exposure to 1 h IMO resulted in a marked activation of the HPA axis as reflected in plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone, and such activation was significantly reduced after the seventh IMO. On the day after the first IMO, higher resting levels of ACTH and corticosterone and sensitization of their responses to a short exposure to an open-field (OF) were observed, together with a marked hypoactivity in this environment. Repeated exposure to IMO partially reduced hypoactivity, the increase in resting levels of HPA hormones and the ACTH responsiveness to the OF on the day after the last exposure to IMO. In contrast, corticosterone response was gradually increased, suggesting partial dissociation from ACTH. These results indicate that daily repeated exposure to the same stressor partially reduced the HPA response to the homotypic stressor as well as the sensitization of HPA axis activity observed the day after chronic stress cessation.
Belda, Xavier; Armario, Antonio
Whereas the role of most biogenic amines in the control of the hypothalamus-pituitary-adrenal (HPA) response to stress has been extensively studied, the role of dopamine has not. We studied the effect of different dopamine receptor antagonists on HPA response to a severe stressor (immobilization, IMO) in adult male Sprague-Dawley rats. Haloperidol administration reduced adrenocorticotropin hormone and corticosterone responses to acute IMO, particularly during the post-IMO period. This effect cannot be explained by a role of dopamine to maintain a sustained activation of the HPA axis as haloperidol did not modify the response to prolonged (up to 6 h) IMO. Administration of more selective D1 and D2 receptor antagonists (SCH23390 and eticlopride, respectively) also resulted in lower and/or shorter lasting HPA response to IMO. Dopamine, acting through both D1 and D2 receptors, exerts a stimulatory role on the activation of the HPA axis in response to a severe stressor. The finding that dopamine is involved in the maintenance of post-stress activation of the HPA axis is potentially important because the actual pathological impact of HPA activation is likely to be related to the area under the curve of plasma glucocorticoid levels, which is critically dependent on how long after stress high levels of glucocorticoid are maintained.
Labad, Javier; Armario, Antonio; Nadal, Roser; Solé, Montse; Gutiérrez-Zotes, Alfonso; Montalvo, Itziar; Moreno-Samaniego, Lorena; Martorell, Lourdes; Sánchez-Gistau, Vanessa; Vilella, Elisabet
Hypothalamic-pituitary-adrenal (HPA) axis alterations in at-risk mental states (ARMS) resemble those observed in established psychosis but are less consistent. We aimed to explore HPA axis abnormalities in both first-episode psychosis (FEP) and ARMS patients, while controlling for psychopathological symptoms. We studied 21 ARMS, 34 FEP patients and 34 healthy subjects. Clinical assessment included psychopathological symptoms (positive, negative, disorganized, excited and depressive symptoms) and stress measures. Saliva cortisol levels were determined at awakening, 30' and 60' post-awakening, 10:00 h, 23:00 h and 10:00 h on the day after the administration of 0.25 mg of dexamethasone, which occurred at 23:00 h. Three HPA axis measures were calculated: cortisol awakening response (CAR), cortisol diurnal slope and cortisol suppression ratio of the dexamethasone suppression test (DST). There were no significant differences between groups in HPA axis measures. However, when exploring the relationship between HPA axis measures and psychopathological symptoms, in ARMS subjects (but not FEP patients), a flatter cortisol slope was associated with more prominent negative symptoms, whereas a blunted CAR was associated with excited symptoms. Although no significant differences in HPA axis measures were found between diagnostic groups, subtle abnormalities in the CAR or circadian cortisol rhythmicity might be important for the phenotype of ARMS individuals. Copyright © 2018. Published by Elsevier B.V.
Rabasa, Cristina; Delgado-Morales, Raúl; Muñoz-Abellán, Cristina; Nadal, Roser; Armario, Antonio
Repeated exposure to the same stressor very often results in a reduction of some prototypical stress responses, namely those related to the hypothalamic-pituitary-adrenal (HPA) and sympatho-medullo-adrenal (SMA) axes. This reduced response to repeated exposure to the same (homotypic) stressor (adaptation) is usually considered as a habituation-like process, and therefore, a non-associative type of learning. However, there is some evidence that contextual cues and therefore associative processes could contribute to adaptation. In the present study we demonstrated in two experiments using adult male rats that repeated daily exposure to restraint (REST) or immobilization on boards (IMO) reduced the HPA (plasma levels of ACTH and corticosterone) and glucose responses to the homotypic stressor and such reduced responses remained intact when all putative cues associated to the procedure (experimenter, way of transporting to the stress room, stress boxes, stress room and colour of the restrainer in the case of REST) were modified on the next day. Therefore, the present results do not favour the view that adaptation after repeated exposure to a stressor may involve associative processes related to signals predicting the imminence of the stressors, but more studies are needed on this issue. Copyright © 2010 Elsevier B.V. All rights reserved.
Full Text Available This prospective, cross-sectional, interventional study was designed to determine the association between the hormones of the pituitary-adrenal and pituitary-thyroid axes and other clinical parameters with the blood glucose perturbations in dogs with naturally occurring Babesia canis rossi babesiosis. Thirty-six dogs with canine babesiosis were studied. Blood samples were obtained from the jugular vein in each dog prior to treatment at admission to hospital and serum endogenous adrenocorticotrophic hormone(ACTH, pre-ACTH cortisol, thyroxine, free thyroxine and TSH concentrations were measured. Immediately thereafter each dog was injected intravenously with 5 µg/kg of ACTH (tetracosactrin. A 2nd blood sample was taken 1 hour later for serumpost-ACTHcortisol measurement. Three patient groups were recruited: hypoglycaemic dogs (glucose 5.5 mmol/ℓ, n = 12. Basal and post-ACTH serum cortisol concentrations were significantly higher in hypoglycaemic dogs, whereas body temperature, serum thyroxine and free thyroxine were significantly lower in hypoglycaemic dogs. Haematocrit was significantly lower in both hypo-and hyperglycaemic dogs compared with normoglycaemic dogs. Low blood glucose concentrations were significantly associated with high basal and post-ACTH cortisol concentrations and with low serum thyroxine and free thyroxine concentrations in dogs suffering from B. canis rossi babesiosis.
Kondoh, Y; Uemura, T; Murase, M; Yokoi, N; Ishikawa, M; Hirahara, F
To longitudinally evaluate disturbances of the hypothalamic-pituitary-adrenal (HPA) axis in women with secondary progestin-negative hypothalamic amenorrhea. Retrospective cohort study. Yokohama City University, Yokohama, Japan. Twenty-four women with progestin-negative hypothalamic amenorrhea. Administration of human corticotropin-releasing hormone (hCRH) and treatment with a combination of estrogen and progesterone. Plasma cortisol and ACTH concentrations and period required for recovery from amenorrhea. Plasma ACTH concentrations 30 and 60 minutes after injection of hCRH and the percent maximum increment (%Cmax) of ACTH were significantly lower in the amenorrheic patients compared with the control group patients. The basal cortisol was significantly higher, and the %Cmax of cortisol was significantly lower. In the 16 patients who recovered from amenorrhea, there was a significant positive correlation (Y = 1.93X-10.8, r = 0.629) between the basal cortisol concentrations (X) and the period for recovery (Y). The serum E2 gradually increased before recovery, and this E2 increase was preceded by changes in the plasma cortisol concentration and the %Cmax values of cortisol and ACTH. The CRH test might be useful for evaluating the roles of stress and for estimating the period required for recovery in hypothalamic amenorrhea.
Barr, C S; Newman, T K; Lindell, S; Becker, M L; Shannon, C; Champoux, M; Suomi, S J; Higley, J D
Studies in rodents demonstrate sex differences in neuroendocrine stress axis activity after treatment with alcohol. In abstinent alcoholics, atypical depressives, and individuals with posttraumatic stress disorder, limbic-hypothalamic-pituitary-adrenal (LHPA)-axis activity is often blunted; among females in these patient populations, however, resistance to glucocorticoid feedback and increased pituitary reactivity is observed. Early parental loss is a major life stressor and is a risk factor for both affective disturbances and LHPA-axis abnormalities later in life. We wanted to determine whether sex and early life parental absence would interact to influence alcohol-induced alterations in LHPA-axis activity after exposure to ethanol in macaques. Animals were reared with their mothers in social groups (MR, n = 94) or without adults in peer-only groups (PR, n = 79). At 5 years of age, they received an intravenous infusion of alcohol (2-2.2 g/kg), and the effects of alcohol, sex, and rearing condition on ACTH and cortisol levels were analyzed by ANOVA. Peer-reared females had higher ACTH levels than did PR males, MR females, and MR males after alcohol infusion. Alcohol-induced cortisol levels were not affected by sex and rearing condition. These findings suggest that there are sex differences in glucocorticoid negative feedback, pituitary responsivity, or release of ACTH secretagogues among individuals exposed to early life stress and emphasize the importance of considering sex effects when studying LHPA-axis dysregulation in alcoholism and other stress-related neuropsychiatric disorders.
Rompala, Gregory R; Finegersh, Andrey; Homanics, Gregg E
A growing number of environmental insults have been shown to induce epigenetic effects that persist across generations. For instance, paternal preconception exposures to ethanol or stress have independently been shown to exert such intergenerational effects. Since ethanol exposure is a physiological stressor that activates the hypothalamic-pituitary-adrenal (HPA) axis, we hypothesized that paternal ethanol exposure would impact stress responsivity of offspring. Adult male mice were exposed to chronic intermittent vapor ethanol or control conditions for 5 weeks before being mated with ethanol-naïve females to produce ethanol (E)- and control (C)-sired offspring. Adult male and female offspring were tested for plasma corticosterone (CORT) levels following acute restraint stress and the male offspring were further examined for stress-evoked 2-bottle choice ethanol-drinking. Paternal ethanol exposure blunted plasma CORT levels following acute restraint stress selectively in male offspring; females were unaffected. In a stress-evoked ethanol-drinking assay, there was no effect of stress on ethanol consumption. However, C-sired males exhibited increased total fluid intake (polydipsia) in response to stress while E-sired males were resistant to this stress-induced phenotype. Taken together, these data suggest that paternal ethanol exposure imparts stress hyporesponsivity to male offspring. Copyright © 2016 Elsevier Inc. All rights reserved.
Full Text Available BackgroundThis study was conducted to examine the effects of ad libitum consumption of highly palatable food (HPF during adolescence on the adverse behavioral outcome of neonatal maternal separation.MethodsMale Sprague-Dawley pups were separated from dam for 3 hours daily during the first 2 weeks of birth (maternal separation, MS or left undisturbed (nonhandled, NH. Half of MS pups received free access to chocolate cookies in addition to ad libitum chow from postnatal day 28 (MS+HPF. Pups were subjected to behavioral tests during young adulthood. The plasma corticosterone response to stress challenge was analyzed by radioimmunoassay.ResultsDaily caloric intake and body weight gain did not differ among the experimental groups. Ambulatory activities were decreased defecation activity and rostral grooming were increased in MS controls (fed with chow only compared with NH rats. MS controls spent less time in open arms, and more time in closed arms during the elevated plus maze test, than NH rats. Immobility duration during the forced swim test was increased in MS controls compared with NH rats. Cookie access normalized the behavioral scores of ambulatory and defecation activities and grooming, but not the scores during the elevated plus maze and swim tests in MS rats. Stress-induced corticosterone increase was blunted in MS rats fed with chow only, and cookie access normalized it.ConclusionProlonged access to HPF during adolescence and youth partly improves anxiety-related, but not depressive, symptoms in rats that experienced neonatal maternal separation, possibly in relation with improved function of the hypothalamic-pituitary-adrenal (HPA axis.
Geronikolou, Styliani A; Chamakou, Aikaterini; Mantzou, Aimilia; Chrousos, George; KanakaGantenbein, Christina
The hypothalamic-pituitary-adrenal (HPA) axis is the main "gate-keeper" of the organism's response to every somatic or mental stress. This prospective study aims to investigate the HPA-axis response to a cellular phone call exposure after mental stress in healthy children and adolescents and to assess the possible predictive role of baseline endocrine markers to this response. Two groups of healthy school-age children aged 11-14 (12.5±1.5) years were included in the study, the one comprising those who are occasional users of a cellular phone (Group A) while the second those who do regularly use one (Group B). Blood samples were obtained from all participants at 8.00 am after a 12-hour overnight fasting for thyroid hormone, glucose, insulin, and cortisol levels determination. The participants performed the Trier Social Stress Test for Children (TSST-C) (5 minoral task followed by 5 min arithmetic task). Salivary cortisol samples were obtained at baseline, 10' and 20' min after the TSST-C and 10' and 20' after a 5 minute cellular phone call. Significant changes in the salivary cortisol levels were noted between 10' and 20' mins after the cellular phone call with different responses between the two groups. Baseline thyroid hormone levels seem to predict the cortisol response to mental stress mainly in group A, while HOMA had no impact on salivary cortisol response at any phase of the test, in either group. HPA axis response to cellular phone after mental stress in children and adolescents follow a different pattern in frequent users than in occasional users that seems to be influenced by the baseline thyroid hormone levels. Copyright © 2015 Elsevier B.V. All rights reserved.
Mattsson, Cecilia; Reynolds, Rebecca M; Simonyte, Kotryna; Olsson, Tommy; Walker, Brian R
Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may underlie disorders including obesity, depression, cognitive decline, and the metabolic syndrome. Conventional tests of HPA axis negative feedback rely on glucocorticoid receptor (GR) agonists such as dexamethasone but do not test feedback by endogenous cortisol, potentially mediated by both GR and mineralocorticoid receptors (MR). The objective of the study was to use a combination of GR (RU38486, mifepristone) and MR (spironolactone) antagonists to explore the poorly understood activation of the HPA axis that occurs in obesity. This was a double-blind, placebo-controlled, randomized, crossover study. The study was conducted at a clinical research facility. Participants included 15 lean (body mass index 22.0 +/- 1.6 kg/m(2)) and 16 overweight/obese (body mass index 30.1 +/- 3.5 kg/m(2)) men. Subjects attended on four occasions for blood and saliva sampling every 30 min between 1800 and 2200 h. At 1100 and 1600 h before visits, subjects took 200 mg spironolactone, 400 mg RU38486, 200 mg spironolactone + 400 mg RU38486, or placebo orally. Serum cortisol levels after drug or placebo were measured. Cortisol levels did not differ between lean and obese after placebo. Spironolactone and RU38486 alone had modest effects, increasing cortisol by less than 50% in both groups. However, combined spironolactone plus RU38486 elevated cortisol concentrations substantially, more so in lean than obese men [2.9- (0.3) vs. 2.2 (0.3)-fold elevation, P = 0.002]. Combined receptor antagonist stimulation of the HPA axis reveals redundancy of MR and GR in negative feedback in humans. Obese men have impaired responses to combined receptor antagonist stimulation, suggesting impaired negative feedback by endogenous cortisol. Such an approach may be useful to dissect abnormal HPA axis control in neuropsychiatric and other disorders.
The effect of regularity of exposure to two different chronic stressors (noise or immobilization (IMO)) on the pattern of habituation of pituitary-adrenal (PA) hormones, prolactin and glucose was evaluated in adult male rats. Animals were chronically subjected to either regular or irregular time schedule of noise (30 min/day) or IMO (2 h/day) for two weeks. The day after the last stress session the rats were killed without stress or after having been subjected to 30 min of the homotypic stressor. Whereas regular noise did not affect food intake, body weight gain or adrenal weight, irregular noise decreased body weight gain and induced a moderate adrenal hypertrophy. In addition, previous daily exposure to regular but not to irregular noise reduced both prolactin and corticosterone responses to acute noise. In contrast, glucose response to acute noise was reduced after both regular and irregular exposure to chronic noise. Either regular or irregular exposure to chronic IMO decreased food intake and body weight and increased adrenal weight to the same extent. Likewise, no influence of regularity of exposure to chronic IMO on corticosterone and prolactin responses to acute IMO was observed. However, habituation of the ACTH response to acute IMO was observed in rats subjected to chronic regular IMO, but not in rats subjected to chronic irregular IMO. Finally, acute IMO-induced hyperglycemia diminished to the same extent after regular and irregular IMO. From these results we can conclude that: first, the process of habituation of the PA axis to chronic stress is greatly dependent upon factors such as regularity of exposure to the stressor and stressor intensity, and second, the influence of regularity on the pattern of habituation to a repeated stressor is dependent on the physiological variable we are dealing with.
Zimmer, C; Spencer, K A
Stress exposure during early-life development can programme individual brain and physiology. The hypothalamic-pituitary-adrenal (HPA) axis is one of the primary targets of this programming, which is generally associated with a hyperactive HPA axis, indicative of a reduced negative-feedback. This reduced feedback efficiency usually results from a reduced level of the glucocorticoid receptor (GR) and/or the mineralocorticoid receptor (MR) within the HPA axis. However, a few studies have shown that early-life stress exposure results in an attenuated physiological stress response, suggesting an enhance feedback efficiency. In the present study, we aimed to determine whether early-life stress had long-term consequences on GR and MR levels in quail and whether the effects on the physiological response to acute stress observed in prenatally stressed individuals were underpinned by changes in GR and/or MR levels in one or more HPA axis components. We determined GR and MR mRNA expression in the hippocampus, hypothalamus and pituitary gland in quail exposed to elevated corticosterone during prenatal development, postnatal development, or both, and in control individuals exposed to none of the stressors. We showed that prenatal stress increased the GR:MR ratio in the hippocampus, GR and MR expression in the hypothalamus and GR expression in the pituitary gland. Postnatal stress resulted in a reduced MR expression in the hippocampus. Both early-life treatments permanently affected the expression of both receptor types in HPA axis regions. The effects of prenatal stress are in accordance with a more efficient negative-feedback within the HPA axis and thus can explain the attenuated stress response observed in these birds. Therefore, these changes in receptor density or number as a consequence of early-life stress exposure might be the mechanism that allows an adaptive response to later-life stressful conditions. © 2014 The Authors. Journal of Neuroendocrinology published by
Gartstein, Maria A; Seamon, Erich; Thompson, Stephanie F; Lengua, Liliana J
Identification of early risk factors related to obesity is critical to preventative public health efforts. In this study, we investigated links between the Hypothalamic-Pituitary-Adrenal (HPA)-axis activity (diurnal cortisol pattern), geospatially operationalized exposure to neighborhood crime, and body mass index (BMI) for a sample of 5-year-old children. Greater community crime exposure and lower HPA-axis activity were hypothesized to contribute to higher BMI, with child HPA-axis moderating the association between crime exposure and BMI. Families residing within the boundaries of the City of Seattle (N = 114) provided information concerning demographic/psychosocial risk factors, used to calculate a Cumulative Risk Index, indicating the number of contextual adversities present. Child BMI and diurnal cortisol pattern (derived from assays of saliva samples) were examined, along with neighborhood crime indices computed with publically available information, based on participants' locations. Hierarchical multiple regression analyses, adjusted for covariates (cumulative risk, age, and sex), indicated that crime proximity made a unique contribution to child BMI, in the direction signaling an increase in the risk for obesity. Consistent with our hypothesis, a significant interaction was observed, indicative of moderation by diurnal cortisol pattern. Follow-up simple slope analyses demonstrated that crime exposure was significantly related to higher BMI for children with low-flat (blunted) diurnal cortisol patterns, where community crime and BMI were not significantly associated at higher levels of cortisol. Community crime exposure contributes to higher BMI as early as the preschool period, and blunted diurnal cortisol patterns may place children experiencing neighborhood adversity at greater risk for obesity.
Flanagan, Shawn D; DuPont, William H; Caldwell, Lydia K; Hardesty, Vincent H; Barnhart, Emily C; Beeler, Matthew K; Post, Emily M; Volek, Jeff S; Kraemer, William J
The effect of GINST15, an enzyme fermented ginseng supplement, on hormonal and inflammatory responses to physical stress in humans is unknown. The purpose of this investigation was to examine the constitutive and stress-induced effects of GINST15 supplement on hypo-pituitary-adrenal (HPA) and antioxidant activity in addition to muscle damage. Ten women (age: 38.7 ± 7.8 years; height: 163.81 ± 4.4 cm; body mass 76.0 ± 11.6 kg) and nine men (age: 41.2. ± 9.7 years; height: 177.4 ± 5.3 cm; body mass: 88.5 ± 5.0 kg) participated in a double-blinded, placebo-controlled, counterbalanced within-group study. Participants completed three 14-day treatment cycles with different doses (high: 960 mg; low: 160 mg; placebo: 0 mg) separated by a 1-week washout period. At the end of treatment, physical stress was imposed with intense resistance exercise work stress. Participants provided blood at rest and various time points after exercise (immediately [IP], 30 min , 60 min , 24 h [+24HR]). Cortisol (CORT), superoxide dismutase (SOD), total glutathione, nonspecific antioxidant activity, total antioxidant power (TAP), and creatine kinase were measured. GINST15 supplementation produced stress-inducible dose-dependent reductions in circulating cortisol and increased enzymatic and nonspecific antioxidant activity. Twenty-four hours after intense exercise, a high dose GINST15, a bioactive ginsenoside metabolite, significantly reduces muscle damage and HPA responses to physical stress in humans; these effects may result from increased antioxidant expression.
Diamantopoulou, Anastasia; Raftogianni, Androniki; Stamatakis, Antonios; Oitzl, Melly S; Stylianopoulou, Fotini
Emotional behavioral traits associated with stress response are well documented to be affected by early life events. In the present work, we used a novel paradigm of neonatal experience, in which pups were trained in a T-maze and either received (RER rats) or were denied (DER) the reward of maternal contact, during postnatal days 10-13. We then evaluated stress coping and key factors controlling the function of the hypothalamic-pituitary-adrenal axis in adulthood. Adult male DER rats exposed to a single session of forced swim stress (FSS) showed increased immobility, while RER rats exhibited increased escape attempts. The corticosterone response following this stressor was higher although not prolonged in the DER rats. Their CRH mRNA levels in the PVN were increased up to 2h after the forced swim. However, basal levels of these hormones did not differ among groups. In addition, the DER neonatal experience induced an increase in hippocampal GR but a decrease in CRH-R1 immunopositive cells in the CA1 area of the hippocampus and the central amygdala. Overall, these data show a distinct stress response profile in the DER male rats, characterized by passive coping during the forced swim, increased hormonal response following stress, increased inhibitory control through GR and an indirect contribution of CRH-R1, the latter two factors resulting in a modified regulation of the response termination. It thus appears that DER rats have an enhanced potential for appropriate reactivity upon an incoming challenge, while maintaining in parallel an adequate control of the duration of their stress responses. Copyright © 2012 Elsevier Ltd. All rights reserved.
Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic-pituitary-adrenal axis activation.
Reynolds, Anna R; Saunders, Meredith A; Brewton, Honoree' W; Winchester, Sydney R; Elgumati, Ibrahim S; Prendergast, Mark A
The development of ethanol dependence is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis and activation of type II glucocorticoid receptors (GR). These effects may contribute to withdrawal-associated anxiety, craving and relapse to drinking. The present studies examined acute and oral administration of the novel, selective and competitive GR antagonist ORG 34517 on the severity of ethanol withdrawal. Adult, male Sprague-Dawley rats were administered ethanol (4g/kg/i.g.) twice daily for 5 days followed by 2 days of withdrawal for 1, 2 or 3 consecutive cycles. Blood ethanol levels (BELs) were determined at 0930 on Day 4 of each week, while blood corticosterone levels (BCLs) were obtained at 11:00hours on the first day of each ethanol withdrawal. During early withdrawal, subjects received oral administration of ORG 345617 (60mg/kg/i.g.) or a placebo and withdrawal was monitored. Peak BELs of 225.52mg/dl were observed during the third week. Withdrawal from three cycles of the regimen produced marked behavioral abnormalities (e.g., aggression, rigidity, and hypoactivity) and significant increases in BCLs of ethanol-dependent subjects. Acute, oral administration of ORG 34517 during early withdrawal significantly reduced both the severity of ethanol withdrawal, as reflected in reduced rigidity, aggression, and hypoactivity, and elevations in BCL without producing any sedative-like effects. The present findings demonstrate that repeated ethanol exposure and withdrawal is associated with significant behavioral abnormalities and dysregulation of HPA axis activation. Further these data suggest that selective GR antagonists should be further considered as putative pharmacotherapies for treatment of ethanol dependence. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Márquez, Cristina; Nadal, Roser; Armario, Antonio
Susceptibility to some stress-induced pathologies may be strongly related to individual differences in the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to stressors. However, there have been few attempts in rodents to study the reliability of the individual differences in the responsiveness of the HPA to stressors and the relationship to resting corticosterone levels. In the present work, we used a normal population of Sprague-Dawley rats, with a within-subject design. Our objectives were to study: (a) the reliability of the ACTH and corticosterone response to three different novel environments widely used in psychopharmacology and (b) the relationship between stress levels of HPA hormones and the daily pattern of corticosterone secretion (six samples over a 24-h-period). Animals were repeatedly sampled using tail-nick procedure. The novel environments were the elevated plus-maze, the hole-board and the circular corridor. Animals were sampled just after 15 min exposure to the tests and again at 15 and 30 min after the termination of exposure to them (post-tests). The hormonal levels just after the tests indicate that the hole-board seems to be more stressful than the circular corridor and the elevated plus-maze, the latter being characterized by the lowest defecation rate. Correlational analysis revealed that daily pattern of resting plasma corticosterone levels did not correlate to HPA responsiveness to the tests, suggesting no relationship between resting and stress levels of HPA hormones. In contrast, the present study demonstrates, for the first time, a good within-subject reliability of the ACTH and corticosterone responses to the three environments, suggesting that HPA responsiveness to these kind of stressors is a consistent individual trait in adult rats, despite differences in the physical characteristics of the novel environments.
Rabasa, Cristina; Pastor-Ciurana, Jordi; Delgado-Morales, Raúl; Gómez-Román, Almudena; Carrasco, Javier; Gagliano, Humberto; García-Gutiérrez, María S; Manzanares, Jorge; Armario, Antonio
There is evidence that endogenous cannabinoids (eCBs) play a role in the control of the hypothalamic-pituitary-adrenal (HPA) axis, although they appear to have dual, stimulatory and inhibitory, effects. Recent data in rats suggest that eCBs, acting through CB1 receptors (CB1R), may be involved in adaptation of the HPA axis to daily repeated stress. In the present study we analyze this issue in male mice and rats. Using a knock-out mice for the CB1 receptor (CB1-/-) we showed that mutant mice presented similar adrenocorticotropic hormone (ACTH) response to the first IMO as wild-type mice. Daily repeated exposure to 1h of immobilization reduced the ACTH response to the stressor, regardless of the genotype, demonstrating that adaptation occurred to the same extent in absence of CB1R. Prototypical changes observed after repeated stress such as enhanced corticotropin releasing factor (CRH) gene expression in the paraventricular nucleus of the hypothalamus, impaired body weight gain and reduced thymus weight were similarly observed in both genotypes. The lack of effect of CB1R in the expression of HPA adaptation to another similar stressor (restraint) was confirmed in wild-type CD1 mice by the lack of effect of the CB1R antagonist AM251 just before the last exposure to stress. Finally, the latter drug did not blunt the HPA, glucose and behavioral adaptation to daily repeated forced swim in rats. Thus, the present results indicate that CB1R is not critical for overall effects of daily repeated stress or proper adaptation of the HPA axis in mice and rats. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
Belda, Xavier; Márquez, Cristina; Armario, Antonio
We have previously observed that a single exposure to immobilization (IMO), a severe stressor, caused long-term (days to weeks) desensitization of the response of the hypothalamic-pituitary-adrenal (HPA) axis to the homotypic stressor, with no changes in behavioral reactivity to novel environments. In contrast, other laboratories have reported that a single exposure to footshock induced a long-term sensitization of both HPA and behavioral responses to novel environments. To test whether these apparent discrepancies can be explained by the use of different stressors or different strains of rats, we studied in the present work the long-term effects of a single exposure to two different stressors (footshock or IMO) in two different strains of rats (Sprague-Dawley from Iffa-Credo and Wistar rats from Harlan). We found that both strains showed desensitization of the HPA response to the same (homotypic) stressor after a previous exposure to either shock or IMO. The long-term effects were higher after IMO than shock. No major changes in behavior in two novel environments (circular corridor, CC and elevated plus-maze, EPM) were observed after a single exposure to shock or IMO in neither strain, despite the fact that shocked rats showed a conditioned freezing response to the shock boxes. The present results demonstrate that long-term stress-induced desensitization of the HPA axis is a reliable phenomenon that can be observed with different stressors and strains. However, only behavioral changes related to shock-induced conditioned fear were found, which suggests that so far poorly characterized factors are determining the long-term behavioral consequences of a single exposure to stress.
Gagliano, Humberto; Ortega-Sanchez, Juan Antonio; Nadal, Roser; Armario, Antonio
We recently reported that simultaneous exposure to amphetamine and various stressors resulted in reduced hypothalamic-pituitary-adrenal (HPA) and glycemic responses to the stressors. Since this is a new and relevant phenomenon, we wanted to further explore this interaction. This study aims (i) to characterize the effect of various doses of amphetamine on the physiological response to a predominantly emotional stressor (forced swim) when the drug was given immediately before stress; (ii) to study if an interaction appears when the drug was given 30 min or 7 days before swim; and (iii) to know whether cocaine causes similar effects when given just before stress. Adult male rats were used and plasma levels of ACTH, corticosterone, and glucose were the outcomes. Amphetamine caused a dose-dependent activation of the HPA axis, but all doses reduced HPA and glycemic responses to swim when given just before the stressor. Importantly, during the post-swim period, the stressor potently inhibited the ACTH response to amphetamine, demonstrating mutual inhibition between the two stimuli. The highest dose of amphetamine also reduced the response to swim when given 30 min before stress, whereas it caused HPA sensitization when given 7 days before. Cocaine also reduced stress-induced HPA activation when given just before swim. The present results demonstrate a negative synergy between psychostimulants (amphetamine and cocaine) and stress regarding HPA and glucose responses when rats were exposed simultaneously to both stimuli. The inhibitory effect of amphetamine is also observed when given shortly before stress, but not some days before.
Belda, Xavier; Daviu, Núria; Nadal, Roser; Armario, Antonio
A single exposure to some severe stressors causes sensitization of the hypothalamic-pituitary-adrenal (HPA) response to novel stressors. However, the putative factors involved in stress-induced sensitization are not known. In the present work we studied in adult male rats the possible role of glucocorticoids and CRH type 1 receptor (CRH-R1), using an inhibitor of glucocorticoid synthesis (metyrapone, MET), the glucocorticoid receptor (GR) antagonist RU38486 (mifepristone) and the non-peptide CRH-R1 antagonist R121919. In a first experiment we demonstrated with different doses of MET (40-150 mg/kg) that the highest dose acted as a pharmacological stressor greatly increasing ACTH release and altering the normal circadian pattern of HPA hormones, but no dose affected ACTH responsiveness to a novel environment as assessed 3 days after drug administration. In a second experiment, we found that MET, at a dose (75 mg/kg) that blocked the corticosterone response to immobilization (IMO), did not alter IMO-induced ACTH sensitization. Finally, neither the GR nor the CRH-R1 antagonists blocked IMO-induced ACTH sensitization on the day after IMO. Thus, a high dose of MET, in contrast to IMO, was unable to sensitize the HPA response to a novel environment despite the huge activation of the HPA axis caused by the drug. Neither a moderate dose of MET that markedly reduced corticosterone response to IMO, nor the blockade of GR or CRH-R1 receptors was able to alter stress-induced HPA sensitization. Therefore, stress-induced sensitization is not the mere consequence of a marked HPA activation and does not involve activation of glucocorticoid or CRH-R1 receptors. Copyright © 2012 Elsevier Inc. All rights reserved.
Rabasa, Cristina; Delgado-Morales, Raúl; Gómez-Román, Almudena; Nadal, Roser; Armario, Antonio
Comparison of exposure to certain predominantly emotional stressors reveals a qualitatively similar neuroendocrine response profile as well as a reduction of physiological responses after daily repeated exposure (adaptation). However, particular physical components of the stressor may interfere with adaptation. As defective adaptation to stress can enhance the probability to develop pathologies, we studied in adult male rats (n = 10/group) swimming behavior (struggling, immobility and mild swim) and physiological responses (ACTH, corticosterone and rectal temperature) to daily repeated exposure to forced swim (20 min, 13 d) at 25 or 36 °C (swim25 or swim36). Rats were repeatedly blood-sampled by tail-nick and hormones measured by radioimmunoassay. Some differences were observed between the two swim temperature groups after the first exposure to forced swim: (a) active behaviors were greater in swim25 than swim36 groups; (b) swim25 but not swim36 caused hypothermia; and (c) swim36 elicited the same ACTH response as swim25, but plasma corticosterone concentration was lower for swim36 at 30 min post-swim. After daily repeated exposure, adaptation in ACTH secretion was observed with swim36 already on day 4, whereas with swim25 adaptation was not observed until day 13 and was of lower magnitude. Nevertheless, after repeated exposure to swim25 a partial protection from hypothermia was observed and the two swim conditions resulted in progressive reduction of active behaviors. Thus, daily repeated swim at 25 °C impairs adaptation of the hypothalamic-pituitary-adrenal axis as compared to swim at 36 °C, supporting the hypothesis that certain physical components of predominantly emotional stressors can interfere with the process of adaptation.
Kapoor, Amita; Matthews, Stephen G
Prenatal stress is associated with altered behavior and hypothalamic-pituitary-adrenal (HPA) axis function postnatally. Recent studies suggest that these outcomes are dependent on the timing of the prenatal stress. The majority of these studies have been carried out in male offspring. We hypothesized that a short period of prenatal stress would result in female offspring that exhibit differences in open-field behavior and HPA axis activity, but the outcome would depend on the timing of the prenatal stress and the stage of the reproductive cycle. Pregnant guinea pigs were exposed to a strobe light during the fetal brain growth spurt [gestational d 50-52 (PS50)] or during the period of rapid brain myelination [gestational d 60-62 (PS60)]. Open-field activity was assessed in juvenile and adult female offspring. HPA axis function was tested in adult offspring. All tests in adulthood were carried out during the estrous and luteal phases of the reproductive cycle to determine the effect of stage on HPA axis programming. Tissues were collected upon completion of the study for analysis by in situ hybridization. PS60 offspring exhibited decreased activity in an open field during the estrous phase of the reproductive cycle compared with control offspring. Both PS50 and PS60 offspring exhibited a lower salivary cortisol response to a stressor, only during the estrous phase. Consistent with the behavioral and endocrine data, PS60 females exhibited lower plasma estradiol levels, reduced ovary weight, and increased glucocorticoid receptor mRNA in the paraventricular nucleus. In conclusion, we have demonstrated that there are effects of prenatal stress on behavior and HPA axis functioning in female offspring but that the outcomes are dependent on the timing of the prenatal stress together with the status of the reproductive cycle.
Xu, D; Wu, Y; Liu, F; Liu, Y S; Shen, L; Lei, Y Y; Liu, J; Ping, J; Qin, J; Zhang, C; Chen, L B; Magdalou, J; Wang, H
Caffeine is a definite factor of intrauterine growth retardation (IUGR). Previously, we have confirmed that prenatal caffeine ingestion inhibits the development of hypothalamic-pituitary-adrenal (HPA) axis, and alters the glucose and lipid metabolism in IUGR fetal rats. In this study, we aimed to verify a programmed alteration of neuroendocrine metabolism in prenatal caffeine ingested-offspring rats. The results showed that prenatal caffeine (120 mg/kg.day) ingestion caused low body weight and high IUGR rate of pups; the concentrations of blood adrenocorticotropic hormone (ACTH) and corticosterone in caffeine group were significantly increased in the early postnatal period followed by falling in late stage; the level of blood glucose was unchanged, while blood total cholesterol (TCH) and triglyceride (TG) were markedly enhanced in adult. After chronic stress, the concentrations and the gain rates of blood ACTH and corticosterone were obviously increased, meanwhile, the blood glucose increased while the TCH and TG decreased in caffeine group. Further, the hippocampal mineralocorticoid receptor (MR) expression in caffeine group was initially decreased and subsequently increased after birth. After chronic stress, the 11β-hydroxysteroid dehydrogenase-1, glucocorticoid receptor (GR), MR as well as the MR/GR ratio were all significantly decreased. These results suggested that prenatal caffeine ingestion induced the dysfunction of HPA axis and associated neuroendocrine metabolic programmed alteration in IUGR offspring rats, which might be related with the functional injury of hippocampus. These observations provide a valuable experimental basis for explaining the susceptibility of IUGR offspring to metabolic syndrome and associated diseases. Copyright © 2012 Elsevier Inc. All rights reserved.
Zhang, W; Li, Q; Deyssenroth, M; Lambertini, L; Finik, J; Ham, J; Huang, Y; Tsuchiya, K J; Pehme, P; Buthmann, J; Yoshida, S; Chen, J; Nomura, Y
Prenatal maternal stress increases the risk for negative developmental outcomes in offspring; however, the underlying biological mechanisms remain largely unexplored. In the present study, alterations in placental gene expression associated with maternal stress were examined to clarify the potential underlying epi/genetic mechanisms. Expression levels of 40 selected genes involved in regulating foetal hypothalamic-pituitary-adrenal axis and neurodevelopment were profiled in placental tissues collected from a birth cohort established around the time of Superstorm Sandy. Objective prenatal traumatic stress was defined as whether mothers were exposed to Superstorm Sandy during pregnancy. Among the 275 mother-infant dyads, 181 dyads were delivered before Superstorm Sandy (ie, Control), 66 dyads were exposed to Superstorm Sandy during the first trimester (ie, Early Exposure) and 28 were exposed to Superstorm Sandy during the second or third trimester (ie, Mid-Late Exposure). Across all trimesters, expression of HSD11B2, MAOA, ZNF507 and DYRK1A was down-regulated among those exposed to Superstorm Sandy during pregnancy. Furthermore, trimester-specific differences were also observed: exposure during early gestation was associated with down-regulation of HSD11B1 and MAOB and up-regulation of CRHBP; exposure during mid-late gestation was associated with up-regulation of SRD5A3. The findings of the present study suggest that placental gene expression may be altered in response to traumatic stress exposure during pregnancy, and the susceptibility of these genes is dependent on the time of the exposure during pregnancy. Further studies should aim to clarify the biological mechanisms that underlie trimester-specific exposure by evaluating the differential impact on offspring neurodevelopment later in childhood. © 2018 British Society for Neuroendocrinology.
Johnson, Elizabeth O; Calogero, Aldo E; Konstandi, Maria; Kamilaris, Themis C; La Vignera, Sandro; Vignera, Sandro La; Chrousos, George P
Hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally responsible for the hypercorticosteronism remains unclear. The purpose of this study was to assess the effects of hyperthyroidism on the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis, to identify the locus in the HPA axis that is principally affected, and address the time-dependent effects of alterations in thyroid status. The functional integrity of each component of the HPA axis was examined in vitro and in situ in sham-thyroidectomized male Sprague-Dawley rats given placebo or in thyroidectomized rats given pharmacological dose (50 μg) of thyroxin for 7 or 60 days. Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days. Basal plasma ACTH levels were similar to controls. Both hypothalamic CRH content and the magnitude of KCL- and arginine vasopressin (AVP)-induced CRH release from hypothalamic culture were increased in long-term hyperthyroid rats. There was a significant increase in the content of both ACTH and β-endorphin in the anterior pituitaries of both short- and long-term hyperthyroid animals. Short-term hyperthyroid rats showed a significant increase in basal POMC mRNA expression in the anterior pituitary, and chronically hyperthyroid animals showed increased stress-induced POMC mRNA expression. Adrenal cultures taken from short-term hyperthyroid rats responded to exogenous ACTH with an exaggerated corticosterone response, while those taken from 60-day hyperthyroid animals showed responses similar to controls. The findings show that hyperthyroidism is associated with hypercorticosteronemia and HPA axis dysfunction that becomes more pronounced as the duration of hyperthyroidism increases. The evidence suggests that experimentally induced hyperthyroidism is associated with central hyperactivity of the HPA axis.
Tirabassi, G; Chelli, F M; Ciommi, M; Lenzi, A; Balercia, G
Functional hypercortisolism (FH) is generated by clinical states able to chronically activate the hypothalamic-pituitary-adrenal (HPA) axis [e.g. diabetes mellitus (DM)]. No study has evaluated FH influence in worsening the metabolic profile of male patients affected by DM-associated hypogonadism. In this retrospective work, we assess the possible association between HPA axis-dysregulation and cardiovascular risk factors in men simultaneously affected by DM and late-onset hypogonadism (LOH). Fourteen DM and LOH subjects affected by FH (Hypercort-DM-LOH) and fourteen DM and LOH subjects who were not suffering from FH (Normocort-DM-LOH) were retrospectively considered. Clinical, hormonal and metabolic parameters were retrieved. All metabolic parameters, except for systolic blood pressure, were significantly worse in Hypercort-DM-LOH than in Normocort-DM-LOH. After adjustment for body mass index, waist and total testosterone, Hypercort-DM-LOH subjects showed significantly worse metabolic parameters than Normocort-DM-LOH ones. In Normocort-DM-LOH, no significant correlation between general/hormonal parameters and metabolic variables was present. In Hypercort-DM-LOH, positive and significant correlations of cortisol area under the curve (AUC) after corticotropin releasing hormone with glycemia, triglycerides and blood pressure were evident; on the other hand, negative and significant correlation was present between cortisol AUC and high density lipoprotein (HDL) cholesterol. The associations of AUC cortisol with glycemia, HDL cholesterol and diastolic blood pressure (DBP) were further confirmed at quantile regression after adjustment for therapy. FH may determine a worsening of the metabolic profile in DM-associated hypogonadism. Copyright © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by
Calhoun, Casey D.; Hastings, Paul D.; Rudolph, Karen D.; Nock, Matthew K.; Prinstein, Mitchell J.
Adopting a multi-level approach, this study examined risk factors for adolescent suicidal ideation, with specific attention to (a) hypothalamic-pituitary-adrenal (HPA) axis stress responses and (b) the interplay between HPA-axis and other risk factors from multiple domains (i.e., psychological, interpersonal and biological). Participants were 138 adolescent females (Mage=14.13 years, SD=1.40) at risk for suicidal behaviors. At baseline, lifetime suicidal ideation and a number of risk factors were assessed (i.e., depressive symptoms, impulsiveness, pubertal status and peer stress). Participants were exposed to a psychosocial stress task and HPA-axis responses were assessed by measuring cortisol levels pre- and post-stressor. At 3 months post-baseline, suicidal ideation again was assessed. Using group-based trajectory modeling, three groups of cortisol stress-response patterns were identified (i.e., hyporesponsive, normative, and hyperresponsive). As compared to females in the normative and hyporesponsive group, females in the hyperresponsive group were more likely to report a lifetime history of suicidal ideation at baseline, above and beyond the effects of the other predictors. Moreover, as compared to females in the normative group, females in the hyperresponsive group were at increased risk for reporting suicidal ideation 3 months later, after controlling for prior ideation. No interactions between cortisol group and the other risk factors were significant, with the exception of a non-significant trend between impulsiveness and cortisol group on lifetime suicidal ideation. Findings highlight the importance of HPA-axis responses to acute stressors as a risk factor for suicidal ideation among adolescents. PMID:24958308
Goncharova, Nadezhda D; Oganyan, Tamara E
Aging is characterized by disturbances in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, associated with disturbances in the adaptation processes and increase of the probability of the onset of post-stress syndrome. However, the individual features of age-related disorders stress reactivity of HPA axis have not been studied. The purpose was to study individual characteristics of the HPA axis responsiveness to acute psycho-emotional stress exposure (restraint, ASE) at different age periods on the model of the young adult and old physically healthy female rhesus monkeys that differ in their behavioral responses to stress, i.e., with depression-like and anxiety-like behavior (DAB) on the one hand and healthy standard (control) adaptive behavior (SB) on the other hand. No significant intergroup differences were observed in HPA axis responses to ASE in young animals. During aging the monkeys with SB showed reduced ACTH response to the ASE, whereas the monkeys with DAB demonstrated its increase. The old animals with DAB in response to ASE demonstrated the most pronounced HPA axis disorders, such as the highest levels of corticotrophin (ACTH), the lowest levels of dehydroepiandrosterone sulfate (DHEAS), reduced cortisol (F) levels and the highest values of the F/DHEAS molar ratio. The ratio F/DHEAS positively correlates with the malondialdehyde concentration in erythrocytes that is considered as the biomarker of oxidative stress. Thus, these data allow us to consider the old monkeys with DAB as individuals with higher vulnerability to the adverse effects of ASE. In addition, depression-like and anxiety-like behavior of aged primates under mild/moderate stress along with reduced DHEAS plasma concentration and increased values of F/DHEAS ratio can be used to identify individuals with increased vulnerability to ASE and accelerated aging. Copyright © 2017 Elsevier Inc. All rights reserved.
