Gupta, Deepashree; Morley, John E
Human aging is associated with increasing frailty and morbidity which can result in significant disability. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to aging-related diseases like depression, cognitive deficits, and Alzheimer's disease in some older individuals. In addition to neuro-cognitive dysfunction, it has also been associated with declining physical performance possibly due to sarcopenia. This article reviews the pathophysiology of HPA dysfunction with respect to increased basal adrenocorticotropic hormone (ACTH) and cortisol secretion, decreased glucocorticoid (GC) negative feedback at the level of the paraventricular nucleus (PVN) of the hypothalamus, hippocampus (HC), and prefrontal cortex (PFC), and flattening of diurnal pattern of cortisol release. It is possible that the increased cortisol secretion is secondary to peripheral conversion from cortisone. There is a decline in pregnolone secretion and C-19 steroids (DHEA) with aging. There is a small decrease in aldosterone with aging, but a subset of the older population have a genetic predisposition to develop hyperaldosteronism due to the increased ACTH stimulation. The understanding of the HPA axis and aging remains a complex area with conflicting studies leading to controversial interpretations.
Ward, Alexandra M. V; Syddall, Holly E; Wood, Peter J; Chrousos, George P; Phillips, David I. W
Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an intermediary in the association between reduced fetal growth and adult cardiovascular and metabolic diseases...
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
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
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 different periods of development leads to long-lasting maladaptive HPA-axis response in the brain. They demonstrate that this maladaptive response is comprised of persistent epigenetic changes in the function of HPA-axis-associated genes that govern homeostatic levels of glucocorticoids. Stressors and/or disruption of glucocorticoid dynamics also target genes such as brain-derived neurotrophic factor (BDNF) and tyrosine hydroxylase (TH) that are important for neuronal function and behavior. While a definitive role for epigenetic mechanisms remains unclear, these emerging studies implicate glucocorticoid signaling and its ability to alter the epigenetic landscape as one of the key mechanisms that alter the function of the HPA-axis and its associated cascades. We also suggest some of the requisite studies and techniques that are important, such as additional candidate gene approaches, genome-wide epigenomic screens, and innovative functional and behavioral studies in order to further explore and define the relationship between epigenetics and HPA-axis biology. Additional studies examining stress-induced epigenetic changes of HPA-axis genes, aided by innovative techniques and methodologies are needed to advance our understanding of this relationship and lead to better preventive, diagnostic, and corrective measures. PMID:25427939
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:
B.E. Evans (Brittany); K. Greaves-Lord (Kirstin); A.S. Euser (Anja); I.H.A. Franken (Ingmar); A.C. Huizink (Anja)
textabstractAims 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
Marković, Vladimir M; Čupić, Željko; Vukojević, Vladana; Kolar-Anić, Ljiljana
Detailed dynamics of the hypothalamic-pituitary-adrenal (HPA) axis is complex, depending on the individual metabolic load of an organism, its current status (healthy/ill, circadian phase (day/night), ultradian phase) and environmental impact. Therefore, it is difficult to compare the HPA axis activity between different individuals or draw unequivocal conclusions about the overall status of the HPA axis in an individual using single time-point measurements of cortisol levels. The aim of this study is to identify parameters that enable us to compare different dynamic states of the HPA axis and use them