Liu, Yulan; Chen, Feng; Li, Quan; Odle, Jack; Lin, Xi; Zhu, Huiling; Pi, Dingan; Hou, Yongqing; Hong, Yu; Shi, Haifeng
Long-chain n-3 (ω-3) polyunsaturated fatty acids exert beneficial effects in neuroendocrine dysfunctions in animal models and clinical trials. However, the mechanism(s) underlying the beneficial effects remains to be elucidated. We hypothesized that dietary treatment with fish oil (FO) could mitigate LPS-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis through inhibition of Toll-like receptor 4 and nucleotide-binding oligomerization domain protein signaling pathways. Twenty-four weaned pigs were used in a 2 × 2 factorial design, and the main factors consisted of diet (5% corn oil vs. 5% FO) and immunological challenge (saline vs. LPS). After 21 d of dietary treatment with 5% corn oil or FO diets, pigs were treated with saline or LPS. Blood samples were collected at 0 (preinjection), 2, and 4 h postinjection, and then pigs were humanely killed by intravenous injection of 40 mg/kg body weight sodium pentobarbital for tissue sample collection. FO led to enrichment of eicosapentaenoic acid and docosahexaenoic acid and total n-3 polyunsaturated fatty acids in hypothalamus, pituitary gland, adrenal gland, spleen, and thymus. FO decreased plasma adrenocorticotrophin and cortisol concentrations as well as mRNA expressions of hypothalamic corticotropin releasing hormone and pituitary proopiomelanocortin. FO also reduced mRNA expression of tumor necrosis factor-α in hypothalamus, adrenal gland, spleen, and thymus, and of cyclooxygenase 2 in hypothalamus. Moreover, FO downregulated the mRNA expressions of Toll-like receptor 4 (TLR4) and its downstream molecules, including cluster differentiation factor 14, myeloid differentiation factor 2, myeloid differentiation factor 88, interleukin-1 receptor-associated kinase 1, tumor necrosis factor-α receptor-associated factor 6, and nuclear factor kappa-light-chain-enhancer of activated B cells p65, and also decreased the mRNA expressions of nucleotide-binding oligomerization domain 1, nucleotide
Surapaneni, Dinesh Kumar; Adapa, Sree Rama Shiva Shanker; Preeti, Kumari; Teja, Gangineni Ravi; Veeraragavan, Muruganandam; Krishnamurthy, Sairam
Shilajit has been used as a rejuvenator for ages in Indian ancient traditional medicine and has been validated for a number of pharmacological activities. The effect of processed shilajit which was standardized to dibenzo-α-pyrones (DBPs;0.43% w/w), DBP-chromoproteins (DCPs; 20.45% w/w) and fulvic acids (56.75% w/w) was evaluated in a rat model of chronic fatigue syndrome (CFS). The mitochondrial bioenergetics and the activity of hypothalamus-pituitary-adrenal (HPA) axis were evaluated for the plausible mechanism of action of shilajit. CFS was induced by forcing the rats to swim for 15mins for 21 consecutive days. The rats were treated with shilajit (25, 50 and 100mg/kg) for 21 days before exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility and the climbing period. The post-CFS anxiety level was assessed by elevated plus maze (EPM) test. Plasma corticosterone and adrenal gland weight were estimated as indices of HPA axis activity. Analysis of mitochondrial complex chain enzymes (Complex I, II, IV and V) and mitochondrial membrane potential (MMP) in prefrontal cortex (PFC) were performed to evaluate the mitochondrial bioenergetics and integrity respectively. Shilajit reversed the CFS-induced increase in immobility period and decrease in climbing behavior as well as attenuated anxiety in the EPM test. Shilajit reversed CFS-induced decrease in plasma corticosterone level and loss of adrenal gland weight indicating modulation of HPA axis. Shilajit prevented CFS-induced mitochondrial dysfunction by stabilizing the complex enzyme activities and the loss of MMP. Shilajit reversed CFS-induced mitochondrial oxidative stress in terms of NO concentration and, LPO, SOD and catalase activities. The results indicate that shilajit mitigates the effects of CFS in this model possibly through the modulation of HPA axis and preservation of mitochondrial function and integrity. The reversal of CFS-induced behavioral symptoms and
Romero, L Michael; Wikelski, Martin
Temporal modulation of the stress response is a ubiquitous characteristic of animals. Here, we investigate possible mechanisms underlying daily changes in corticosterone release in an ectotherm model system. Earlier work indicated that free-living Galápagos marine iguanas (Amblyrhynchus cristatus) have lower corticosterone concentrations during the night than during the day. This could result from: (i) a lower circadian secretion of adrenocorticotropic hormone (ACTH) as seen in mammals; (ii) from an increase in corticosterone negative feedback; or (iii) reflect lower metabolic activity during the night when core body temperature falls (from 35 degrees C during the day to as low as 21 degrees C during the night). To begin to distinguish between these three possibilities, exogenous ACTH was used to compare diel differences in adrenocortical tissue responsiveness, and dexamethasone was used to compare diel differences in the efficacy of corticosterone negative feedback. Low levels of exogenous ACTH (30 IU/kg body weight) potently stimulated both daytime and nighttime corticosterone release. Dexamethasone (1 mg/kg) inhibited only daytime, but not nighttime endogenous corticosterone release. Because the response to ACTH was similar between day and night we suggest that a simple lowering of core body temperature cannot explain the nighttime reduction in corticosterone release. However, the failure of negative feedback at night suggests that the response is not equivalent to the controlled downregulation seen in mammals.
Full Text Available The release of adrenocorticotropin (ACTH from the corticotrophs is controlled principally by vasopressin and corticotropin-releasing hormone (CRH. Oxytocin may augment the release of ACTH under certain conditions, whereas atrial natriuretic peptide acts as a corticotropin release-inhibiting factor to inhibit ACTH release by direct action on the pituitary. Glucocorticoids act on their receptors within the hypothalamus and anterior pituitary gland to suppress the release of vasopressin and CRH and the release of ACTH in response to these neuropeptides. CRH neurons in the paraventricular nucleus also project to the cerebral cortex and subcortical regions and to the locus ceruleus (LC in the brain stem. Cortical influences via the limbic system and possibly the LC augment CRH release during emotional stress, whereas peripheral input by pain and other sensory impulses to the LC causes stimulation of the noradrenergic neurons located there that project their axons to the CRH neurons stimulating them by alpha-adrenergic receptors. A muscarinic cholinergic receptor is interposed between the alpha-receptors and nitric oxidergic interneurons which release nitric oxide that activates CRH release by activation of cyclic guanosine monophosphate, cyclooxygenase, lipoxygenase and epoxygenase. Vasopressin release during stress may be similarly mediated. Vasopressin augments the release of CRH from the hypothalamus and also augments the action of CRH on the pituitary. CRH exerts a positive ultrashort loop feedback to stimulate its own release during stress, possibly by stimulating the LC noradrenergic neurons whose axons project to the paraventricular nucleus to augment the release of CRH.
Martinac, Marko; Babić, Dragan; Bevanda, Milenko; Vasilj, Ivan; Glibo, Danijela Bevanda; Karlović, Dalibor; Jakovljević, Miro
The aim of the present study was to explore the differences in serum CRP, IL-6, TNF-α, ACTH and cortisol among patients with major depressive disorder with or without metabolic syndrome (MS) compared to a healthy control group. The MDD study group consisted of 80 patients (mean age of 50.03±9.55 years). The control group was recruited from the hospital personnel and it consisted of 40 examinees (mean age of 47.20±7.99 years). All patients who participated in the study were diagnosed with depressive disorder using MINI questionnaire, and Hamilton rating scale for depression. Diagnosis of the metabolic syndrome was set by NCEP ATP III criteria. Examinees with depression but without MS had significantly more cortisol concentration when compared to the control group. CRP was significantly higher in the MDD group when compared to the control group and in MDD+MS group when compared to the control group. IL6 serum levels were significantly higher in the MDD group when compared to the healthy control group, and in MDD+MS group when compared to the healthy control group. ACTH had significant independent predictive values for abdominal obesity. Levels of TNF-α were statistically significant independent predictors for hyperglycaemia. Statistically significant predictive values for MDD were found for cortisol, and IL-6. Results shown here emphasise the importance of neuroendocrine and inflammatory factors in pathogenesis of depressive disorder and MS. Further prospective research is necessary to clarify possible causal relationship between depression and MS. It is necessary to investigate the possibility of a joint biological mechanism in pathogenesis of these two disorders with the special attention given to the disturbances in the immune system.
Goble, K H; Bain, Z A; Padow, V A; Lui, P; Klein, Z A; Romeo, R D
Pubertal development is marked by profound changes in stress reactivity. For example, following a brief stressor, such as foot shock, ether inhalation or restraint, prepubertal rats display a prolonged adrenocorticotrophic hormone (ACTH) and corticosterone response that takes twice as long to return to baseline compared to adults. Pubertal-related differences in the recovery of the hormonal stress response following a more protracted systemic stressor, such as an immunological challenge, have not yet been investigated. Moreover, it is unclear whether an immunological stressor leads to a differential cytokine response in animals before and after pubertal maturation. To examine these issues, we used a single injection of lipopolysaccharide (LPS; 0.1 mg/kg) to induce a hormonal stress and innate immune response and measured plasma ACTH, corticosterone, and the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 in prepubertal and adult male rats 0, 2, 4, 6, 8, or 24 h after LPS exposure. In a follow-up experiment, we assessed neural activation, as indexed by FOS immunohistochemistry, in the paraventricular nucleus of the hypothalamus (PVN) in prepubertal and adult males 0, 4, 8, or 24 h after a 0.1 mg/kg injection of LPS. By contrast to the prolonged response observed in prepubertal animals following a variety of acute stressors, we found that corticosterone and IL-6 responses induced by LPS recover toward baseline faster in prepubertal compared to adult rats. Along with these different peripheral responses, we also found that LPS-induced neural activation in the PVN of prepubertal animals showed a faster return to baseline compared to adults. Together, these data indicate that prepubertal and adult animals react in distinct ways, both peripherally and centrally, to an immunological stressor. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.
A single ozone exposure causes pulmonary injury and systemic metabolic alterations through neuronal and hypothalamus pituitary adrenal axis activation. Metabolically impaired Goto Kakizaki (GK) rats with non-obese type-2 diabetes are more sensitive to ozone induced changes than h...
Bao, A.-M.; Meynen, G.; Swaab, D.F.
The stress response is mediated by the hypothalamo-pituitary-adrenal (HPA) system. Activity of the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) forms the basis of the activity of the HPA-axis. The CRH neurons induce adrenocorticotropin (ACTH)
Dieleman, G.C.; Huizink, A.C.; Tulen, J.H.M.; Utens, E.M.W.J.; Creemers, H.E.; van der Ende, J.; Verhulst, F.C.
Background: It is of debate whether or not childhood anxiety disorders (AD) can be captured by one taxonomic construct. This study examined whether perceived arousal (PA), autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis measures can distinguish children with different
Dieleman, Gwendolyn C.; Huizink, Anja C.; Tulen, Joke H. M.; Utens, Elisabeth M. W. J.; Creemers, Hanneke E.; van der Ende, Jan; Verhulst, Frank C.
It is of debate whether or not childhood anxiety disorders (AD) can be captured by one taxonomic construct. This study examined whether perceived arousal (PA), autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis measures can distinguish children with different primary
Enhancement of BDNF Concentration and Restoration of the Hypothalamic-Pituitary-Adrenal Axis Accompany Reduced Depressive-Like Behaviour in Stressed Ovariectomised Rats Treated with Either Tualang Honey or Estrogen
Full Text Available A possible interaction between glucocorticoids and estrogen-induced increases in brain-derived-neurotrophic factor (BDNF expression in enhancing depressive-like behaviour has been documented. Here we evaluated the effects of Tualang honey, a phytoestrogen, and 17β-estradiol (E2 on the depressive-like behaviour, stress hormones, and BDNF concentration in stressed ovariectomised (OVX rats. The animals were divided into six groups: (i nonstressed sham-operated control, (ii stressed sham-operated control, (iii nonstressed OVX, (iv stressed OVX, (v stressed OVX treated with E2 (20 μg daily, sc, and (vi stressed OVX treated with Tualang honey (0.2 g/kg body weight daily, orally. Two months after surgery, the animals were subjected to social instability stress procedure followed by forced swimming test. Struggling time, immobility time, and swimming time were scored. Serum adrenocorticotropic hormone (ACTH and corticosterone levels, and the BDNF concentration were determined using commercially available ELISA kits. Stressed OVX rats displayed increased depressive-like behaviour with significantly increased serum ACTH and corticosterone levels, while the BDNF concentration was significantly decreased compared to other experimental groups. These changes were notably reversed by both E2 and Tualang honey. In conclusion, both Tualang honey and E2 mediate antidepressive-like effects in stressed OVX rats, possibly acting via restoration of hypothalamic-pituitary-adrenal axis and enhancement of the BDNF concentration.
Influence of early life stress on later hypothalamic-pituitary-adrenal axis functioning and its covariation with mental health symptoms: a study of the allostatic process from childhood into adolescence.
Essex, Marilyn J; Shirtcliff, Elizabeth A; Burk, Linnea R; Ruttle, Paula L; Klein, Marjorie H; Slattery, Marcia J; Kalin, Ned H; Armstrong, Jeffrey M
The hypothalamic-pituitary-adrenal (HPA) axis is a primary mechanism in the allostatic process through which early life stress (ELS) contributes to disease. Studies of the influence of ELS on children's HPA axis functioning have yielded inconsistent findings. To address this issue, the present study considers multiple types of ELS (maternal depression, paternal depression, and family expressed anger), mental health symptoms, and two components of HPA functioning (traitlike and epoch-specific activity) in a long-term prospective community study of 357 children. ELS was assessed during the infancy and preschool periods; mental health symptoms and cortisol were assessed at child ages 9, 11, 13, and 15 years. A three-level hierarchical linear model addressed questions regarding the influences of ELS on HPA functioning and its covariation with mental health symptoms. ELS influenced traitlike cortisol level and slope, with both hyper- and hypoarousal evident depending on type of ELS. Further, type(s) of ELS influenced covariation of epoch-specific HPA functioning and mental health symptoms, with a tighter coupling of HPA alterations with symptom severity among children exposed previously to ELS. Results highlight the importance of examining multiple types of ELS and dynamic HPA functioning in order to capture the allostatic process unfolding across the transition into adolescence.
Depression is a stress-related disorder, with an often chronic course. Studies into the biology of depression have often focused on a major component of the stress system, the hypothalamic-pituitary-adrenal (HPA) axis, which increases the release of the hormone cortisol upon activation by stress.
Animal models currently represent a viable route for gaining further insights into the mechanisms involved in the pathogenesis of particular diseases. Depression, in this respect, constitutes a major challenge since the characterization of disease-specific traits is complicated due to the multifactorial nature of the disorder. The understanding of diverse factors, e.g. neurotrophic circuits and the role of the HPA axis, which have to be considered in the pathophysiology of the disease represe...
Orexin receptor expression in the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes of free-living European beavers (Castor fiber L.) in different periods of the reproductive cycle.
Czerwinska, Joanna; Chojnowska, Katarzyna; Kaminski, Tadeusz; Bogacka, Iwona; Smolinska, Nina; Kaminska, Barbara
Orexins are hypothalamic neuropeptides acting via two G protein-coupled receptors in mammals: orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). In European beavers, which are seasonally breeding animals, the presence and functions of orexins and their receptors remain unknown. Our study aimed to determine the expression of OXR mRNAs and the localization of OXR proteins in hypothalamic-pituitary-adrenal/gonadal (HPA/HPG) axes in free-living beavers. The expression of OXR genes (OX1R, OX2R) and proteins was found in all analysed tissues during three periods of beavers' reproductive cycle (April, July, November). The expression of OXR mRNAs in the beaver HPA axis varied seasonally (Ppituitary and adrenals, OX1R mRNA levels were relatively constant in females and peaked in July in males (P<0.05), whereas the OX2R was most highly expressed in males in November and in females in April (P<0.05). In gonads, OX1R expression did not fluctuate between seasons or sexes, but transcript levels were elevated in the testes in November and in the ovaries in July (P<0.05). In turn, OX2R mRNA levels varied between the sexes (P<0.05) and were higher in females (July and November) than in males (P<0.05). The circannual variations in OXR mRNA levels in HPA and HPG axes suggest that the expression of these receptors is associated with sex-specific changes in beavers' reproductive activity and their environmental adaptations. Copyright Â© 2016 Elsevier Inc. All rights reserved.
Emotional exhaustion and overcommitment to work are differentially associated with hypothalamus-pituitary-adrenal (HPA) axis responses to a low-dose ACTH1-24 (Synacthen) and dexamethasone-CRH test in healthy school teachers.
Wolfram, Maren; Bellingrath, Silja; Feuerhahn, Nicolas; Kudielka, Brigitte M
Evidence for a detrimental impact of chronic work stress on health has accumulated in epidemiological research. Recent studies indicate altered hypothalamus-pituitary-adrenal (HPA) axis regulation as a possible biological pathway underlying the link between stress and disease. However, the direction of dysregulation remains unclear, with reported HPA hyper- or hyporeactivity. To disentangle potential effects on different functional levels in the HPA axis, we examined responses using two pharmacological stimulation tests in 53 healthy teachers (31 females, 22 males; mean age: 49.3 years; age range: 30-64 years): a low-dose adrenocorticotrophic hormone (ACTH(1-24), Synacthen) test was used to assess adrenal cortex sensitivity and the combined dexamethasone-corticotropin releasing hormone (DEX-CRH) test to examine pituitary and adrenal cortex reactivity. Blood and saliva samples were collected at - 1,+15,+30,+45,+60,+90,+120 min. Emotional exhaustion (EE), the core dimension of burnout, was measured with the Maslach Burnout Inventory. Overcommitment (OC) was assessed according to Siegrist's effort-reward-imbalance model. We found a significant association between EE and higher plasma cortisol profiles after Synacthen (p = 0.045). By contrast, OC was significantly associated with attenuated ACTH (p = 0.045), plasma cortisol (p = 0.005), and salivary cortisol (p = 0.023) concentrations following DEX-CRH. Results support the notion of altered HPA axis regulation in chronically work-stressed teachers, with differential patterns of hyper- and hyporeactivity depending on individual stress condition and the tested functional level of the HPA axis.
Zu, Xianpeng; Zhang, Mingjian; Li, Wencai; Xie, Haisheng; Lin, Zhang; Yang, Niao; Liu, Xinru; Zhang, Weidong
Preliminary studies conducted in our laboratory have confirmed that Bacopaside I (BS-I), a saponin compound isolated from Bacopa monnieri, displayed antidepressant-like activity in the mouse behavioral despair model. The present investigation aimed to verify the antidepressant-like action of BS-I using a mouse model of behavioral deficits induced by chronic unpredictable mild stress (CUMS) and further probe its underlying mechanism of action. Mice were exposed to CUMS for a period of 5 consecutive weeks to induce depression-like behavior. Then, oral gavage administrations with vehicle (model group), fluoxetine (12 mg/kg, positive group) or BS-I (5, 15, 45 mg/kg, treated group) once daily were started during the last two weeks of CUMS procedure. The results showed that BS-I significantly ameliorated CUMS-induced depression-like behaviors in mice, as characterized by an elevated sucrose consumption in the sucrose preference test and reduced immobility time without affecting spontaneous locomotor activity in the forced swimming test, tail suspension test and open field test. It was also found that BS-I treatment reversed the increased level of plasma corticosterone and decreased mRNA and protein expressions of glucocorticoid receptor induced by CUMS exposure, indicating that hypothalamic-pituitary-adrenal (HPA) axis hyperactivity of CUMS-exposed mice was restored by BS-I treatment. Furthermore, chronic administration of BS-I elevated expression levels of brain-derived neurotrophic factor (BDNF) (mRNA and protein) and activated the phosphorylation of extracellular signal-regulated kinase and cAMP response element-binding protein in the hippocampus and prefrontal cortex in mice subjected to CUMS procedure. Taken together, these results indicated that BS-I exhibited an obvious antidepressant-like effect in mouse model of CUMS-induced depression that was mediated, at least in part, by modulating HPA hyperactivity and activating BDNF signaling pathway.
Schmikli, Sándor L; de Vries, Wouter R; Brink, Michel S; Backx, Frank Jg
To verify if in male elite junior soccer players a minimum 1-month performance decrease is accompanied by a mood profile and hormone levels typical of non-functional over-reaching (NFOR). A prospective case-control study using a monthly performance monitor with a standardised field test to detect the performance changes. Players with a performance decrease lasting at least 1 month were compared with control players without a performance decrease on mood scores and pre-exercise and postexercise levels of stress hormones. Sporting field and sports medical laboratory. Ninety-four young elite soccer players were monitored during the 2006-2008 seasons. Twenty-one players were invited to the laboratory, seven of whom showed a significant performance decrease. Performance change over time, scores on the profile of mood states and premaximal and postmaximal exercise serum levels of adrenocorticotropic hormone (ACTH), growth hormone (GH) and cortisol. Players with a performance decrease showed psychological and hormonal changes typical of the non-functional state of over-reaching. Scores were higher on depression and anger, whereas the resting GH levels and ACTH levels after maximal exercise were reduced. ACTH and GH were capable of classifying all but one player correctly as either NFOR or control. Performance-related criteria in field tests are capable of identifying players with worsened mood and adaptations of the endocrine system that fit the definition of NFOR. Performance, mood and hormone levels may therefore be considered as valid instruments to diagnose NFOR in young elite soccer players.
Domes, G; Heinrichs, M; Reichwald, U; Hautzinger, M
According to recent studies, elevated cortisol levels are associated with impaired declarative memory performance. This specific effect of cortisol has been shown in several studies using pharmacological doses of cortisol. The present study was designed to determine the effects of endogenously stimulated cortisol secretion on memory performance in healthy middle-aged women. For psychological stress challenging, we employed the Trier Social Stress Test (TSST). Subjects were assigned to either the TSST or a non-stressful control condition. Declarative and non-declarative memory performance was measured by a combined priming-free-recall-task. No significant group differences were found for memory performance. Post hoc analyses of variance indicated that regardless of experimental condition the subjects with remarkably high cortisol increase in response to the experimental procedure (high responders) showed increased memory performance in the declarative task compared to subjects with low cortisol response (low responders). The results suggest that stress-induced cortisol failed to impair memory performance. The results are discussed with respect to gender-specific effects and modulatory effects of the sympathetic nervous system and psychological variables. Copyright 2002 Elsevier Science Ltd.
Curtò, L; Trimarchi, F
Hypopituitarism is an uncommon and under-investigated endocrine disorder in old age since signs and symptoms are unspecific and, at least in part, can be attributed to the physiological effects of aging and related co-morbidities. Clinical presentation is often insidious being characterized by non-specific manifestations, such as weight gain, fatigue, low muscle strength, bradipsychism, hypotension or intolerance to cold. In these circumstances, hypopituitarism is a rarely life-threatening condition, but evolution may be more dramatic as a result of pituitary apoplexy, or when a serious condition of adrenal insufficiency suddenly occurs. Clinical presentation depends on the effects that each pituitary deficit can cause, and on their mutual relationship, but also, inevitably, it depends on the severity and duration of the deficit itself, as well as on the general condition of the patient. Indeed, indications and methods of hormone replacement therapy must include the need to normalize the endocrine profile without contributing to the worsening of intercurrent diseases, such as those of glucose and bone metabolism, and the cardiovascular system, or to the increasing cancer risk. Hormonal requirements of elderly patients are reduced compared to young adults, but a prompt diagnosis and appropriate treatment of pituitary deficiencies are strongly recommended, also in this age range.
Weik, Ulrike; Kuepper, Yvonne; Hennig, Juergen; Deinzer, Renate
Being socially excluded is associated with a variety of psychological changes and with an increased risk of disease. Today, the immediate physiological consequences of being socially excluded are not well understood. In two recent studies employing a standardized exclusion paradigm (Cyberball) we found social exclusion in this virtual game did not alter cortisol secretion directly. However, exclusion pre-experience suppresses the normal cortisol response to public speaking stress in women. The present study aims to replicate our previous finding and further elucidate it by analyzing for the first time whether this alteration of cortisol-responsiveness is associated to ACTH and whether the catecholaminergic system is affected as well. Women were randomly assigned to Cyberball-induced exclusion (SE, n = 22) or inclusion (SI, n = 21), respectively. Immediately afterwards they were subjected to public speaking stress. Salivary cortisol, plasma ACTH, catecholamines and estradiol were assessed as were psychological distress and mood. Cyberball exclusion led to a highly significant immediate increase in negative affect in excluded women. After public speaking negative affect in included women increased as well and groups no longer differed. We replicate our previous finding of cortisol non-responsiveness to public speaking stress after exclusion pre-experience and find this effect to be significantly correlated with ACTH alterations. No such effects are observed for catecholamines. We replicated our previous study result of a suppressed cortisol stress response after a short exclusion experience via Cyberball, thereby underlining the profound effects of social exclusion on a subsequent cortisol stress response. This further demonstrates that these alterations are associated with ACTH. Lack of effects on catecholamines is discussed in view of the tend-and-befriend hypothesis but also from a methodological perspective.
Chris A. Rudyk
Full Text Available Little is known of the age-dependent and long-term consequences of low exposure levels of the herbicide and dopaminergic toxicant, paraquat. Thus, we assessed the dose-dependent effects of paraquat using a typical short-term (3 week exposure procedure, followed by an assessment of the effects of chronic (16 weeks exposure to a very low dose (1/10th of what previously induced dopaminergic neuronal damage. Short term paraquat treatment dose-dependently induced deficits in locomotion, sucrose preference and Y-maze performance. Chronic low dose paraquat treatment had a very different pattern of effects that were also dependent upon the age of the animal: in direct contrast to the short-term effects, chronic low dose paraquat increased sucrose consumption and reduced forced swim test (FST immobility. Yet these effects were age-dependent, only emerging in mice older than 13 months. Likewise, Y-maze spontaneous alternations and home cage activity were dramatically altered as a function of age and paraquat chronicity. In both the short and long-term exposure studies, increased corticosterone and altered hippocampal glucocorticoid receptor (GR levels were induced by paraquat, but surprisingly these effects were blunted in the older mice. Thus, paraquat clearly acts as a systemic stressor in terms of corticoid signaling and behavioral outcomes, but that paradoxical effects may occur with: (a repeated exposure at; (b very low doses; and (c older age. Collectively, these data raise the possibility that repeated “hits” with low doses of paraquat in combination with aging processes might have promoted compensatory outcomes.
Full Text Available BACKGROUND: Being socially excluded is associated with a variety of psychological changes and with an increased risk of disease. Today, the immediate physiological consequences of being socially excluded are not well understood. In two recent studies employing a standardized exclusion paradigm (Cyberball we found social exclusion in this virtual game did not alter cortisol secretion directly. However, exclusion pre-experience suppresses the normal cortisol response to public speaking stress in women. The present study aims to replicate our previous finding and further elucidate it by analyzing for the first time whether this alteration of cortisol-responsiveness is associated to ACTH and whether the catecholaminergic system is affected as well. METHODS: Women were randomly assigned to Cyberball-induced exclusion (SE, n = 22 or inclusion (SI, n = 21, respectively. Immediately afterwards they were subjected to public speaking stress. Salivary cortisol, plasma ACTH, catecholamines and estradiol were assessed as were psychological distress and mood. RESULTS: Cyberball exclusion led to a highly significant immediate increase in negative affect in excluded women. After public speaking negative affect in included women increased as well and groups no longer differed. We replicate our previous finding of cortisol non-responsiveness to public speaking stress after exclusion pre-experience and find this effect to be significantly correlated with ACTH alterations. No such effects are observed for catecholamines. CONCLUSIONS: We replicated our previous study result of a suppressed cortisol stress response after a short exclusion experience via Cyberball, thereby underlining the profound effects of social exclusion on a subsequent cortisol stress response. This further demonstrates that these alterations are associated with ACTH. Lack of effects on catecholamines is discussed in view of the tend-and-befriend hypothesis but also from a methodological
Hillard, Cecilia J
Some of the earliest reports of the effects of cannabis consumption on humans were related to endocrine system changes. In this review, the effects of cannabinoids and the role of the CB1 cannabinoid receptor in the regulation of the following endocrine systems are discussed: the hypothalamic-pituitary-gonadal axis, prolactin and oxytocin, thyroid hormone and growth hormone, and the hypothalamic-pituitary-adrenal axis. Preclinical and human study results are presented.
Os efeitos do estresse na função do eixo hipotalâmico-pituitário-adrenal em indivíduos com esquizofrenia The effects of stress on hypothalamic-pituitary-adrenal (HPA axis function in subjects with schizophrenia
Francesca L. Guest
Full Text Available Nas últimas décadas, têm surgido evidências sugerindo que a patogênese de desordens psiquiátricas, tais como a esquizofrenia, pode envolver perturbações no eixo hipotalâmico-pituitário-adrenal (HPA. Variações na manifestação desses efeitos poderiam estar relacionadas a diferenças em sintomas clínicos entre os indivíduos afetados, assim como a diferenças na resposta ao tratamento. Tais efeitos podem também ser originados de complexas interações entre genes e fatores ambientais. Aqui, revisamos os efeitos do estresse maternal em anormalidades na regulação do eixo HPA e desenvolvimento de desordens psiquiátricas, incluindo a esquizofrenia. Estudos nessa área podem gerar o aumento do nosso entendimento da natureza multidimensional da esquizofrenia. Posterior pesquisa nesse campo poderia, em última instância, levar ao desenvolvimento de melhores diagnósticos e novas abordagens terapêuticas para essa debilitante condição psiquiátrica.Over the last few decades, evidence has been emerging that the pathogenesis of psychiatric disorders such as schizophrenia can involve perturbations of the hypothalamic-pituitary-adrenal (HPA axis. Variations in the manifestation of these effects could be related to the differences in clinical symptoms between affected individuals as well as to differences in treatment response. Such effects can also arise from the complex interaction between genes and environmental factors. Here, we review the effects of maternal stress on abnormalities in HPA axis regulation and the development of psychiatric disorders including schizophrenia. Studies in this area may prove critical for increasing our understanding of the multi-dimensional nature of schizophrenia. Further research in this area could ultimately lead to the development of improved diagnostics and novel therapeutic approaches for treating this debilitating psychiatric condition.
Effects of moderate treadmill exercise and fluoxetine on behavioural and cognitive deficits, hypothalamic-pituitary-adrenal axis dysfunction and alternations in hippocampal BDNF and mRNA expression of apoptosis - related proteins in a rat model of post-traumatic stress disorder.
Shafia, Sakineh; Vafaei, Abbas Ali; Samaei, Seyed Afshin; Bandegi, Ahmad Reza; Rafiei, Alireza; Valadan, Reza; Hosseini-Khah, Zahra; Mohammadkhani, Raziyeh; Rashidy-Pour, Ali
Post-traumatic stress disorder (PTSD) is a condition that develops after an individual has experienced a major trauma. Currently, selective serotonin reuptake inhibitors (SSRIs) like fluoxetine are the first-line choice in PTSD drug treatment but their moderate response rates and side effects indicate an urgent need for the development of new treatment. Physical activity is known to improve symptoms of certain neuropsychiatric disorders. The present study investigated the effects of moderate treadmill exercise, the antidepressant fluoxetine and the combined treatment on behavioural deficits, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. We also examined alternations in hippocampal brain-derived neurotrophic factor (BDNF) and mRNA expression of apoptosis - related proteins in a rat model of PTSD: the single prolonged stress (SPS) model. Rats were exposed to SPS (restraint for 2h, forced swimming for 20min and ether anaesthesia) and were then kept undisturbed for 14days. After that, SPS rats were subjected to chronic treatment with fluoxetine (10mg/kg/day, for 4weeks), moderate treadmill running (4weeks, 5day per week) and the combined treatment (fluoxetine plus treadmill exercise), followed by behavioural, biochemical and apoptosis markers assessments. SPS rats exhibited increased anxiety levels in the elevated plus maze and light/dark box, impaired fear conditioning and extinction in inhibitory avoidance (IA) task, impaired spatial memory in a recognition location memory task and enhanced negative feedback on the HPA axis following a dexamethasone suppression test. SPS rats also showed reduced hippocampal BDNF and enhanced apoptosis. Moderate treadmill exercise, fluoxetine and the combined treatment alleviated the SPS-induced alterations in terms of anxiety levels, HPA axis inhibition, IA conditioning and extinction, hippocampal BDNF and apoptosis markers. Furthermore, the combined treatment was more effective than fluoxetine alone, but in most tests
Floam, Samantha; Simpson, Norah; Nemeth, Emese; Scott-Sutherland, Jennifer; Gautam, Shiva; Haack, Monika
This study investigates the extent to which sleep characteristics serve as predictor variables for inflammatory, hypothalamic-pituitary-adrenal and autonomic systems markers. Twenty-nine participants with a diagnosis of insomnia disorder based on the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (age 25.3 ± 1.6 years, insomnia duration 6.6 ± 0.8 years) and 19 healthy control sleepers (age 25.4 ± 1.4 years) underwent a 2-week at-home evaluation keeping a sleep diary and wearing an actigraph, followed by a visit to the Research Center to measure blood pressure, and collect blood and urine samples. The actigraphy- and diary-based variables of sleep duration, sleep-onset latency, wake after sleep onset and sleep fragmentation/number of night-time awakenings were averaged and entered as dependent variables in regression analyses. Composite scores were calculated for the autonomic (blood pressure, norepinephrine), inflammatory (monocyte counts, interleukin-6, C-reactive protein) and hypothalamic-pituitary-adrenal systems (cortisol), and used as predictor variables in regression models. Compared with controls, individuals with insomnia had a shorter sleep duration (P insomnia disorder, cortisol is upregulated and associated with actigraphy- and diary-based wake after sleep onset, suggesting that wake after sleep onset may serve as a marker to identify individuals at increased risks for disorders associated with a hyperactive hypothalamic-pituitary-adrenal system. The absence of autonomic and pro-inflammatory changes (interleukin-6, C-reactive protein), despite a substantial decrease in actigraphic sleep duration, may relate to a higher resilience to the adverse biological consequences of insomnia in this young age group. © 2014 European Sleep Research Society.
Lithium ameliorates sleep deprivation-induced mania-like behavior, hypothalamic-pituitary-adrenal (HPA) axis alterations, oxidative stress and elevations of cytokine concentrations in the brain and serum of mice.
Valvassori, Samira S; Resende, Wilson R; Dal-Pont, Gustavo; Sangaletti-Pereira, Heron; Gava, Fernanda F; Peterle, Bruna R; Carvalho, André F; Varela, Roger B; Dal-Pizzol, Felipe; Quevedo, João
The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice subjected to an animal model of mania induced by paradoxical sleep deprivation (PSD). Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels. The results showed that PSD induced hyperactivity in mice, which is considered a mania-like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania-like behavior, oxidative damage and cytokine alterations induced by PSD. Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system - alterations presented in the animal models of mania - is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Olivia S. Edgar
Full Text Available Purpose: Prader Willi syndrome (PWS is a rare genetic condition that has concurrent endocrinological insufficiencies. The presence of growth hormone deficiency has been well documented, but adrenal insufficiency (AI is not widely reported. A review was conducted to investigate its prevalence and relevance in PWS in both adults and children. Methodology: A literature review was performed with the search terms “Prader-Willi syndrome” and “adrenal insufficiency”. Results: The review found studies disagree on the prevalence and method of investigation of AI in PWS. Case studies demonstrate that patients with PWS are at risk of premature death, often secondary to respiratory infections. The possibility that this may be the result of the inability to mount an effective cortisol response has been studied, with some evidence confirming AI in PWS patients. Most reports agreed AI is present in PWS, however, Farholt et al. showed no HPA axis dysfunction in adults, suggesting that perhaps it is rare in adults, and children should be the focus of further studies. Conclusion: AI is present in some patients with PWS. Further research is required to ensure optimal treatment can be implemented and to prevent premature deaths related to adrenal insufficiency. Clinicians should have a low threshold for testing the adrenal axis and considering treatment for adrenal insufficiency in PWS patients.
Relation of anterior cingulate cortex metabolic characteristics to hypothalamic-pituitary -adrenal axis functional in depressive patients: A 1H-magnetic resonance spectroscope study%抑郁症患者前扣带回代谢特征与下丘脑-垂体-肾上腺轴活性水平的氢质子波谱研究
彭红军; 李凌江; 贺忠
目的:用磁共振氢质子波谱的方法探讨抑郁症患者前扣带回(ACC)代谢特征与下丘脑-垂体-肾上腺轴(HPA轴)功能活性的关系.方法:选取68例符合美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)诊断标准的抑郁症患者及30例正常对照,采用磁共振扫描检测前扣带回氢质子波谱N-乙酰天门冬氨酸(NAA)、胆碱(Cho)、肌酸(Cr)、谷氨酸复合物(Glx)及肌醇(mI)等5种代谢物的含量,计算NAA/Cr、Glx/Cr、Cho/Cr、mI/Cr比值.用皮质醇醒觉反应(CAR)检测HPA轴活性,定义为连续2天醒后30 min觉醒时皮质醇浓度差值的均值.根据抑郁症组HPA轴活性均值将抑郁症组分为HPA轴高活性组35例(＞6.6 nmol/L)及HPA轴低活性组33例(≤6.6nmol/L).结果:与正常对照相比,抑郁症患者两侧ACC的NAA/Cr[左侧(1.6±0.5)vs.(2.0±0.5),右侧(1.7±0.4)vs.(2.2±0.5)]和Glx/Cr[左侧(0.1±0.03) vs.(0.1 ±0.03),右侧(0.1±0.01) vs.(0.2±0.04)]较低(均P＜0.05),右侧Cho/Cr较高[(1.5±0.9)vs.(0.9±0.3),P＜0.01]；与低HPA轴活性组相比,高HPA轴活性组左侧NAA/Cr较低[(1.6±0.4)vs.(1.7±0.4),P＜0.05],右侧Cho/Cr较高[(1.7±0.2)vs.(1.2±0.1),P＜0.01].结论:抑郁症患者可能存在双侧前扣带回N-乙酰天门冬氨酸、谷氨酸及胆碱等代谢紊乱,高HPA轴活性可能与部分代谢物质存在相关.%Objective:To investigate the relationship between metabolic characteristics and hypothalamic-pituitary-adrenal axis (HPA) in anterior cingulate lobes (ACC) in depressive patients with 1H-magnetic resonance spectroscope (1H-MRS).Methods:Totally 68 patients with major depression disorder meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition (DSM-Ⅳ) and 30 healthy controls were scanned by magnetic resonance and 1 H-MRS data were collected.The bilateral anterior cingulate lobes were selected as region of interest.The levels of N-acetyl aspartic acid (NAA),choline (Cho),creatine (Cr),glutamic acid
陈燕惠; 陈辉; 刘艳艳; 林桂秀; 韦立新; 陈丹玲
目的 通过研究注意力缺陷多动障碍(ADHD)儿童下丘脑-垂体-肾上腺轴(HPA)的功能状态,探讨HPA轴在ADHD发生中的作用.方法 128例6～14岁ADHD男童根据DSM-IV ADHD诊断和分型标准,其中注意缺陷为主型(ADHD-I)44例,多动-冲动为主型(ADHD-HI)32例,混合型(ADHD-C)52例,对照组为年龄匹配健康男童30名,于8:00 am空腹采血.分别采用全自动微粒酶免疫分析法及电化学发光法检测血浆皮质醇及促肾上腺皮质激素(ACTH),智力测验采用瑞文标准推理测验.结果 ADHD组IQ(84.5±11.3)低于对照组(94.6±12.4,P<0.01),ADHD 3个亚型组间比较差异有显著性(P<0.01),ADHD-I和ADHD-C两个亚组IQ水低于对照组(P<0.01),ADHD-HI组与对照组比较差异无显著性.ADHD组血浆皮质醇水平(226.5±129.1 mnol/L)较对照组(384.5±141.4 nmol/L)明显降低(P<0.01),ADHD-HI组(154.4±71.6 nmol/L)下降程度较ADHD-I组(219.4±117.7 nmol/L)及ADHD-C组(258.3±136.4 nmol/L)为著(P<0.01),而ADHD各组血浆ACTH水平与对照组比较差异无显著性.结论 在非应激状态下ADHD儿童存在着HPA轴调节功能障碍,这可能系HPA轴低反应性所致.低血浆皮质醇对认知行为影响较小,而与注意缺陷、多动、冲动行为关系更为密切.%Objective To study the function of the hypothalamus-pituitary-adrenal (HPA) axis in children with attention deficit hyperactivity disorder (ADHD). Methods One hundred and twenty-eight boys with ADHD at ages of 6 to 14 years were enrolled. The diagnosis and grouping of ADHD were based on the Diagnostic and Statistical Manual of Mental Disorders ( DSM-IV) : ADHD-predominantly inattention type (ADHD-I, n =44), ADHD-predominantly hyperactive impulsivetype (ADHD-HI, n = 32) and ADHD-combined type (ADHD-C, n =52). Thirty healthy boys served as the control group. Plasma levels of cortisol and adrenocorticotropic hormone ( ACTH) were measured by automatic particle enzyme immunoassay and electrochemiluminescence
Full Text Available Fibromyalgia is considered a stress-related disorder, and hypo- as well as hyperactive stress systems (sympathetic nervous system and hypothalamic-pituitary-adrenal axis have been found. Some observations raise doubts on the view that alterations in these stress systems are solely responsible for fibromyalgia symptoms. Cumulative evidence points at dysfunctional transmitter systems that may underlie the major symptoms of the condition. In addition, all transmitter systems found to be altered in fibromyalgia influence the body's stress systems. Since both transmitter and stress systems change during chronic stress, it is conceivable that both systems change in parallel, interact, and contribute to the phenotype of fibromyalgia. As we outline in this paper, subgroups of patients might exhibit varying degrees and types of transmitter dysfunction, explaining differences in symptomatoloy and contributing to the heterogeneity of fibromyalgia. The finding that not all fibromyalgia patients respond to the same medications, targeting dysfunctional transmitter systems, further supports this hypothesis.
Zhou, Yan; Leri, Francesco
Opiate addiction, similarly to addiction to other psychoactive drugs, is chronic relapsing brain disease caused by drug-induced short-term and long-term neuroadaptations at the molecular, cellular, and behavioral levels. Preclinical research in laboratory animals has found important interactions between opiate exposure and stress-responsive systems. In this review, we will discuss the dysregulation of several stress-responsive systems in opiate addiction: vasopressin and its receptor system, endogenous opioid systems (including proopiomelanocortin/mu opioid receptor and dynorphin/kappa opioid receptor), orexin and its receptor system, and the hypothalamic-pituitary-adrenal axis. A more complete understanding of how opiates alter these stress systems, through further laboratory-based studies, is required to identify novel and effective pharmacological targets for the long-term treatment of heroin addiction. © 2016 Elsevier B.V. All rights reserved.
Révész, Dóra; Verhoeven, Josine E; Milaneschi, Yuri; de Geus, Eco J C N; Wolkowitz, Owen M; Penninx, Brenda W J H
Exposure to chronic stressors is associated with accelerated biological aging as indicated by reduced leukocyte telomere length (LTL). This impact could be because of chronic overactivation of the body's physiological stress systems. This study examined the associations between LTL and the immune system, hypothalamic-pituitary-adrenal axis and autonomic nervous system. LTL was assessed in 2936 adults from the Netherlands Study of Depression and Anxiety. Inflammation markers (interleukin-6, c-reactive protein, tumor necrosis factor-alpha), hypothalamic-pituitary-adrenal-axis indicators (salivary cortisol awakening curve [area under the curve indicators, with respect to the ground and increase], evening levels, 0.5 mg dexamethasone cortisol suppression ratio), and autonomic nervous system measures (heart rate, respiratory sinus arrhythmia, pre-ejection period) were determined. Linear regression analyses were performed and adjusted for sociodemographic, lifestyle and clinical factors. Shorter LTL was significantly associated with higher c-reactive protein, interleukin-6, area under the curve with respect to increase, and heart rate. A cumulative index score was calculated based on the number of highest tertiles of these 4 stress markers. LTL demonstrated a significant gradient within subjects ranging from having zero (5528 base pairs) to having 4 elevated stress markers (5371 base pairs, p for trend = 0.002), corresponding to a difference of 10 years of accelerated biological aging. Contrary to the expectations, shorter LTL was also associated with longer pre-ejection period, indicating lower sympathetic tone. This large-scale study showed that inflammation, high awakening cortisol response, and increased heart rate are associated with shorter LTL, especially when they are dysregulated cumulatively. Copyright © 2014 Elsevier Inc. All rights reserved.
Full Text Available In the article, the literature on the effects of TNFa-antagonists (etanercept, infliximab and adalimumab on the immune system is reviewed. These biologic agents are employed in chronic inflammatory diseases such as rheumatoid arthritis, seronegative spondyloarthritides, as well as psoriasis and Crohn’s disease. The differences of these drugs, testified by the different effects on the immune response, are discussed. These molecules exert their effect through cytokine inhibition, but they present striking differences since they can modulate macrophage activity, T cells apoptosis, leukocyte migration, and angiogenesis to a different degree. Some studies showed that these agents also affect the hypothalamo- pituitary-adrenal axis. The potential immunogenicity of these biologic agents is also discussed.
Generaal, Ellen; Vogelzangs, Nicole; Macfarlane, Gary J; Geenen, Rinie; Smit, Johannes H; de Geus, Eco J C N; Dekker, Joost; Penninx, Brenda W J H
Dysfunction of biological stress systems and adverse life events, independently and in interaction, have been hypothesized to predict chronic pain persistence. Conversely, these factors may hamper the improvement of chronic pain. Longitudinal evidence is currently lacking. We examined whether: 1) function of biological stress systems, 2) adverse life events, and 3) their combination predict the improvement of chronic multisite musculoskeletal pain. Subjects of the Netherlands Study of Depression and Anxiety (NESDA) with chronic multisite musculoskeletal pain at baseline (N = 665) were followed-up 2, 4, and 6 years later. The Chronic Pain Grade Questionnaire was used to determine improvement (not meeting the criteria) of chronic multisite musculoskeletal pain at follow-up. Baseline assessment of biological stress systems included function of hypothalamic-pituitary-adrenal axis (1-hour cortisol awakening response, evening level, and post dexamethasone level), the immune system (basal and lipopolysaccharide-stimulated inflammatory markers), the autonomic nervous system (heart rate, pre-ejection period, SD of the normal-to-normal interval, and respiratory sinus arrhythmia). The number of adverse life events were assessed at baseline and 2-year follow-up using the List of Threatening Events Questionnaire. We showed that hypothalamic-pituitary-adrenal axis, immune system, and autonomic nervous system functioning and adverse life events were not associated with the improvement of chronic multisite musculoskeletal pain, either as a main effect or in interaction. This longitudinal study could not confirm that biological stress system dysfunction and adverse life events affect the course of chronic multisite musculoskeletal pain. Biological stress systems and adverse life events are not associated with the improvement of chronic multisite musculoskeletal pain over 6 years of follow-up. Other determinants should thus be considered in future research to identify in which
O eixo hipotálamo-pituitária-adrenal, a função dos receptores de glicocorticóides e sua importância na depressão The Hypothalamic Pituitary Adrenal axis, Glucocorticoid receptor function and relevance to depression
Mario F Juruena
abordagem eficaz para maximizar os efeitos terapêuticos dos antidepressivos. Hipóteses referentes aos mecanismos destes receptores envolvem compostos não esteróides que regulam a função dos RGs via segundos mensageiros. A pesquisa nesta área trará novos entendimentos à fisiopatologia e ao tratamento dos transtornos afetivos, em especial na depressão.OBJECTIVES: Changes in the hypothalamic-pituitary-adrenocortical (HPA system are characteristic of depression. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR, several studies have examined the number and/or function of GRs in depressed patients. METHODS: Review scientific evidences have consistently demonstrated that GR function is impaired in major depression, resulting in reduced GR-mediated negative feedback on the HPA axis and increased production and secretion of CRF in various brain regions postulated to be involved in the causality of depression. RESULTS: This article summarizes the literature on GR in depression and on the impact of antidepressants on the GR in clinical and preclinical studies, and supports the concept that impaired GR signalling is a key mechanism in the pathogenesis of depression, in the absence of clear evidence of decreased GR expression. The data also indicate that antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Although the effects of antidepressants on glucocorticoid hormones and their receptors are relevant for the therapeutic action of these drugs, the molecular mechanisms underlying these effects are unclear. We propose that antidepressants in humans could inhibit steroid transporters localised on the blood-brain barrier and in neurones, like the multidrug resistance p-glycoprotein, and thus increase the access of cortisol to the brain and the glucocorticoid-mediated negative feedback on the HPA axis. CONCLUSION: Enhanced cortisol action
Madsen, Kathrine Skak; Jernigan, Terry L; Iversen, Pernille
It is well-established that prolonged high levels of cortisol have adverse effects on hippocampal neurons and glial cells. Morphometric studies linking hippocampus volume to basal HPA-axis activity, however, have yielded less consistent results. Asymmetry may also be considered, since there is gr......It is well-established that prolonged high levels of cortisol have adverse effects on hippocampal neurons and glial cells. Morphometric studies linking hippocampus volume to basal HPA-axis activity, however, have yielded less consistent results. Asymmetry may also be considered, since....... Observed associations raise a number of possibilities, among them an asymmetric role of the hippocampus on HPA-axis regulation, or conversely, that individual variations in secreted cortisol, perhaps associated with stress, may have lateralized effects on hippocampal microstructure. Our results point...
Skovira, Emily J; Behrend, Ellen N; Martin, Linda G; Palmer, Lee E; Kemppainen, Robert J; Lee, Hollie P
OBJECTIVE To assess effects of major abdominal surgery on serum cortisol and aldosterone and plasma canine ACTH (cACTH) concentrations. ANIMALS 39 healthy dogs undergoing laparotomy during veterinary student surgical laboratories. PROCEDURES Blood samples were obtained before and at completion of surgery. Serum cortisol and aldosterone and plasma cACTH concentrations were measured by use of validated radioimmunoassays. Changes in concentrations (postoperative concentration minus preoperative concentration) were calculated. Data were analyzed by use of the Wilcoxon signed rank test, Pearson correlation analysis, and Mann-Whitney rank sum test. RESULTS Cortisol, aldosterone, and cACTH concentrations increased significantly from before to after surgery. Although cortisol and aldosterone concentrations increased in almost all dogs, cACTH concentrations decreased in 6 of 32 (19%) dogs. All dogs had preoperative cortisol concentrations within the reference range, but 24 of 39 (62%) dogs had postoperative concentrations above the reference range. A correlation between the change in cACTH concentration and the change in cortisol concentration was not detected. CONCLUSIONS AND CLINICAL RELEVANCE Laparotomy caused a significant increase in serum cortisol and aldosterone concentrations. In most dogs, but not all dogs, plasma cACTH concentrations increased. Lack of correlation between the change in cACTH concentration and the change in cortisol concentration suggested that increased postoperative cortisol concentrations may have been attributable to ACTH-independent mechanisms, an early ACTH increase that caused a sustained cortisol release, or decreased cortisol clearance. Further studies are indicated to evaluate the effects of various anesthetic protocols and minimally invasive surgical techniques on the stress response.
Kokavec, Anna; Lindner, Amy J; Ryan, Jaymee E; Crowe, Simon F
There is an increasing evidence that long-term alcohol intake can promote damage to most of the body's major organs. However, regular consumption of a small-moderate amount of alcohol is often recommended as being beneficial to health and of concern is that the effect of ingesting commercially available alcohol products on steroid hormone synthesis under variable nutritional conditions has not been thoroughly investigated. Many individuals consume alcohol alone prior to a meal and the aim of the present study was to assess the effect of consuming a small-moderate amount of commercially available alcohol on the level of salivary cortisol and salivary dehydroepiandrosterone sulfate (DHEAS) before and after a meal. A total of 24 males aged 19-22 years participated in the current investigation. The experimental procedure required participants to fast for 6 h before being asked to ingest either 40 g alcohol in the form of red wine (n=8), low alcohol and high beer (n=8), white wine (n=8) or the equivalent amount of placebo over a 135-min period before consuming food for 45-min. The level of blood alcohol, salivary cortisol and salivary DHEAS was assessed upon arrival and then at regular 45-min intervals during the 180-min experimental period. The results showed that the consumption of alcohol and placebo can significantly lower the level of salivary cortisol. However, the effect of consuming a small-moderate amount of commercially available alcohol on the level of salivary DHEAS was dependent on the nutritional content of the beverage with red wine promoting no change, white wine promoting a significant decrease, and beer having a variable effect on salivary DHEAS concentration when compared to placebo. It was concluded that the effect of commercially available alcohol on the HPA axis is not the same for all alcohol products and both the nutritional status of participants and the nutritional content of the alcoholic beverage being administered should be taken into consideration when investigating the effect of alcohol on the HPA axis.
Burkhardt, Till; Rotermund, Roman; Schmidt, Nils-Ole; Kiefmann, Rainer; Flitsch, Jörg
Postoperative nausea and vomiting (PONV) is common after general anesthesia and are reported by approximately 20% to 25% of all patients and up to 39% of patients undergoing neurosurgical procedures. The most common standard prophylaxis is a single application of 4 mg of dexamethasone before initiating anesthesia. Dexamethasone is known to suppress adreno-corticotroph hormone and cortisol levels. The objective was to find out whether this prophylaxis has an effect on the postoperative levels of cortisol in patients undergoing transsphenoidal pituitary surgery, and therefore simulates pituitary deficiency. A retrospective analysis of the files of 136 consecutive patients who were operated during a course of 6 months were included. Nineteen patients with a known history of PONV received a standard dose of 4 mg of dexamethasone perioperatively. Blood tests were drawn at the first postoperative day and were compared with blood tests of patients who had no history of PONV and therefore received no prophylaxis. Patients who were treated with a dexamethasone PONV prophylaxis showed no significant changes in cortisol levels; preoperative median of 93 μg/L (range, 39 to 427) and a postoperative median of 87 μg/L (range, 10 to 733; P=0.798) opposed to patients who did not receive such treatment; preoperative cortisol 114 μg/L (range, 10 to 387) and postoperative levels of 273 μg/L (range, 10 to 1352; Ptranssphenoidal surgery, the probability that dexamethasone PONV prophylaxis suppresses postoperative cortisol levels should be considered.
Takahashi, L K; Kim, H
Recent investigations revealed that adrenalectomized (ADX) rat pups exhibit deficits in behavioral inhibition. Furthermore, administration of exogenous corticosterone (CORT) restores behavioral inhibition in ADX pups. Although these studies suggest that CORT has an important role in the development of behavioral inhibition, the relative behavioral effects of elevated pituitary hormone secretion induced by ADX are not known. Therefore, experiments were conducted to assess the potential behavioral effects of elevated adrenocorticotropin (ACTH) secretion induced by ADX and to further evaluate the contribution of endogenous CORT to the development of behavioral inhibition. In Experiment 1., we verified that 10-day-old ADX rats exhibit high levels of plasma ACTH throughout the preweaning period associated with the development of behavioral inhibition. In Experiment 2, 10-day-old pups were hypophysectomized (HYPOX) and ADX and were compared behaviorally to sham-operated controls on day 14. When tested in the presence of an anesthetized unfamiliar adult male rat, HYPOX + ADX pups exhibited low levels of freezing accompanied by ultrasonic vocalizations. These pups also had reduced concentrations of plasma ACTH and CORT. In Experiment 3, 10-day-old pups were HYPOX and tested for behavioral inhibition on day 14. In comparison to sham-operated controls, HYPOX rats exhibited significantly lower levels of freezing and had reduced plasma concentrations of ACTH and CORT. Results demonstrate clearly that deficits in freezing occur even in the presence of low plasma ACTH concentrations. Therefore, elevated secretion of pituitary hormones is not a major factor that contributes to the ADX-induced deficits in behavioral inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Levine, R; Levine, S
Adrenalectomized female rats failed to develop schedule-induced polydipsia (SIP). Dexamethasone (DEX) injections failed to reinstate SIP in adrenalectomized rats. They did not prevent intact rats from acquiring SIP but interfered with subsequent expression of this behavior. In contrast, corticosterone, the rats' normally occurring glucocorticoid, fully restored the acquisition and subsequent expression of SIP in adrenalectomized rats. This strongly suggests that corticosterone plays an essential role in the normal acquisition and development of this behavior. Data are interpreted in the context of current information concerning adrenal hormone receptors. It is hypothesized SIP acquisition is at least partly regulated by the Type I (mineralocorticoid) receptor.
While it is known that adrenal steroids impact reproduction and a variety of other physiological and behavioral functions, disruption of the HPA-axis is not typically considered in toxicological studies. Here we characterize changes in basal corticosterone (CORT) and progesterone...
Kaneko, Motohisa; And Others
This study with 30 children showing attention deficit hyperactivity disorder (ADHD) found a normal diurnal saliva cortisol rhythm in only 43.3 percent of the subjects and a dexamethasone suppression in 46.7 percent, with both these abnormalities more frequent in the severely than the mildly hyperactive group. Results suggest abnormalities in…
While it is known that adrenal steroids impact reproduction and a variety of other physiological and behavioral fimctions, disruption of the HPA-axis is not typically considered in toxicological studies. Here we characterize changes in basal corticosterone (CORT) and progesterone...
Parental and environmental factors during the prenatal and postnatal periods permanently affect the physiology and metabolism of offspring, potentially increasing risk of disease later in life. Underlying mechanisms are beginning to be elucidated, and effects on a number of organ...
Crippa, S; Mussi, C; Angelini, C; Caprotti, R; Bonardi, C; Muselli, P; Scotti, M; Piacentini, G; Uggeri, F
In advanced cancer patients a cell-mediated immunological impairment, both at baseline and during postoperative period, is often found and is associated with poor prognosis. Cortisol is strictly involved in the response to major surgical stress, is an immunosuppressor and causes a redistribution of immunological population cells in different tissues. The aim of the study was to verify serum levels and circadian rhythm of cortisol in patients with colorectal cancer at baseline before surgery and in the postoperative period, and relate it to the immune status. In 21 patients with colorectal cancer undergoing surgery we evaluated the assessment of total lymphocytes, CD4+, cortisolemia, circadian rhythm of cortisol (11 p.m. and 8 a.m.) at baseline and in 3(rd) and 7(th) postoperative days. Increase of cortisolemia, as decrease of total and CD4+ lymphocytes in the postoperative period versus baseline was statistically significant. Patients with an altered circadian rhythm were 47% and 36% at 3rd and 7th postoperative days, respectively. At baseline 19% of patients had an altered cortisol circadian rhythm and it was more frequent in patients with nodal involvement (pcancer patients seems not to be associated with cortisol level and circadian rhythm alteration, either at baseline or after surgical stress. An impairment of circadian rhythm of cortisol was found at baseline in 19% of patients. It was significantly associated with the presence of metastatic disease.
Seed, J A; Dixon, R A; McCluskey, S E; Young, A H
Anorexia nervosa is associated with abnormalities in neuroendocrine function including sustained hypercortisolism, which has been shown elsewhere to be associated with impairment of function in learning, memory and attention. Cognitive impairment has also been observed in anorexia nervosa. These effects may be mediated in part through cortisol effects on the hippocampus, which is dense with glucocorticoid receptors. We investigated the association between cortisol levels and cognitive function in anorexia nervosa by measuring both 24-hour urinary cortisol counts and performance on tasks of learning, memory and attention in patients suffering from the disorder. Cortisol secretion was shown to be significantly higher in the patient group than in a matched control group and patients were also shown to be impaired in memory and attention. However, no correlations were found between the cognitive deficits and cortisol measures. It is suggested that more sensitive profiling of cortisol levels throughout the circadian cycle may be useful in future studies of cognitive function in anorexia nervosa.
Staufenbiel, Sabine M; Andela, Cornelie D; Manenschijn, Laura; Pereira, Alberto M; van Rossum, Elisabeth F C; Biermasz, Nienke R
Intrinsic imperfections and lack of reliable biomarkers preclude optimal individual dosing of hydrocortisone replacement in adrenal insufficiency (AI). However, the clinical relevance of optimal dosing is exemplified by frequently occurring side effects of overreplacement and the dangers of underreplacement. Cortisol in scalp hair has been identified as a retrospective biomarker for long-term cortisol exposure. We compared hair cortisol concentrations (CORT(hair)) of patients with primary or secondary AI on replacement therapy with those of patient controls with a pituitary disease without AI (PCs) and of healthy controls (HCs). In this cross-sectional study, hair samples and anthropometric data were collected in 132 AI patients (52 males), 42 PCs (11 males), and 195 HCs (90 males). The proximal 3 cm of hair were used. CORT(hair) were measured using an ELISA. CORT(hair) were higher in AI patients than in HCs and PCs (P AI patients demonstrated higher CORT(hair) than female patients (P AI patients had higher body mass index (BMI) than HCs (P AI.
M.J.H.J. Dekker (Marieke)
textabstractGlucocorticoids (GCs) are ubiquitous, nuclear hormones, which are essential for life. In man, the main GC is cortisol, produced by the adrenals, endocrine glands that are situated on top of the kidneys. Cortisol exerts its functions in nearly all tissues and is crucial in the
Akcali, Aylin; Zengin, Fatma; Aksoy, Sefika Nur; Zengin, Orhan
Fatigue is a common symptom of Multiple Sclerosis (MS) that diminishes the quality of life of patients, but its exact mechanism remains poorly understood. There is not a generally adopted scale to determine MS fatigue. Studies that investigated physiopathology of fatigue symptom have shown dysregulation of hypothalamic-pituitaryadrenal (HPA) axis. In the current study, we aimed to compare the results obtained with two separate scales, namely the Fatigue Severity Scale (FSS) and the Neurological Fatigue Index-Multiple Sclerosis (NFI-MS), and assess the relationship between fatigue and serum IL-1β, TNF-α, IL-35, IL-2, IL-10, ACTH, cortisol, α-MSH, β-MSH, γ-MSH and CLIP (Corticotropinlike intermediate lobe peptide) in MS patients categorized as fatigued and non-fatigued on the basis of FSS scores. For the study, a total of 54 (29 females, 25 males) patients diagnosed with RRMS including 26 with fatigue symptom (48.1%), and 26 healthy controls (13 females, 13 males) were enrolled. A FSS score ≥36 was considered as cut-off score to separate fatigued patients from nonfatigued patients. A significant positive correlation was determined between FSS score and NFI-MS scale, NFI-MS 1, NFI-MS 2, NFI-MS 3 and NFI-MS 4 scores. IL-1β, IL-10 and TNF-α levels did not differ between patient and control groups. IL-35 and IL-2 levels were significantly higher among MS patients (pfatigued and nonfatigued patients in the cytokines and HPA parameters studied. ACTH, cortisol and α-MSH were significantly higher in MS group (p=0.02, pfatigue; thus, it may also be widely used to evaluate that symptom. Generally HPA axis is hyperactive in MS patients, but it is not correlated with fatigue in our study. For the first time, levels of CLIP (a type of melanocortin) are studied, and determined to be lower among MS patients. Elevated levels of IL-35 and IL-2 suggest that these cytokines may have a prominent role in MS pathophysiology and can be investigated as potential targets for development of novel therapies. Copyright © 2017 Elsevier B.V. All rights reserved.
Frederico G. Graeff
Full Text Available A bibliographic search has been performed in MEDLINE using cortisol and panic as key-words, occurring in the title and/or in the abstract. Human studies were selected, with no time limit. The following publications were excluded: reviewarticles, case reports, panic attacks in disorders other than panic disorder, and studies on changes that occurred in-between panic attacks. The results showed that real-life panic attacks as well as those induced by selective panicogenic agents such as lactate and carbon dioxide do not activate the hypothalamicpituitary- adrenal (HPA axis. Agonists of the colecystokinin receptor B, such as the colecystokinin-4 peptide and pentagastrin, increase stress hormones regardless of the occurrence of a panic attack and thus, seem to activate the HPA axis directly. The benzodiazepine antagonist flumazenil does not increase stress hormones, but this agent does not reliably induce panic attacks. Pharmacological agents that increased anxiety in both normal subjects and panic patients raised stress hormone levels; among them are the alpha2-adrenergic antagonist yohimbine, the serotonergic agents 1-(m-chlorophenyl piperazine (mCPP and fenfluramine, as well as the psychostimulant agent caffeine. Therefore, the panic attack does not seem to activate the HPAaxis, in contrast to anticipatory anxiety.Realizou-se levantamento bibliográfico no indexadorMEDLINE, através das palavras-chave "cortisol" e "panic", sem limite de tempo, restringindo-se a sereshumanos e à localização das palavras-chave no título e no resumo. Foram excluídos artigos de revisão e relatos de caso, estudos sobre alterações ocorridas entre dois ataques, e os que tratavam de outras doenças psiquiátricas ou de sujeitos sadios, quando não comparados com pacientes de pânico. Os resultados mostraram que ataques de pânico naturais ou provocados pelos agentes panicogênicos seletivos, lactato de sódio e dióxido de carbono, não ativam o eixo hipotálamo-pituitária-adrenal (HPA. Agonistas do receptor de colecistocinina B elevam os hormônios de estresse, quer haja ataque de pânico ou não, parecendo ativar diretamente o eixo HPA. O antagonista benzodiazepínico flumazenil não eleva o nível dos hormônios de estresse, porém não induz ataques de pânico de modo consistente. Agentes farmacológicos que produzem ansiedade em pacientes de pânico e em voluntários saudáveis elevam o nível dos hormônios de estresse, entre estes o antagonista alfa2-adrenérgico ioimbina, os agentes serotonérgicos 1-(m-clorofenil piperazina (mCPP e fenfluramina, bem como o agente psicostimulante cafeína. Portanto, o ataque de pânico não parece ativar o eixo HPA, ao contrário da ansiedade antecipatória.
Kahn, S.E.; Maxwell, J.U.; Barron, J.L.
A simple, short and sensitive direct radio-immunoassay technique for the determination of salivary cortisol concentration was employed to assess saliva as a medium for evaluating cortisol response during endocrine testing in 9 controls and 40 patients. Results in controls suggested that an adequate salivary cortisol response to insulin hypoglycaemia was an increase of 150% above the basal value with a minimum peak of 15 nmol/l. Thirty-three patients were classified as being either good or poor responders to insulin hypoglycaemia on the basis of criteria for plasma cortisol levels. When the defined salivary cortisol response was used for assessment, all 33 patients were correctly categorized into the same response groups. The salivary cortisol response to intramuscular tetracosactin in 3 patients and an intravenous dexamethasone infusion in 4 patients confirmed the value of saliva as an assay medium. These studies show that the salivary cortisol response parallels that of total plasma cortisol in all cases. However, with sampling at short intervals a lag in secretion of the free fraction from the plasma into the saliva becomes apparent. The relative change in cortisol levels from the basal value is greater in saliva than in plasma
Parker, Karen J.; Buckmaster, Christine L.; Lindley, Steven E.; Schatzberg, Alan F.; Lyons, David M.
Monkeys exposed to stress inoculation protocols early in life subsequently exhibit diminished neurobiological responses to moderate psychological stressors and enhanced cognitive control of behavior during juvenile development compared to non-inoculated monkeys. The present experiments extended these findings and revealed that stress inoculated…
Bjelobaba, Ivana; Janjic, Marija M; Stojilkovic, Stanko S
Adenosine-5'-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5'-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5'-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5'-triphosphate hydrolysis to adenosine-5'-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. Published by Elsevier B.V.
Bjelobaba, Ivana; Janjic, Marija M.; Stojilkovic, Stanko S.
Adenosine-5′-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5′-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5′-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5′-triphosphate hydrolysis to adenosine-5′-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. PMID:25960051
Previous studies have demonstrated that exposure to the pulmonary irritant ozone causes myriad systemic metabolic and pulmonary effects attributed to sympathetic and hypothalamus-pituitary-adrenal (HPA) axis activation, which are exacerbated in metabolically impaired models. We examined respiratory and systemic effects following exposure to a sensory irritant acrolein to elucidate the systemic and pulmonary consequences in healthy and diabetic rat models. Male Wistar and Goto Kakizaki (GK) rats, a nonobese type II diabetic Wistar-derived model, were exposed by inhalation to 0, 2, or 4 ppm acrolein, 4 h/d for 1 or 2 days. Exposure at 4 ppm significantly increased pulmonary and nasal inflammation in both strains with vascular protein leakage occurring only in the nose. Acrolein exposure (4 ppm) also caused metabolic impairment by inducing hyperglycemia and glucose intolerance (GK > Wistar). Serum total cholesterol (GKs only), low-density lipoprotein (LDL) cholesterol (both strains), and free fatty acids (GK > Wistar) levels increased; however, no acrolein-induced changes were noted in branched-chain amino acid or insulin levels. These responses corresponded with a significant increase in corticosterone and modest but insignificant increases in adrenaline in both strains, suggesting activation of the HPA axis. Collectively, these data demonstrate that acrolein exposure has a profound effect on nasal and pulmonary inflammation, as well as glucose and lipid metabolis
Previous studies have demonstrated that exposure to ozone, a pulmonary irritant, causes myriad systemic metabolic and pulmonary effects that are attributed to neuronal and hypothalamus-pituitary-adrenal (HPA) axis activation, which are exacerbated in metabolically-impaired models. In order to elucidate the systemic consequences and the contribution of the HPA axis in mediating metabolic and respiratory effects of acrolein, a sensory irritant, we examined pulmonary, nasal, and systemic effects in rats following exposure. Male, 10 week old Wistar and Goto Kakizaki (GK) rats, a non-obese type II diabetic Wistar-derived model, were exposed to 0, 2 or 4 ppm acrolein, 4h/day for 1 or 2 days. Acrolein exposure at 4 ppm significantly increased pulmonary and nasal damage in both strains as demonstrated by increased inspiratory and expiratory times indicating labored breathing, elevated biomarkers of injury, and neutrophilic inflammation. Overall, at both time points acrolein exposure caused noticeably more damage in the nasal passages as opposed to the lung with vascular protein leakage occurring only in the nose. Acrolein exposure (4 ppm) also led to metabolic impairment by inducing hyperglycemia and glucose intolerance (GK>Wistar) as indicated by glucose tolerance testing. In addition, serum total cholesterol (GKs only), LDL cholesterol (both strains), and free fatty acids (GK>Wistar) levels increased; however, no acrolein-induced changes were noted in branched-c
Boris, Gorzalka; Hanson, Laura; Harrington, J
Two experiments were designed to elucidate the involvement of the hypothalamic-pituitary-adrenal axis and the 5-hydroxytryptamine (5-HT) system in the acquisition of lithium chloride-conditioned taste aversion. In Experiment 1, rats were administered either vehicle or 50 mg/kg nefazodone daily fo......, corticosterone-treated animals required more trials to reach extinction. These results suggest the involvement of both the 5-HT system and the hypothalamic-pituitary-adrenal axis in lithium chloride-conditioned taste aversion....
Full Text Available The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long- term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms.
Rachdaoui, Nadia; Sarkar, Dipak K
Alcohol can permeate virtually every organ and tissue in the body, resulting in tissue injury and organ dysfunction. Considerable evidence indicates that alcohol abuse results in clinical abnormalities of one of the body's most important systems, the endocrine system. This system ensures proper communication between various organs, also interfacing with the immune and nervous systems, and is essential for maintaining a constant internal environment. The endocrine system includes the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, the hypothalamic-pituitary-thyroid axis, the hypothalamic-pituitary-growth hormone/insulin-like growth factor-1 axis, and the hypothalamic-posterior pituitary axis, as well as other sources of hormones, such as the endocrine pancreas and endocrine adipose tissue. Alcohol abuse disrupts all of these systems and causes hormonal disturbances that may result in various disorders, such as stress intolerance, reproductive dysfunction, thyroid problems, immune abnormalities, and psychological and behavioral disorders. Studies in both humans and animal models have helped shed light on alcohol's effects on various components of the endocrine system and their consequences.
Jang, Tae Young; Kim, Young Hyo
Allergic rhinitis is a global health problem, and its prevalence rate and socioeconomic burden continue to increase. Intranasal steroid (INS) is the first treatment choice in the majority of patients, because of its ability to effectively control allergic symptoms. However, patients and clinicians are concerned about the potential adverse effects of prolonged INS use. We performed to review for evaluating systemic and local safety of INS use, by searching MEDLINE, EMBASE, and Cochrane Library database for identification of relevant articles. In the present study, the systemic bioavailabilities of several commercially available INSs were researched, and then systemic safeties were reviewed with focus on suppression of the hypothalamus-pituitary-adrenal axis and their effects on pediatric growth. In addition, local adverse effects, such as, epistaxis and nasal septal perforation, were investigated. Finally, the authors proposed some techniques in order to avoid these complications. INSs offer a safe, effective means of treating allergic rhinitis in the short- and long-term with no or minimal adverse systemic and local effects. Copyright© Bentham Science Publishers; For any queries, please email at firstname.lastname@example.org.
James, Morgan H; Campbell, Erin J; Dayas, Christopher V
Orexins (hypocretins) are critically involved in coordinating appropriate physiological and behavioral responses to aversive and threatening stimuli. Acute stressors engage orexin neurons via direct projections from stress-sensitive brain regions. Orexin neurons, in turn, facilitate adaptive behavior via reciprocal connections as well as via direct projections to the hypophysiotropic neurons that coordinate the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Consequently, hyperactivity of the orexin system is associated with increased motivated arousal and anxiety, and is emerging as a key feature of panic disorder. Accordingly, there has been significant interest in the therapeutic potential of pharmacological agents that antagonize orexin signaling at their receptors for the treatment of anxiety disorders. In contrast, disorders characterized by inappropriately low levels of motivated arousal, such as depression, generally appear to be associated with hypoactivity of the orexin system. This includes narcolepsy with cataplexy, a disorder characterized by the progressive loss of orexin neurons and increased rates of moderate/severe depression symptomology. Here, we provide a comprehensive overview of both clinical and preclinical evidence highlighting the role of orexin signaling in stress reactivity, as well as how perturbations to this system can result in dysregulated behavioral phenotypes.
Jasper H B de Groot
Full Text Available Humans can register another person's fear not only with their eyes and ears, but also with their nose. Previous research has demonstrated that exposure to body odors from fearful individuals elicited implicit fear in others. The odor of fearful individuals appears to have a distinctive signature that can be produced relatively rapidly, driven by a physiological mechanism that has remained unexplored in earlier research. The apocrine sweat glands in the armpit that are responsible for chemosignal production contain receptors for adrenalin. We therefore expected that the release of adrenalin through activation of the rapid stress response system (i.e., the sympathetic-adrenal medullary system is what drives the release of fear sweat, as opposed to activation of the slower stress response system (i.e., hypothalamus-pituitary-adrenal axis. To test this assumption, sweat was sampled while eight participants prepared for a speech. Participants had higher heart rates and produced more armpit sweat in the fast stress condition, compared to baseline and the slow stress condition. Importantly, exposure to sweat from participants in the fast stress condition induced in receivers (N = 31 a simulacrum of the state of the sender, evidenced by the emergence of a fearful facial expression (facial electromyography and vigilant behavior (i.e., faster classification of emotional facial expressions.
Jessica M. F. Hall
Full Text Available Psychological stress, an evolutionary adaptation to the fight-or-flight response, triggers a number of physiological responses that can be deleterious under some circumstances. Stress signals activate the hypothalamus-pituitary-adrenal (HPA axis and the sympathetic nervous system. Elements derived from those systems (e.g., cortisol, catecholamines and neuropeptides can impact the immune system and possible disease states. Skin provides a first line of defense against many environmental insults. A number of investigations have indicated that the skin is especially sensitive to psychological stress, and experimental evidence shows that the cutaneous innate and adaptive immune systems are affected by stressors. For example, psychological stress has been shown to reduce recovery time of the stratum corneum barrier after its removal (innate immunity and alters antigen presentation by epidermal Langerhans cells (adaptive immunity. Moreover, psychological stress may trigger or exacerbate immune mediated dermatological disorders. Understanding how the activity of the psyche-nervous -immune system axis impinges on skin diseases may facilitate coordinated treatment strategies between dermatologists and psychiatrists. Herein, we will review the roles of the HPA axis and the sympathetic nervous system on the cutaneous immune response. We will selectively highlight how the interplay between psychological stress and the immune system affects atopic dermatitis and psoriasis.
Sullivan, Elinor L.; Riper, Kellie M.; Lockard, Rachel; Valleau, Jeanette C.
Maternal obesity, metabolic state, and diet during gestation have profound effects on offspring development. The prevalence of neurodevelopmental and mental health disorders has risen rapidly in the last several decades in parallel with the rise in obesity rates. Evidence from epidemiological studies indicates that maternal obesity and metabolic complications increase the risk of offspring developing behavioral disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and schizophrenia. Animal models show that a maternal diet high in fat similarly disrupts behavioral programming of offspring, with animals showing social impairments, increased anxiety and depressive behaviors, reduced cognitive development, and hyperactivity. Maternal obesity, metabolic conditions, and high fat diet consumption increase maternal leptin, insulin, glucose, triglycerides, and inflammatory cytokines. This leads to increased risk of placental dysfunction, and altered fetal neuroendocrine development. Changes in brain development that likely contribute to the increased risk of behavioral and mental health disorders include increased inflammation in the brain, as well as alterations in the serotonergic system, dopaminergic system and hypothalamic pituitary adrenal (HPA) axis. PMID:25913366
Hagymási, Krisztina; Reismann, Péter; Rácz, Károly; Tulassay, Zsolt
The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.
Full Text Available A substantial number of studies on basal forebrain cholinergic neurons (BFCN have provided compelling evidence for their role in the etiology of stress, cognitive aging, Alzheimer’s disease (AD, and other neurodegenerative diseases. BFCN project to a broad range of cortical sites and limbic structures, including the hippocampus, and are involved in stress and cognition. In particular, the hippocampus, the primary target tissue of the glucocorticoid stress hormones, is associated with cognitive function in tandem with hypothalamic-pituitary-adrenal (HPA axis modulation. The present review summarizes glucocorticoid and HPA axis research to date in an effort to establish the manner in which stress affects the release of acetylcholine, glucocorticoids, and their receptor in the context of cognitive processes. We attempt to provide the molecular interactive link between the glucocorticoids and cholinergic system that contributes to BFCN degeneration in stress-induced acceleration of cognitive decline in aging and AD. We also discuss the importance of animal models in facilitating such studies for pharmacological use, which could help decipher disease states and propose leads for pharmacological intervention.
Cattane, Nadia; Rossi, Roberta; Lanfredi, Mariangela; Cattaneo, Annamaria
According to several studies, the onset of the Borderline Personality Disorder (BPD) depends on the combination between genetic and environmental factors (GxE), in particular between biological vulnerabilities and the exposure to traumatic experiences during childhood. We have searched for studies reporting possible alterations in several biological processes and brain morphological features in relation to childhood trauma experiences and to BPD. We have also looked for epigenetic mechanisms as they could be mediators of the effects of childhood trauma in BPD vulnerability. We prove the role of alterations in Hypothalamic-Pituitary-Adrenal (HPA) axis, in neurotrasmission, in the endogenous opioid system and in neuroplasticity in the childhood trauma-associated vulnerability to develop BPD; we also confirm the presence of morphological changes in several BPD brain areas and in particular in those involved in stress response. Not so many studies are available on epigenetic changes in BPD patients, although these mechanisms are widely investigated in relation to stress-related disorders. A better comprehension of the biological and epigenetic mechanisms, affected by childhood trauma and altered in BPD patients, could allow to identify "at high risk" subjects and to prevent or minimize the development of the disease later in life.
Blasiak, Anna; Gundlach, Andrew L; Hess, Grzegorz; Lewandowski, Marian H
Many physiological processes fluctuate throughout the day/night and daily fluctuations are observed in brain and peripheral levels of several hormones, neuropeptides and transmitters. In turn, mediators under the "control" of the "master biological clock" reciprocally influence its function. Dysregulation in the rhythmicity of hormone release as well as hormone receptor sensitivity and availability in different tissues, is a common risk-factor for multiple clinical conditions, including psychiatric and metabolic disorders. At the same time circadian rhythms remain in a strong, reciprocal interaction with the hypothalamic-pituitary-adrenal (HPA) axis. Recent findings point to a role of circadian disturbances and excessive stress in the development of obesity and related food consumption and metabolism abnormalities, which constitute a major health problem worldwide. Appetite, food intake and energy balance are under the influence of several brain neuropeptides, including the orexigenic agouti-related peptide, neuropeptide Y, orexin, melanin-concentrating hormone and relaxin-3. Importantly, orexigenic neuropeptide neurons remain under the control of the circadian timing system and are highly sensitive to various stressors, therefore the potential neuronal mechanisms through which disturbances in the daily rhythmicity and stress-related mediator levels contribute to food intake abnormalities rely on reciprocal interactions between these elements.
Full Text Available Empirically validated interventions addressing childhood psychological problems are now readily available, but success likely depends in part on accurately identifying which children will benefit from which intervention. This pilot study examined the stress activation and response system, first as a way to differentiate high versus low-risk children, and second to explore indicators of the stress system associated with favorable intervention response. Method. Participants (N = 43, 58% male were school-aged children who qualified for inclusion in the Early Risers “Skills for Success” Prevention Program based on their elevated levels of aggressive and/or socially withdrawn behavior and a normally developing comparison group. Compared to the normally developing group, children who were participants in the intervention exhibited a more blunted cortisol response to the stress paradigm. However, for the children in the intervention group, elevated cortisol levels at the start of the stress paradigm were concurrently associated with internalizing problems and predictive of improvement in internalizing problems over time. These findings provide preliminary evidence that hypothalamic pituitary adrenal (HPA axis biological variables may be helpful tools for identifying children who would benefit from intervention and personalizing interventions.
Brandewiede, Joerg; Jakovcevski, Mira; Stork, Oliver; Schachner, Melitta
The neural cell adhesion molecule (NCAM) plays a crucial role in stress-related brain function, emotional behavior and memory formation. In this study, we investigated the functions of the glucocorticoid and serotonergic systems in mice constitutively deficient for NCAM (NCAM-/- mice). Our data provide evidence for a hyperfunction of the hypothalamic-pituitary-adrenal axis, with enlarged adrenal glands and increased stress-induced corticosterone release, but reduced hippocampal glucocorticoid receptor expression in NCAM-/- mice when compared to NCAM+/+ mice. We also obtained evidence for a hypofunction of 5-HT1A autoreceptors as indicated by increased 8-0H-DPAT-induced hypothermia. These findings suggest a disturbance of both humoral and neural stress systems in NCAM-/- mice. Accordingly, we not only confirmed previously observed hyperarousal of NCAM-/- mice in various anxiety tests, but also observed an increased response to novelty exposure in these animals. Spatial learning deficits of the NCAM-/- mice in a Morris Water maze persisted, even when mice were pretrained to prevent effects of novelty or stress. We suggest that NCAM-mediated processes are involved in both novelty/stress-related emotional behavior and in cognitive function during spatial learning.
Ding, Xiu-Fang; Zhao, Xiao-Hua; Tao, Yang; Zhong, Wei-Chao; Fan, Qin; Diao, Jian-Xin; Liu, Yuan-Liang; Chen, Yu-Yao; Chen, Jia-Xu; Lv, Zhi-Ping
Most research focuses on the hypothalamic-pituitary-adrenal (HPA) axis, hypothalamus-pituitary-thyroid (HPT) axis, and hypothalamus-pituitary-gonadal (HPGA) axis systems of abnormalities of emotions and behaviors induced by stress, while no studies of Chinese herbal medicine such as Xiao Yao San (XYS) on the mechanisms of locus coeruleus-norepinephrine (LC-NE) system have been reported. Therefore, experiments were carried out to observe mechanism of LC-NE system in response to chronic immobilization stress (CIS) and explore the antidepressant effect of XYS. Rat model was established by CIS. LC morphology in rat was conducted. The serum norepinephrine (NE) concentrations and NE biosynthesis such as tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH), and corticotrophin-releasing-factor (CRF) in LC were determined. Results showed that there were no discernible alterations in LC in rats. The serum NE concentrations, positive neurons, mean optical density (MOD), and protein levels of TH, DBH, and CRF in model group were significantly increased compared to the control group. But XYS-treated group displayed a significantly decreased in NE levels and expressions of TH, DBH, and CRF compared to the model group. In conclusion, CIS can activate LC-NE system to release NE and then result in a significant decrease in rats. XYS treatment can effectively improve depressive-like behaviors in rats through inhibition of LC-NE neurons activity.
Ros-Simó, Clara; Valverde, Olga
Early-life stressful experiences are associated to alterations in behavioural responses and development of psychiatric and neurodegenerative diseases. In rodents, individual housing is considered as a stressful condition whilst enriched environment can protect against stress and its negative consequences. Neuroendocrine responses to stress can also be altered by early-life experiences and seem to contribute to behavioural alterations induced by changes in housing conditions. To develop an improved procedure of social isolation throughout development (from pre-adolescence to adulthood) in CD1 mice and to elucidate its effects on behavioural parameters related to stress and neuroendocrine responses compared to enriched or social conditions. CD1 male mice (PND 21) were housed in social/standard conditions, enriched conditions or isolated conditions during seven weeks. After that, different relevant behaviours were evaluated, including locomotor activity, anxiety-like and despair behaviour. Levels of plasma corticosterone were also analysed before and after a stressful event. CD1 mice exposed to an isolated environment exhibited higher locomotion and anxiety-like responses than animals exposed to social or enriched conditions. In addition, isolated animals showed lower basal plasma corticosterone than social or enriched ones but after a stressful event the elevation of plasma corticosterone was higher, suggesting an enhanced response of the HPA axis to a novel and stressful situation. Social interaction is an important feature to display an appropriate behavioural and neuronal development. Habituation to novel stimuli is impaired in subjects exposed to social isolation and induces increased excitability response to stressful events. Social deprivation increases the possibility of altered neuronal function and could facilitate the development of neuropsychiatric disorders in adulthood. Copyright © 2012 Elsevier Inc. All rights reserved.
Heitkemper, M M; Cain, K C; Deechakawan, W; Poppe, A; Jun, S-E; Burr, R L; Jarrett, M E
Evidence suggests that subgroups of patients with irritable bowel syndrome (IBS) are hyper-responsive to a variety of laboratory stress conditions. This study compared sleep quality and night time plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels in response to anticipation of public speaking between 43 women with IBS and 24 healthy control women. In addition, comparisons were made between subgroups within the IBS sample based on predominant stool patterns, 22 IBS-constipation and 21 IBS-diarrhea. Subjects slept three nights in a sleep laboratory, and on the third night serial blood samples were drawn every 20 min from 08:00 PM until awakening. As the subjects had different sleep onsets, each subject's results were synchronized to the first onset of stage 2 sleep. Compared the healthy control group, women with IBS had significantly worse sleep efficiency, and higher cortisol but not ACTH levels over the night. However, there were no IBS bowel pattern subgroup differences. Among IBS subjects, cortisol levels early in the night were higher than found in our previous study with a similar protocol but without the threat of public speaking. These results suggest that a social stressor, such as public speaking prior to bedtime, increases cortisol but not ACTH levels suggesting HPA dysregulation in women with IBS. This response to a social stressor contributes to our understanding of the relationship of stress to symptom expression in IBS. © 2012 Blackwell Publishing Ltd.
Sarah M. Dinces
Full Text Available In the rat, repeated brief exposures to novelty early in life can induce long-lasting enhancements in adult cognitive, social, emotional, and neuroendocrine function. Family-to-family variations in these intervention effects on adult offspring are predicted by the mother’s ability to mount a rapid corticosterone (CORT response to the onset of an acute stressor. Here, in Long-Evans rats, we investigated whether neonatal and adulthood novelty exposure, each individually and in combination, can enhance offspring HPA regulation. Using a 2x2 within-litter design, one half of each litter were exposed to a relatively novel non-home environment for 3-min (Neo_Novel daily during infancy (PND1-21 and the other half of the litter remained in the home cage (Neo_Home; we further exposed half of these two groups to early adulthood (PND54-63 novelty exposure in an open field and the remaining siblings stayed in their home cages. Two aspects of HPA regulation were assessed: the ability to maintain a low level of resting CORT (CORTB and the ability to mount a large rapid CORT response (CORTE to the onset of an acute stressor. Assessment of adult offspring’s ability to regulate HPA regulation began at 370 days of age. We further investigated whether the novelty exposure effects on offspring HPA regulation are sensitive to the context of maternal HPA regulation by assessing maternal HPA regulation similarly beginning 7 days after her pups were weaned. We found that at the population level, rats receiving neonatal, but not early adulthood exposure or both, showed a greater rapid CORTE than their home-staying siblings. At the individual family level, these novelty effects are positively associated with maternal CORTE. These results suggest that early experience of novelty can enhance the offspring’s ability to mount a rapid response to environmental challenge and the success of such early life intervention is critically dependent upon the context of maternal HPA regulation.
Major depression (MD) is frequently accompanied by a relatively increased production of the stress hormone cortisol. During pregnancy corticotrophin releasing hormone (CRH) is secreted from the placenta and critically high levels of CRH are one of the key triggers for parturition. Maternal cortisol promotes the secretion of placental CRH. In this study, we examined the hypothesis that women suffering with MD in pregnancy would have relatively increased cortisol secretion, a time-advanced rise in placental CRH production and an earlier delivery of the baby.
Armario, A; Montero, J L; Jolin, T
Adult male Sprague-Dawley rats were subjected to food restriction so that they ate 65% of food ingested by control rats. While control rats had free access to food over the 24-hour period, food-restricted rats were provided with food daily at 10 a.m. The experimental period lasted for 34 days. On day 35, rats from both experimental groups were killed at 08.00, 11.00, 14.00, 24.00 and 02.00 h. Food restriction modified the circadian rhythms of ACTH and corticosterone. In addition, total circulating corticosterone throughout the day was higher in food-restricted than in control rats. In contrast, food restriction resulted in depressed secretion of thyroid-stimulating hormone and growth hormone. The results indicate that time of food availability entrained circadian corticosterone rhythm but not thyroid-stimulating hormone and growth hormone rhythms.
Bloch, M; Schmidt, P J; Su, T P; Tobin, M B; Rubinow, D R
Premenstrual syndrome (PMS) is a cyclic mood disorder, widely believed, yet not conclusively shown, to be of endocrine etiology. This study examines basal levels of several hormones reported, albeit inconsistently, to differ in women with PMS compared with controls. Subjects (10 PMS patients and 10 controls) had their blood drawn for one full menstrual cycle. Subjects' mood and behavioral symptoms were assessed by daily self-ratings and objective ratings. Plasma was assayed for total and free testosterone (T), beta-endorphin (beta-EP), adrenocorticotropic hormone (ACTH), and cortisol. No differences were observed between the PMS and control groups for beta-EP, ACTH, or cortisol. PMS subjects had significantly lower total and free T plasma levels with a blunting of the normal periovulatory peak, a finding that may be epiphenomenal to age. This study does not confirm previous reports of abnormalities in plasma levels of either ACTH or beta-EP in women with PMS; it also fails to replicate a previous observation of high free T levels in women with PMS. These results are not supportive of a primary endocrine abnormality in PMS patients.
Tak, Lineke M.; Bakker, Stephan J. L.; Rosmalen, Judith G. M.
In persons with functional somatic symptoms (FSS), no conventionally defined organic pathology is apparent. It has been suggested that complex interactions of psychological, physiological, and social factors are involved in the etiology of FSS. One of the physiological mechanisms that may contribute
Full Text Available This study was to investigate antidepressant activities of Shuyusan (a Chinese herb, using a rats model of depression induced by unpredictable chronic mild stress (UCMS. The administration groups were treated with Shuyusan decoction for 3 weeks and compared with fluoxetine treatment. In order to understand the potential antidepressant-like activities of Shuyusan, tail suspension test (TST and forced swimming test (FST were used as behavioral despair study. The level of corticotropin-releasing factor (CRH, adrenocorticotropic hormone (ACTH, corticosterone (CORT and hippocampus glucocorticoid receptor expression were examined. After modeling, there was a significant prolongation of immobility time in administration groups with the TST and FST. High-dose Shuyusan could reduce the immobility time measured with the TST and FST. The immobility time in high-dose herbs group and fluoxetine group was increased significantly compared with the model group. After 3 weeks herbs fed, the serum contents level of CRH, ACTH, and CORT in high-dose herb group was significantly decreased compared to the model group. The result indicated that Shuyusan had antidepressant activity effects on UCMS model rats. The potential antidepressant effect may be related to decreasing glucocorticoid levels activity, regulating the function of HPA axis, and inhibiting glucocorticoid receptor expression in hippocampus.
Wetherell, Mark A; Montgomery, Catharine
Ecstasy (MDMA) is a psychostimulant drug which is increasingly associated with psychobiological dysfunction. While some recent studies suggest acute changes in neuroendocrine function, less is known about long-term changes in HPA functionality in recreational users. The current study is the first to explore the effects of ecstasy-polydrug use on psychological distress and basal functioning of the HPA axis through assessing the secretion of cortisol across the diurnal period. Seventy-six participants (21 nonusers, 29 light ecstasy-polydrug users, 26 heavy ecstasy-polydrug users) completed a substance use inventory and measures of psychological distress at baseline, then two consecutive days of cortisol sampling (on awakening, 30 min post awakening, between 1400 and 1600 hours and pre bedtime). On day 2, participants also attended the laboratory to complete a 20-min multitasking stressor. Both user groups exhibited significantly greater levels of anxiety and depression than nonusers. On day 1, all participants exhibited a typical cortisol profile, though light users had significantly elevated levels pre-bed. On day 2, heavy users demonstrated elevated levels upon awakening and all ecstasy-polydrug users demonstrated elevated pre-bed levels compared to non-users. Significant between group differences were also observed in afternoon cortisol levels and in overall cortisol secretion across the day. The increases in anxiety and depression are in line with previous observations in recreational ecstasy-polydrug users. Dysregulated diurnal cortisol may be indicative of inappropriate anticipation of forthcoming demands and hypersecretion may lead to the increased psychological and physical morbidity associated with heavy recreational use of ecstasy.
Snake-bite is one of the high priority health problems in Myanmar, causing high mortality and mobility rates among the rural population. In 1982 the Department of Medical Research (DMR) of the Ministry of Health launched a research programme for the comprehensive studies of snake (Russell's viper) bites and since then various research divisions of the DMR have been actively engaged in both basic and clinical studies aimed at obtaining adequate knowledge of the biochemical, clinical and pathophysiological mechanisms to guide rational management of snake-bite cases. Also, a clinical research unit has been established in a particular area where the incidence of Russell's viper bite is quite high. Project MYA/6/015 was initiated in 1989 with the objective of determining the incidence, facilitating early diagnosis and assessing the value of therapy in hypopituitarism following snake bite, through the measurements of pituitary and adreno-cortical hormones in serum and their changes in response to dynamic tests. The project was completed in July 1993. The review was undertaken upon request by the Asia and Pacific Section, to assess the overall performance of the project
De Kloet, E R; De Kock, Susanne E.; Schild, V; Veldhuis, H D
Adrenalectomized rats displayed a deficiency in retention of an immobility response acquired during an initial 15-min forced swimming procedure (Porsolt swimming test) and measured 24 h later in a 5-min retest session. The deficit could be restored dose dependently with the glucocorticoid
Snake-bite is one of the high priority health problems in Myanmar, causing high mortality and mobility rates among the rural population. In 1982 the Department of Medical Research (DMR) of the Ministry of Health launched a research programme for the comprehensive studies of snake (Russell`s viper) bites and since then various research divisions of the DMR have been actively engaged in both basic and clinical studies aimed at obtaining adequate knowledge of the biochemical, clinical and pathophysiological mechanisms to guide rational management of snake-bite cases. Also, a clinical research unit has been established in a particular area where the incidence of Russell`s viper bite is quite high. Project MYA/6/015 was initiated in 1989 with the objective of determining the incidence, facilitating early diagnosis and assessing the value of therapy in hypopituitarism following snake bite, through the measurements of pituitary and adreno-cortical hormones in serum and their changes in response to dynamic tests. The project was completed in July 1993. The review was undertaken upon request by the Asia and Pacific Section, to assess the overall performance of the project.
Manzanares, Núria; Monseny, Rosa; Ortega, Laura; Montalvo, Itziar; Franch, Joan; Gutiérrez-Zotes, Alfonso; Reynolds, Rebecca M; Walker, Brian R; Vilella, Elisabet; Labad, Javier
An unhealthy lifestyle is thought to contribute to the metabolic syndrome in subjects with psychoses. In the present study we aimed to study whether life stress or cortisol measures may influence dietary patterns in subjects with early stages of psychoses. We studied 81 subjects with early psychoses (65 subjects with a psychotic disorder [PD] and food intake (24h recall). Physical activity was assessed by validated questionnaire. Life stress was assessed with Holmes-Rahe Social Readjustment Scale. Fasting morning salivary and plasma cortisol levels were determined. We found that PD and HR reported an unhealthier lifestyle with more smoking, reduced physical activity and poorer dietary habits. HR reported increased intake of calories and saturated fatty acids and reduced protein consumption, when compared to HS. Life stress was a predictor of these adverse behaviours, although we found opposite associations in HR and PD. Life stress was associated with increased intake of refined sugar in PD and decreased intake in HR and HS. Salivary cortisol was related to increased intake of saturated fat only in HR subjects, but cortisol levels in plasma or saliva were not associated with other dietary habits or obesity measures (BMI, waist circumference). Our study suggests that unhealthy diet in early psychoses is influenced by stress, but our data do not support this effect being mediated by hypercortisolism. Future preventive interventions in psychosis may target dietary habits, particularly for those who are at risk for psychosis. Copyright © 2013 Elsevier Ltd. All rights reserved.
Pearce, B.D.; Grove, J.; Bonney, E.A.; Bliwise, N.; Dudley, D.J.; Schendel, D.E.; Thorsen, P.
Background/Aims To examine the relationship of biological mediators (cytokines, stress hormones), psychosocial, obstetric history, and demographic factors in the early prediction of preterm birth (PTB) using a comprehensive logistic regression model incorporating diverse risk factors. Methods In this prospective case-control study, maternal serum biomarkers were quantified at 9–23 weeks’ gestation in 60 women delivering at order interactions. Results Among individual biomarkers, we found that macrophage migration inhibitory factor (MIF), interleukin-10, C-reactive protein (CRP), and tumor necrosis factor-α were statistically significant predictors of PTB at all cutoff levels tested (75th, 85th, and 90th percentiles). We fit multifactor models for PTB prediction at each biomarker cutoff. Our best models revealed that MIF, CRP, risk-taking behavior, and low educational attainment were consistent predictors of PTB at all biomarker cutoffs. The 75th percentile cutoff yielded the best predicting model with an area under the ROC curve of 0.808 (95% CI 0.743–0.874). Conclusion Our comprehensive models highlight the prominence of behavioral risk factors for PTB and point to MIF as a possible psychobiological mediator. PMID:20160447
Full Text Available Exposure to stress leads to physiological changes called “stress response” which are the result ofthe changes in the adrenomedullary hormone system, hypothalamus-pituitary-adrenal (HPA and sympatheticnervous system (SNS activity. In the present study, the effects of chronic physical and psychological stressand also the role of sympathetic system effects in stress on ischemia/reperfusion (I/R injuries have beenstudied in isolated rat heart. Rat heart was isolated and subjected to 30 min regional ischemia and 120 minreperfusion. The daily stress was induced for one week prior to I/R induction. Sympathectomy was donechemically by injection of hydroxyl-dopamine prior to stress induction. There were no significant changes inheart rate and Coronary Flow between groups. Left ventricular developed pressure (LVDP and rate productpressure (RPP in both physical and psychological stress groups decreased significantly compared to those incontrol group (Pgroups. Infarct size significantly increased in both physical and psychological stress groups and control group(Pas compared with stress groups (Ppsychological stress prior to ischemia/reperfusion causes enhancement of myocardial injuries and it seemsthat increased sympathetic activity in response to stress is responsible for these adverse effects of stress onischemic/reperfused heart.
Full Text Available The adaptation of an organism to a change in environmental conditions is a complex and in some aspects a poorly understood physiological process. The activating influence of stress on the sympathetic nervous system, the hypothalamic - pituitary - adrenal axis and the suppression of TSH, LH, FSH release is well known. The interplay of communication between the endocrine and immune systems plays an essential role in modulating the response to stress related mediators. The basis of many contradictory and incoherent results of experiments is due to the various methodologies of creating changes in environmental conditions, the way of collecting blood samples which influence stress mediators, the case of assessing the influence of many factors on reproductive functions and the performance of experiments without synchronization with the reproductive cycle. The review will focus on the presentation of simple and repeatable methods of development of an adaptation stress to changed environmental conditions (temperature, oxygenation, humidity and the technique of blood collection during hour-long estimation of interactions between the endocrine, nervous and immune systems. We would like to place emphasis on appropriate ways of performing experiments on female rats, with regards to the choice of a suitable phase of the reproductive cycle. Also on ways of anaesthesia and microsurgical techniques of vein catheterisation for repeated blood sampling. The performance of all phases of the experiment allow us to estimate only the influence of environmental conditions and eliminate interfering factors during the process of preparing animal for the experiment.
Baran, Arkadiusz; Jakiel, Grzegorz; Wójcik, Grazyna
The adaptation of an organism to a change in environmental conditions is a complex and in some aspects a poorly understood physiological process. The activating influence of stress on the sympathetic nervous system, the hypothalamic - pituitary - adrenal axis and the suppression of TSH, LH, FSH release is well known. The interplay of communication between the endocrine and immune systems plays an essential role in modulating the response to stress related mediators. The basis of many contradictory and incoherent results of experiments is due to the various methodologies of creating changes in environmental conditions, the way of collecting blood samples which influence stress mediators, the case of assessing the influence of many factors on reproductive functions and the performance of experiments without synchronization with the reproductive cycle. The review will focus on the presentation of simple and repeatable methods of development of an adaptation stress to changed environmental conditions (temperature, oxygenation, humidity) and the technique of blood collection during hour-long estimation of interactions between the endocrine, nervous and immune systems. We would like to place emphasis on appropriate ways of performing experiments on female rats, with regards to the choice of a suitable phase of the reproductive cycle. Also on ways of anaesthesia and microsurgical techniques of vein catheterisation for repeated blood sampling. The performance of all phases of the experiment allow us to estimate only the influence of environmental conditions and eliminate interfering factors during the process of preparing animal for the experiment.
Tarter, Ralph E; Kirisci, Levent; Kirillova, Galina; Reynolds, Maureen; Gavaler, Judy; Ridenour, Ty; Horner, Michelle; Clark, Duncan; Vanyukov, Michael
Research has shown involvement of hormones of the hypothalamic pituitary adrenal (HPA) axis and hypothalamic pituitary gonadal (HPG) axis in the regulation of behaviors that contribute to SUD risk and its intergenerational transmission. Neighborhood environment has also been shown to relate to hormones of these two neuroendocrine systems and behaviors associated with SUD liability. Accordingly, it was hypothesized that (1) parental SUD severity and neighborhood quality correlate with activity of the HPG axis (testosterone level) and HPA axis (cortisol stability), and (2) transmissible risk during childhood mediates these hormone variables on development of SUD measured in adulthood. Transmissible risk for SUD measured by the transmissible liability index (TLI; Vanyukov et al., 2009) along with saliva cortisol and plasma testosterone were prospectively measured in boys at ages 10-12 and 16. Neighborhood quality was measured using a composite score encompassing indicators of residential instability and economic disadvantage. SUD was assessed at age 22. Neither hormone variable cross-sectionally correlated with transmissible risk measured at ages 10-12 and 16. However, the TLI at age 10-12 predicted testosterone level and cortisol stability at age 16. Moreover, testosterone level, correlated with cortisol stability at age 16, predicted SUD at age 22. HPA and HPG axes activity do not underlie variation in TLI, however, high transmissible risk in childhood predicts neuroendocrine system activity presaging development of SUD. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Stress-induced inummosuppression is a well known phenomenon and mostly attributed to actions of steroid hormones released upon activation of the hypothalamus-pituitary-adrenal (HPA)-axis. In mammals, this endocrine-immune interaction is part of a
Swaab, D.F.; Bao, A.-M.; Lucassen, P.J.
Corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response. The action of CRH on ACTH release is strongly potentiated by vasopressin, that is co-produced in increasing amounts
Swaab, D.F.; Bao, A.M; Lucassen, P.J.
Corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response. The action of CRH on ACTH release is strongly potentiated by vasopressin, that is co-produced in increasing amounts
Lim, Dong Wook; Jung, Jae-Woo; Park, Ji-Hae; Baek, Nam-In; Kim, Yun Tai; Kim, In-Ho; Han, Daeseok
The root bark of Morus alba is commonly used as an alternative medicine due to its numerous health benefits in humans. However, the antidepressant effects of various active components from M. alba have not been fully elucidated. In this study, we aimed to determine whether sanggenon G, an active compound isolated from the root bark of M. alba, exhibited antidepressant-like activity in rats subjected to forced swim test (FST)-induced depression. Acute treatment of rats with sanggenon G (30 mg/kg, intraperitoneally (i.p.)) significantly reduced immobility time and increased swimming time without any significant change in climbing. Rats treated with sanggenon G also exhibited a decrease in the limbic hypothalamic-pituitary-adrenal (HPA) axis response to the FST, as indicated by attenuation of the corticosterone response and decreased c-Fos immunoreactivity in the hypothalamic paraventricular nucleus (PVN). In addition, the antidepressant-like effects of sanggenon G were significantly inhibited by WAY100635 (1 mg/kg, i.p.; a selective 5-hydroxytryptamine1A (5-HT1A) receptor antagonist), but not SCH23390 (0.05 mg/kg, i.p.; a dopamine D1 receptor antagonist). Our findings suggested that the antidepressant-like effects of sanggenon G were mediated by an interaction with the serotonergic system. Further studies are needed to evaluate the potential of sanggenon G as an alternative therapeutic approach for the treatment of depression.
Gulevich, R G; Shikhevich, S G; Konoshenko, M Yu; Kozhemyakina, R V; Herbeck, Yu E; Prasolova, L A; Oskina, I N; Plyusnina, I Z
The influence of social disturbance in early life on behavior, response of blood corticosterone level to restraint stress, and endocrine and morphometric indices of the testes was studied in 2-month Norway rat males from three populations: not selected for behavior (unselected), selected for against aggression to humans (tame), and selected for increased aggression to humans (aggressive). The experimental social disturbance included early weaning, daily replacement of cagemates from days 19 to 25, and subsequent housing in twos till the age of 2months. The social disturbance increased the latent period of aggressive behavior in the social interaction test in unselected males and reduced relative testis weights in comparison to the corresponding control groups. In addition, experimental unselected rats had smaller diameters of seminiferous tubules and lower blood testosterone levels. In the experimental group, tame rats had lower basal corticosterone levels, and aggressive animals had lower hormone levels after restraint stress in comparison to the control. The results suggest that the selection in two directions for attitude to humans modifies the response of male rats to social disturbance in early life. In this regard, the selected rat populations may be viewed as a model for investigation of (1) neuroendocrinal mechanisms responsible for the manifestation of aggression and (2) interaction of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal systems in stress. Copyright © 2015 Elsevier Inc. All rights reserved.
Morena, Maria; Patel, Sachin; Bains, Jaideep S; Hill, Matthew N
Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.
Lorey K. Takahashi
Full Text Available When prey animals detect the odor of a predator a constellation of fear-related autonomic, endocrine, and behavioral responses rapidly occur to facilitate survival. How olfactory sensory systems process predator odor and channel that information to specific brain circuits is a fundamental issue that is not clearly understood. However, research in the last 15 years has begun to identify some of the essential features of the sensory detection systems and brain structures that underlie predator odor fear. For instance, the main (MOS and accessory olfactory systems (AOS detect predator odors and different types of predator odors are sensed by specific receptors located in either the MOS or AOS. However, complex predator chemosignals may be processed by both the MOS and AOS, which complicate our understanding of the specific neural circuits connected directly and indirectly from the MOS and AOS to activate the physiological and behavioral components of unconditioned and conditioned fear. Studies indicate that brain structures including the dorsal periaqueductal gray, paraventricular nucleus of the hypothalamus, and the medial amygdala appear to be broadly involved in predator odor induced autonomic activity and hypothalamic-pituitary-adrenal stress hormone secretion. The medial amygdala also plays a key role in predator odor unconditioned fear behavior and retrieval of contextual fear memory associated with prior predator odor experiences. Other neural structures including the bed nucleus of the stria terminalis and the ventral hippocampus appear prominently involve in predator odor fear behavior. The basolateral amygdala, medial hypothalamic nuclei, and medial prefrontal cortex are also activated by some but not all predator odors. Future research that characterizes how distinct predator odors are uniquely processed in olfactory systems and neural circuits will provide significant insights into the differences of how diverse predator odors activate
Takahashi, Lorey K.
When prey animals detect the odor of a predator a constellation of fear-related autonomic, endocrine, and behavioral responses rapidly occur to facilitate survival. How olfactory sensory systems process predator odor and channel that information to specific brain circuits is a fundamental issue that is not clearly understood. However, research in the last 15 years has begun to identify some of the essential features of the sensory detection systems and brain structures that underlie predator odor fear. For instance, the main (MOS) and accessory olfactory systems (AOS) detect predator odors and different types of predator odors are sensed by specific receptors located in either the MOS or AOS. However, complex predator chemosignals may be processed by both the MOS and AOS, which complicate our understanding of the specific neural circuits connected directly and indirectly from the MOS and AOS to activate the physiological and behavioral components of unconditioned and conditioned fear. Studies indicate that brain structures including the dorsal periaqueductal gray (DPAG), paraventricular nucleus (PVN) of the hypothalamus, and the medial amygdala (MeA) appear to be broadly involved in predator odor induced autonomic activity and hypothalamic-pituitary-adrenal (HPA) stress hormone secretion. The MeA also plays a key role in predator odor unconditioned fear behavior and retrieval of contextual fear memory associated with prior predator odor experiences. Other neural structures including the bed nucleus of the stria terminalis and the ventral hippocampus (VHC) appear prominently involved in predator odor fear behavior. The basolateral amygdala (BLA), medial hypothalamic nuclei, and medial prefrontal cortex (mPFC) are also activated by some but not all predator odors. Future research that characterizes how distinct predator odors are uniquely processed in olfactory systems and neural circuits will provide significant insights into the differences of how diverse predator
Bekdash, Rola; Zhang, Changqing; Sarkar, Dipak
Hypothalamic proopiomelanocortin (POMC) neurons, one of the major regulators of the hypothalamic-pituitary-adrenal (HPA) axis, immune functions, and energy homeostasis, are vulnerable to the adverse effects of fetal alcohol exposure (FAE). These effects are manifested in POMC neurons by a decrease in Pomc gene expression, a decrement in the levels of its derived peptide β-endorphin and a dysregulation of the stress response in the adult offspring. The HPA axis is a major neuroendocrine system with pivotal physiological functions and mode of regulation. This system has been shown to be perturbed by prenatal alcohol exposure. It has been demonstrated that the perturbation of the HPA axis by FAE is long-lasting and is linked to molecular, neurophysiological, and behavioral changes in exposed individuals. Recently, we showed that the dysregulation of the POMC system function by FAE is induced by epigenetic mechanisms such as hypermethylation of Pomc gene promoter and an alteration in histone marks in POMC neurons. This developmental programming of the POMC system by FAE altered the transcriptome in POMC neurons and induced a hyperresponse to stress in adulthood. These long-lasting epigenetic changes influenced subsequent generations via the male germline. We also demonstrated that the epigenetic programming of the POMC system by FAE was reversed in adulthood with the application of the inhibitors of DNA methylation or histone modifications. Thus, prenatal environmental influences, such as alcohol exposure, could epigenetically modulate POMC neuronal circuits and function to shape adult behavioral patterns. Identifying specific epigenetic factors in hypothalamic POMC neurons that are modulated by fetal alcohol and target Pomc gene could be potentially useful for the development of new therapeutic approaches to treat stress-related diseases in patients with fetal alcohol spectrum disorders. Copyright © 2014 by the Research Society on Alcoholism.
Slominski, Andrzej T; Zmijewski, Michal A; Skobowiat, Cezary; Zbytek, Blazej; Slominski, Radomir M; Steketee, Jeffery D
Skin, the body's largest organ, is strategically located at the interface with the external environment where it detects, integrates, and responds to a diverse range of stressors including solar radiation. It has already been established that the skin is an important peripheral neuro-endocrine-immune organ that is tightly networked to central regulatory systems. These capabilities contribute to the maintenance of peripheral homeostasis. Specifically, epidermal and dermal cells produce and respond to classical stress neurotransmitters, neuropeptides, and hormones. Such production is stimulated by ultraviolet radiation (UVR), biological factors (infectious and noninfectious), and other physical and chemical agents. Examples of local biologically active products are cytokines, biogenic amines (catecholamines, histamine, serotonin, and N-acetyl-serotonin), melatonin, acetylocholine, neuropeptides including pituitary (proopiomelanocortin-derived ACTH, beta-endorphin or MSH peptides, thyroid-stimulating hormone) and hypothalamic (corticotropin-releasing factor and related urocortins, thyroid-releasing hormone) hormones as well as enkephalins and dynorphins, thyroid hormones, steroids (glucocorticoids, mineralocorticoids, sex hormones, 7-delta steroids), secosteroids, opioids, and endocannabinoids. The production of these molecules is hierarchical, organized along the algorithms of classical neuroendocrine axes such as hypothalamic-pituitary-adrenal axis (HPA), hypothalamic-thyroid axis (HPT), serotoninergic, melatoninergic, catecholaminergic, cholinergic, steroid/secosteroidogenic, opioid, and endocannbinoid systems. Dysregulation of these axes or of communication between them may lead to skin and/ or systemic diseases. These local neuroendocrine networks are also addressed at restricting maximally the effect of noxious environmental agents to preserve local and consequently global homeostasis. Moreover, the skin-derived factors/systems can also activate cutaneous nerve
Slominski, Andrzej T; Zmijewski, Michal A; Plonka, Przemyslaw M; Szaflarski, Jerzy P; Paus, Ralf
The skin, a self-regulating protective barrier organ, is empowered with sensory and computing capabilities to counteract the environmental stressors to maintain and restore disrupted cutaneous homeostasis. These complex functions are coordinated by a cutaneous neuro-endocrine system that also communicates in a bidirectional fashion with the central nervous, endocrine, and immune systems, all acting in concert to control body homeostasis. Although UV energy has played an important role in the origin and evolution of life, UV absorption by the skin not only triggers mechanisms that defend skin integrity and regulate global homeostasis but also induces skin pathology (e.g., cancer, aging, autoimmune responses). These effects are secondary to the transduction of UV electromagnetic energy into chemical, hormonal, and neural signals, defined by the nature of the chromophores and tissue compartments receiving specific UV wavelength. UV radiation can upregulate local neuroendocrine axes, with UVB being markedly more efficient than UVA. The locally induced cytokines, corticotropin-releasing hormone, urocortins, proopiomelanocortin-peptides, enkephalins, or others can be released into circulation to exert systemic effects, including activation of the central hypothalamic-pituitary-adrenal axis, opioidogenic effects, and immunosuppression, independent of vitamin D synthesis. Similar effects are seen after exposure of the eyes and skin to UV, through which UVB activates hypothalamic paraventricular and arcuate nuclei and exerts very rapid stimulatory effects on the brain. Thus, UV touches the brain and central neuroendocrine system to reset body homeostasis. This invites multiple therapeutic applications of UV radiation, for example, in the management of autoimmune and mood disorders, addiction, and obesity.
Leff-Gelman, Philippe; Mancilla-Herrera, Ismael; Flores-Ramos, Mónica; Cruz-Fuentes, Carlos; Reyes-Grajeda, Juan Pablo; García-Cuétara, María Del Pilar; Bugnot-Pérez, Marielle Danitza; Pulido-Ascencio, David Ellioth
Major depression during pregnancy is a common psychiatric disorder that arises from a complex and multifactorial etiology. Psychosocial stress, sex, hormones, and genetic vulnerability increase the risk for triggering mood disorders. Microglia and toll-like receptor 4 play a crucial role in triggering wide and varied stress-induced responses mediated through activation of the inflammasome; this leads to the secretion of inflammatory cytokines, increased serotonin metabolism, and reduction of neurotransmitter availability along with hypothalamic-pituitary-adrenal axis hyperactivity. Dysregulation of this intricate neuroimmune communication network during pregnancy modifies the maternal milieu, enhancing the emergence of depressive symptoms and negative obstetric and neuropsychiatric outcomes. Although several studies have clearly demonstrated the role of the innate immune system in major depression, it is still unclear how the placenta, the brain, and the monoaminergic and neuroendocrine systems interact during perinatal depression. Thus, in the present review we describe the cellular and molecular interactions between these systems in major depression during pregnancy, proposing that the same stress-related mechanisms involved in the activation of the NLRP3 inflammasome in microglia and peripheral myeloid cells in depressed patients operate in a similar fashion in the neuroimmune placenta during perinatal depression. Thus, activation of Toll-like receptor 2 and 4 signaling and the NLRP3 inflammasome in placental immune cells may promote a shift of the Th1/Th2 bias towards a predominant Th1/Th17 inflammatory response, associated with increased secretion of pro-inflammatory cytokines, among other secreted autocrine and paracrine mediators, which play a crucial role in triggering and/or exacerbating depressive symptoms during pregnancy.
van Reedt Dortland, Arianne K B; Vreeburg, Sophie A; Giltay, Erik J; Licht, Carmilla M M; Vogelzangs, Nicole; van Veen, Tineke; de Geus, Eco J C; Penninx, Brenda W J H; Zitman, Frans G
Dyslipidemia and obesity have been observed in persons with severe anxiety or depression, and in tricyclic antidepressant (TCA) users. This likely contributes to the higher risk of cardiovascular disease (CVD) in anxiety and depressive disorders. We aimed to elucidate whether biological stress systems or lifestyle factors underlie these associations. If so, they may be useful targets for CVD prevention and intervention. Within 2850 Netherlands Study of Depression and Anxiety (NESDA) participants, we evaluated the explaining impact of biological stress systems (i.e., the hypothalamic-pituitary-adrenal [HPA] axis, autonomic nervous system [ANS] and inflammation) and lifestyle factors (i.e., tobacco and alcohol use, and physical activity) on adverse associations of anxiety and depression severity and TCA use with high and low-density lipoprotein cholesterol, triglycerides, body mass index and waist circumference. Through linear regression analyses, percentual change (%Δ) in β was determined and considered significant when %Δ>10. The inflammatory marker C-reactive protein had the most consistent impact (explaining 14-53% of the associations of anxiety and depression severity and TCA use with lipid and obesity levels), followed by tobacco use (explaining 34-43% of the associations with lipids). The ANS mediated all associations with TCA use (explaining 32-61%). The HPA axis measures did not explain any of the associations. Increased dyslipidemia and (abdominal) obesity risk in patients with more severe anxiety disorders and depression may be partly explained by chronic low-grade inflammation and smoking. TCAs may increase metabolic risk through enhanced sympathetic and decreased parasympathetic ANS activity. That the HPA axis had no impact in our sample may reflect the possibility that the HPA axis only plays a role in acute stress situations rather than under basal conditions. Copyright © 2012 Elsevier Ltd. All rights reserved.
Full Text Available Zhifeng Zhong,1 Jing Han,1 Jizhou Zhang,1 Qing Xiao,1 Juan Hu,1,2 Lidian Chen1,2 1Institute of Materia Medica, Fujian Academy of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China; 2School of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China Abstract: The primary objective of this review article was to summarize comprehensive information related to the neuropharmacological activity, mechanisms of action, toxicity, and safety of salidroside in medicine. A number of studies have revealed that salidroside exhibits neuroprotective activities, including anti-Alzheimer’s disease, anti-Parkinson’s disease, anti-Huntington’s disease, anti-stroke, anti-depressive effects, and anti-traumatic brain injury; it is also useful for improving cognitive function, treating addiction, and preventing epilepsy. The mechanisms underlying the potential protective effects of salidroside involvement are the regulation of oxidative stress response, inflammation, apoptosis, hypothalamus-pituitary-adrenal axis, neurotransmission, neural regeneration, and the cholinergic system. Being free of side effects makes salidroside potentially attractive as a candidate drug for the treatment of neurological disorders. It is evident from the available published literature that salidroside has potential use as a beneficial therapeutic medicine with high efficacy and low toxicity to the central nervous system. However, the definite target protein molecules remain unclear, and clinical trials regarding this are currently insufficient; thus, guidance for further research on the molecular mechanisms and clinical applications of salidroside is urgent. Keywords: salidroside, Alzheimer’s disease, Parkinson’s disease, stroke, cognitive impairment, clinical trials
Full Text Available Neonatal exposure of rodents to an immune challenge alters a variety of behavioural and physiological parameters in adulthood. In particular, neonatal lipopolysaccharide (LPS; 0.05 mg/kg, i.p. exposure produces robust increases in anxiety-like behaviour, accompanied by persistent changes in hypothalamic-pituitary-adrenal (HPA axis functioning. Altered autonomic nervous system (ANS activity is an important physiological contributor to the generation of anxiety. Here we examined the long term effects of neonatal LPS exposure on ANS function and the associated changes in neuroendocrine and behavioural indices. ANS function in Wistar rats, neonatally treated with LPS, was assessed via analysis of tyrosine hydroxylase (TH in the adrenal glands on postnatal days (PNDs 50 and 85, and via plethysmographic assessment of adult respiratory rate in response to mild stress (acoustic and light stimuli. Expression of genes implicated in regulation of autonomic and endocrine activity in the relevant brain areas was also examined. Neonatal LPS exposure produced an increase in TH phosphorylation and activity at both PNDs 50 and 85. In adulthood, LPS-treated rats responded with increased respiratory rates to the lower intensities of stimuli, indicative of increased autonomic arousal. These changes were associated with increases in anxiety-like behaviours and HPA axis activity, alongside altered expression of the GABA-A receptor α2 subunit, CRH receptor type 1, CRH binding protein, and glucocorticoid receptor mRNA levels in the prefrontal cortex, hippocampus and hypothalamus. The current findings suggest that in addition to the commonly reported alterations in HPA axis functioning, neonatal LPS challenge is associated with a persistent change in ANS activity, associated with, and potentially contributing to, the anxiety-like phenotype. The findings of this study reflect the importance of changes in the perinatal microbial environment on the ontogeny of
Markov, Dmitrii D; Yatsenko, Ksenia A; Inozemtseva, Lyudmila S; Grivennikov, Igor A; Myasoedov, Nikolai F; Dolotov, Oleg V
Emerging evidence implicates impaired self-regulation of the hypothalamic-pituitary-adrenal (HPA) axis and inflammation as important and closely related components of the pathophysiology of major depression. Antidepressants show anti-inflammatory effects and are suggested to enhance glucocorticoid feedback inhibition of the HPA axis. HPA axis activity is also negatively self-regulated by the adrenocorticotropic hormone (ACTH), a potent anti-inflammatory peptide activating five subtypes of melanocortin receptors (MCRs). There are indications that ACTH-mediated feedback can be activated by noncorticotropic N-terminal ACTH fragments such as a potent anti-inflammatory MC1/3/4/5R agonist α-melanocyte-stimulating hormone (α-MSH), corresponding to ACTH(1-13), and a MC3/5R agonist ACTH(4-10). We investigated whether intraperitoneal administration of rats with these peptides affects anhedonia, which is a core symptom of depression. Inflammation-related anhedonia was induced by a single intraperitoneal administration of a low dose (0.025mg/kg) of lipopolysaccharide (LPS). Stress-related anhedonia was induced by the chronic unpredictable stress (CUS) procedure. The sucrose preference test was used to detect anhedonia. We found that ACTH(4-10) pretreatment decreased LPS-induced increase in serum corticosterone and tumor necrosis factor (TNF)-α, and a MC3/4R antagonist SHU9119 blocked this effect. Both α-MSH and ACTH(4-10) alleviated LPS-induced anhedonia. In the CUS model, these peptides reduced anhedonia and normalized body weight gain. The data indicate that systemic α-MSH and ACTH(4-10) produce an antidepressant-like effect on anhedonia induced by stress or inflammation, the stimuli that trigger the release of ACTH and α-MSH into the bloodstream. The results suggest a counterbalancing role of circulating melanocortins in depression and point to a new approach for antidepressant treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.
Sominsky, Luba; Fuller, Erin A; Bondarenko, Evgeny; Ong, Lin Kooi; Averell, Lee; Nalivaiko, Eugene; Dunkley, Peter R; Dickson, Phillip W; Hodgson, Deborah M
Neonatal exposure of rodents to an immune challenge alters a variety of behavioural and physiological parameters in adulthood. In particular, neonatal lipopolysaccharide (LPS; 0.05 mg/kg, i.p.) exposure produces robust increases in anxiety-like behaviour, accompanied by persistent changes in hypothalamic-pituitary-adrenal (HPA) axis functioning. Altered autonomic nervous system (ANS) activity is an important physiological contributor to the generation of anxiety. Here we examined the long term effects of neonatal LPS exposure on ANS function and the associated changes in neuroendocrine and behavioural indices. ANS function in Wistar rats, neonatally treated with LPS, was assessed via analysis of tyrosine hydroxylase (TH) in the adrenal glands on postnatal days (PNDs) 50 and 85, and via plethysmographic assessment of adult respiratory rate in response to mild stress (acoustic and light stimuli). Expression of genes implicated in regulation of autonomic and endocrine activity in the relevant brain areas was also examined. Neonatal LPS exposure produced an increase in TH phosphorylation and activity at both PNDs 50 and 85. In adulthood, LPS-treated rats responded with increased respiratory rates to the lower intensities of stimuli, indicative of increased autonomic arousal. These changes were associated with increases in anxiety-like behaviours and HPA axis activity, alongside altered expression of the GABA-A receptor α2 subunit, CRH receptor type 1, CRH binding protein, and glucocorticoid receptor mRNA levels in the prefrontal cortex, hippocampus and hypothalamus. The current findings suggest that in addition to the commonly reported alterations in HPA axis functioning, neonatal LPS challenge is associated with a persistent change in ANS activity, associated with, and potentially contributing to, the anxiety-like phenotype. The findings of this study reflect the importance of changes in the perinatal microbial environment on the ontogeny of physiological processes.
Knorr, Ulla; Vinberg, Maj; Hansen, Allan
Introduction The mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. The aim of the AGENDA trial was to investigate whether long-ter...
Maniaci, G.; Goudriaan, A. E.; Cannizzaro, C.; van Holst, R. J.
Gambling has been associated with increased sympathetic nervous system output and stimulation of the hypothalamic-pituitary-adrenal axis. However it is unclear how these systems are affected in pathological gambling. This study aimed to investigate the effect of the Trier Social Stress Test (TSST)
Booij, Sanne H; Bos, Elisabeth H; de Jonge, Peter; Oldehinkel, Albertine J
The hypothalamic-pituitary-adrenal axis, autonomic nervous system, and immune system have been proposed to underlie the antidepressant effect of exercise. Using a population sample of 715 adolescents, we examined whether pathways from exercise to affective and somatic symptoms of depression were
Laurent, Heidemarie K.; Ablow, Jennifer C.; Measelle, Jeffrey
This study investigated continuity and stability of hypothalamic-pituitary-adrenal (HPA) and sympathetic nervous system (SNS) response measures in mother-infant dyads across 2 different types of social stress sessions. Synchrony of response trajectories across systems (SNS-HPA coordination) and partners (mother-infant attunement) was addressed, as…
Knorr, Ulla Benedichte Søsted; Vinberg, Maj; Hansen, Allan
Abstract Introduction: The mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. The aim of the AGENDA trial was to investigate whether...
Alexandre A da Silva
Full Text Available The hypothalamic-pituitary-adrenal (HPA axis has been postulated to play a major role in mediating the antidiabetic effects of leptin. We tested if the pituitary is essential for the chronic central nervous system mediated actions of leptin on metabolic and cardiovascular function in insulin-dependent diabetic and non-diabetic rats. Male 12-week-old hypophysectomized Sprague-Dawley rats (Hypo, n = 5 were instrumented with telemetry probes for determination of mean arterial pressure (MAP and heart rate (HR 24-hrs/day and an intracerebroventricular (ICV cannula was placed into the brain lateral ventricle for continuous leptin infusion. In additional groups of Hypo and control rats (n = 5/group, diabetes was induced by single injection of streptozotocin (50 mg/kg, IP. Hypo rats were lighter, had lower MAP and HR (83±4 and 317±2 vs 105±4 mmHg and 339±4 bpm, with similar caloric intake per kilogram of body weight and fasting plasma glucose levels (84±4 vs 80±4 mg/dl compared to controls. Chronic ICV leptin infusion (7 days, 0.62 μg/hr in non-diabetic rats reduced caloric intake and body weight (-10% in Hypo and control rats and markedly increased HR in control rats (~25 bpm while causing only modest HR increases in Hypo rats (8 bpm. In diabetic Hypo and control rats, leptin infusion reduced caloric intake, body weight and glucose levels (323±74 to 99±20 and 374±27 to 108±10 mg/dl, respectively; however, the effects of leptin on HR were abolished in Hypo rats. These results indicate that hypophysectomy attenuates leptin's effect on HR regulation without altering leptin's ability to suppress appetite or normalize glucose levels in diabetes.
Dieleman, Gwendolyn C; Huizink, Anja C; Tulen, Joke H M; Utens, Elisabeth M W J; Creemers, Hanneke E; van der Ende, Jan; Verhulst, Frank C
It is of debate whether or not childhood anxiety disorders (AD) can be captured by one taxonomic construct. This study examined whether perceived arousal (PA), autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis measures can distinguish children with different primary diagnoses of clinical anxiety disorders (AD) from each other, and from a general population reference group (GP). The study sample consisted of 152 AD children (comparing separation anxiety disorder, generalized anxiety disorder, social phobia and specific phobia), aged 8- to 12-years, and 200 same-aged reference children. HPA-axis functioning was measured by a diurnal cortisol profile. ANS functioning was measured by continuous measures of skin conductance level in rest and during a mental arithmetic task and high frequency heart rate variability in rest. PA was assessed by a questionnaire. The AD sample showed lower high frequency heart rate variability during rest, heightened anticipatory PA, higher basal and reactive skin conductance levels and lower basal HPA-axis functioning compared to the GP sample. The existence of three or more clinical disorders, i.e. a high clinical 'load', was associated with lower basal HPA-axis functioning, higher skin conductance level and lower posttest PA. Specific phobia could be discerned from social phobia and separation anxiety disorder on higher skin conductance level. Our findings indicated that children with AD have specific psychophysiological characteristics, which resemble the psychophysiological characteristics of chronic stress. A high clinical 'load' is associated with an altered ANS and HPA-axis functioning. Overall, ANS and HPA-axis functioning relate to AD in general, accept for specific phobia. Copyright © 2014 Elsevier Ltd. All rights reserved.
The body's ability to adapt to stressors is essential for survival. Failure of stress adaptation may lead to the development of stress-related disorders. The traditionally known adaptation system in vertebrates, is the hypothalamo-pituitary-adrenal (HPA-) axis, in which corticotropin-releasing
Larsen, J.K.; Ramshorst, B. van; Doornen, L.J.P. van; Geenen, R.
Background Binge eating episodes characterized by loss of control are hypothesized to be accompanied by changes in hypothalamic pituitary adrenal (HPA) axis functioning. Cortisol is an end product of this neuroendocrine stress system. Purpose The aim of this study was to examine the cortisol
Breivik, T.; Thrane, P.S.; Gjermo, P.; Cools, A.R.; Myhrer, T.
The hippocampus, which is a brain structure involved in learning and memory processes, plays a key role in the feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic sympathetic nervous system, and the subsequent secretion of immuno-modulatory hormones in response to
Breivik, T.; Thrane, P.S.; Gjermo, P.; Cools, A.R.; Myhrer, T.
The hippocampus, which is a brain structure involved in learning and memory processes, plays a key role in the feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic sympathetic nervous system, and the subsequent secretion of immuno-modulatory hormones in response to
Bakvis, P.; Spinhoven, P.; Giltay, E.J.; Kuyk, J.; Edelbroek, P.M.; Zitman, F.G.; Roelofs, K.
Purpose: Several studies have indicated that psychogenic nonepileptic seizures (PNES) are associated with psychological trauma, but only a few studies have examined the associations with neurobiologic stress systems, such as the hypothalamus-pituitary-adrenal (HPA) axis and its end-product cortisol.
In response to a stressful situation the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis are activated, eventually leading to the release of catecholamines and corticosteroids. These stress hormones bind to different receptors in the brain (in case of corticosteroids,
Vigil, Jacob M.; Geary, David C.; Granger, Douglas A.; Flinn, Mark V.
The study examines group and individual differences in psychological functioning and hypothalamic-pituitary-adrenal and sympathetic nervous system (SNS) activity among adolescents displaced by Hurricane Katrina and living in a U.S. government relocation camp (n = 62, ages 12-19 years) 2 months postdisaster. Levels of salivary cortisol, salivary…
Rudolph, Karen D.; Troop-Gordon, Wendy; Granger, Douglas A.
This research examined whether variations in salivary measures of the hypothalamic-pituitary-adrenal axis (cortisol) and autonomic nervous system (alpha amylase [sAA]) contribute to individual differences in the association between peer victimization and aggression. Children (N = 132; M age = 9.46 years, SD = 0.33) completed a measure of peer…
Hatfield, Bridget E.; Hestenes, Linda L.; Kintner-Duffy, Victoria L.; O'Brien, Marion
Accumulating evidence suggests children enrolled in full-time child care often display afternoon elevations of the hormone cortisol, which is an indicator of stress. Recent advances in immunoassays allow for measurement of activity in the hypothalamic-pituitary-adrenal axis and the autonomic sympathetic nervous system from saliva, and measurement…
Brødsgaard, Anne; Nielsen, Tove; Mølgaard, Ulla
, such as suppression of the hypothalamic-pituitary-adrenal axis, as we did not investigate this. However, the risk of meaningful systemic side effects may be considered negligible, as only a small amount of cream, of between 2-5 mg per application, was applied to a very small surface area. This article is protected...
McCormick, Cheryl M.; Mathews, Iva Z.; Thomas, Catherine; Waters, Patti
Developmental differences in hypothalamic-pituitary-adrenal (HPA) axis responsiveness to stressors and ongoing development of glucocorticoid-sensitive brain regions in adolescence suggest that similar to the neonatal period of ontogeny, adolescence may also be a sensitive period for programming effects of stressors on the central nervous system.…
Haussmann, Mark F.; Vleck, Carol M; Farrar, Eugenia S.
Perceived stress activates the hypothalamus-pituitary-adrenal axis, resulting in the release of glucocorticoids into the systemic circulation. Glucocorticoids cause the elevation of blood glucose, providing the necessary energy for the organism to cope with stress. Here, we outline a laboratory exercise that uses a competitive ELISA kit to…
In this thesis we investigated (traumatic) stress and psychopathology with a focus on the potential roles of the hypothalamus-pituitary-adrenal (HPA) axis, the GABA system, their association, and the general genetic background of major depressive disorder (MDD) and posttraumatic stress disorder
Pulmonary and systemic effects of ozone (O3) are mediated by hypothalamus pituitary adrenal (HPA)-axis activation. Fish oil (FO) and olive oil (OO) dietary supplementation have several cardioprotective benefits, but it is not established if these supplements can protect against t...
Benthem, L; Keizer, Klaas-Jan; Wiegman, CH; De Boer, SF; Strubbe, JH; Steffens, AB; Kuipers, F; Scheurink, AJW
We tested the hypothesis that excessive portal venous supply of long-chain fatty acids to the liver contributes to the development of insulin resistance via activation of the hypothalamus-pituitary-adrenal axis (HPA axis) and sympathetic system. Rats received an intraportal infusion of the
cortex. Physiology a Behavior, IQ, 203-206, 1983. Garcia, J., Hankins, W. G., Coil, S. D. Koalas , men and other conditional gastronomes. In Food...Conditioned taste aversion and the pituitary-adrenal system. Behavioral Biology , 16, 413-424, 1976. Kalat, J. W., Rozin, P. "Learned safety" as a
Pecoraro, Norman; Dallman, Mary F.; Warne, James P.; Ginsberg, Abigail B.; Laugero, Kevin D.; la Fleur, Susanne E.; Houshyar, Hani; Gomez, Francisca; Bhargava, Aditi; Akana, Susan F.
The hypothalamo-pituitary-adrenal (HPA) axis is the critical mediator of the vertebrate stress response system, responding to environmental stressors by maintaining internal homeostasis and coupling the needs of the body to the wants of the mind. The HPA axis has numerous complex drivers and highly
Lechner, O; Dietrich, H; Oliveira dos Santos, A; Wiegers, G J; Schwarz, S; Harbutz, M; Herold, M; Wick, G
The immune system interacts with the hypothalamo-pituitary-adrenal axis via so-called glucocorticoid increasing factors, which are produced by the immune system during immune reactions, causing an elevation of systemic glucocorticoid levels that contribute to preservation of the immune reactions specificities. Previous results from our laboratory had already shown an altered immuno-neuroendocrine dialogue via the hypothalamo-pituitary-adrenal axis in autoimmune disease-prone chicken and mouse strains. In the present study, we further investigated the altered glucocorticoid response via the hypothalamo-pituitary-adrenal axis in murine lupus. We established the circadian rhythms of corticosterone, dehydroepiandrosterone-sulfate, adrenocorticotropic hormone and melatonin, as well as the time response curves after injection of interleukin-1 of the first three parameters in normal SWISS and lupus-prone MRL/MP-fas(Ipr) mice. The results show that lupus-prone MRL/ MP-fas(Ipr) mice do not react appropriately to changes of the light/dark cycle, circadian melatonin rhythms seem to uncouple from the light/dark cycle, and plasma corticosterone levels are elevated during the resting phase. Diurnal changes of dehydroepiandrosterone-sulfate and adrenocorticotropic hormone were normal compared to healthy controls. These data indicate that MRL/ MP-fas(Ipr) mice not only show an altered glucocorticoid response mediated via the hypothalamo pituitary adrenal axis to IL-1, but are also affected by disturbances of corticosterone and melatonin circadian rhythms. Our findings may have implications for intrathymic T cell development and the emergence of autoimmune disease.
Yam, Kit-Yi; Naninck, Eva F G; Schmidt, Mathias V; Lucassen, Paul J; Korosi, Aniko
Clinical and pre-clinical studies have shown that early-life adversities, such as abuse or neglect, can increase the vulnerability to develop psychopathologies and cognitive decline later in life. Remarkably, the lasting consequences of stress during this sensitive period on the hypothalamic-pituitary-adrenal axis and emotional function closely resemble the long-term effects of early malnutrition and suggest a possible common pathway mediating these effects. During early-life, brain development is affected by both exogenous factors, like nutrition and maternal care as well as by endogenous modulators including stress hormones. These elements, while mostly considered for their independent actions, clearly do not act alone but rather in a synergistic manner. In order to better understand how the programming by early-life stress takes place, it is important to gain further insight into the exact interplay of these key elements, the possible common pathways as well as the underlying molecular mechanisms that mediate their effects. We here review evidence that exposure to both early-life stress and early-life under-/malnutrition similarly lead to life-long alterations on the neuroendocrine stress system and modify emotional functions. We further discuss how the different key elements of the early-life environment interact and affect one another and next suggest a possible role for the early-life adversity induced alterations in metabolic hormones and nutrient availability in shaping later stress responses and emotional function throughout life, possibly via epigenetic mechanisms. Such knowledge will help to develop intervention strategies, which gives the advantage of viewing the synergistic action of a more complete set of changes induced by early-life adversity.
Bunce, Scott C; Harris, Jonathan D; Bixler, Edward O; Taylor, Megan; Muelly, Emilie; Deneke, Erin; Thompson, Kenneth W; Meyer, Roger E
There is growing evidence for a neuroadaptive model underlying vulnerability to relapse in opioid dependence. The purpose of this study was to evaluate clinical measures hypothesized to mirror elements of allostatic dysregulation in patients dependent on prescription opioids at 2 time points after withdrawal, compared with healthy control participants. Recently withdrawn (n = 7) prescription opioid-dependent patients were compared with the patients in supervised residential care for 2 to 3 months (extended care; n = 7) and healthy controls (n = 7) using drug cue reactivity, affect-modulated startle response tasks, salivary cortisol, and 8 days of sleep actigraphy. Prefrontal cortex was monitored with functional near-infrared spectroscopy during the cue reactivity task. Startle response results indicated reduced hedonic response to natural rewards among patients recently withdrawn from opioids relative to extended care patients. The recently withdrawn patients showed increased activation to pill stimuli in right dorsolateral prefrontal cortex relative to extended care patients. Cortisol levels were elevated among recently withdrawn patients and intermediate for extended care relative to healthy controls. Actigraphy indicated disturbed sleep between recently withdrawn patients and extended care patients; extended care patients were similar to controls. Dorsolateral prefrontal cortex activation to drug and natural reward cues, startle responses to natural reward cues, day-time cortisol levels, time in bed, and total time spent sleeping were all correlated with the number of days since last drug use (ie, time in supervised residential treatment). These results suggest possible re-regulation of dysregulated hypothalamic-pituitary-adrenal axis and brain reward systems in prescription opioid-dependent patients over the drug-free period in residential treatment.
Bosch, Oliver J; Nair, Hemanth P; Ahern, Todd H; Neumann, Inga D; Young, Larry J
Social relationships significantly influence physiology and behavior, including the hypothalamo-pituitary-adrenal axis, anxiety, and mental health. Disruption of social bonds through separation or death often results in profound grieving, depression, and physical illness. As the monogamous prairie vole forms enduring, selective pair bonds with the mating partner, they provide an animal model to study the physiological consequences of pair bonding and, thus, the loss of the bonded partner. Male prairie voles were paired with a novel female or male sibling. After 5 days, half of the males of each group were separated from the partner. Elevated plus-maze, forced swim, and tail suspension tests were used to assess anxiety-like and passive stress-coping behaviors indicative of depressive-like behavior. Following 4 days of separation from the female but not the male partner, experimental males displayed increased passive stress-coping. This effect was abolished by long-term intracerebroventricular infusion of a nonselective corticotropin-releasing factor (CRF) receptor antagonist without disrupting the bond itself. Both CRF type 1 and 2 receptors were involved in the emergence of passive stress-coping behavior. Furthermore, pairing with a female was associated with elevated CRF mRNA in the bed nucleus of the stria terminalis, and partner loss elicited a pronounced increase in circulating corticosteroid and adrenal weight. We speculate that the CRF system may mediate an aversive affect following separation from the female partner, which may facilitate proximity seeking between the pair-bonded individuals. Hence, the prairie vole model may provide insights into brain mechanisms involved in the psychopathological consequences of partner loss.
Gemmel, Mary; Hazlett, Mariah; Bögi, Eszter; De Lacalle, Sonsoles; Hill, Lesley A; Kokras, Nikolaos; Hammond, Geoffrey L; Dalla, Christina; Charlier, Thierry D; Pawluski, Jodi L
Selective serotonin reuptake inhibitor medications (SSRIs) are the first lines of treatment for maternal affective disorders, and are prescribed to up to 10% of pregnant women. Concern has been raised about how perinatal exposure to these medications affect offspring neurobehavioral outcomes, particularly those related to social interactions, as recent research has reported conflicting results related to autism spectrum disorder (ASD) risk in children prenatally exposed to SSRIs. Therefore, the aim of this work was to investigate the effects of perinatal exposure to the SSRI fluoxetine on social play behaviors and the hypothalamic pituitary adrenal system, using a model of pre-gestational maternal stress. We also investigated synaptic proteins in the CA2, CA3, and dentate gyrus of the hippocampus, as well as number of immature neurons in the granule cell layer, as both measures of plasticity in the hippocampus have been linked to social behaviors. In pre-adolescent male and female Sprague-Dawley rat offspring, main findings show that perinatal fluoxetine prevents the negative effect of maternal stress on sibling play behavior. However, perinatal fluoxetine increased social aggressive play with a novel conspecific in both sexes and decreased time grooming a novel conspecific in males only. Perinatal fluoxetine also increased serum corticosteroid binding globulin levels, 5-HT levels in the hippocampus, and pre-synaptic density assessed via synaptophysin in the dentate gyrus. Social interaction was significantly correlated with changes in plasticity in the CA2 region of the hippocampus. Pre-gestational maternal stress exposure resulted in significantly decreased rates of hippocampal neurogenesis and synaptophysin density in the dentate gyrus of pre-adolescent males, but not females. Together, these results further characterize the role of perinatal SSRIs, maternal stress prior to conception, and sex/gender on developing social behaviors and related plasticity in the
Schmikli, Sandor L.; de Vries, Wouter R.; Brink, Michel S.; Backx, Frank J. G.
Objective To verify if in male elite junior soccer players a minimum 1-month performance decrease is accompanied by a mood profile and hormone levels typical of non-functional over-reaching (NFOR). Design A prospective case-control study using a monthly performance monitor with a standardised field
Effects of prenatal dexamethasone treatment on physical growth, pituitary-adrenal hormones, and performance of motor, motivational, and cognitive tasks in juvenile and adolescent common marmoset monkeys.
Hauser, Jonas; Knapman, Alana; Zürcher, Nicole R; Pilloud, Sonia; Maier, Claudia; Diaz-Heijtz, Rochellys; Forssberg, Hans; Dettling, Andrea; Feldon, Joram; Pryce, Christopher R
Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to prevent respiratory distress syndrome in preterm infants, but there is emerging evidence of subsequent neurobehavioral abnormalities (e.g. problems with inattention/hyperactivity). In the present study, we exposed pregnant common marmosets (Callithrix jacchus, primates) to daily repeated DEX (5 mg/kg by mouth) during either early (d 42-48) or late (d 90-96) pregnancy (gestation period of 144 days). Relative to control, and with a longitudinal design, we investigated DEX effects in offspring in terms of physical growth, plasma ACTH and cortisol titers, social and maintenance behaviors, skilled motor reaching, motivation for palatable reward, and learning between infancy and adolescence. Early DEX resulted in reduced sociability in infants and increased motivation for palatable reward in adolescents. Late DEX resulted in a mild transient increase in knee-heel length in infants and enhanced reversal learning of stimulus-reward association in adolescents. There was no effect of either early or late DEX on basal plasma ACTH or cortisol titers. Both treatments resulted in impaired skilled motor reaching in juveniles, which attenuated in early DEX but persisted in late DEX across test sessions. The increased palatable-reward motivation and decreased social motivation observed in early DEX subjects provide experimental support for the clinical reports that prenatal glucocorticoid treatment impairs social development and predisposes to metabolic syndrome. These novel primate findings indicate that fetal glucocorticoid overexposure can lead to abnormal development of motor, affective, and cognitive behaviors. Importantly, the outcome is highly dependent upon the timing of glucocorticoid overexposure.
Rotllant, David; Ons, Sheila; Carrasco, Javier; Armario, Antonio
Metyrapone, a 11-beta steroid hydroxylase inhibitor that blocks stress-induced glucocorticoid release, is extensively used to study the physiological and behavioural roles of glucocorticoids. However, there is circumstantial evidence suggesting that metyrapone could act as a pharmacological stressor. Thus, the effects of various doses of metyrapone on two well-characterized stress markers (ACTH and glucose) were studied in male rats. Metyrapone administration, while exerting a modest effect on plasma corticosterone levels, dose-dependently increased plasma ACTH and glucose levels. Using the highest doses previously tested (200 mg/kg) we further observed, as evaluated by fos-like immunoreactivity (FLI), a strong activation of a wide range of brain areas, including the parvocellular region of the hypothalamic paraventricular nucleus (PVNp), the origin of the main ACTH secretagogues. Metyrapone-induced FLI was observed in neocortical and allocortical areas, in several limbic, thalamic and hypothalamic nuclei and, to a lesser extent, in the brainstem. In a final experiment, a dose-response study of metyrapone-induced FLI was carried out focusing on selected brain areas. The study revealed that the paraventricular thalamic nucleus and central amygdala were the areas most sensitive to metyrapone as they responded even to the lowest dose of the drug. Most areas, among them the PVNp, only showed enhanced FLI with the two highest doses, i.e. when it was associated with ACTH and glucose responses. These data suggest that some of the effects of metyrapone could be due to its stressful properties rather than its ability to inhibit glucocorticoid synthesis. The exact mechanisms involved remain to be established.
Previous work has shown that a single oral administration of atrazine (ATR), a chlorotriazine herbicide, induces dose-dependent increases in plasma adrenocorticotropic hormone (ACTH), serum corticosterone (CORT) and progesterone. The mechanism for these effects is unknown. To tes...
McNeal, Neal; Appleton, Katherine M; Johnson, Alan Kim; Scotti, Melissa-Ann L; Wardwell, Joshua; Murphy, Rachel; Bishop, Christina; Knecht, Alison; Grippo, Angela J
Positive social interactions may protect against stress. This study investigated the beneficial effects of pairing with a social partner on behaviors and neuroendocrine function in response to chronic mild stress (CMS) in 13 prairie vole pairs. Following 5 days of social bonding, male and female prairie voles were exposed to 10 days of CMS (mild, unpredictable stressors of varying durations, for instance, strobe light, white noise, and damp bedding), housed with either the social partner (paired group) or individually (isolated group). Active and passive behavioral responses to the forced swim test (FST) and tail-suspension test (TST), and plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone, were measured in all prairie voles following the CMS period. Both female and male prairie voles housed with a social partner displayed lower durations of passive behavioral responses (immobility, a maladaptive behavioral response) in the FST (mean ± SEM; females: 17.3 ± 5.4 s; males: 9.3 ± 4.6 s) and TST (females: 56.8 ± 16.4 s; males: 40.2 ± 11.3 s), versus both sexes housed individually (females, FST: 98.6 ± 12.9 s; females, TST: 155.1 ± 19.3 s; males, FST: 92.4 ± 14.1 s; males, TST: 158.9 ± 22.0 s). Female (but not male) prairie voles displayed attenuated plasma stress hormones when housed with a male partner (ACTH: 945 ± 24.7 pg/ml; corticosterone: 624 ± 139.5 ng/ml), versus females housed individually (ACTH: 1100 ± 23.2 pg/ml; corticosterone: 1064 ± 121.7 ng/ml). These results may inform understanding of the benefits of social interactions on stress resilience. Lay Summary: Social stress can lead to depression. The study of social bonding and stress using an animal model will inform understanding of the protective effects of social bonds. This study showed that social bonding in a rodent model can protect against behavioral responses to stress, and may also be protective against the elevation of stress hormones. This study provides evidence that bonding and social support are valuable for protecting against stress in humans.
Jindal, Ankur; Mahesh, Radhakrishnan; Bhatt, Shvetank
Preliminary study in our laboratory showed that etazolate produced antidepressant- and anxiolytic-like effects in rodent models, however, the ability of etazolate to produce antidepressant- and anxiolytic-like effects and underlying mechanism(s) in chronic unpredictable mild stress (CUMS) model have not been adequately addressed. This study was aimed to investigate the beneficial effects of etazolate on CUMS-induced behavioral deficits (depression- and anxiety-like behaviors). In addition, the possible underlying mechanism(s) of etazolate in CUMS model was also investigated by measuring serum corticosterone (CORT) and brain-derived neurotrophic factor (BDNF) levels. Mice were subjected to a battery of stressors for 28 days. Etazolate (0.5 and 1 mg/kg, p.o.) and fluoxetine (20mg/kg, p.o.) were administered during the last 21 days (8-28th) of the CUMS paradigm. The results showed that 4-weeks CUMS produces significant depression-like behavior in tail suspension test (TST) and partial anxiety-like behavior in elevated plus maze (EPM) and open field test (OFT). Stressed mice have also shown a significant high serum CORT and low BDNF level. Chronic treatment with etazolate (0.5 and 1mg/kg., p.o.) and fluoxetine (20mg/kg., p.o.) produced significant antidepressant-like behavior in TST (decreased duration of immobility), whereas, partial anxiolytic-like behavior in EPM (increased percentage of open arm entries) and OFT (increased % central ambulation score, total ambulation score and time spent in center zone). In addition, etazolate and fluoxetine treatment significantly (pBDNF level and inhibited the hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity, as evidenced by low serum CORT level in stressed mice. In addition, etazolate and fluoxetine also showed significant antidepressant- and anxiolytic-like effects in normal control mice. In this study no significant changes were observed in locomotor activity in actophotometer test. Moreover, we did not find any effect of etazolate and fluoxetine on CORT and BDNF levels in normal control mice. In conclusion, the results of the present study suggested compelling evidences that etazolate has more marked effect on depression-like behavior in mice, which is atleast in part may be related to their modulating effects on the HPA axis and BDNF level. Copyright © 2013 Elsevier Ltd. All rights reserved.
Naert, Gaelle; Ixart, Guy; Maurice, Tangui; Tapia-Arancibia, Lucia; Givalois, Laurent
Depression is potentially life-threatening. The most important neuroendocrine abnormality in this disorder is hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivity. Recent findings suggest that all depression treatments may boost the neurotrophin production especially brain-derived neurotrophic factor (BDNF). Moreover, BDNF is highly involved in the regulation of HPA axis activity. The aim of this study was to determine the impact of chronic stress (restraint 3h/day for 3 weeks) on animal behavior and HPA axis activity in parallel with hippocampus, hypothalamus and pituitary BDNF levels. Chronic stress induced changes in anxiety (light/dark box test) and anhedonic states (sucrose preference test) and in depressive-like behavior (forced swimming test); general locomotor activity and body temperature were modified and animal body weight gain was reduced by 17%. HPA axis activity was highly modified by chronic stress, since basal levels of mRNA and peptide hypothalamic contents in CRH and AVP and plasma concentrations in ACTH and corticosterone were significantly increased. The HPA axis response to novel acute stress was also modified in chronically stressed rats, suggesting adaptive mechanisms. Basal BDNF contents were increased in the hippocampus, hypothalamus and pituitary in chronically stressed rats and the BDNF response to novel acute stress was also modified. This multiparametric study showed that chronic restraint stress induced a depressive-like state that was sustained by mechanisms associated with BDNF regulation. Copyright Â© 2010 Elsevier Inc. All rights reserved.
Wang, Ming; Chen, Qian; Li, Mei; Zhou, Wei; Ma, Tengfei; Wang, Yun; Gu, Shuling
Alarin is a newly identified member of the galanin family of peptides. Galanin has been shown to exert regulatory effects on depression. Similar to galanin in distribution, alarin is also expressed in the medial amygdala and hypothalamus, i.e., regions interrelated with depression. However, it remains a puzzle whether alarin is involved in depression. Accordingly, we established the depression-like mouse model using behavioral tests to ascertain the possible involvement of alarin, with fluoxetine as a positive control. With the positive antidepressant-like effects of alarin, we further examined its relationship to HPA axis activity and brain-derived neurotrophic factor (BDNF) levels in different brain areas in a chronic unpredictable mild stress (CUMS) paradigm. In the acute studies, alarin produced a dose-related reduction in the immobility duration in tail suspension test (TST) in mice. In the open-field test, intracerebroventricular (i.c.v.) injection of alarin (1.0 nmol) did not impair locomotion or motor coordination in the treated mice. In the CUMS paradigm, alarin administration (1.0 nmol, i.c.v.) significantly improved murine behaviors (FST and locomotor activity), which was associated with a decrease in corticotropin-releasing hormone (CRH) mRNA levels in the hypothalamus, as well as a decline in serum levels of CRH, adrenocorticotropic hormone (ACTH) and corticosterone (CORT), all of which are key hormones of the HPA axis. Furthermore, alarin upregulated BDNF mRNA levels in the prefrontal cortex and hippocampus. These findings suggest that alarin may potentiate the development of new antidepressants, which would be further secured with the identification of its receptor(s). Copyright © 2014 Elsevier Inc. All rights reserved.
Stark, R.; Santos, V.V.; Geenen, B.; Cabral, A.; Dinan, T.; Bayliss, J.A.; Lockie, S.H.; Reichenbach, A.; Lemus, M.B.; Perello, M.; Spencer, S.J.; Kozicz, L.T.; Andrews, Z.B.
Ghrelin exists in two forms in circulation, acyl ghrelin and des-acyl ghrelin, both of which have distinct and fundamental roles in a variety of physiological functions. Despite this fact, a large proportion of papers simply measure and refer to plasma ghrelin without specifying the acylation
Full Text Available Sigma-1 receptor knockout (σ1R-KO mice exhibit a depressive-like phenotype. Because σ1R is highly expressed in the neuronal cells of hypothalamic paraventricular nuclei (PVN, this study investigated the influence of σ1R deficiency on the regulation of the hypothalamic-pituitary-adrenocortical (HPA axis. Here, we show that the levels of basal serum corticosterone (CORT, adrenocorticotropic hormone (ACTH and corticotrophin releasing factor (CRF as well as the level of CRF mRNA in PVN did not significantly differ between adult male σ1R-KO mice and wild-type (WT mice. Acute mild restraint stress (AMRS induced a higher and more sustainable increase in activity of HPA axis and CRF expression in σ1R-KO mice. Percentage of dexamethasone (Dex-induced reduction in level of CORT was markedly attenuated in σ1R−/− mice. The levels of glucocorticoid receptor (GR and protein kinase C (PKC phosphorylation were reduced in the PVN of σ1R-KO mice and σ1R antagonist NE100-treated WT mice. The exposure to AMRS in σ1R-KO mice induced a stronger phosphorylation of cAMP-response element binding protein (CREB in PVN than that in WT mice. Intracerebroventricular (i.c.v. injection of PKC activator PMA for 3 days in σ1R-KO mice not only recovered the GR phosphorylation and the percentage of Dex-reduced CORT but also corrected the AMRS-induced hyperactivity of HPA axis and enhancement of CRF mRNA and CREB phosphorylation. Furthermore, the injection (i.c.v. of PMA in σ1R-KO mice corrected the prolongation of immobility time in forced swim test (FST and tail suspension test (TST. These results indicate that σ1R deficiency causes down-regulation of GR by reducing PKC phosphorylation, which attenuates GR-mediated feedback inhibition of HPA axis and facilitates the stress response of HPA axis leading to the production of depressive-like behaviors.
Schwinn, A. -C.; Knight, C. H.; Bruckmaier, R. M.
, current research focuses on noninvasive sampling of media other than blood, for example, saliva. The aim of this study was to assess the suitability of saliva cortisol as a biomarker under different physiological and immunological states in dairy cows. Our objectives were to 1) evaluate the relationship...... between HPA axis activation and saliva cortisol concentration, 2) investigate effects of some feeding action (as influenced by feed and water consumption) on saliva cortisol concentration, and 3) evaluate the time lag between plasma and saliva cortisol during induced inflammatory conditions...... administration. Saliva and blood samples were taken before, during, and after drinking, feeding, and ruminating. Only a low correlation between saliva and plasma cortisol concentrations (r = 0.03, P = 0.83) but no significant effects of the different feeding actions on saliva cortisol were observed. When...
Jørgensen, L S; Christiansen, P; Raundahl, U
A mental arithmetic test (the stressor; 15 min) significantly increased systolic and diastolic blood pressure, heart rate and plasma adrenaline by 11%, 12%, 28% and 152% respectively, with a prompt return to resting values after the test. Plasma noradrenaline and serum cortisol did not increase s...
Finucane, Francis M
The insulin tolerance test (ITT) is the gold standard for assessing GH and cortisol production in pituitary disease. However, areas of uncertainty remain regarding its safety in older people, the optimal duration of the test and its performance in insulin resistant states. Whether basal cortisol concentration can reliably predict an adequate adrenal response to hypoglycaemia remains to be determined.
Jørgensen, L S; Christiansen, P; Raundahl, U
A mental arithmetic test (the stressor; 15 min) significantly increased systolic and diastolic blood pressure, heart rate and plasma adrenaline by 11%, 12%, 28% and 152% respectively, with a prompt return to resting values after the test. Plasma noradrenaline and serum cortisol did not increase...... of the stressor. As a measure of parasympathetic nervous function, the beat-to-beat variation of heart rate, expressed as the mean successive square difference (MSSD), was employed. Four to 14 months later, the investigation was repeated, and resting values of all measures were found to be stable. The increments...
Doelen, R.H.A. van der; Deschamps, W.; D'Annibale, C.; Peeters, D.; Wevers, R.A.; Zelena, D.; Homberg, J.R.; Kozicz, L.T.
The short allelic variant of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) has been associated with the etiology of major depression by interaction with early life stress (ELS). Furthermore, 5-HTTLPR has been associated with abnormal functioning of the
Adam, Tanja C; Epel, Elissa S
An increasing number of people report concerns about the amount of stress in their life. At the same time obesity is an escalating health problem worldwide. Evidence is accumulating rapidly that stress related chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and resulting excess glucocorticoid exposure may play a potential role in the development of visceral obesity. Since adequate regulation of energy and food intake under stress is important for survival, it is not surprising that the HPA axis is not only the 'conductor' of an appropriate stress response, but is also tightly intertwined with the endocrine regulation of appetite. Here we attempt to link animal and human literatures to tease apart how different types of psychological stress affect eating. We propose a theoretical model of Reward Based Stress Eating. This model emphasizes the role of cortisol and reward circuitry on motivating calorically dense food intake, and elucidating potential neuroendocrine mediators in the relationship between stress and eating. The addiction literature suggests that the brain reward circuitry may be a key player in stress-induced food intake. Stress as well as palatable food can stimulate endogenous opioid release. In turn, opioid release appears to be part of an organisms' powerful defense mechanism protecting from the detrimental effects of stress by decreasing activity of the HPA axis and thus attenuating the stress response. Repeated stimulation of the reward pathways through either stress induced HPA stimulation, intake of highly palatable food or both, may lead to neurobiological adaptations that promote the compulsive nature of overeating. Cortisol may influence the reward value of food via neuroendocrine/peptide mediators such as leptin, insulin and neuropeptide Y (NPY). Whereas glucocorticoids are antagonized by insulin and leptin acutely, under chronic stress, that finely balanced system is dysregulated, possibly contributing to increased food
Glaucie Jussilane Alves
Full Text Available OBJETIVO: Trabalhos de pesquisa provenientes do campo da neuroimunomodulação vêm tornando explícitas as intrincadas relações existentes entre o sistema nervoso central e o sistema imune. Uma revisão bibliográfica foi realizada com o objetivo de descrever as bases de estudo da neuroimunomodulação. MODELOS EXPERIMENTAIS: Sabe-se, hoje, que estados emocionais como ansiedade e depressão são capazes de modificar a atividade do sistema imune como também o fazem o estresse e fármacos com ação no sistema nervoso central. COMPORTAMENTO DOENTIO: Os comportamentos apresentados por um organismo doente devem ser encarados como decorrência de estratégias homeostáticas de cada indivíduo. POSSÍVEIS MECANISMOS DE SINALIZAÇÃO DO SISTEMA IMUNE PARA O SISTEMA NERVOSO CENTRAL: Grande destaque tem sido atribuído para a participação do eixo hipotálamo-pituitária-adrenal, do sistema nervoso autônomo simpático e das citocinas nas sinalizações entre o sistema nervoso central e o sistema imune. CONCLUSÃO: O presente artigo pretende mostrar a relevância dos fenômenos de neuroimunomodulação; ele faz uma análise crítica das influências do sistema nervoso central sobre o sistema imune e vice-versa.OBJECTIVE: Several papers arriving from the neuroimmunomodulation field are showing the relevant relationships between the nervous and the immune systems. A review of studies was carried out to describe the bases of the studies on neuroimmunomodulation. EXPERIMENTAL MODELS: It is clear nowadays that emotional states such as anxiety and depression change immune system activity, an affect also observed after both stress and use of nervous system acting drugs. SICK BEHAVIOR: The behavior displayed by sick organisms might be thought as being a consequence of homeostatic strategies. POSSIBLE MECHANISM OF THE ACTION BY MEANS OF IMMUNE SYSTEM TO NERVOUS SYSTEM: A very big emphasis is being given to Hipothalamus-pituitary-adrenal axis, simpathetic
Summary: Salivary alpha-amylase: More than an enzyme - Investigating confounders of stress-induced and basal amylase activity (Dipl.-Psych. Jana Strahler) The hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) are two of the major systems playing a role in the adaptation of organisms to developmental changes that threaten homeostasis. The HPA system involves the secretion of glucocorticoids, including cortisol, into the circulatory system. Numerous studies hav...
Full Text Available Opioids have been the mainstay for pain relief and palliation over a long period of time. They are commonly abused by drug addicts and such dependence usually imparts severe physiologic effects on multiple organ systems. The negative impact of opioids on the endocrine system is poorly understood and often underestimated. We describe a patient who developed severe suppression of the hypothalamic-pituitary adrenal (HPA axis leading to secondary adrenal insufficiency due to long standing abuse of opioids.
the peripheral nervous system. The latter is divided into two: the sympathetic (norepinephrine) that accelerates the motor response and the parasympathetic (acetylcholine), which slows it down. These two systems work in tandem. As for the second release of information, it is endocrine, thus it will follow the hypothalamus-pituitary-adrenal axis to cortisol, the hypothalamus-pituitary axis to endorphin and oxytocin and the hypothalamus-pineal axis to melatonin. The different emotional behaviours result from one of these two sources of information or from a combination of these two and are then managed by the limbic system, which is in continuous connection with the neocortex.In short, no specific centre totally controls human behaviour. Control is achieved through a group of brain structures and relays, permitting adaptive behaviour and maintenance of balance by means of permanent exchanges. Anger, for instance, is a survival emotion, which allows protecting one's physical integrity. It is very useful as an immediate response in an emergency situation, but it can also be harmful if it is used extensively in all situations, giving way to conduct disorders. Thus, the other neurohormonal circuits will regulate anger.Emotions are an integral part of human behaviour. They allow the individual to constantly adapt to the physical and social environment. This approach brings a new perspective to understand how each person maintains balance to avoid the onset of clinical disorders. The understanding of neurochemical mechanisms underlying basic emotions opens up the door to several clinical applications.
Agertoft, Lone; Pedersen, Søren
BACKGROUND: Measurement of short-term lower-leg growth rate in children by means of knemometry has become established as an integral part of the available measures of systemic activity of topical steroids in children. OBJECTIVE: We sought to determine the effects of clinically effective doses....... There was no statistically significant dose-response effect. Likewise, no statistically significant differences or dose-response effects were found for urinary cortisol adjusted for creatinine. CONCLUSION: Short-term lower-leg growth rate and hypothalamic-pituitary-adrenal axis function are not affected by treatment...... of the novel inhaled corticosteroid ciclesonide on lower-leg growth rate and hypothalamic-pituitary-adrenal axis function in children with asthma. METHODS: In a double-blind, placebo-controlled, 4-period crossover study, 24 children aged 6 to 12 years sequentially received ciclesonide (40, 80, and 160 microg...
Suicide is a major clinical problem in psychiatry and suicidal behaviours can be seen as a nosological entity per se. Predicting suicide is difficult due to its low base-rate and the limited specificity of clinical predictors. Prospective biological studies suggest that dysfunctions in the hypothalamo pituitary adrenal (HPA) axis and the serotonergic system have predictive power for suicide in mood disorders. Suicide attempt is the most robust clinical predictor making suici...
Urwyler, Sandrine Andrea; Schuetz, Philipp; Ebrahimi, Fahim; Donath, Marc Y.; Christ-Crain, Mirjam
Increased cortisol levels in obesity may contribute to the associated metabolic syndrome. In obesity, the activated innate immune system leads to increased interleukin (IL)-1β, which is known to stimulate the release of adrenocorticotropin hormone (ACTH).; We hypothesized that in obesity IL-1 antagonism would result in downregulation of the hypothalamo-pituitary-adrenal axis, leading to decreased cortisol levels.; In this prospective intervention study, we included 73 patients with obesity (b...
Larsen, Junilla K.; van Ramshorst, Bert; van Doornen, Lorenz J. P.; Geenen, Rinie
Background Binge eating episodes characterized by loss of control are hypothesized to be accompanied by changes in hypothalamic pituitary adrenal (HPA) axis functioning. Cortisol is an end product of this neuroendocrine stress system. Purpose The aim of this study was to examine the cortisol levels and the awakening cortisol response (ACR) in obese persons showing binge eating after surgery for morbid obesity. Method Sixteen obese women with binge eating disorder (BED) and 18 obese women with...
Smith, Adam S.; Wang, Zuoxin
Social relationships are a fundamental aspect of life, affecting social, psychological, physiological, and behavioral functions. While social interactions can attenuate stress and promote health, disruption, confrontations, isolation, or neglect in the social environment can each be major stressors. Social stress can impair the basal function and stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, impairing function of multiple biological systems and posing a risk to m...
neurosis triad of hypochondriasis (HS), depression (D), and hysteria (Hy). There were also three studies summarized that used the 16 PF. All three...Britain: Praeger Publishers, 1979. 33. Mason, J. "A Review of Psychoendocrine Research on the Pituitary-Adrenal Cortical System," Psycho- somatic ...34 Journal of Psycho- somatic Research, Vol. 5 (1961), pp. 183-190. 56. Switzer, Ellen. "Type A People," Vogue, Vol. 169 (August 1979), pp. 237+. 57. Troxler
Andrea Rodrigues Vasconcelos; João Victor eCabral-Costa; Caio Henrique Mazucanti; Cristoforo eScavone; Elisa Mitiko Kawamoto
Steroid hormones, such as sex hormones and glucocorticoids, have been demonstrated to play a role in different cellular processes in the central nervous system, ranging from neurodevelopment to neurodegeneration. Environmental factors, such as calorie intake or fasting frequency, may also impact on such processes, indicating the importance of external factors in the development and preservation of a healthy brain.The hypothalamic-pituitary-adrenal axis and glucocorticoid activity play a role ...
Marks, David F
When eating control is overridden by hedonic reward, a condition of obesity dyshomeostasis occurs. Appetitive hedonic reward is a natural response to an obesogenic environment containing endemic stress and easily accessible and palatable high-energy foods and beverages. Obesity dyshomeostasis is mediated by the prefrontal cortex, amygdala and hypothalamic?pituitary?adrenal axis. The ghrelin axis provides the perfect signalling system for feeding dyshomeostasis, affect control and hedonic rewa...
In this thesis we investigated (traumatic) stress and psychopathology with a focus on the potential roles of the hypothalamus-pituitary-adrenal (HPA) axis, the GABA system, their association, and the general genetic background of major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). We first reviewed the evidence on the cortisol response to psychosocial stress across psychiatric disorders and found that sex and symptomatic state are crucial factors to consider when compari...
Vendruscolo, Leandro F.; Barbier, Estelle; Schlosburg, Joel E.; Misra, Kaushik K.; Whitfield, Timothy W.; Logrip, Marian L.; Rivier, Catherine; Repunte-Canonigo, Vez; Zorrilla, Eric P.; Sanna, Pietro P.; Heilig, Markus; Koob, George F.
Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal [HPA] axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol dri...
Habib, George; Khatib, Muhamad; Sakas, Fahed; Artul, Suheil; Jabaly-Habib, Haneen
Intra-articular injection (IAI) of both hyaluronic acid (HA) and depot-steroid preparations had the advantage of quick and prolonged favorable effects on pain relief among patients with symptomatic osteoarthritis of the knee (OAK). The effect of IAI of HA on the systemic effects of the intra-articular steroids had not been investigated. Non-selected patients attending the rheumatology clinic with symptomatic OAK who failed NSAIDS and physical therapy were offered an IAI of HA at the knee joint followed 20 min later by an IAI of 1 ml of Celestone Chronodose at the same joint (group 1). Morning serum levels of cortisol were obtained just prior to the IAI and 1, 2 and 8 days later. Demographic, clinical, and laboratory parameters were obtained also from all the patients. Age- and sex-matched group of patients from the same clinic were recruited as a control group (group 2). Mean baseline serum cortisol levels in group 1 was 381 ± 154 mmol/l vs. 376 ± 119 in group 2 (p = 0.954). Morning serum cortisol levels at day 1 and day 2 were 24 ± 6 and 22 ± 6 mmol/l, respectively, in group 1 patients vs. 27 ± 5.8 (p = 0.214) and 25 ± 5.6 mmol/l (p = 0.200), respectively, in group 2. These levels were significantly lower than baseline levels in each group. Morning serum cortisol levels at day 8 in group 1 and group 2 were 349 ± 128 and 314 ± 99 mmol/l, respectively (p = 0.419). Pre-injection of HA at the knee joint did not affect the systemic effect on the hypothalamic-pituitary-adrenal axis of IAI of Celestone Chronodose.
[Choice of informative laboratory biomarkers for the early identification of changes in neurohumoral regulation and carbohydrate exchange in workers of the mining and mechanical engineering industry].
Lapko, I V; Kiryakov, V A; Pavlovskaya, N A; Oshkoderov, O A; Klimkina, K V
The diagnostic significance of hormones and integral indices of pituitary-adrenal, pituitary-thyroid and pituitary-gonadal system and carbohydrate metabolism (ACTH (corticotropin), aldosterone, cortisol, TSH (thyroid-stimulating hormone), free triiodothyronine (fT3), free thyroxine (fT4), luteinizing hormone (LH), follicle-stimulating hormone (FSH), total and free testosterone, insulin, integral pituitary-adrenal index (IPAI), the pituitary-thyroid index (PTI), indices of carbohydrate metabolism (Caro and HOMA-IR) was studied for the early diagnostics of disorders of neurohumoral regulation in workers of mining and mechanical engineering industries. The most informative indices, permitting to identify disorders of carbohydrate metabolism are established to be indices of insulin resistance (index Caro and index NOMA-IR) and the determination of insulin in serum. For the identification of changes in pituitary adrenal, pituitary-thyroid and pituitary-gonadal system in patients with vibration disease, sensory-neural hearing loss, comorbidity indexes IGNI, ITI, concentrations of LH and total testosterone are of the most diagnostically significance.
Márquez, Cristina; Belda, Xavier; Armario, Antonio
Acute immobilization in male rats elicited the same ACTH, corticosterone and glucose response as foot shock when measured immediately after stress. However, post-stress recovery of plasma ACTH, corticosterone and glucose levels were delayed in immobilized versus shocked rats. Similarly, stress-induced anorexia was much greater in the former animals. All these data suggest that post-stress speed of recovery of some physiological variables is positively related to stressor intensity and could be used to evaluate it.
Antidepressant-Like Effects of Fractions Prepared from Danzhi-Xiaoyao-San Decoction in Rats with Chronic Unpredictable Mild Stress: Effects on Hypothalamic-Pituitary-Adrenal Axis, Arginine Vasopressin, and Neurotransmitters
Full Text Available The aim of the present study was to investigate the antidepressant-like effects of two fractions, including petroleum ether soluble fraction (Fraction A, FA and water-EtOH soluble fraction (Fraction B, FB prepared from the Danzhi-xiaoyao-san (DZXYS by using chronic unpredictable mild stress-induced depressive rat model. The results indicated that DZXYS could ameliorate the depression-like behavior in chronic stress model of rats. The inhibition of hyperactivity of HPA axis and the modulation of monoamine and amino acid neurotransmitters in the hippocampus may be the important mechanisms underlying the action of DZXYS antidepressant-like effect in chronically stressed rats.
Bao, A-M; Meynen, G; Swaab, D F
The stress response is mediated by the hypothalamo-pituitary-adrenal (HPA) system. Activity of the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) forms the basis of the activity of the HPA-axis. The CRH neurons induce adrenocorticotropin (ACTH) release from the pituitary, which subsequently causes cortisol release from the adrenal cortex. The CRH neurons co-express vasopressin (AVP) which potentiates the CRH effects. CRH neurons project not only to the median eminence but also into brain areas where they, e.g., regulate the adrenal innervation of the autonomic system and affect mood. The hypothalamo-neurohypophysial system is also involved in stress response. It releases AVP from the PVN and the supraoptic nucleus (SON) and oxytocin (OXT) from the PVN via the neurohypophysis into the bloodstream. The suprachiasmatic nucleus (SCN), the hypothalamic clock, is responsible for the rhythmic changes of the stress system. Both centrally released CRH and increased levels of cortisol contribute to the signs and symptoms of depression. Symptoms of depression can be induced in experimental animals by intracerebroventricular injection of CRH. Depression is also a frequent side effect of glucocorticoid treatment and of the symptoms of Cushing's syndrome. The AVP neurons in the hypothalamic PVN and SON are also activated in depression, which contributes to the increased release of ACTH from the pituitary. Increased levels of circulating AVP are also associated with the risk for suicide. The prevalence, incidence and morbidity risk for depression are higher in females than in males and fluctuations in sex hormone levels are considered to be involved in the etiology. About 40% of the activated CRH neurons in mood disorders co-express nuclear estrogen receptor (ER)-alpha in the PVN, while estrogen-responsive elements have been found in the CRH gene promoter region, and estrogens stimulate CRH production. An androgen
Kakihana, R.; Butte, J. C.
Many endocrine systems are sensitive to external changes in the environment. Both the pituitary adrenal and pituitary gonadal systems are affected by stress including centrifugation stress. The effect of centrifugation on the pituitary gonadal and pituitary adrenocortical systems was examined by measuring the gonadal and adrenal steroids in the plasma and brain following different duration and intensity of centrifugation stress in rats. Two studies were completed and the results are presented. The second study was carried out to describe the developmental changes of brain, plasma and testicular testosterone and dihydrotestosterone in Sprague Dawley rats so that the effect of centrifugation stress on the pituitary gonadal syatem could be better evaluated in future studies.
María Cristina García
Full Text Available The purpose of this article is to revise evidence from human and animal research around the stressregulation pathway. The data from research studies are based on the hypothalamus-pituitary-adrenal gland system andon the way stress early experiences can condition the circuit reactivity. The role of sensible rearing practices to promote the development of adequate self-regulatory systems. Te risk of negligent experiences as well as chronic stress on early childhood.Finally base on existing evidence we propose activities to prevent chronic stress on early childhood.
Contoreggi, Carlo; Rice, Kenner C; Chrousos, George
Overproduction of corticotropin-releasing hormone (CRH) and stress system abnormalities are seen in psychiatric diseases such as depression, anxiety, eating disorders, and addiction. Investigations of CRH type 1 receptor (CRHR1) nonpeptide antagonists suggest therapeutic potential for treatment of these and other neuropsychiatric diseases. However, overproduction of CRH in the brain and on its periphery and disruption of the hypothalamic-pituitary-adrenal axis are also found in 'somatic' disorders. Some rare forms of Cushing's disease and related pituitary/adrenal disorders are obvious applications for CRHR1 antagonists. In addition, however, these antagonists may also be effective in treating more common somatic diseases. Patients with obesity and metabolic syndrome who often have subtle, but chronic hypothalamic-pituitary-adrenal hyperactivity, which may reflect central dysregulation of CRH and consequently glucocorticoid hypersecretion, could possibly be treated by administration of CRHR1 antagonists. Hormonal, autonomic, and immune aberrations are also present in chronic inflammatory, autoimmune, and allergic diseases, with considerable evidence linking CRH with the observed abnormalities. Furthermore, autonomic dysregulation is a prominent feature of common gastrointestinal disorders, such as irritable bowel syndrome and peptic ulcer disease. Patients with irritable bowel syndrome and other gastrointestinal disorders frequently develop altered pain perception and affective symptoms. CRH acts peripherally to modulate bowel activity both directly through the autonomic system and centrally by processing viscerosensory and visceromotor neural signals. This review presents clinical and preclinical evidence for the role of CRH in the pathophysiology of these disorders and for potential diagnostic and therapeutic applications of CRHR1 antagonists. Recognition of a dysfunctional stress system in these and other diseases will alter the understanding and treatment of
endocrine systems. OBJECTIVES: To analyze the role of the immune-inflammatory system on depression and, furthermore, the interactions between antidepressants and this system, from basic and clinical points of view. METHODS: Literature review was carried out in the MedLine and SciELO databases. Patients suffering of chronic stress and depression present an activation of both inflammatory responses and hypothalamic-pituitary-adrenal axis, which, directly or indirectly, influence neurotransmission. Therefore, the use of antidepressants not only increases the availability of neurotransmitters in the synaptic cleft, but also changes the pattern of Th1 immune response - pro-inflammatory - to the Th2, which is antiinflammatory. Moreover, it is known that patients who do not respond to antidepressant treatment have hyperactive immune-inflammatory response system. However, there are several controversies in the literature, and evidences suggest a different immune profile according to the type of depression. DISCUSSION: The understanding of the neuroimmune aspects of depression might contribute to a better comprehension of the biological basis of this disorder and, therefore, to a new perspective in the search for a more effective therapy.
Ebstrup, Jeanette Frost; Jørgensen, Torben
Risk factors of cardiovascular disease (CVD) have been studied intensely since the 1950s. Results on stress as a risk factor for CVD have been inconsistent, but mainly positive. The risk is mediated through lifestyle, but more direct physiological mechanisms (e.g. autonomous nervous system...... and hypothalamic-pituitary-adrenal axis) are also found. Personality and general coping resources influence stress-appraisal, stress-coping and stress-response. Future studies should integrate stress as a cause (stressor), as a subjective reaction (perception), and as a physiological reaction in the same...
Vinogradov, D B; Mingazov, A Kh; Izarovskaya, I V; Babin, K A; Sinitsky, A I
to study the relationship between dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and free-radical oxidation in old age alcoholism. Authors examined 46 men and women, aged 60-80 years, with alcoholism. Contents of cortisol, lipid peroxidation products and the level of an oxidatively modified protein were measured. A decrease in blood cortisol content and correlations between its level and activity of free-radical oxidation were identified. The severity of neuroendocrine dysfunction in old patients was sex-related. It has been suggested that the impairment of HPA system activity may be a cause of oxidative stress and development of alcoholism.
Aznar, Susana; Knudsen, Gitte M
The existence of a high co-morbidity between Alzheimer's disease (AD) and depression has been known for a long time. More interesting though are recent studies indicating that depression and number of depressive episodes earlier in life is associated with increased risk of AD development....... This suggests the existence of common neuropathological mechanisms behind depression and AD. Here we propose that the brain changes associated with depressive episodes that compromise the brain's ability to cope with stress may constitute risk factors for development of AD. Furthermore, in individuals...... serotonergic and cholinergic system, hypothalamic-pituitary-adrenal axis and brain derived neurotrophic factor, and discussed in relation to AD....
Musina, R.Kh.; Kiseleva, N.S.; Modnikov, O.P.
A radioimmunoassay was conducted in the pituitary-ovary and pituitary-adrenals systems in 37 cases of endometrial carcinoma treatment and 1, 3, 5 and 14 days after extirpation of the uterus and appendages. The levels of follicle - stimulating (FSH) and luteinizing (LH) hormones of the pituitary, prolactin, ACTH, estradiol, progesterone, testosterone, cortisol and aldosterone were studied. Such disturbances as decreased production of FSH, LH, progesterone and testosterone were observed before operation. Surgery was followed by a considerable rise in prolactin production and basal levels of FSH and LH, a decrease in estradiol, progesterone and testosterone concentrations and was accompanied by a sizeable release of cortisol and aldosterone
Effect of escitalopram versus placebo on GRα messenger RNA expression in peripheral blood cells of healthy individuals with a family history of depression - a secondary outcome analysis from the randomized AGENDA trial
Knorr, Ulla; Koefoed, Pernille; Gluud, Christian
Background Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed as first-line drugs for the treatment of depression. However, the mechanisms of action for SSRIs are unclear and besides neurotransmitter modulation may depend on modulation of the hypothalamic-pituitary-adrenal (HPA......) system. The glucocorticoid receptor (GR) isoform α plays an important role in the negative feedback regulation of the HPA axis and reduced GRα messenger RNA (mRNA) expression has been shown in mood disorder patients and first-degree relatives compared to healthy individuals with no family history...
Młyniec, Katarzyna; Budziszewska, Bogusława; Holst, Birgitte
Background: Zinc may act as a neurotransmitter in the central nervous system by activation of the GPR39 metabotropic receptors. Methods: In the present study, we investigated whether GPR39 knockout would cause depressive-like and/or anxiety-like behavior, as measured by the forced swim test, tail...... investigated activity in the hypothalamus-pituitary-adrenal axis under both zinc- and GPR39-deficient conditions. Zinc-deficient mice had higher serum corticosterone levels and lower glucocorticoid receptor levels in the hippocampus and frontal cortex. Conclusions: There were no changes in the GPR39 knockout...
Pravosudova, N A; Bykova, I O
The influence of a single injection of haloperidol on basic carboxypeptidases (biologically active peptide processing enzymes) activity in rat tissues was studied. Acute exposure to haloperidol increased the activity of carboxypeptidases H (CP H) in hypothalamic-pituitary-adrenal system and cerebellum and reduced such activity in testes. Multidirectional changes of PMSF-inhibited carboxypeptidases activity (PMSF-CP) were observed after a single haloperidol injection in all studied tissues except testes. It is suggested that changes of CP H and PMSF-CP activity might affect levels of regulatory peptides in the brain and blood and thus may be involved in general and side effects of haloperidol on the organism.
Madsen, Kathrine Skak; Jernigan, Terry L; Iversen, Pernille
associated with higher CAR, were also correlated with higher right relative to left cingulum FA. Elevated CAR was associated with the degree of FA asymmetry within both the cingulum and the uncinate fasciculus, but in opposing directions. These results suggest that the balance between left- and right......The limbic system plays an important role in regulating the hypothalamic-pituitary-adrenal (HPA) axis as well as aspects of emotion, and both neuroendocrine disturbance and increased negative emotionality are associated with risk for developing affective disorders. However, the extent to which...
Zotova, I.A.; Firsova, P.P.; Matveenko, E.G.
Radioimmunoassay of hormonal homeostasis was performed in 200 lung cancer patients before and after combined and radiation treatment and in 25 healthy subjects (controls). The study showed an increase in the basal level of hormones of pituitary - adrenal system matched by a decline in thyroid function. Adequate combined and radiation treatment brought hormone levels to normal. Hormonal disorders accompanying recurrence were identical to those registered at disease onset. In some cases, changes in hormonal homeostasis developed as early as 3-6 months prior to clinically manifest recurrences or dissemination
AbstractThe Role of the Hypothalamic-Pituitary-Adrenal Axis on Stres and Demantia An organism responds to a stressor with activation of the hypothalamo-pituitary-adrenal axis, culminating in the secretion of glucocorticoids from the adrenal cortex. Activity of the hypothalamo-pituitary-adrenal axis is regulated by a negative feedback loop that dampens central drive of the axis via the actions of the secreted glucocorticoids. Conversely, under conditions of chronic stress, glucocorticoi...
Scott, Lucinda V
Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key biological abnormalities described in major depressive disorder, occurring in 30-50% of depressed subjects. Corticotropin-releasing hormone (CRH) and vasopressin (AVP) are the main regulators of this stress system, with the two neuropeptides acting synergistically in bringing about adrenocorticotropin (ACTH) release from the anterior pituitary and cortisol from the adrenal gland. Based on the demonstration of elevated cerebrospinal fluid levels of CRH in depressives, and other evidence, it has been postulated that excess CRH and the resultant increased HPA forward drive form the basis of neuroendocrine dysregulation in depression. However, there is an accumulating body of evidence to support a significant role for AVP in the regulation of pituitary-adrenal activity in health and also in depressive disorder. This review, based on a Medline search from 1980 to 2001, focuses on the functional neuroanatomy, receptor pharmacology, VP synergism with CRH, and the data from clinical and pre-clinical studies that support an important role for AVP in the pathophysiology of major depression. We suggest that future antidepressants may target the vasopressinergic system.
Raff, Hershel; Sharma, Susmeeta T.; Nieman, Lynnette K.
The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing’s syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing’s syndrome). Endogenous Cushing’s syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing’s syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control. PMID:24715566
de Kloet, E Ron
Corticosteroids secreted as end product of the hypothalamic-pituitary-adrenal axis act like a double-edged sword in the brain. The hormones coordinate appraisal processes and decision making during the initial phase of a stressful experience and promote subsequently cognitive performance underlying the management of stress adaptation. This action exerted by the steroids on the initiation and termination of the stress response is mediated by 2 related receptor systems: mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). The receptor types are unevenly distributed but colocalized in abundance in neurons of the limbic brain to enable these complementary hormone actions. This contribution starts from a historical perspective with the observation that phasic occupancy of GR during ultradian rhythmicity is needed to maintain responsiveness to corticosteroids. Then, during stress, initially MR activation enhances excitability of limbic networks that are engaged in appraisal and emotion regulation. Next, the rising hormone concentration occupies GR, resulting in reallocation of energy to limbic-cortical circuits with a role in behavioral adaptation and memory storage. Upon MR:GR imbalance, dysregulation of the hypothalamic-pituitary-adrenal axis occurs, which can enhance an individual's vulnerability. Imbalance is characteristic for chronic stress experience and depression but also occurs during exposure to synthetic glucocorticoids. Hence, glucocorticoid psychopathology may develop in susceptible individuals because of suppression of ultradian/circadian rhythmicity and depletion of endogenous corticosterone from brain MR. This knowledge generated from testing the balance hypothesis can be translated to a rational glucocorticoid therapy.
Swaab, Dick F; Bao, Ai-Min; Lucassen, Paul J
Corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response. The action of CRH on ACTH release is strongly potentiated by vasopressin, that is co-produced in increasing amounts when the hypothalamic paraventricular neurons are chronically activated. Whereas vasopressin stimulates ACTH release in humans, oxytocin inhibits it. ACTH release results in the release of corticosteroids from the adrenal that, subsequently, through mineralocorticoid and glucocorticoid receptors, exert negative feedback on, among other things, the hippocampus, the pituitary and the hypothalamus. The most important glucocorticoid in humans is cortisol, present in higher levels in women than in men. During aging, the activation of the CRH neurons is modest compared to the extra activation observed in Alzheimer's disease (AD) and the even stronger increase in major depression. The HPA-axis is hyperactive in depression, due to genetic factors or due to aversive stimuli that may occur during early development or adult life. At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression. Increased production of vasopressin in depression does not only occur in neurons that colocalize CRH, but also in neurons of the supraoptic nucleus (SON), which may lead to increased plasma levels of vasopressin, that have been related to an enhanced suicide risk. The increased activity of oxytocin neurons in the paraventricular nucleus (PVN) may be related to the eating disorders in depression. The suprachiasmatic nucleus (SCN), i.e., the biological clock of the brain, shows lower vasopressin production and a smaller circadian amplitude in depression, which may explain the sleeping problems in this disorder and may contribute to the strong CRH activation. The hypothalamo-pituitary thyroid (HPT)-axis is inhibited in depression. These hypothalamic
Evaluación del eje hipotálamo hipófisis adrenal después de la quimioterapia de inducción en niños con Leucemia Linfoide Aguda (LLA) / Evaluation of the hypothalamo - pituitary- adrenal axis after induction chemotherapy in children with acute lymphoid leukemia (ALL)
Acevedo Sedano, Gizeth Lorena
Antecedentes: La insuficiencia suprarrenal no ha sido en cuenta en los niños que reciben dosis altas de esteroides, como los de la quimioterapia de inducción para Leucemia Linfoide Aguda (LLA). Algunos autores han reportado una incidencia de disfuncion suprarrenal entre 46% a 81,5% en este grupo de pacientes. Objetivos: Evaluar la frecuencia de insuficiencia suprarrenal en pacientes pediátricos con LLA después de recibir quimioterapia de inducción que incluye esteroides a...
Alboni, Paolo; Alboni, Marco
Conventional risk factors (abnormal lipids, hypertension, etc.) are independent predictors of atherosclerosis and cardiovascular events; however, these factors are not specific since about half patients with acute myocardial infarction paradoxically result at low cardiovascular risk. Recent prospective studies provide convincing evidence that some psychosocial factors are independent predictors of atherosclerosis and cardiovascular events, as well. Psychosocial factors that promote atherosclerosis can be divided into two general categories: chronic stressors, including social isolation/low social support and work stress (subordination without job control) and emotional factors, including affective disorders such as depression, severe anxiety and hostility/anger. The emotional factors, such as the chronic stressors, activate the biological mechanisms of chronic stress: increased activity of the hypothalamic-pituitary-adrenal axis, sympathetic system and inflammation processes, which have atherogenic effects, and an increase in blood coagulation. In spite of the amount of published data, psychosocial factors receive little attention in the medical setting. About 30 years ago, Kuller defined the criteria for a causal relation between a risk factor and atherosclerosis and cardiac events. The first of these criteria states that experimental research should demonstrate that any new factor would increase the extent of atherosclerosis or its complications in suitable animal models. We carried out a bibliographic research in order to investigate whether the results of the studies dealing with animal examination and experimentation support the psychosocial factors as predictors of atherosclerosis. Contributions related to some of the psychosocial factors such as social isolation, subordination and hostility/anger have been found. In these studies atherosclerotic extension has been evaluated at necroscopy; however, the incidence of cardiovascular events has not been
Vamvakopoulos, N.C. [Univ. of Thessaly School of Medicine, Larisa (Greece); Sioutopoulou, T.O. [Univ. of Athens Medical School (Greece); Durkin, S.A. [American Type Culture Collection, Rockville, MD (United States)
Unexpected stimulation or stress activates the heat shock protein (hsp) system at the cellular level and the hypothalamic-pituitary-adrenal (HPA) axis at the level of the whole organism. At the molecular level, these two systems communicate through the functional interaction between hsp90 and glucocorticoid receptor (GR). The corticotropin releasing hormone (CRH) system regulates the mammalian stress response by coordinating the activity of the HPA axis. It consists of the 41-amino-acid-long principal hypothalamic secretagogue for pituitary adrenocorticotropic hormone (ACTH), CRH, its receptor (CRHR), and its binding protein (CRHBP). Because of its central role in the coordination of stress response and whole body homeostasis, the CRH system has been implicated in the pathogenesis of neuroendocrine and psychiatric disease. 19 refs., 1 fig.
Knorr, Ulla Benedichte
.37). In univariate analyses, no statistically significant correlations were found between change in the primary and secondary outcomes, respectively, and the covariates age, sex, Hamilton depression score 17-items, and plasma escitalopram levels. In conclusion, the present trial does not support an effect......The mechanisms of action for selective serotonin re-uptake in-hibitors (SSRI) in depressed patients remain widely unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. Further, the serotonergic neurotransmitter system seems closely...... linked to personality and cognition. It is not known if SSRIs have a direct effect on the HPA system, personality or cognition that is independent of their effect on depression. Thus, healthy individuals with a genetic liability for depression represent a group of particular interest when investigating...
Papers in this session describe the concept of mined geologic disposal system and methods for ensuring that the system, when developed, will meet all technical requirements. Also presented in the session are analyses of system parameters, such as cost and nuclear criticality potential, as well as a technical analysis of a requirement that the system permit retrieval of the waste for some period of time. The final paper discusses studies under way to investigate technical alternatives or complements to the mined geologic disposal system. Titles of the presented papers are: (1) Waste Isolation System; (2) Waste Isolation Economics; (3) BWIP Technical Baseline; (4) Criticality Considerations in Geologic Disposal of High-Level Waste; (5) Retrieving Nuclear Wastes from Repository; (6) NWTS Programs for the Evaluation of Technical Alternatives or Complements to Mined Geologic Repositories - Purpose and Objectives
Full Text Available A nonlinear robust control-system design framework predicated on a hierarchical switching controller architecture parameterized over a set of moving nominal system equilibria is developed. Specifically, using equilibria-dependent Lyapunov functions, a hierarchical nonlinear robust control strategy is developed that robustly stabilizes a given nonlinear system over a prescribed range of system uncertainty by robustly stabilizing a collection of nonlinear controlled uncertain subsystems. The robust switching nonlinear controller architecture is designed based on a generalized (lower semicontinuous Lyapunov function obtained by minimizing a potential function over a given switching set induced by the parameterized nominal system equilibria. The proposed framework robustly stabilizes a compact positively invariant set of a given nonlinear uncertain dynamical system with structured parametric uncertainty. Finally, the efficacy of the proposed approach is demonstrated on a jet engine propulsion control problem with uncertain pressure-flow map data.
Argaman, Miriam; Gidron, Yori; Ariad, Shmuel
A model of the relations between psychological factors and cancer progression should include brain and systemic components and their link with critical cellular stages in cancer progression. We present a psychoneuroimmunological (PNI) model that links helplessness-hopelessness (HH) with cancer progression via interleukin-1beta (IL-1beta). IL-1beta was elevated in the brain following exposure to inescapable shock, and HH was minimized by antagonizing cerebral IL-1beta. Elevated cerebral IL-1beta increased cancer metastasis in animals. Inescapable shock was associated with systemic elevations of IL-1beta and peripheral IL-1beta was associated with escape from apoptosis, angiogenesis, and metastasis. Involvement of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis are discussed. Future studies need to identify the role of additional factors in this PNI pathway.
Full Text Available Life on earth has adapted to the day-night cycle by evolution of internal, so-called circadian clocks that adjust behavior and physiology to the recurring changes in environmental conditions. In mammals, a master pacemaker located in the suprachiasmatic nucleus (SCN of the hypothalamus receives environmental light information and synchronizes peripheral tissues and central non-SCN clocks to geophysical time. Regulatory systems such as the hypothalamus-pituitary-adrenal (HPA axis and the autonomic nervous system (ANS, both being important for the regulation of stress responses, receive strong circadian input. In this review, we summarize the interaction of circadian and stress systems and the resulting physiological and pathophysiological consequences. Finally, we critically discuss the relevance of rodent stress studies for humans, addressing complications of translational approaches and offering strategies to optimize animal studies from a chronobiological perspective.
Carol, Emily E; Spencer, Robert L; Mittal, Vijay A
Recent studies have posited a relationship between cannabis use and the biological stress system, but this critical relationship has not been evaluated during the ultra high-risk (UHR) period immediately preceding the onset of psychotic disorders. Salivary cortisol samples were collected on 46 UHR and 29 control adolescents; these individuals were assessed for current cannabis use with a urine panel and self-report. UHR participants where separated into two groups: Current Cannabis Use (UHR-CU) and No Current Cannabis Use (UHR-NC). Healthy Control participants (HC) were free of cannabis use. Consistent with the literature, results indicate UHR individuals showed elevated cortisol levels when compared to HC participants. Further, we also observed that UHR-CU participants exhibited elevated levels when compared to both the non-using UHR and HC groups. Findings suggest that cannabis use may interact with underlying biological vulnerability associated with the hypothalamic-pituitary-adrenal (HPA) axis system. Published by Elsevier Ltd.
Jönsson, Peter; Österberg, Kai; Wallergård, Mattias
-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activations in both V-TSST sessions, together with habituation of cortisol and heart rate in the second session, but without any significant group differences. However, the former ED patients showed considerable variation in self-reported signs...... cortisol samples were collected. In addition, high frequency heart rate variability (HF-HRV), heart rate (HR), t-wave amplitude (TWA), and α-amylase were assessed to examine stress reactivity and habituation in the autonomic nervous system (ANS). The initial analyses showed clear hypothalamic...... of exhaustion (SMBQ). This led us to assign former ED patients with lower ratings into the low SMBQ group (LOWS) and those with higher ratings to the high SMBQ group (HIGHS). When repeating the analyses a different picture emerged; the HIGHS showed a lower cortisol response to the V-TSST than did the LOWS. Both...
Bangsgaard, Elisabeth; Ottesen, Johnny T.
A novel model of the hypothalamic-pituitary-adrenal axis is presented. The axis is an endocrine system responsible for coping with stress and it is likely to be involved in depression. The dynamics of the system is studied and existence, uniqueness and positivity of the solution and the existence...... of an attracting trapping region are proved. The model is calibrated and compared to data for healthy and depressed subjects. A sensitivity analysis resulting in a set of identifiable physiological parameters is provided. A subset is selected for parameter estimation and a reduced version of the model is stated...... and an approximated version is discussed. The model is physiologically based, thus parameters are representative for gland functions or elimination processes. Hence the model may be used for pointing out pathologies by parameter estimation and hypothesis testing whereby it may be used as an objective and refined...
Licht, Cecilie L; Kirkegaard, Lisbeth; Zueger, Maha
. The olfactory bulbectomized mice displayed increased activity in the open field test, a characteristic depression-like feature of this model. After bulbectomy, 5-HT(4) receptor binding was increased in the ventral hippocampus (12%) but unchanged in the dorsal hippocampus, frontal and caudal caudate putamen......]citalopram in two murine models of depression-related states, olfactory bulbectomy and glucocorticoid receptor heterozygous (GR(+/-)) mice. The olfactory bulbectomy model is characterized by 5-HT system changes, while the GR(+/-) mice have a deficit in hypothalamic-pituitary-adrenal (HPA) system control....... Among post hoc analyzed regions, there was a 14% decrease in 5-HT(4) receptor binding in the olfactory tubercles. The 5-HTT binding was unchanged in the hippocampus and caudate putamen of bulbectomized mice but post hoc analysis showed small decreases in lateral septum and lateral globus pallidus...
O'Mahony, Siobhain M
Early life stress has been implicated in many psychiatric disorders ranging from depression to anxiety. Maternal separation in rodents is a well-studied model of early life stress. However, stress during this critical period also induces alterations in many systems throughout the body. Thus, a variety of other disorders that are associated with adverse early life events are often comorbid with psychiatric illnesses, suggesting a common underlying aetiology. Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is thought to involve a dysfunctional interaction between the brain and the gut. Essential aspects of the brain-gut axis include spinal pathways, the hypothalamic pituitary adrenal axis, the immune system, as well as the enteric microbiota. Accumulating evidence suggest that stress, especially in early life, is a predisposing factor to IBS.
Elliott, Jennifer A; Opper, Susan E; Agarwal, Sonali; Fibuch, Eugene E
Opioids are among the oldest known and most widely used analgesics. The application of opioids has expanded over the last few decades, especially in the treatment of chronic non-malignant pain. This upsurge in opioid use has been accompanied by the increasingly recognized occurrence of opioid-associated endocrinopathy. This may arise after exposure to enteral, parenteral, or neuraxial opioids. Opioid-associated endocrinopathy consists primarily of hypothalamic-pituitary-gonadal axis or hypothalamic-pituitary-adrenal axis dysfunction and may manifest with symptoms of hypogonadism, adrenal dysfunction, and other hormonal disturbances. Additionally, opioid related endocrine dysfunction may be coupled with such disorders as osteoporosis and mood disturbances including depression. Undesirable changes in pain sensitivity such as opioid-induced hyperalgesia, and reduced potency of opioid analgesia may also be potential consequences of chronic opioid consumption. Few studies to date have been able to establish what degree of opioid exposure, in terms of dose or duration of therapy, may predispose patients to opioid-associated endocrinopathy. This article will review the currently available literature concerning opioid-associated endocrinopathy and will provide recommendations for the evaluation, monitoring, and management of opioid-associated endocrinopathy and its other accompanying undesired effects.
Doerr, Johanna M; Fischer, Susanne; Nater, Urs M; Strahler, Jana
Fatigue is a defining characteristic and one of the most debilitating features of fibromyalgia syndrome (FMS). The mechanisms underlying different dimensions of fatigue in FMS remain unclear. The aim of the current study was to test whether stress-related biological processes and physical activity modulate fatigue experience. Using an ambulatory assessment design, 26 female FMS patients reported general, mental, and physical fatigue levels at six time points per day for 14 consecutive days. Salivary cortisol and alpha-amylase were analyzed as markers of neuroendocrine functioning. Participants wore wrist actigraphs for the assessment of physical activity. Lower increases in cortisol after awakening predicted higher mean daily general and physical fatigue levels. Additionally, mean daily physical activity positively predicted next-day mean general fatigue. Levels of physical fatigue at a specific time point were positively associated with momentary cortisol levels. The increase in cortisol after awakening did not mediate the physical activity - fatigue relationship. There were no associations between alpha-amylase and fatigue. Our findings imply that both changes in hypothalamic-pituitary-adrenal axis activity and physical activity contribute to variance in fatigue in the daily lives of patients with FMS. This study helps to paint a clearer picture of the biological and behavioral underpinnings of fatigue in FMS and highlight the necessity of interdisciplinary treatment approaches targeting biological, behavioral and psychological aspects of FMS. Copyright © 2016 Elsevier Inc. All rights reserved.
Full Text Available Abstract Background Polycystic ovary syndrome (PCOS is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, abdominal obesity, hyperandrogenism, hypertension, and insulin resistance. Methods Our objectives in this study were (1 to estimate sympathetic-adrenal medullary (SAM activity by measuring mean systolic blood pressure (MSAP in rats with estradiol valerate (EV-induced PCO; (2 to estimate alpha1a and alpha2a adrenoceptor expression in a brain area thought to mediate central effects on MSAP regulation and in the adrenal medulla; (3 to assess hypothalamic-pituitary-adrenal (HPA axis regulation by measuring adrenocorticotropic hormone (ACTH and corticosterone (CORT levels in response to novel-environment stress; and (4 to measure abdominal obesity, sex steroids, and insulin sensitivity. Results The PCO rats had significantly higher MSAP than controls, higher levels of alpha1a adrenoceptor mRNA in the hypothalamic paraventricular nucleus (PVN, and lower levels of alpha2a adrenoceptor mRNA in the PVN and adrenal medulla. After exposure to stress, PCO rats had higher ACTH and CORT levels. Plasma testosterone concentrations were lower in PCO rats, and no differences in insulin sensitivity or in the weight of intraabdominal fat depots were found. Conclusion Thus, rats with EV-induced PCO develop hypertension and increased sympathetic and HPA-axis activity without reduced insulin sensitivity, obesity, or hyperandrogenism. These findings may have implications for mechanisms underlying hypertension in PCOS.
Full Text Available The cane toad (Rhinella marina has undergone rapid evolution during its invasion of tropical Australia. Toads from invasion front populations (in Western Australia have been reported to exhibit a stronger baseline phagocytic immune response than do conspecifics from range core populations (in Queensland. To explore this difference, we injected wild-caught toads from both areas with the experimental antigen lipopolysaccharide (LPS, to mimic bacterial infection and measured whole-blood phagocytosis. Because the hypothalamic-pituitary-adrenal axis is stimulated by infection (and may influence immune responses, we measured glucocorticoid response through urinary corticosterone levels. Relative to injection of a control (phosphate-buffered saline, LPS injection increased both phagocytosis and the proportion of neutrophils in the blood. However, responses were similar in toads from both populations. This null result may reflect the ubiquity of bacterial risks across the toad’s invaded range; utilization of this immune pathway may not have altered during the process of invasion. LPS injection also induced a reduction in urinary corticosterone levels, perhaps as a result of chronic stress.
Petra, Anastasia I; Panagiotidou, Smaro; Hatziagelaki, Erifili; Stewart, Julia M; Conti, Pio; Theoharides, Theoharis C
Gut microbiota regulate intestinal function and health. However, mounting evidence indicates that they can also influence the immune and nervous systems and vice versa. This article reviews the bidirectional relationship between the gut microbiota and the brain, termed the microbiota-gut-brain (MGB) axis, and discusses how it contributes to the pathogenesis of certain disorders that may involve brain inflammation. Articles were identified with a search of Medline (starting in 1980) by using the key words anxiety, attention-deficit hypersensitivity disorder (ADHD), autism, cytokines, depression, gut, hypothalamic-pituitary-adrenal (HPA) axis, inflammation, immune system, microbiota, nervous system, neurologic, neurotransmitters, neuroimmune conditions, psychiatric, and stress. Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, and essential metabolites all convey information to the central nervous system about the intestinal state. Conversely, the hypothalamic-pituitary-adrenal axis, the central nervous system regulatory areas of satiety, and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions seem to influence the pathogenesis of a number of disorders in which inflammation is implicated, such as mood disorder, autism-spectrum disorders, attention-deficit hypersensitivity disorder, multiple sclerosis, and obesity. Recognition of the relationship between the MGB axis and the neuroimmune systems provides a novel approach for better understanding and management of these disorders. Appropriate preventive measures early in life or corrective measures such as use of psychobiotics, fecal microbiota transplantation, and flavonoids are discussed. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.
Talabér, Gergely; Jondal, Mikael; Okret, Sam
Systemic glucocorticoids (GCs) mainly originate from de novo synthesis in the adrenal cortex under the control of the hypothalamus-pituitary-adrenal (HPA)-axis. However, research during the last 1-2 decades has revealed that additional organs express the necessary enzymes and have the capacity for de novo synthesis of biologically active GCs. This includes the thymus, intestine, skin and the brain. Recent research has also revealed that locally synthesized GCs most likely act in a paracrine or autocrine manner and have significant physiological roles in local homeostasis, cell development and immune cell activation. In this review, we summarize the nature, regulation and known physiological roles of extra-adrenal GC synthesis. We specifically focus on the thymus in which GC production (by both developing thymocytes and epithelial cells) has a role in the maintenance of proper immunological function. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Putman, Peter; Antypa, Niki; Crysovergi, Panagiota; van der Does, Willem A J
The glucocorticoid (GC) hormone cortisol is the end product of the hypothalamic-pituitary-adrenal axis (HPA axis). Acute psychological stress increases HPA activity and GC release. In humans, chronic disturbances in HPA activity have been observed in affective disorders and in addictive behaviour. Recent research indicates that acute effects of GCs may be anxiolytic and increase reward sensitivity. Furthermore, cortisol acutely influences early cognitive processing of emotional stimuli. In order to extend such findings to more complex emotional-cognitive behaviour, the present study tested acute effects of 40 mg cortisol on motivated decision making in 30 healthy young men. Results showed that cortisol indeed increased risky decision making, as predicted. This effect occurred for decisions where making a risky choice could potentially yield a big reward. These results are discussed with respect to currently proposed mechanisms for cortisol's potential anxiolytic effect and GCs' involvement in reward systems.
We evaluated the relationship between the ultradian rhythm of sleep and the secretory episodes of pituitary-adrenal hormones. Prolactin (PRL) and TSH exhibited opposite phase relationships with delta waves, PRL increasing and TSH decreasing when delta waves developed. Delta waves never increased together with an increase in cortisol secretion. They oscillated independently from each other throughout the 24 hour period, but when they were present at the same time, they oscillated in opposing phases. Concerning growth hormone (GH), its major peak which occurred shortly after sleep onset in association with the first slow wave sleep episode was blunted during sleep deprivation. However, this blunting was compensated during the day, so that the amount of GH secreted during a 24-hr period was similar whether or not a person had slept during the night. The physiological significance and the clinical implications of the various relationships of the endocrine systems with sleep are poorly known.
Goldstein, JM; Handa, RJ; Tobet, SA
Comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) represents the fourth leading cause of morbidity and mortality worldwide, and women have a two times greater risk than men. Thus understanding the pathophysiology has widespread implications for attenuation and prevention of disease burden. We suggest that sex-dependent MDD-CVD comorbidity may result from alterations in fetal programming consequent to the prenatal maternal environments that produce excess glucocorticoids, which then drive sex-dependent developmental alterations of the fetal hypothalamic-pituitary-adrenal (HPA) axis circuitry impacting mood, stress regulation, autonomic nervous system (ANS), and the vasculature in adulthood. Evidence is consistent with the hypothesis that disruptions of pathways associated with gamma aminobutyric acid (GABA) in neuronal and vascular development and growth factors have critical roles in key developmental periods and adult responses to injury in heart and brain. Understanding the potential fetal origins of these sex differences will contribute to development of novel sex-dependent therapeutics. PMID:24355523
Sukhumthammarat, Weera; Putthapiban, Prapaipan
Many different non systemic corticosteroid administrations can cause iatrogenic Cushing’s Syndrome (CS). We herein report a case series of iatrogenic CS from keloid scars treatment and aesthetic regimen called mesotherapy. Our first patient developed CS after having exceeded recommended dose of intralesional injection of Triamcinolone Acetonide (TAC). Second case presented with CS followed by unidentified mesotherapy treatment for local fat reduction. Subcutaneous injections of dexamethasone were found to be the part of mesotherapy regimen in one case. Physicians should be insightful in prescribing TAC especially in those patients who have high predisposing factors for developing CS. In the same way, off-label mesotherapy combine with corticosteroid can lead to iatrogenic CS and Hypothalamic-Pituitary-Adrenal (HPA) axis suppression. Currently, there are no standard guidelines for mesotherapy treatment. Therefore, further clinical trials on dosage, duration and effective combination of mesotherapy regimens are needed to increase safety uses. PMID:28764237
Hoyt, Lindsay T.; Falconi, April
This scoping review synthesizes existing research on two major transitions in females’ lives: puberty and perimenopause. These two periods of vast physiological change demarcate the beginning and the end of the reproductive life cycle and are associated with major neuroendocrine reorganization across two key systems, the hypothalamic-pituitary-gonadal (HPG) axis the hypothalamus-pituitary-adrenal (HPA) axis. Despite growing evidence suggesting that the timing and experience of puberty and perimenopause are related to various physical and mental health outcomes (e.g., mood disorders, metabolism, cardiovascular health, autoimmune conditions and cancer), these two processes are rarely examined together. In this paper, we bridge these disparate literatures to highlight similarities, isolate inconsistencies, and identify important areas for future research in women’s health. PMID:25797100
Peng, Guo-jiang; Tian, Jun-sheng; Gao, Xiao-xia; Zhou, Yu-zhi; Qin, Xue-mei
Depression is one of the prevalent and persistent psychiatric illnesses. It brings heavy socioeconomic burden such as healthcare expenditures and even higher suicide rates. Despite many hypotheses about its mechanism have been put forward, so far it is still unclear, not to mention the precise and effective diagnostic or therapeutic methods. In this paper, the current conditions of pathological and pharmacological mechanism of depression were reviewed systematically. Firstly, the most recent hypotheses and metabolomics based research including hereditary, neurotransmitter systems, brain derived neurotrophic factor (BDNF), hyperactivity of the hypothalamic pituitary adrenal (HPA) axis and inflammatory as well as metabolomics were summarized. Secondly, the present situation and development on antidepressant drugs at home and abroad were reviewed. Finally, a conclusion and prospect on the pathological and pharmacological mechanism of depression were provided primarily.
Guest, Francesca L; Guest, Paul C
Over the last few decades, evidence has emerged that the pathogenesis of psychiatric disorders such as schizophrenia can involve perturbations of the hypothalamic-pituitary-adrenal (HPA) axis and other neuroendocrine systems. Variations in the manifestation of these effects could be related to differences in clinical symptoms between affected individuals and to differences in treatment response. Such effects can also arise from the complex interaction between genes and environmental factors. Here, we review the effects of maternal stress on abnormalities in HPA axis regulation and the development of psychiatric disorders such as schizophrenia. Studies in this area may prove critical for increasing our understanding of the multidimensional nature of mental disorders and could lead to the development of improved diagnostics and novel therapeutic approaches for treating individuals who suffer from these conditions.
Full Text Available Depression is a life-threatening, debilitating, and common disease affecting different segments of community. Chemical and synthetic drugs available to treat this disease cause many adverse effects and may lead to complete recovery in only 50% of patients. At the same time, medicinal plants have been reported to exert optimal pharmacological effects in treating depression in different models. In this review, the relevant articles indexed in the reliable databases PubMed, PubMed central, Scopus and Web of Science were review-ed. The review indicated that most medicinal plants exerted antidepressant effects through synaptic regulation of serotonin, noradrenaline, and dopamine, regulating activity of hypothalamic-pituitary-adrenal axis, reinfor-cing anti-oxidant defense system, and decreasing inflammatory mediators. The medicinal plants and their active compounds can relieve depression through different pathways and hence are considered a new source to produce antidepressants.
Son, Gi Hoon; Cha, Hyo Kyeong; Chung, Sooyoung; Kim, Kyungjin
Adrenal glucocorticoids (GCs) control a wide range of physiological processes, including metabolism, cardiovascular and pulmonary activities, immune and inflammatory responses, and various brain functions. During stress responses, GCs are secreted through activation of the hypothalamic-pituitary-adrenal axis, whereas circulating GC levels in unstressed states follow a robust circadian oscillation with a peak around the onset of the active period of a day. A recent advance in chronobiological research has revealed that multiple regulatory mechanisms, along with classical neuroendocrine regulation, underlie this GC circadian rhythm. The hierarchically organized circadian system, with a central pacemaker in the suprachiasmatic nucleus of the hypothalamus and local oscillators in peripheral tissues, including the adrenal gland, mediates periodicities in physiological processes in mammals. In this review, we primarily focus on our understanding of the circadian regulation of adrenal GC rhythm, with particular attention to the cooperative actions of the suprachiasmatic nucleus central and adrenal local clocks, and the clinical implications of this rhythm in human diseases.
Doan, Stacey N; Dich, Nadya; Evans, Gary W
State, followed for 8 years (between the ages 9 and 17). Poverty- related stress was computed using the cumulative risk approach, assessing stressors across 9 domains, including environmental, psychosocial, and demographic factors. Allostatic load captured a range of physiological responses, including......Objective: The present study investigated the long-term impact of exposure to poverty-related stressors during childhood on allostatic load, an index of physiological dysregulation, and the potential mediating role of substance use. Method: Participants (n = 162) were rural children from New York...... cardiovascular, hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and metabolic activity. Smoking and alcohol/drug use were tested as mediators of the hypothesized childhood risk-adolescent allostatic load relationship. Results: Cumulative risk exposure at age 9 predicted increases...
Hu, Lili; Han, Bo; Zhao, Xiaoge; Mi, Lihua; Song, Qiang; Huang, Chen
To investigate the effect of early scream sound stress on the ability of spatial learning and memory, the levels of norepinephrine (NE) and corticosterone (CORT) in serum, and the morphology of adrenal gland. Female Sprague-Dawley (SD) rats were treated daily with scream sound from postnatal day 1(P1) for 21 d. Morris water maze was used to measure the spatial learning and memory ability. The levels of serum NE and CORT were determined by radioimmunoassay. Adrenal gland of SD rats was collected and fixed in formalin, and then embedded with paraffin. The morphology of adrenal gland was observed by HE staining. Exposure to early scream sound decreased latency of escape and increased times to cross the platform in Morris water maze test (Psound stress can enhance spatial learning and memory ability in adulthood, which is related to activation of the hypothalamo-pituitary-adrenal axis and sympathetic nervous system.
Møller, Martin Nue; Kirkeby, Svend; Vikeså, Jonas
: Several natriuretic peptides were found expressed significantly in the ES, including uroguanylin and brain natriuretic peptide, but also peptides regulating vascular tone, including adrenomedullin 2. In addition, both neurophysin and oxytocin (OXT) were found significantly expressed. All peptides were...... verified by immunohistochemistry. CONCLUSION: The present data support the hypothesis that the human ES may have an endocrine/paracrine capacity through expression of several peptides with potent natriuretic activity. Furthermore, the ES may influence the hypothalamo-pituitary-adrenal axis and may regulate...... vasopressin receptors and aquaporin-2 channels in the inner ear via OXT expression. We hypothesize that the ES is likely to regulate inner ear endolymphatic homeostasis, possibly through secretion of several peptides, but it may also influence systemic and/or intracranial blood pressure through direct...
Paratz, Elizabeth D; Katz, Benny
In recent years, a phenomenon of "late effects of the Holocaust" has emerged, with impacts on the psychological and physical health of ageing Holocaust survivors. As Holocaust survivors age, they may experience heightened anxiety around normal processes of ageing, worsened post-traumatic stress disorder with cognitive decline, and fear of the medical system. Holocaust survivors are at increased risk of osteoporosis, cardiometabolic disease due to hypothalamic-pituitary-adrenal axis dysfunction, cancer, and sequelae of Nazi medical experiments. From existing medical literature on this topic, practical principles of management are derived to create a framework for sensitive medical management of Holocaust survivors in Australia. The issues discussed are also relevant to the wider geriatric refugee or prisoner-of-war experience.
Moltesen, Maria Møller
of the stress response. In mammals, the hippocampus and amygdala in the telencephalon play central roles in the process of discriminating sensory inputs that, potentially, will threaten the homeostasis of an individual. These regions are part of the limbic system, which interacts with the hypothalamic......-pituitary-adrenal axis (HPA axis). This neuroendocrine stress axis includes corticotropin-releasing factor (CRF), which regulates the release of adrenocorticotropic hormone (ACTH) from the pituitary. A peptide is released to the circulation, inducing release of glucocorticoids from the adrenal cortex....... The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) also plays an important role in the neuroendocrine stress response by controlling CRF release in hypothalamus. The transmission of 5-HT and CRF are under feedback control of glucocorticoids and interact with the stress response by affecting processes...
The phenomenon of higher rates of affective disorders in women illustrates many of the difficulties as well as promises of translating preclinical models to human disorders. Abnormalities in the regulation of the hypothalamic-pituitary adrenal axis and the sympathoadrenomedullary system have been identified in depression and anxiety disorders, and these disorders are clearly precipitated and exacerbated by stress. Despite the striking sex difference in the prevalence of depression and anxiety disorders, attempts to identify corresponding sex differences in stress response reactivity in animal models have met with limited success. Processes which may contribute to increased rates of affective disorders in women are greater fluxes in reproductive hormones across the life span, and increased sensitivity to catecholamine augmentation of emotional memory consolidation.
Malenchenko, A F; Matveenko, E G; Livshits, I B; Seregin, V V; Spesivtseva, V G
A description is given of research on iodine metabolism both under normal and pathological conditions employing the method of clinical dynamic radiometry. Possible uses of radioisotopes are indicated for evaluating the function of the parathyroid glands, the pancreas, and the pituitary-adrenal system. Data are given on the practical use of radio-immune, radio-receptor methods as well as the competitive bonding method for determining a number of hormonal and other biologically active metabolites and substances with low antigen activity in various pathological states both clinically and in experiments. The use of neutron-activation methods in biology and medicine is demonstrated. The book is intended for endocrinologists, biologists, and scientific associates interested in the study of the functional state of endocrine glands by radioisotopic methods. 46 figures, 16 tables.
Mario Francisco Juruena
Full Text Available OBJETIVO: Foram revisados estudos que descrevem que as alterações na função do eixo hipotálamo-hipófise-adrenal são relacionadas com o estado psicopatológico em depressão. Além da depressão melancólica, uma série de condições podem ser associadas à hiperativação prolongada do eixo hipotálamo-pituitária-adrenal. Um outro grupo de psicopatologias é caracterizado por hipoativação do mesmo eixo com redução crônica na secreção do fator de liberação de corticotrofina. Pacientes com depressão atípica, doença afetiva sazonal e síndrome da fadiga crônica estão inclusos nesta categoria. MÉTODO: Foram revisados os dados da literatura que incluem a interseção entre estes descritores, resumidos e discutidos os principais e recentes achados. RESULTADOS: Muitos estudos têm enfatizado que estes quadros se sobrepõem biologicamente, demonstrando hipofunção no sistema relacionado ao fator de liberação de corticotrofina. CONCLUSÕES: Na prática clínica, os pacientes frequentemente se apresentam de forma intermediária entre a fadiga e a depressão atípica crônica e/ou a depressão sazonal. Isto enfatiza o potencial biológico comum que fundamenta o grupo de sintomas não somente entre depressão (atípica e sazonal e a síndrome da fadiga crônica e as condições caracterizadas por alterações no eixo hipotálamo-pituitária-adrenal, principalmente hipofunção e, em particular, diminuição da atividade do fator de liberação de corticotrofina.OBJECTIVE: We reviewed previous studies that have described an association between abnormal functioning of the hypothalamic-pituitary-adrenal axis and depression. In addition to melancholic depression, a spectrum of conditions may be associated with increased and prolonged activation of the hypothalamic-pituitary-adrenal axis. In contrast another group of states is characterized by hypoactivation of the stress system, rather than sustained activation, in which chronically
Maniaci, G; Goudriaan, A E; Cannizzaro, C; van Holst, R J
Gambling has been associated with increased sympathetic nervous system output and stimulation of the hypothalamic-pituitary-adrenal axis. However it is unclear how these systems are affected in pathological gambling. This study aimed to investigate the effect of the Trier Social Stress Test (TSST) on cortisol and on cardiac interbeat intervals in relation to impulsivity, in a sample of male pathological gamblers compared to healthy controls. In addition, we investigated the correlation between the TSST, duration of the disorder and impulsivity. A total of 35 pathological gamblers and 30 healthy controls, ranging from 19 to 58 years old and all male, participated in this study. Stress response was measured during and after the TSST by salivary cortisol and cardiac interbeat intervals; impulsivity was assessed with the Barratt Impulsiveness Scale (BIS-11). Exposure to the TSST produced a significant increase in salivary cortisol and interbeat intervals in both groups, without differences between groups. We found a negative correlation between baseline cortisol and duration of pathological gambling indicating that the longer the duration of the disorder the lower the baseline cortisol levels. Additionally, we found a main effect of impulsivity across groups on interbeat interval during the TSST, indicating an association between impulsivity and the intensity of the neurovegetative stress response during the TSST. Involvement of the hypothalamic-pituitary-adrenal axis in pathological gambling was confirmed together with evidence of a correlation between length of the disorder and diminished baseline cortisol levels. Impulsivity emerged as a personality trait expressed by pathological gamblers; however the neurovegetative response to the TSST, although associated with impulsivity, appeared to be independent of the presence of pathological gambling.
Full Text Available Risk analysis of urban aquatic systems due to heavy metals turns significant due to their peculiar properties viz. persis tence, non-degradab ility, toxicity, and accumulation. Akkulam Veli (AV, an urba n tropical lake in south India is subjected to various environmental stresses due to multiple waste discharge, sand mining, developmental activities, tour ism related activitie s etc. Hence, a comprehensive approach is adopted for risk assessment using modified degree of contamination factor, toxicity units based on numerical sediment quality guidelines (SQGs, and potentialecological risk indices. The study revealed the presence of toxic metals such as Cr, C d, Pb and As and the lake is rated under ‘low ecological risk’ category.
Chen, Chieh V; Brummet, Jennifer L; Jordan, Cynthia L; Breedlove, S Marc
We previously found that androgen receptor (AR) activity mediates two effects of T in adult male mice: reduction of anxiety-like behaviors and dampening of the hypothalamic-pituitary-adrenal response to stress. To determine whether brain ARs mediate these effects, we used the Cre/loxP technology seeking to disable AR throughout the central nervous system (CNS). Female mice carrying the floxed AR allele (ARlox) were crossed with males carrying cre recombinase transgene controlled by the nestin promoter (NesCre), producing cre in developing neurons and glia. Among male offspring, four genotypes resulted: males carrying ARlox and NesCre (NesARko), and three control groups (wild types, NesCre, and ARlox). Reporter mice indicated ubiquitous Cre expression throughout the CNS. Nevertheless, AR immunocytochemistry in NesARko mice revealed efficient knockout (KO) of AR in some brain regions (hippocampus and medial prefrontal cortex [mPFC]), but not others. Substantial AR protein was seen in the amygdala and hypothalamus among other regions, whereas negligible AR remained in others like the bed nucleus of the stria terminalis and dorsal periaqueductal gray. This selective KO allowed for testing the role of AR in hippocampus and mPFC. Males were castrated and implanted with T at postnatal day 60 before testing on postnatal day 90-100. In contrast with males with global KO of AR, T still modulated anxiety-related behavior and hypothalamic-pituitary-adrenal activity in NesARko males. These results leave open the possibility that AR acting in the CNS mediates these effects of T, but demonstrate that AR is not required in the hippocampus or mPFC for T's anxiolytic effects.
Smeijers, Loes; Szabó, Balázs M; van Dammen, Lotte; Wonnink, Wally; Jakobs, Bernadette S; Bosch, Jos A; Kop, Willem J
Tako-Tsubo cardiomyopathy (TTC) is characterized by apical ballooning of the left ventricle and symptoms and signs mimicking acute myocardial infarction. The high catecholamine levels in the acute phase of TTC and common emotional triggers suggest a dysregulated stress response system. This study examined whether patients with TTC show exaggerated emotional, neurohormonal, and hemodynamic responses to mental stress. Patients with TTC (n = 18; mean age 68.3 ± 11.7, 78% women) and 2 comparison groups (healthy controls, n = 19; mean age 60.0 ± 7.6, 68% women; chronic heart failure, n = 19; mean age 68.8 ± 10.1, 68% women) performed a structured mental stress task (anger recall and mental arithmetic) and low-grade exercise with repeated assessments of negative emotions, neurohormones (catecholamines: norepinephrine, epinephrine, dopamine, hypothalamic-pituitary-adrenal axis hormones: adrenocorticotropic hormone [ACTH], cortisol), echocardiography, blood pressure, and heart rate. TTC was associated with higher norepinephrine (520.7 ± 125.5 vs 407.9 ± 155.3 pg/ml, p = 0.021) and dopamine (16.2 ± 10.3 vs 10.3 ± 3.9 pg/ml, p = 0.027) levels during mental stress and relatively low emotional arousal (p stress and exercise were elevated in TTC compared with healthy controls. No evidence was found for a dysregulated hypothalamic-pituitary-adrenal axis or hemodynamic responses. Patients with TTC showed blunted emotional arousal to mental stress. This study suggests that catecholamine hyper-reactivity and not emotional hyper-reactivity to stress is likely to play a role in myocardial vulnerability in TTC. Copyright © 2015 Elsevier Inc. All rights reserved.
Młyniec, Katarzyna; Budziszewska, Bogusława; Holst, Birgitte; Ostachowicz, Beata; Nowak, Gabriel
Zinc may act as a neurotransmitter in the central nervous system by activation of the GPR39 metabotropic receptors. In the present study, we investigated whether GPR39 knockout would cause depressive-like and/or anxiety-like behavior, as measured by the forced swim test, tail suspension test, and light/dark test. We also investigated whether lack of GPR39 would change levels of cAMP response element-binding protein (CREB),brain-derived neurotrophic factor (BDNF) and tropomyosin related kinase B (TrkB) protein in the hippocampus and frontal cortex of GPR39 knockout mice subjected to the forced swim test, as measured by Western-blot analysis. In this study, GPR39 knockout mice showed an increased immobility time in both the forced swim test and tail suspension test, indicating depressive-like behavior and displayed anxiety-like phenotype. GPR39 knockout mice had lower CREB and BDNF levels in the hippocampus, but not in the frontal cortex, which indicates region specificity for the impaired CREB/BDNF pathway (which is important in antidepressant response) in the absence of GPR39. There were no changes in TrkB protein in either structure. In the present study, we also investigated activity in the hypothalamus-pituitary-adrenal axis under both zinc- and GPR39-deficient conditions. Zinc-deficient mice had higher serum corticosterone levels and lower glucocorticoid receptor levels in the hippocampus and frontal cortex. There were no changes in the GPR39 knockout mice in comparison with the wild-type control mice, which does not support a role of GPR39 in hypothalamus-pituitary-adrenal axis regulation. The results of this study indicate the involvement of the GPR39 Zn(2+)-sensing receptor in the pathophysiology of depression with component of anxiety. © The Author 2015. Published by Oxford University Press on behalf of CINP.
Full Text Available Objective To observe the regularity of the changes in neuroendocrine-immune system caused by fatigue due to military operations, and explore the mechanism by which fatigue occurs in military operations. Methods The subjects were 240 soldiers belonging to a field artillery force. The medical history and physical examination were taken before military operations, and fatigue assessment scale was accomplished as well. The following variables were measured in all the subjects: pituitary-adrenal [adrenocorticotropic hormone (ACTH, cortical hormone (B, 24-h urinary free cortisol (UFC], pituitary-gonadal [luteinizing hormone (LH, testosterone (T, estradiol (E2], pituitary-thyroid functions [serum thyroid stimulating hormone (TSH, tetraiodothyronine (TT4, triiodothyronine (TT3, free thyroxine (FT4, and free triiodothyronine (FT3], and cellular immune parameters (CD3+, CD4+, CD8+, CD4+/CD8+, B, NK. After 7 d of large-scale and high-intensity field exercises, the above variables were again measured in all the subjects. Results After high-intensity military operations, the unpleasant feelings were significantly increased, and the compulsive and psychotic scores significantly decreased in the soldiers. In addition, the pituitary-adrenal and pituitary-gonadal hormone levels also decreased (all PPPConclusion The depressed psychological tolerance in soldiers is the psychological factor of fatigue after a high-intensity military operation. The hypocorticoidism and inhibition of hypothalamic-pituitary-gonadal axis are the pathophysiological basis of military operation fatigue. Suppression of immune function is an important reason for an increase of susceptibility to disease after high-intensity military operations.
Rationale: We have shown that acute ozone inhalation promotes activation of the sympathetic and hypothalamic-pituitary-adrenal (HPA) axis leading to release of cortisol and epinephrine from the adrenals. Adrenalectomy (ADREX) inhibits ozone-induced pulmonary vascular leakage and ...
Toxicology is increasingly focused on molecular events comprising adverse outcome pathways. Atrazine activates the hypothalamic-pituitary adrenal axis, but relationships to gonadal alterations are unknown. We characterized hormone profiles and adrenal (intact and castrate) and te...
Bleker, Laura S.; Roseboom, Tessa J.; Vrijkotte, Tanja G.; Reynolds, Rebecca M.; de Rooij, Susanne R.
Background. Psychosocial stress during pregnancy has been proposed as a major contributor of glucocorticoid-mediated programming of the fetal hypothalamic-pituitary adrenal (HPA) axis, with later adverse health consequences. However, evidence linking maternal stress to maternal cortisol values
Bleker, Laura S; Roseboom, Tessa J; Vrijkotte, Tanja G; Reynolds, Rebecca M; de Rooij, Susanne R
BACKGROUND: Psychosocial stress during pregnancy has been proposed as a major contributor of glucocorticoid-mediated programming of the fetal hypothalamic-pituitary adrenal (HPA) axis, with later adverse health consequences. However, evidence linking maternal stress to maternal cortisol values
Seldenrijk, A.; Hamer, M.; Lahiri, A.; Penninx, B.W.J.H.; Steptoe, A.
Objectives: Poor mental health has been associated with coronary heart disease (CHD). One hypothesized underlying mechanism is hypothalamus pituitary adrenal axis dysfunction. We examined the associations between psychological distress, cortisol response to laboratory-induced mental stress and
Kavelaars, A; Heijnen, CJ; Tennekes, R; Bruggink, JE; Koolhaas, JM
Neuroendocrine-immune interactions are thought to be important in determining susceptibility to autoimmune disease. Animal studies have revealed that differences in susceptibility to experimental autoimmune encephalomyelitis (EAE) are related to:reactivity in the hypothalamo-pituitary-adrenal axis.
Deuster, Patricia A
Obesity has reached epidemic levels and yet the incidence continues to rise. The current study is seeking to examine the hypothesis that obesity may reflect dysfunctioning of the hypothalamic-pituitary-adrenal (HPA...
Obesity has reached epidemic levels and yet the incidence continues to rise. The current study is seeking to examine the hypothesis that obesity may reflect dysfunctioning of the hypothalamic-pituitary-adrenal (HPA...
Deuster, Patricia A
Obesity has reached epidemic levels and yet the incidence continues to rise. The current study is seeking to examine the hypothesis that obesity may reflect dysfunctioning of the hypothalamic-pituitary-adrenal (H PA...
Deuster, Patricia A; Poth, Merrily; Sbrocco, Tracey; Faraday, Martha
Obesity has reached epidemic levels and yet the incidence continues to rise. The current study is seeking to examine the hypothesis that obesity may reflect dysfunctioning of the hypothalamic-pituitary-adrenal (HPA...
Dallman, Mary F.; Pecoraro, Norman; Akana, Susan F.; la Fleur, Susanne E.; Gomez, Francisca; Houshyar, Hani; Bell, M. E.; Bhatnagar, Seema; Laugero, Kevin D.; Manalo, Sotara
The effects of adrenal corticosteroids on subsequent adrenocorticotropin secretion are complex. Acutely (within hours), glucocorticoids (GCs) directly inhibit further activity in the hypothalamo-pituitary-adrenal axis, but the chronic actions (across days) of these steroids on brain are directly
Our recent work demonstrated that circulating stress hormones, epinephrine and corticosterone/cortisol, are involved in mediating ozone pulmonary effects through the activation of hypothalamus-pituitary-adrenal (HPA) axis. Adrenalectomy in Wistar Kyoto (WKY) rats diminished circu...
Haeck, I.M.; Timmer-de Mik, L.; Lentjes, E.G.; Buskens, E.; Hijnen, D.J.; Guikers, C.; Bruijnzeel-Koomen, C.A.; de Bruin-Weller, M.S.
BACKGROUND: Topical corticosteroids are used extensively to treat inflammatory skin disorders including atopic dermatitis (AD). Several studies have described temporary reversible suppression of hypothalamic-pituitary-adrenal function. However, sound evidence of permanent disturbance of adrenal
Background: Prenatal malnutrition and stress have been associated with the regulation of the offspring hypothalamic-pituitary-adrenal (HPA) axis. Objective: To evaluate whether maternal and infant nutritional supplementation was associated with salivary cortisol concentrations in Malawian infants. ...
van den Bosch, J.A.; de Geus, E.J.C.; Carroll, D.; Goedhart, A.D.; Anane, L.A.; van Zanten, J.J.; Helmerhorst, E.J.; Edwards, K.M.
Objective: To examine the Social Self Preservation Theory, which predicts that stressors involving social evaluative threat (SET) characteristically activate the hypothalamic-pituitary-adrenal (HPA) axis. The idea that distinct psychosocial factors may underlie specific patterns of neuroendocrine
Huizink, A.C.; Bartels, M.; Rose, R.J.; Pulkkinen, L.; Eriksson, C.J.P.; Kaprio, J.
Background: Animal research suggests a programming effect of prenatal stress in the fetal period, resulting in disruptions in behavioural and neuromotor development. Physiological changes that mediate these effects include alterations in the hypothalamic-pituitary-adrenal axis and in testosterone
Holleman, M.; Vreeburg, S.A.; Dekker, J.J.M.; Penninx, B.W.J.H.
Background: An etiological model has been suggested where stress leads to high cortisol levels and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, resulting in somatic diseases and psychopathology. To evaluate this model we examined the association of different stressors (working
Holleman, Michiel; Vreeburg, Sophie A.; Dekker, Jack J. M.; Penninx, Brenda W. J. H.
Background: An etiological model has been suggested where stress leads to high cortisol levels and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, resulting in somatic diseases and psychopathology. To evaluate this model we examined the association of different stressors (working
Melief, Jeroen; Koper, Jan W; Endert, Erik
As high cortisol levels are implicated in suppressed disease activity of multiple sclerosis (MS), glucocorticoid receptor (GR) polymorphisms that affect glucocorticoid (GC) sensitivity may impact on this by changing local immunomodulation or regulation of the hypothalamus-pituitary-adrenal (HPA...
Sanada, Kazue; Sugimoto, Koji; Shutoh, Fumihiro; Hisano, Setsuji
Perception of particular sensory stimuli from the surroundings can influence emotion in individuals. In an uncomfortable situation, humans protect themselves from some aversive stimulus by acutely evoking a stress response. Animal model studies have contributed to an understanding of neuronal mechanisms underlying the stress response in humans. To study a possible anti-stressful effect of lemon odor, an excitation of neurons secreting corticotropin-releasing hormone (CRH) as a primary factor of the hypothalamic-pituitary-adrenal axis (HPA) was analyzed in animal model experiments, in which rats are restrained in the presence or absence of the odor. The effect was evaluated by measuring expression of c-Fos (an excited neuron marker) in the hypothalamic paraventricular nucleus (PVN), a key structure of the HPA in the brain. We prepared 3 animal groups: Groups S, L and I. Groups S and L were restrained for 30 minutes while being blown by air and being exposed to the lemon odor, respectively. Group I was intact without any treatment. Two hours later of the onset of experiments, brains of all groups were sampled and processed for microscopic examination. Brain sections were processed for c-Fos immunostaining and/or in situ hybridization for CRH. In Group S but not in Group I, c-Fos expression was found in the PVN. A combined in situ hybridization-immunohistochemical dual labeling revealed that CRH mRNA-expressing neurons express c-Fos. In computer-assisted automatic counting, the incidence of c-Fos-expressing neurons in the entire PVN was statistically lower in Group L than in Group S. Detailed analysis of PVN subregions demonstrated that c-Fos-expressing neurons are fewer in Group L than in Group S in the dorsal part of the medial parvocellular subregion. These results may suggest that lemon odor attenuates the restraint stress-induced neuronal activation including CRH neurons, presumably mimicking an aspect of stress responses in humans.
Farideh Zafari Zangeneh
Full Text Available Background: Polycystic ovary syndrome (PCOS is a common complex condition in women associated with reproductive and metabolic systems and also psychological disorders. There is considerable evidence to suggest that the sympathetic nervous system is involved in PCO and metabolic syndromes. Noradrenalin (NA, corticotrophin releasing hormone (CRH and nerve growth factor (NGF are the strong stimulants for two axes: hypothalamic-pituitary-adrenal (HPA and hypothalamic-pituitary-ovarian (HPO axes which are regulators for the female reproductive system. Following previous studies on sympathetic nervous system over activity in PCOS, the main purpose of this study is to evaluate the role of CRH and NGF as two important findings from the perspective of the psycho-emotional. Methods: This case-control study was conducted in Reproductive Health Research Center of Imam Khomeini Hospital, Tehran, Iran in the September of 2011. 170 women participated in this study. The diagnosis of PCOS was made according to the joint criteria of the European Society of Human Reproduction and Embryology and the American Society of Reproductive Medicine (ESHRE/ASRM. All women have 20-40 years of age and body mass index (BMI of less than 28. Demographic questionnaire was used in this study and blood sample was obtained from all participants before 8AM. All analysis was done in SPSS software, version 19 (IBM SPSS, Armonk, NY, USA. P-value less than 0.05 considered as significant level. Results: Serum levels of CRH and NGF in patients with polycystic ovary was significantly lower than the control group (P< 0.001. This reduction can disrupt two neural axes: the sympathetic nervous system (SAS and hypothalamus-pituitary-adrenal (HPA. These axes have a fundamental role in psycho-emotional reactions in women with PCOS. Moreover, using demographic questionnaire quantitative and qualitative characteristics of the population studied, the results of which are reported in the regression
Shevchuk Nikolai A
Full Text Available Abstract Background Physiological fatigue can be defined as a reduction in the force output and/or energy-generating capacity of skeletal muscle after exertion, which may manifest itself as an inability to continue exercise or usual activities at the same intensity. A typical example of a fatigue-related disorder is chronic fatigue syndrome (CFS, a disabling condition of unknown etiology and with uncertain therapeutic options. Recent advances in elucidating pathophysiology of this disorder revealed hypofunction of the hypothalamic-pituitary-adrenal axis and that fatigue in CFS patients appears to be associated with reduced motor neurotransmission in the central nervous system (CNS and to a smaller extent with increased fatigability of skeletal muscle. There is also some limited evidence that CFS patients may have excessive serotonergic activity in the brain and low opioid tone. Presentation of the hypothesis This work hypothesizes that repeated cold stress may reduce fatigue in CFS because brief exposure to cold may transiently reverse some physiological changes associated with this illness. For example, exposure to cold can activate components of the reticular activating system such as raphe nuclei and locus ceruleus, which can result in activation of behavior and increased capacity of the CNS to recruit motoneurons. Cold stress has also been shown to reduce the level of serotonin in most regions of the brain (except brainstem, which would be consistent with reduced fatigue according to animal models of exercise-related fatigue. Finally, exposure to cold increases metabolic rate and transiently activates the hypothalamic-pituitary-adrenal axis as evidenced by a temporary increase in the plasma levels of adrenocorticotropic hormone, beta-endorphin and a modest increase in cortisol. The increased opioid tone and high metabolic rate could diminish fatigue by reducing muscle pain and accelerating recovery of fatigued muscle, respectively. Testing
Kovalenko, E A
Hypokinesia is an important problem in modern medicine. In the pathogenetic effect of prolonged hypokinesia the main etiological factor is diminished motor activity; of major importance are disorders in the energy and plastic metabolism which affect the muscle system; the contributing factors are cardiovascular deconditioning and orthostatic intolerance. This is attributed to a decreased oxygen supply and eliminated hydrostatic influences during a prolonged recumbency. Blood redistribution in the vascular bed is related to the Gauer-Henry reflex and subsequent changes in the fluid-electrolyte balance. Decreased load on the bone system induces changes in the protein-phosphate-calcium metabolism, diminished bone density and increased calcium content in the blood and urine. Changes in the calcium metabolism are systemic. The activity of the higher nervous system and reflex functions is lowered. Changes in the function of the autonomic nervous system which include a noticeable decline of its adaptive-trophic role as a result of the decrease of afferent and efferent impulsation are of great importance. Changes in the hormonal function involve a peculiar stress-reaction which develops at an early stage of hypokinesia as a response to an unusual situation. Prolonged hypokinesia may result in a disturbed function of the pituitary-adrenal system. It is assumed that prolonged hypokinesia may induce a specific disease of hypokinesia during which man cannot lead a normal mode of life and work.
Walker, David J; Spencer, Karen A
Throughout life physiological systems strive to maintain homeostasis and these systems are susceptible to exposure to maternal or environmental perturbations, particularly during embryonic development. In some cases, these perturbations may influence genetic and physiological processes that permanently alter the functioning of these physiological systems; a process known as developmental programming. In recent years, the neuroimmune system has garnered attention for its fundamental interactions with key hormonal systems, such as the hypothalamic pituitary adrenal (HPA) axis. The ultimate product of this axis, the glucocorticoid hormones, play a key role in modulating immune responses within the periphery and the CNS as part of the physiological stress response. It is well-established that elevated glucocorticoids induced by developmental stress exert profound short and long-term physiological effects, yet there is relatively little information of how these effects are manifested within the neuroimmune system. Pre and post-natal periods are prime candidates for manipulation in order to uncover the physiological mechanisms that underlie glucocorticoid programming of neuroimmune responses. Understanding the potential programming role of glucocorticoids may be key in uncovering vulnerable windows of CNS susceptibility to stressful experiences during embryonic development and improve our use of glucocorticoids as therapeutics in the treatment of neurodegenerative diseases. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.
Kim, Hei Sung; Yosipovitch, Gil
Perceived stress has long been known to alter the dynamic equilibrium established between the nervous, endocrine and immune system and is widely recognised to trigger or enhance pruritus. However, the exact mechanism of how the major stress response systems, such as the hypothalamus-pituitary adrenal (HPA) axis and the autonomic nervous system induce or aggravate chronic itch, has not been elucidated. The limbic regions of the brain such as the prefrontal cortex and hippocampus are deeply involved in the regulation of the stress response and intersect with circuits that are responsible for memory and reward. According to the 'Polyvagal Theory', certain limbic structures that serve as a 'higher brain equivalent of the parasympathetic nervous system' play a foremost role in maintaining body homoeostasis by functioning as an active vagal brake. In addition, the limbic system has been postulated to regulate two distinct, yet related aspects of itch: (i) the sensory-discriminative aspect; and (ii) the affective-cognitive aspect. Chronic stress-induced itch is hypothesised to be caused by stress-related changes in limbic structure with subsequent rewiring of both the peripheral and central pruriceptive circuits. Herein, we review data suggesting that a dysfunctional parasympathetic nervous system associated with chronic stress may play a critical role in the regulatory control of key candidate molecules, receptors and brain structures involved in chronic itch. © 2012 John Wiley & Sons A/S.
Full Text Available Survival of all living organisms depends on maintenance of a steady state of homeostasis, which process relies on its ability to react and adapt to various physical and emotional threats. The defense against stress is executed by the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal medullary system. Adrenal gland is a major effector organ of stress system. During stress adrenal gland rapidly respond with increased secretion of glucocorticoids and catecholamines into circulation, which hormones, in turn, affect metabolism, to provide acutely energy, vasculature to increase blood pressure and the immune system to prevent it from extensive activation. Sepsis resulting from microbial infections is a sustained and extreme example of stress situation. In many critical ill patients levels of both corticotropin-releasing hormone and adrenocorticotropin, two major regulators of adrenal hormone production, are suppressed. Levels of glucocorticoids however, remain normal or are elevated in these patients, suggesting a shift from central to local intraadrenal regulation of adrenal stress response. Among many mechanisms potentially involved in this process, reduced glucocorticoid metabolism and local intraadrenal activation of hormone production mediated by adrenocortical and chromaffin cell interactions, the adrenal vascular system and the immune-adrenal crosstalk play a key role. Consequently, any impairment in function of these systems, can ultimately affect adrenal stress response. The purpose of this mini review is to present and discuss recent advances in our understanding of the adrenal gland microenvironment, and its role in regulation of stress-induced hormone secretion.
Rohleder, N.; Wirth, D.; Fraßl, W.; Kowoll, R.; Schlemmer, M.; Vogler, S.; Kirsch, K. A.; Kirschbaum, C.; Gunga, H.-C.
Limited data are available on the response of stress systems to microgravity. Increased activity of stress systems is reported during space flight, but unchanged or decreased activity during simulated microgravity. We here investigated the impact of head-out water immersion on the activity of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) system.Eight healthy young men were exposed to a six-hour water immersion in a thermo neutral bath and a control condition. Saliva samples were taken before, during, and after interventions to assess cortisol as an index for HPA axis activity, and salivary α-amylase as an index for SAM system activity.Cortisol levels uniformly decreased during both conditions. Amylase levels increased during both conditions, but were significantly lower during the first half of water immersion compared to the control condition.In conclusion, the HPA axis is not influenced by simulated microgravity, while SAM system activity shows initial decreases during water immersion.
Derendorf, H; Meltzer, E O
Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34-49%. Studies, including 1-year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic-pituitary-adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.
Oquendo, Maria A.; Sullivan, Gregory M.; Sudol, Katherin; Baca-Garcia, Enrique; Stanley, Barbara H.; Sublette, M. Elizabeth; Mann, J. John
Objective Suicide, a major cause of death worldwide, has distinct biological underpinnings. The authors review and synthesize the research literature on biomarkers of suicide, with the aim of using the findings of these studies to develop a coherent model for the biological diathesis for suicide. Method The authors examined studies covering a large range of neurobiological systems implicated in suicide. They provide succinct descriptions of each system to provide a context for interpreting the meaning of findings in suicide. Results Several lines of evidence implicate dysregulation in stress response systems, especially the hypothalamic-pituitary-adrenal axis, as a diathesis for suicide. Additional findings related to neuroinflammatory indices, glutamatergic function, and neuronal plasticity at the cellular and circuitry level may reflect downstream effects of such dysregulation. Whether serotonergic abnormalities observed in individuals who have died by suicide are independent of stress response abnormalities is an unresolved question. Conclusions The most compelling biomarkers for suicide are linked to altered stress responses and their downstream effects, and to abnormalities in the serotonergic system. Studying these systems in parallel and in the same populations may elucidate the role of each and their interplay, possibly leading to identification of new treatment targets and biological predictors. PMID:25263730
Full Text Available Stress is a constant factor in today′s fastpaced life that can jeopardize our health if left unchecked. It is only in the last half century that the role of stress in every ailment from the common cold to AIDS has been emphasized, and the mechanisms involved in this process have been studied. Stress influences the immune response presumably through the activation of the hypothalamic-pituitary adrenal axis, hypothalamic pituitary-gonadal axis, and the sympathetic-adrenal-medullary system. Various neurotransmitters, neuropeptides, hormones, and cytokines mediate these complex bidirectional interactions between the central nervous system (CNS and the immune system. The effects of stress on the immune responses result in alterations in the number of immune cells and cytokine dysregulation. Various stress management strategies such as meditation, yoga, hypnosis, and muscle relaxation have been shown to reduce the psychological and physiological effects of stress in cancers and HIV infection. This review aims to discuss the effect of stress on the immune system and examine how relaxation techniques such as Yoga and meditation could regulate the cytokine levels and hence, the immune responses during stress.
Cowell, Whitney J; Wright, Rosalind J
Environmental toxicants and psychosocial stressors share many biological substrates and influence overlapping physiological pathways. Increasing evidence indicates stress-induced changes to the maternal milieu may prime rapidly developing physiological systems for disruption by concurrent or subsequent exposure to environmental chemicals. In this review, we highlight putative mechanisms underlying sex-specific susceptibility of the developing neuroendocrine system to the joint effects of stress or stress correlates and environmental toxicants (bisphenol A, alcohol, phthalates, lead, chlorpyrifos, and traffic-related air pollution). We provide evidence indicating that concurrent or tandem exposure to chemical and non-chemical stressors during windows of rapid development is associated with sex-specific synergistic, potentiated and reversed effects on several neuroendocrine endpoints related to hypothalamic-pituitary-adrenal axis function, sex steroid levels, neurotransmitter circuits, and innate immune function. We additionally identify gaps, such as the role that the endocrine-active placenta plays, in our understanding of these complex interactions. Finally, we discuss future research needs, including the investigation of non-hormonal biomarkers of stress. We demonstrate multiple physiologic systems are impacted by joint exposure to chemical and non-chemical stressors differentially among males and females. Collectively, the results highlight the importance of evaluating sex-specific endpoints when investigating the neuroendocrine system and underscore the need to examine exposure to chemical toxicants within the context of the social environment.
Knaepen, Liesbeth; Pawluski, Jodi L; Patijn, Jacob; van Kleef, Maarten; Tibboel, Dick; Joosten, Elbert A
It has been estimated that 20% of pregnant women are facing perinatal stress and depression. Perinatal maternal stress has been shown to increase pain sensitivity in offspring. For the treatment of their depressive symptoms, pregnant women are frequently prescribed selective serotonin reuptake inhibitors (SSRIs). Since the descending pain inhibitory circuit matures perinatally, perinatal SSRI exposure has been shown to affect pain sensitivity in offspring. In the present review, we summarize experimental and clinical evidence for the effect of perinatal maternal stress and SSRI exposure on pain sensitivity in offspring. Both experimental and clinical studies show the effect of perinatal maternal stress on regulation of the hypothalamic-pituitary-adrenal (HPA) system and the serotonin pain inhibitory system. Alterations in these two systems likely underlie long-term alterations in the development of pain sensitivity. This review sheds light on the effect of perinatal maternal stress and treatment with SSRIs on offspring pain sensitivity, in relation to the developing HPA system and 5-HT signaling. © 2013 Wiley Periodicals, Inc.
Results linking stress, production and welfare in farmed mink, with special focus on the hypothalamic-pituitary-adrenal (HPA)-axis, are presented. Interpretation of stress responses are discussed, combining context, neuroendocrine and behavioural indicators. Results from the development and valid......Results linking stress, production and welfare in farmed mink, with special focus on the hypothalamic-pituitary-adrenal (HPA)-axis, are presented. Interpretation of stress responses are discussed, combining context, neuroendocrine and behavioural indicators. Results from the development...... animals and whether fur-chewing/stereotypic behaviour is associated with hippocampal neurogenesis in mink. Perspectives and suggested future research aiming to improve production and welfare in farmed mink are given....
Feyer, P.; Titlbach, O.; Hoffmann, F.A.; Kubel, M.; Helbig, W.; Leipzig Univ.
Data regarding changes of endocrine parameters after total body irradiation (TBI) and bone marrow transplantation (BMT) are described. Endocrine glands are usually resistant to irradiation under morphological aspects. But new methods of determination and sensitive tests were developed in the last few years. Now it is possible to detect already small functional changes. Endocrine studies in the course of the disease were followed serially in 16 patients with TBI and BMT. Pretransplant conditioning consisted of single-dose irradiation combined with a high-dose, short-term chemotherapy. Reactions of the endocrine system showed a defined temporary order. Changes of ACTH and cortisol were in the beginning. The pituitary-adrenal cortex system responds in a different way. The pituitary-thyroid system develops a short-term 'low-T 3 -syndrome' reflecting the extreme stress of the organism. At the same time we obtained an increase of thyroxine. Testosterone and luteotropic hormone, the sexual steroids showed levels representing a primary gonadal insufficiency. The studies in the posttransplant period yielded a return to the normal range at most of the hormonal levels with the exception of the sexual steroids. Sterility is one of the late effects of TBI. A tendency towards hypothyroidism could be noticed in some cases being only subclinical forms. Reasons and possible therapy are discussed. (author)
Hidalgo, Vanesa; Almela, Mercedes; Villada, Carolina; Salvador, Alicia
Stress has been associated with negative changes observed during the aging process. However, very little research has been carried out on the role of age in acute stress effects on memory. We aimed to explore the role of age and sex in the relationship between hypothalamus-pituitary-adrenal axis (HPA-axis) and sympathetic nervous system (SNS) reactivity to psychosocial stress and short-term declarative memory performance. To do so, sixty-seven participants divided into two age groups (each group with a similar number of men and women) were exposed to the Trier Social Stress Test (TSST) and a control condition in a crossover design. Memory performance was assessed by the Rey Auditory Verbal Learning Test (RAVLT). As expected, worse memory performance was associated with age; but more interestingly, the stressor impaired recall after interference only in the older group. In addition, this effect was negatively correlated with the alpha-amylase over cortisol ratio, which has recently been suggested as a good marker of stress system dysregulation. However, we failed to find sex differences in memory performance. These results show that age moderates stress-induced effects on declarative memory, and they point out the importance of studying both of the physiological systems involved in the stress response together. Copyright © 2014 Elsevier Inc. All rights reserved.
Joseph, Joshua J; Golden, Sherita H
Controversy exists over the role of stress and depression in the pathophysiology of type 2 diabetes mellitus. Depression has been shown to increase the risk for progressive insulin resistance and incident type 2 diabetes mellitus in multiple studies, whereas the association of stress with diabetes is less clear, owing to differences in study designs and in forms and ascertainment of stress. The biological systems involved in adaptation that mediate the link between stress and physiological functions include the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous and immune systems. The HPA axis is a tightly regulated system that represents one of the body's mechanisms for responding to acute and chronic stress. Depression is associated with cross-sectional and longitudinal alterations in the diurnal cortisol curve, including a blunted cortisol awakening response and flattening of the diurnal cortisol curve. Flattening of the diurnal cortisol curve is also associated with insulin resistance and type 2 diabetes mellitus. In this article, we review and summarize the evidence supporting HPA axis dysregulation as an important biological link between stress, depression, and type 2 diabetes mellitus. © 2016 New York Academy of Sciences.
Wieke de Vente
Full Text Available There is mounting evidence that burnout is a risk factor for cardiovascular disease (CVD. Stress-related dysregulation of the sympathetic and parasympathetic system and the hypothalamic pituitary adrenal (HPA axis may explain the enhanced risk for CVD. To test this hypothesis, 55 patients (34 males and 21 females with burnout on sickness absence and 40 healthy participants (16 males and 24 females were exposed to a psychosocial stressor consisting of mental arithmetic and public speech. Physiological variables (i.e., blood pressure, heart rate, cardiac output, vascular resistance, cortisol, and alpha-amylase were measured. Basal levels, reactivity, and recovery were compared between groups. In male patients, baseline systolic blood pressure was higher, whereas basal alpha-amylase and cortisol reactivity were lower than in healthy males. In female patients, a tendency for lower basal cortisol was found as compared to healthy females. Furthermore, reduced basal heart rate variability and a trend for elevated basal cardiac output were observed in both male and female patients. Burnout is characterised by dysregulation of the sympathetic and parasympathetic system and the HPA axis, which was more pronounced in males than in females. This study further supports burnout as being a risk factor for CVD through dysregulation of the sympathetic and parasympathetic system and the HPA axis.
Laurent, Heidemarie K; Powers, Sally I; Granger, Douglas A
This study investigated associations among young adults' hypothalamic-pituitary-adrenal axis activity, autonomic nervous system activity, and subjective stress in response to interpersonal conflict to better characterize coordination across stress systems. Seven saliva samples were collected from 199 young adult opposite-sex couples before, during, and after they discussed an unresolved relationship conflict. Samples were later assayed for cortisol and alpha-amylase (sAA). Couples rated anticipatory stress prior to the conflict and perceived stress immediately following the task. Growth curve modeling was used to examine two possible levels of within-person coordination across physiological systems: alignment between cortisol and sAA responses throughout the sampling period ("matched phase coordination"), and association between overall levels of cortisol and sAA in response to conflict ("average level coordination"). Whereas both partners showed the former type of coordination, only women showed the latter type. Positive anticipation of the stressor predicted stronger cortisol-sAA matched phase coordination for women. Pre-task ratings related to women's sAA, and post-task ratings related to both partners' cortisol responses. Implications for a multisystem interpretation of normal and pathological responses to daily stress are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.
Pukhal'skiĭ, A L; Shmarina, G V; Aleshkin, V A
The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets. The brain, immune and endocrine systems being the principal adaptive systems in the body permanently share information both in the form of neural impulses and soluble mediators. The CNS differs from other organs due to several peculiarities that affect local immune surveillance. The brain cells secluded from the blood flow by a specialized blood-brain-barrier (BBB) can endogenously express pro- and anti-inflammatory cytokines without the intervention of the immune system. In normal brain the cytokine signaling rather contributes to exclusive brain function (e.g. long-term potentiation, synaptic plasticity, adult neurogenesis) than serves as immune communicator. The stress of different origin increases the serum cytokine levels and disrupts BBB. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Mass intrusion of biologically active peptides having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. In addition owing to BBB disruption dendritic cells and T cells also penetrate into the brain where they take up a perivascular position. The changes observed in stressed subject may accumulate during repeated episodes of stress forming a picture typical of the aging brain. Moreover long-term stress as well as physiological aging result in hormonal and immunological disturbances including hypothalamic-pituitary-adrenal axis depletion, regulatory T-cell accumulation and dehydroepiandrosterone decrease.
Full Text Available Abstract The manifestations of stress, defined as a biological response to an event that the individual perceives as a threat to its homeostasis, are commonly linked to enhanced activity of the hypothalamo-pituitary-adrenal (HPA axis and the activation of the sympathetic adreno-medullary (SA system. Activation of the HPA system results in the secretion of peptides from the hypothalamus, principally corticotropin releasing hormone (CRH, which stimulates the release of adrenocorticotropic hormone (ACTH and beta-endorphin. ACTH induces the secretion of corticosteroids from the adrenal cortex, which can be seen in pigs exposed to acute physical and/or psychological stressors. The present paper is a review of studies on the influence of stressors on reproduction in pigs. The effects of stress on reproduction depend on the critical timing of stress, the genetic predisposition to stress, and the type of stress. The effect of stress on reproduction is also influenced by the duration of the responses induced by various stressors. Prolonged or chronic stress usually results in inhibition of reproduction, while the effects of transient or acute stress in certain cases is stimulatory (e.g. anoestrus, but in most cases is of impairment for reproduction. Most sensitive of the reproductive process are ovulation, expression of sexual behaviour and implantation of the embryo, since they are directly controlled by the neuroendocrine system.
Gu, Simeng; Wang, Wei; Wang, Fushun; Huang, Jason H
Affective disorders are a leading cause of disabilities worldwide, and the etiology of these many affective disorders such as depression and posttraumatic stress disorder is due to hormone changes, which includes hypothalamus-pituitary-adrenal axis in the peripheral nervous system and neuromodulators in the central nervous system. Consistent with pharmacological studies indicating that medical treatment acts by increasing the concentration of catecholamine, the locus coeruleus (LC)/norepinephrine (NE) system is regarded as a critical part of the central "stress circuitry," whose major function is to induce "fight or flight" behavior and fear and anger emotion. Despite the intensive studies, there is still controversy about NE with fear and anger. For example, the rats with LC ablation were more reluctant to leave a familiar place and took longer to consume the food pellets in an unfamiliar place (neophobia, i.e., fear in response to novelty). The reason for this discrepancy might be that NE is not only for flight (fear), but also for fight (anger). Here, we try to review recent literatures about NE with stress induced emotions and their relations with mental disorders. We propose that stress induced NE release can induce both fear and anger. "Adrenaline rush or norepinephrine rush" and fear and anger emotion might act as biomarkers for mental disorders.
Full Text Available Affective disorders are a leading cause of disabilities worldwide, and the etiology of these many affective disorders such as depression and posttraumatic stress disorder is due to hormone changes, which includes hypothalamus-pituitary-adrenal axis in the peripheral nervous system and neuromodulators in the central nervous system. Consistent with pharmacological studies indicating that medical treatment acts by increasing the concentration of catecholamine, the locus coeruleus (LC/norepinephrine (NE system is regarded as a critical part of the central “stress circuitry,” whose major function is to induce “fight or flight” behavior and fear and anger emotion. Despite the intensive studies, there is still controversy about NE with fear and anger. For example, the rats with LC ablation were more reluctant to leave a familiar place and took longer to consume the food pellets in an unfamiliar place (neophobia, i.e., fear in response to novelty. The reason for this discrepancy might be that NE is not only for flight (fear, but also for fight (anger. Here, we try to review recent literatures about NE with stress induced emotions and their relations with mental disorders. We propose that stress induced NE release can induce both fear and anger. “Adrenaline rush or norepinephrine rush” and fear and anger emotion might act as biomarkers for mental disorders.
Full Text Available Prolactin is one of the most versatile hormones known. It is considered an adaptive hormone due to the key roles it plays in the modulation of the stress response and during pregnancy and lactation. Within the brain, prolactin acts as a neuropeptide to promote physiological responses related to reproduction, stress adaptation, neurogenesis, and neuroprotection. The action of prolactin on the nervous system contributes to the wide array of changes that occur in the female brain during pregnancy and result in the attenuation of the hypothalamic pituitary adrenal axis. Together, all these changes promote behavioral and physiological adaptations of the new mother to enable reproductive success. Brain adaptations driven by prolactin are also important for the regulation of maternal emotionality and wellbeing Prolactin also affects the male brain during the stress response but its effects have been less studied. Prolactin regulates neurogenesis both in the subventricular zone and in the hippocampus. Therefore, alterations in the prolactin system due to stress, or exposure to substances that reduce neurogenesis or other conditions, could contribute to maladaptive responses and pathological behavioral outcomes. Here we review the prolactin system and the role it plays in the modulation of stress response and emotion regulation. We discuss the effects of prolactin on neurogenesis and neuroprotection, the putative neuronal mechanisms underlying these effects, and their contribution to the onset of psychopathological states like depression.
Powers, Sally I.; Granger, Douglas A.
This study investigated associations among young adults' hypothalamic-pituitary-adrenal axis activity, autonomic nervous system activity, and subjective stress in response to interpersonal conflict to better characterize coordination across stress systems. Seven saliva samples were collected from 199 young adult opposite-sex couples before, during, and after they discussed an unresolved relationship conflict. Samples were later assayed for cortisol and alpha-amylase (sAA). Couples rated anticipatory stress prior to the conflict and perceived stress immediately following the task. Growth curve modeling was used to examine two possible levels of within-person coordination across physiological systems: alignment between cortisol and sAA responses throughout the sampling period (“matched phase coordination”), and association between overall levels of cortisol and sAA in response to conflict (“average level coordination”). Whereas both partners showed the former type of coordination, only women showed the latter type. Positive anticipation of the stressor predicted stronger cortisol-sAA matched phase coordination for women. Pre-task ratings related to women's sAA, and post-task ratings related to both partners' cortisol responses. Implications for a multisystem interpretation of normal and pathological responses to daily stress are discussed. PMID:23684904
Ozone, a major component of smog generated through the interaction of light and anthropogenic emissions, induces adverse pulmonary, cardiovascular, and systemic health effects upon inhalation. It is generally accepted that ozone-induced lung injury is mediated by its interaction with lung lining components causing local oxidative changes, which then leads to cell damage and recruitment of inflammatory cells. It is postulated that the spillover of reactive intermediates and pro-inflammatory molecules from lung to systemic circulation mediates extra-pulmonary effects. However, recent work from our laboratory supports an alternative hypothesis that circulating stress hormones, such as epinephrine and corticosterone/cortisol, are involved in mediating ozone pulmonary effects. We have shown in rats and humans that ozone increases the levels of circulating stress hormones through activation of the hypothalamus- pituitary-adrenal (HPA) axis before any measurable effects are observed in the lung. The surgical removal of adrenals diminishes circulating stress hormones and at the same time, the pulmonary effects of ozone suggesting a significant contribution of these hormones in ozone-induced lung injury and inflammation. While ozone effects in the lung have been extensively studied, the contribution of central nervous system -mediated hormonal stress response has not been examined. In order to understand the signaling pathways that might be involved in ozone-induced lun
Inga D Neumann
Full Text Available Psychopathologies such as anxiety- and depression-related disorders are often characterized by impaired social behaviours including excessive aggression and violence. Excessive aggression and violence likely develop as a consequence of generally disturbed emotional regulation, such as abnormally high or low levels of anxiety. This suggests an overlap between brain circuitries and neurochemical systems regulating aggression and anxiety. In this review, we will discuss different forms of male aggression, rodent models of excessive aggression, and neurobiological mechanisms underlying male aggression in the context of anxiety. We will summarize our attempts to establish an animal model of high and abnormal aggression using rats selected for high (HAB versus low (LAB anxiety-related behaviour. Briefly, male LAB rats and, to a lesser extent, male HAB rats show high and abnormal forms of aggression compared with non-selected (NAB rats, making them a suitable animal model for studying excessive aggression in the context of extremes in innate anxiety. In addition, we will discuss differences in the activity of the hypothalamic-pituitary-adrenal axis, brain arginine vasopressin, and the serotonin systems, among others, which contribute to the distinct behavioural phenotypes related to aggression and anxiety. Further investigation of the neurobiological systems in animals with distinct anxiety phenotypes might provide valuable information about the link between excessive aggression and disturbed emotional regulation, which is essential for understanding the social and emotional deficits that are characteristic of many human psychiatric disorders.
Doyle, P; Rohner-Jeanrenaud, F; Jeanrenaud, B
An animal model often used to investigate the aetiology of obesity is the genetically obese fa/fa rat. It has many abnormalities, including hyperphagia, hyper-insulinemia, insulin resistance, low cerebral glucose utilization and an overactive hypothalamo-pituitary adrenal (HPA) axis with resulting hypercorticism. Due to the latter consideration, the aim of this work was to study the impact of acute adrenalectomy (ADX) on the local cerebral glucose utilization (LCGU) of lean and obese fa/fa rats. ADX resulted in discrete increases in LCGU of regions common to both lean and obese rats. These common regions were found to belong to be related to the limbic system. Within this system, the LCGU of the brain of obese rats was either normalized to lean sham operated values or increased by ADX to a similar degree in both groups on a percentage basis. It was concluded that the LCGU of both lean and obese animals appears to be negatively regulated, albeit to different extents, by glucocorticoids. Such negative regulation is particularly salient within the limbic system of the lean rat and even more so in the fa/fa rat. It is suggested that the long-term hypercorticism of obese fa/fa rats due to abnormal regulation of the HPA axis may result in a decreased LCGU in limbic and related regions of the brain of fa/fa rats and contribute to the expression of the obese phenotype.
Raja-Khan, Nazia; Stener-Victorin, Elisabet; Wu, XiaoKe; Legro, Richard S
Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is characterized by chronic hyperandrogenic anovulation leading to symptoms of hirsutism, acne, irregular menses, and infertility. Multiple metabolic and cardiovascular risk factors are associated with PCOS, including insulin resistance, obesity, type 2 diabetes, hypertension, inflammation, and subclinical atherosclerosis. However, current treatments for PCOS are only moderately effective at controlling symptoms and preventing complications. This article describes how the physiological effects of major complementary and alternative medicine (CAM) treatments could reduce the severity of PCOS and its complications. Acupuncture reduces hyperandrogenism and improves menstrual frequency in PCOS. Acupuncture's clinical effects are mediated via activation of somatic afferent nerves innervating the skin and muscle, which, via modulation of the activity in the somatic and autonomic nervous system, may modulate endocrine and metabolic functions in PCOS. Chinese herbal medicines and dietary supplements may also exert beneficial physiological effects in PCOS, but there is minimal evidence that these CAM treatments are safe and effective. Mindfulness has not been investigated in PCOS, but it has been shown to reduce psychological distress and exert positive effects on the central and autonomic nervous systems, hypothalamic-pituitary-adrenal axis, and immune system, leading to reductions in blood pressure, glucose, and inflammation. In conclusion, CAM treatments may have beneficial endocrine, cardiometabolic, and reproductive effects in PCOS. However, most studies of CAM treatments for PCOS are small, nonrandomized, or uncontrolled. Future well-designed studies are needed to further evaluate the safety, effectiveness, and mechanisms of CAM treatments for PCOS.
Contarino, Angelo; Kitchener, Pierre; Vallée, Monique; Papaleo, Francesco; Piazza, Pier-Vincenzo
Stimulant drugs produce reward but also activate stress-responsive systems. The corticotropin-releasing factor (CRF) and the related hypothalamus-pituitary-adrenal (HPA) axis stress-responsive systems are activated by stimulant drugs. However, their role in stimulant drug-induced reward remains poorly understood. Herein, we report that CRF 1 receptor-deficient (CRF 1 -/-), but not wild-type, mice show conditioned place preference (CPP) responses to a relatively low cocaine dose (5 mg/kg, i.p.). Conversely, wild-type, but not CRF 1 -/-, mice display CPP responses to a relatively high cocaine dose (20 mg/kg, i.p.), indicating that CRF 1 receptor-deficiency alters the rewarding effects of cocaine. Acute pharmacological antagonism of the CRF 1 receptor by antalarmin also eliminates cocaine reward. Nevertheless, CRF 1 -/- mice display higher stereotypy responses to cocaine than wild-type mice. Despite the very low plasma corticosterone concentration, CRF 1 -/- mice show higher nuclear glucocorticoid receptor (GR) levels in the brain region of the hippocampus than wild-type mice. Full rescue of wild-type-like corticosterone and GR circadian rhythm and level in CRF 1 -/- mice by exogenous corticosterone does not affect CRF 1 receptor-dependent cocaine reward but induces stereotypy responses to cocaine. These results indicate a critical role for the CRF 1 receptor in cocaine reward, independently of the closely related HPA axis activity. Copyright © 2017 Elsevier Ltd. All rights reserved.
Allen, Andrew P; Kennedy, Paul J; Cryan, John F; Dinan, Timothy G; Clarke, Gerard
Validated biological and psychological markers of acute stress in humans are an important tool in translational research. The Trier Social Stress Test (TSST), involving public interview and mental arithmetic performance, is among the most popular methods of inducing acute stress in experimental settings, and reliably increases hypothalamic-pituitary-adrenal axis activation. However, although much research has focused on HPA axis activity, the TSST also affects the sympathetic-adrenal-medullary system, the immune system, cardiovascular outputs, gastric function and cognition. We critically assess the utility of different biological and psychological markers, with guidance for future research, and discuss factors which can moderate TSST effects. We outline the effects of the TSST in stress-related disorders, and if these responses can be abrogated by pharmacological and psychological treatments. Modified TSST protocols are discussed, and the TSST is compared to alternative methods of inducing acute stress. Our analysis suggests that multiple readouts are necessary to derive maximum information; this strategy will enhance our understanding of the psychobiology of stress and provide the means to assess novel therapeutic agents. Copyright © 2013 Elsevier Ltd. All rights reserved.
Kubo, Kin-ya; Iinuma, Mitsuo; Chen, Huayue
Exposure to chronic stress induces various physical and mental effects that may ultimately lead to disease. Stress-related disease has become a global health problem. Mastication (chewing) is an effective behavior for coping with stress, likely due to the alterations chewing causes in the activity of the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Mastication under stressful conditions attenuates stress-induced increases in plasma corticosterone and catecholamines, as well as the expression of stress-related substances, such as neurotrophic factors and nitric oxide. Further, chewing reduces stress-induced changes in central nervous system morphology, especially in the hippocampus and hypothalamus. In rodents, chewing or biting on wooden sticks during exposure to various stressors reduces stress-induced gastric ulcer formation and attenuates spatial cognitive dysfunction, anxiety-like behavior, and bone loss. In humans, some studies demonstrate that chewing gum during exposure to stress decreases plasma and salivary cortisol levels and reduces mental stress, although other studies report no such effect. Here, we discuss the neuronal mechanisms that underline the interactions between masticatory function and stress-coping behaviors in animals and humans.
Harrell, C S; Gillespie, C F; Neigh, G N
The worldwide epidemic of metabolic syndromes and the recognized burden of mental health disorders have driven increased research into the relationship between the two. A maladaptive stress response is implicated in both mental health disorders and metabolic disorders, implicating the hypothalamic-pituitary-adrenal (HPA) axis as a key mediator of this relationship. This review explores how an altered energetic state, such as hyper- or hypoglycemia, as may be manifested in obesity or diabetes, affects the stress response and the HPA axis in particular. We propose that changes in energetic state or energetic demands can result in "energetic stress" that can, if prolonged, lead to a dysfunctional stress response. In this review, we summarize the role of the hypothalamus in modulating energy homeostasis and then briefly discuss the relationship between metabolism and stress-induced activation of the HPA axis. Next, we examine seven mechanisms whereby energetic stress interacts with neuroendocrine stress response systems, including by glucocorticoid signaling both within and beyond the HPA axis; by nutrient-induced changes in glucocorticoid signaling; by impacting the sympathetic nervous system; through changes in other neuroendocrine factors; by inducing inflammatory changes; and by altering the gut-brain axis. Recognizing these effects of energetic stress can drive novel therapies and prevention strategies for mental health disorders, including dietary intervention, probiotics, and even fecal transplant. Copyright © 2015 Elsevier Inc. All rights reserved.
Chitra D Mandyam
Full Text Available The development of alcohol dependence involves elevated anxiety, low mood, and increased sensitivity to stress, collectively labeled negative affect. Particularly interesting is the recent accumulating evidence that sensitized extrahypothalamic stress systems (e.g., hyperglutamatergic activity, blunted hypothalamic-pituitary-adrenal [HPA] hormonal levels, altered corticotropin-releasing factor signaling, and altered glucocorticoid receptor signaling in the extended amygdala are evident in withdrawn dependent rats, supporting the hypothesis that pathological neuroadaptations in the extended amygdala contribute to the negative affective state. Notably, hippocampal neurotoxicity observed as aberrant dentate gyrus (DG neurogenesis (neurogenesis is a process where neural stem cells in the adult hippocampal subgranular zone generate DG granule cell neurons and DG neurodegeneration are observed in withdrawn dependent rats. These correlations between withdrawal and aberrant neurogenesis in dependent rats suggest that alterations in the DG could be hypothesized to be due to compromised HPA axis activity and associated hyperglutamatergic activity originating from the basolateral amygdala in withdrawn dependent rats. This review discusses a possible link between the neuroadaptations in the extended amygdala stress systems and the resulting pathological plasticity that could facilitate recruitment of new emotional memory circuits in the hippocampus as a function of aberrant DG neurogenesis.
Kuhlman, Kate Ryan; Chiang, Jessica J; Horn, Sarah; Bower, Julienne E
Childhood adversity has been repeatedly and robustly linked to physical and mental illness across the lifespan. Yet, the biological pathways through which this occurs remain unclear. Functioning of the inflammatory arm of the immune system and the hypothalamic-pituitary-adrenal (HPA)-axis are both hypothesized pathways through which childhood adversity leads to disease. This review provides a novel developmental framework for examining the role of adversity type and timing in inflammatory and HPA-axis functioning. In particular, we identify elements of childhood adversity that are salient to the developing organism: physical threat, disrupted caregiving, and unpredictable environmental conditions. We propose that existing, well-characterized animal models may be useful in differentiating the effects of these adversity elements and review both the animal and human literature that supports these ideas. To support these hypotheses, we also provide a detailed description of the development and structure of both the HPA-axis and the inflammatory arm of the immune system, as well as recent methodological advances in their measurement. Recommendations for future basic, developmental, translational, and clinical research are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.
Reader, B F; Jarrett, B L; McKim, D B; Wohleb, E S; Godbout, J P; Sheridan, J F
The development and exacerbation of depression and anxiety are associated with exposure to repeated psychosocial stress. Stress is known to affect the bidirectional communication between the nervous and immune systems leading to elevated levels of stress mediators including glucocorticoids (GCs) and catecholamines and increased trafficking of proinflammatory immune cells. Animal models, like the repeated social defeat (RSD) paradigm, were developed to explore this connection between stress and affective disorders. RSD induces activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis activation, increases bone marrow production and egress of primed, GC-insensitive monocytes, and stimulates the trafficking of these cells to tissues including the spleen, lung, and brain. Recently, the observation that these monocytes have the ability to traffic to the brain perivascular spaces and parenchyma have provided mechanisms by which these peripheral cells may contribute to the prolonged anxiety-like behavior associated with RSD. The data that have been amassed from the RSD paradigm and others recapitulate many of the behavioral and immunological phenotypes associated with human anxiety disorders and may serve to elucidate potential avenues of treatment for these disorders. Here, we will discuss novel and key data that will present an overview of the neuroendocrine, immunological and behavioral responses to social stressors. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
Martínez Cerón, Elisabet; Casitas Mateos, Raquel; García-Río, Francisco
Epidemiological data suggest that sleep apnea-hypopnea syndrome (SAHS) is independently associated with the development of insulin resistance and glucose intolerance. Moreover, despite significant methodological limitations, some studies report a high prevalence of SAHS in patients with type 2 diabetes mellitus (DM2). A recent meta-analysis shows that moderate-severe SAHS is associated with an increased risk of DM2 (relative risk=1.63 [1.09 to 2.45]), compared to the absence of apneas and hypopneas. Common alterations in various pathogenic pathways add biological plausibility to this relationship. Intermittent hypoxia and sleep fragmentation, caused by successive apnea-hypopnea episodes, induce several intermediate disorders, such as activation of the sympathetic nervous system, oxidative stress, systemic inflammation, alterations in appetite-regulating hormones and activation of the hypothalamic-pituitary-adrenal axis which, in turn, favor the development of insulin resistance, its progression to glucose intolerance and, ultimately, to DM2. Concomitant SAHS seems to increase DM2 severity, since it worsens glycemic control and enhances the effects of atherosclerosis on the development of macrovascular complications. Furthermore, SAHS may be associated with the development of microvascular complications: retinopathy, nephropathy or diabetic neuropathy in particular. Data are still scant, but it seems that DM2 may also worsen SAHS progression, by increasing the collapsibility of the upper airway and the development of central apneas and hypopneas. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.
Mielock, Alyssa S; Morris, Matthew C; Rao, Uma
Childhood maltreatment can trigger enduring changes in major stress response systems, particularly in the context of major depressive disorder (MDD). However, the relative impact of maltreatment versus MDD on hypothalamic-pituitary-adrenal axis and sympathetic-adrenal-medullary system stress reactivity is not well understood. This study examined salivary cortisol and alpha-amylase responses to the Trier Social Stress Test (TSST) in 26 maltreated (15 with current MDD) and 26 non-maltreated (17 with current MDD) women. Maltreated women showed greater anticipatory cortisol reactivity during the TSST protocol compared to non-maltreated women. Maltreated women also showed rapid deceleration in cortisol levels. Whereas non-maltreated women showed initial declines in alpha-amylase levels but rapidly increasing alpha-amylase levels during the TSST protocol, maltreated women did not exhibit changes in alpha-amylase levels during the TSST protocol. Contrary to expectation, MDD did not impact cortisol or alpha-amylase responses. The present study is limited by retrospective report of childhood maltreatment, cross-sectional design, and modest sample sizes. These findings suggest that childhood maltreatment plays a greater role driving alterations in cortisol and alpha-amylase stress reactivity than MDD. Understanding the biological embedding of maltreatment is critical for elucidating mechanisms linking these experiences to risk for negative mental and physical health outcomes. Copyright © 2016 Elsevier B.V. All rights reserved.
Gupta, Madhulika A
Post-traumatic stress disorder (PTSD) is associated with both (1) 'ill-defined' or 'medically unexplained' somatic syndromes, e.g. unexplained dizziness, tinnitus and blurry vision, and syndromes that can be classified as somatoform disorders (DSM-IV-TR); and (2) a range of medical conditions, with a preponderance of cardiovascular, respiratory, musculoskeletal, neurological, and gastrointestinal disorders, diabetes, chronic pain, sleep disorders and other immune-mediated disorders in various studies. Frequently reported medical co-morbidities with PTSD across various studies include cardiovascular disease, especially hypertension, and immune-mediated disorders. PTSD is associated with limbic instability and alterations in both the hypothalamic- pituitary-adrenal and sympatho-adrenal medullary axes, which affect neuroendocrine and immune functions, have central nervous system effects resulting in pseudo-neurological symptoms and disorders of sleep-wake regulation, and result in autonomic nervous system dysregulation. Hypervigilance, a central feature of PTSD, can lead to 'local sleep' or regional arousal states, when the patient is partially asleep and partially awake, and manifests as complex motor and/or verbal behaviours in a partially conscious state. The few studies of the effects of standard PTSD treatments (medications, CBT) on PTSD-associated somatic syndromes report a reduction in the severity of ill-defined and autonomically mediated somatic symptoms, self-reported physical health problems, and some chronic pain syndromes.
Lopez-Duran, Nestor L; McGinnis, Ellen; Kuhlman, Kate; Geiss, Elisa; Vargas, Ivan; Mayer, Stefanie
Given the link between youth depression and stress exposure, efforts to identify related biomarkers have involved examinations of stress regulation systems, including the hypothalamic-pituitary-adrenal (HPA) axis. Despite these vast efforts, the underlying mechanisms at play, as well as factors that may explain heterogeneity of past findings, are not well understood. In this study, we simultaneously examined separate components of the HPA-axis response (e.g. activation intensity, peak levels, recovery) to the Socially Evaluated Cold-Pressor Test in a targeted sample of 115 youth (age 9-16), recruited to overrepresent youth with elevated symptoms of depression. Among youth who displayed a cortisol response to the task, depression symptoms were associated with higher peak responses but not greater rate of activation or recovery in boys only. Among those who did not respond to the task, depression symptoms were associated with greater cortisol levels throughout the visit in boys and girls. Results suggest that depression symptoms are associated with a more prolonged activation of the axis and impaired recovery to psychosocial stressors primarily in boys. We discussed two potential mechanistic explanations of the link between depression symptoms and the duration of activation: (1) inhibitory shift (i.e. point at which the ratio of inhibitory and excitatory input into the axis shifts from greater excitatory to greater inhibitory input) or (2) inhibitory threshold (i.e. level of cortisol exposure required to activate the axis' feedback inhibition system).
Bakvis, Patricia; Spinhoven, Philip; Giltay, Erik J; Kuyk, Jarl; Edelbroek, Peter M; Zitman, Frans G; Roelofs, Karin
Several studies have indicated that psychogenic nonepileptic seizures (PNES) are associated with psychological trauma, but only a few studies have examined the associations with neurobiologic stress systems, such as the hypothalamus-pituitary-adrenal (HPA) axis and its end-product cortisol. We tested several relevant HPA-axis functions in patients with PNES and related them to trauma history. Cortisol awakening curve, basal diurnal cortisol, and negative cortisol feedback (using a 1 mg dexamethasone suppression test) were examined in 18 patients with PNES and 19 matched healthy controls (HCs) using saliva cortisol sampling on two consecutive days at 19 time points. Concomitant sympathetic nervous system (SNS) activity was assessed by analyzing saliva alpha-amylase (sAA). Patients with PNES showed significantly increased basal diurnal cortisol levels compared to HCs. This effect was driven mainly by patients reporting sexual trauma who showed a trend toward higher cortisol levels as compared to patients without a sexual trauma report. Importantly, the increased basal diurnal cortisol levels in patients were not explained by depression, medication, or smoking, or by current seizures or group differences in SNS activity. This is the first study showing that basal hypercortisolism in patients with PNES is independent of the acute occurrence of seizures. In addition, basal hypercortisolism was more pronounced in traumatized patients with PNES as compared to nontraumatized patients with PNES. These findings suggest that HPA-axis activity provides a significant neurobiologic marker for PNES.
Laurent, Heidemarie K; Gilliam, Kathryn S; Wright, Dorianne B; Fisher, Philip A
Cross-sectional research suggests that individuals at risk for internalizing disorders show differential activation levels and/or dynamics of stress-sensitive physiological systems, possibly reflecting a process of stress sensitization. However, there is little longitudinal research to clarify how the development of these systems over time relates to activation during acute stress, and how aspects of such activation map onto internalizing symptoms. We investigated children's (n = 107) diurnal hypothalamic-pituitary-adrenal activity via salivary cortisol (morning and evening levels) across 29 assessments spanning 6+ years, and related longitudinal patterns to acute stress responses at the end of this period (age 9-10). Associations with child psychiatric symptoms at age 10 were also examined to determine internalizing risk profiles. Increasing morning cortisol levels across assessments predicted less of a cortisol decline following interpersonal stress at age 9, and higher cortisol levels during performance stress at age 10. These same profiles of high and/or sustained cortisol elevation during psychosocial stress were associated with child anxiety symptoms. Results suggest developmental sensitization to stress-reflected in rising morning cortisol and eventual hyperactivation during acute stress exposure-may distinguish children at risk for internalizing disorders. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
Smith, Adam S.; Wang, Zuoxin
Social relationships are a fundamental aspect of life, affecting social, psychological, physiological, and behavioral functions. While social interactions can attenuate stress and promote health, disruption, confrontations, isolation, or neglect in the social environment can each be major stressors. Social stress can impair the basal function and stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, impairing function of multiple biological systems and posing a risk to mental and physical health. In contrast, social support can ameliorate stress-induced physiological and immunological deficits, reducing the risk of subsequent psychological distress and improving an individual's overall well-being. For better clinical treatment of these physiological and mental pathologies, it is necessary to understand the regulatory mechanisms of stress-induced pathologies as well as determine the underlying biological mechanisms that regulate social buffering of the stress system. A number of ethologically relevant animal models of social stress and species that form strong adult social bonds have been utilized to study the etiology, treatment, and prevention of stress-related disorders. While undoubtedly a number of biological pathways contribute to the social buffering of the stress response, the convergence of evidence denotes the regulatory effects of oxytocin in facilitating social bond-promoting behaviors and their effect on the stress response. Thus, oxytocin may be perceived as a common regulatory element of the social environment, stress response, and stress-induced risks on mental and physical health. PMID:22178036
Cozma, S; Dima-Cozma, L C; Ghiciuc, C M; Pasquali, V; Saponaro, A; Patacchioli, F R
Currently, the potential for cardiovascular (CV) stress-induced risk is primarily based on the theoretical (obvious) side effects of stress on the CV system. Salivary cortisol and α-amylase, produced respectively by the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic-adrenomedullary (SAM) system during stress response, are still not included in the routine evaluation of CV risk and require additional and definitive validation. Therefore, this article overviews studies published between 2010 and 2015, in which salivary cortisol and α-amylase were measured as stress biomarkers to examine their associations with CV/CMR (cardiometabolic risk) clinical and subclinical indicators. A comprehensive search of PubMed, Web of Science and Scopus electronic databases was performed, and 54 key articles related to the use of salivary cortisol and α-amylase as subclinical indicators of stress and CV/CMR factors, including studies that emphasized methodological biases that could influence the accuracy of study outcomes, were ultimately identified. Overall, the biological impact of stress measured by salivary cortisol and α-amylase was associated with CV/CMR factors. Results supported the use of salivary cortisol and α-amylase as potential diagnostic tools for detecting stress-induced cardiac diseases and especially to describe the mechanisms by which stress potentially contributes to the pathogenesis and outcomes of CV diseases.
van Veen, J Frederieke; van Vliet, Irene M; de Rijk, Roel H; van Pelt, Johannes; Mertens, Bart; Fekkes, Durk; Zitman, Frans G
In generalized social anxiety disorder (gSAD), serotonergic dysfunctions are found, as well as abnormalities of the autonomic nervous system (ANS) in basal conditions and of the hypothalamic pituitary adrenal (HPA) axis in response to psychological challenges. These findings raise the question whether these phenomena are interrelated. Therefore we designed a study in which two groups with nine pair wise age and gender matched gSAD patients (total of 10 men and 8 women), who were successfully treated with a selective serotonin reuptake inhibitor (SSRI), underwent a tryptophan depletion challenge (TD) or a placebo condition. A TD procedure temporarily decreases serotonergic neurotransmission. In order to activate the stress system the TD/placebo challenge was combined with a public speaking task. We assessed ANS responses, as measured with the promising new marker salivary alpha-amylase (sAA), and HPA-axis responses, as measured with salivary cortisol. The most important result was that the TD group showed a significant larger sAA response to the public speaking task as compared to the placebo group, reflecting hyperresponsivity of the ANS in this group, whereas no differences were seen in cortisol responses. This suggests that in gSAD there is a vulnerability of the ANS more than the HPA-axis.
Pázmány, Péter; Petschner, Péter; Ádori, Csaba; Kirilly, Eszter; Andó, Dénes Rómeó; Balogh, Brigitta; Gyöngyösi, Norbert; Bagdy, György
The recreational drug ecstasy is widely used among dance clubbers for its acute euphoric and entactogenic effects. Ecstasy exerts its acute effects by increasing the extracellular concentration of monoamines in the brain by reversing the functions of reuptake mechanisms. These elevations in extracellular monoamine concentrations result in wake promoting effects, body hyperthermia and reductions in local cerebral blood flow. However, on the long-run, ecstasy reduces serotonin concentration and density of serotonergic markers in several brain areas. Functional deficits, like sleep disturbances, anxiogenic- and aggressive behavioral responses and mood disorders also may occur. However, one of the most prominent adverse effects is related to the cognitive functions. Following ecstasy use attenuated retro- and prospective memory and defective higher order cognitive functions can be observed, especially in heavy users. Several studies indicated the involvement of the endocannabinoid system, the sleep regulating centers and the hypothalamic-pituitary-adrenal axis based on or parallel to serotonergic damage in these processes. Recent evidence, however, also showed that changes in one of the latter systems can influence the functions of each other. In this review we summarize the related literature, and propose a complex mechanism for the long-lasting cognitive deficits following heavy ecstasy use.
Braquehais, M Dolores; Oquendo, Maria A; Baca-García, Enrique; Sher, Leo
Childhood abuse and neglect are known to affect psychological states through behavioral, emotional, and cognitive pathways. They increase the risk of having psychiatric diseases in adulthood and have been considered risk factors for suicidal behavior in all diagnostic categories. Early, prolonged, and severe trauma is also known to increase impulsivity, diminishing the capacity of the brain to inhibit negative actions and to control and modulate emotions. Many neurobiological studies hold that childhood maltreatment may lead to a persistent failure of the inhibitory processes ruled mainly by the frontal cortex over a fear-motivated hyperresponsive limbic system. Multiple neurotransmitters and hormones are involved in the stress response, but, to our knowledge, the two major biological consequences of the chronic exposure to trauma are the hypofunction of the serotonergic system and changes in the hypothalamic-pituitary-adrenal axis function. Some of these findings overlap with the neurobiological features of impulsivity and of suicidal behavior. Impulsivity has also been said to be both a consequence of trauma and a risk factor for the development of a pathological response to trauma. Thus, we suggest that impulsivity could be one of the links between childhood trauma and suicidal behavior. Prevention of childhood abuse could significantly reduce suicidal behavior in adolescents and adults, in part, through a decrease in the frequency of impulsive behaviors in the future. Copyright 2010 Elsevier Inc. All rights reserved.
Wu, Li-Min; Hu, Mei-Hong; Tong, Xian-Hong; Han, Hui; Shen, Ni; Jin, Ren-Tao; Wang, Wei; Zhou, Gui-Xiang; He, Guo-Ping; Liu, Yu-Sheng
Brain-derived neurotropic factor (BDNF) was originally described in the nervous system but has been shown to be expressed in ovary tissues recently, acting as a paracrine/autocrine regulator required for developments of follicles and oocytes. Although it is generally accepted that chronic stress impairs female reproduction and decreases the expression of BDNF in limbic structures of central nervous system, which contributes to mood disorder. However, it is not known whether chronic stress affects oocytes developments, nor whether it affects expression of BDNF in ovary. Mice were randomly assigned into control group, stressed group, BDNF-treated group and BDNF-treated stressed group. The chronic unpredictable mild stress model was used to produce psychosocial stress in mice, and the model was verified by open field test and hypothalamic-pituitary-adrenal (HPA) axis activity. The methods of immunohistochemistry and western blotting were used to detect BDNF protein level and distribution. The number of retrieved oocytes, oocyte maturation, embryo cleavage and the rates of blastocyst formation after parthenogenetic activation were evaluated. Chronic unpredictable stress decreased the BDNF expression in antral follicles, but didn't affect the BDNF expression in primordial, primary and secondary follicles. Chronic unpredictable stress also decreased the number of retrieved oocytes and the rate of blastocyst formation, which was rescued by exogenous BDNF treatment. BDNF in mouse ovaries may be related to the decreased number of retrieved oocytes and impaired oocytes developmental potential induced by chronic unpredictable stress.
Full Text Available BACKGROUND: Brain-derived neurotropic factor (BDNF was originally described in the nervous system but has been shown to be expressed in ovary tissues recently, acting as a paracrine/autocrine regulator required for developments of follicles and oocytes. Although it is generally accepted that chronic stress impairs female reproduction and decreases the expression of BDNF in limbic structures of central nervous system, which contributes to mood disorder. However, it is not known whether chronic stress affects oocytes developments, nor whether it affects expression of BDNF in ovary. METHODS: Mice were randomly assigned into control group, stressed group, BDNF-treated group and BDNF-treated stressed group. The chronic unpredictable mild stress model was used to produce psychosocial stress in mice, and the model was verified by open field test and hypothalamic-pituitary-adrenal (HPA axis activity. The methods of immunohistochemistry and western blotting were used to detect BDNF protein level and distribution. The number of retrieved oocytes, oocyte maturation, embryo cleavage and the rates of blastocyst formation after parthenogenetic activation were evaluated. RESULTS: Chronic unpredictable stress decreased the BDNF expression in antral follicles, but didn't affect the BDNF expression in primordial, primary and secondary follicles. Chronic unpredictable stress also decreased the number of retrieved oocytes and the rate of blastocyst formation, which was rescued by exogenous BDNF treatment. CONCLUSION: BDNF in mouse ovaries may be related to the decreased number of retrieved oocytes and impaired oocytes developmental potential induced by chronic unpredictable stress.
Ricardo Borges Machado
Full Text Available Studies have shown that sleep recovery following different protocols of forced waking varies according to the level of stress inherent to each method. Sleep deprivation activates the hypothalamic-pituitary-adrenal axis and increased corticotropin-releasing hormone (CRH impairs sleep. The purpose of the present study was to evaluate how manipulations of the CRH system during the sleep deprivation period interferes with subsequent sleep rebound. Throughout 96 hours of sleep deprivation, separate groups of rats were treated i.c.v. with vehicle, CRH or with alphahelical CRH9−41, a CRH receptor blocker, twice/day, at 07:00 h and 19:00 h. Both treatments impaired sleep homeostasis, especially in regards to length of rapid eye movement sleep (REM and theta/delta ratio and induced a later decrease in NREM and REM sleep and increased waking bouts. These changes suggest that activation of the CRH system impact negatively on the homeostatic sleep response to prolonged forced waking. These results indicate that indeed, activation of the HPA axis—at least at the hypothalamic level—is capable to reduce the sleep rebound induced by sleep deprivation.
D'Orsogna, Maria; Chou, Tom; Kim, Lae
The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates numerous physiological processes. Disruptions in its activity are correlated with stress-related diseases such as post-traumatic stress disorder (PTSD) and major depressive disorder. We characterize ``normal'' and ``diseased'' states of the HPA axis as basins of attraction of a dynamical system describing the inhibition of peptide hormones, corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH), by circulating glucocorticoids such as cortisol (CORT). Our model includes ultradian oscillations, CRH self-upregulation of CRH release, and distinguishes two components of negative feedback by cortisol on circulating CRH levels: a slow direct suppression of CRH synthesis and a fast indirect effect on CRH release. The slow regulation mechanism mediates external stress-driven transitions between the stable states in novel, intensity, duration, and timing-dependent ways. We find that the timing of traumatic events may be an important factor in determining if and how the hallmarks of depressive disorders will manifest. Our model also suggests a mechanism whereby exposure therapy of stress disorders may act to normalize downstream dysregulation of the HPA axis.
Intensive physical training and participation in competitive sports during childhood and early adolescence may affect athletes' pubertal development. On the other hand, pubertal timing, early or late, may impact on an athlete selection for a particular sport. Genetic predisposition, training load, nutritional status and psychological stress determine athletes' pubertal timing. Athletes that practice esthetic sports, especially gymnasts, are predisposed to a delay in pubertal development. The growing evidence indicates that energy deficiency, not a systemic training per se, plays a crucial role in the pathogenesis of functional hypothalamic hypogonadism in female athletes. Metabolic and psychologic stress activate hypothalamic-pituitary-adrenal axis and suppress hypothalamic-pituitary-ovarian axis. Female athletes who do not begin secondary sexual development by the age of 14 or menstruation by the age of 16 warrant a comprehensive evaluation and a targeted treatment. Somatic growth and sexual maturation of elite female athletes are largely sport-specific since each sport favors a particular somatotype and requires a specific training. Chronic negative energy balance resulting from a systemic physical training and inadequate energy intake may delay pubertal development in elite athletes. Youth athletes, especially those engaged in competitive sports that emphasize prepubertal or lean appearance, are at risk of developing relative energy deficiency in sport associated with disordered eating or eating disorders. Management strategies should address the complex conditions underlying functional hypothalamic hypogonadism.
Full Text Available Exposure to chronic stress induces various physical and mental effects that may ultimately lead to disease. Stress-related disease has become a global health problem. Mastication (chewing is an effective behavior for coping with stress, likely due to the alterations chewing causes in the activity of the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Mastication under stressful conditions attenuates stress-induced increases in plasma corticosterone and catecholamines, as well as the expression of stress-related substances, such as neurotrophic factors and nitric oxide. Further, chewing reduces stress-induced changes in central nervous system morphology, especially in the hippocampus and hypothalamus. In rodents, chewing or biting on wooden sticks during exposure to various stressors reduces stress-induced gastric ulcer formation and attenuates spatial cognitive dysfunction, anxiety-like behavior, and bone loss. In humans, some studies demonstrate that chewing gum during exposure to stress decreases plasma and salivary cortisol levels and reduces mental stress, although other studies report no such effect. Here, we discuss the neuronal mechanisms that underline the interactions between masticatory function and stress-coping behaviors in animals and humans.
Dreau, Didier; Morton, Darla S.; Foster, Mareva; Swiggett, Jeanene P.; Sonnenfeld, Gerald
Administration of 2-deoxy-D-glucose (2-DG), an analog of glucose which inhibits glycolysis by competitive antagonism for phosphohexose isomerase, results in acute periods of intracellular glucoprivation and hyperglycemia resulting in hyperphagia. In addition to these changes in the carbohydrate metabolism, injection of 2-DG results in alterations of both the endocrine and neurological systems as suggested by modifications in oxytocin and glucocorticoid levels and norepinephrine production. Moreover, alterations of the immune response, such as a decrease in the in vitro proliferation of splenocytes after mitogen-stimulation, were observed in mice injected with 2-DG. Sex, genotype and environment are among the factors that may modulate effects of catecholamines and hypothalamo-pituitary-adrenal axis on these immune changes. Sexual dimorphism in immune function resulting from the effects of sex hormones on immune effector cells has been shown in both animals and humans. These observations have important implications, especially with regard to higher incidence of many autoimmune diseases in females. Evidence exists that reproductive hormones influence the immune system and increase the risk of im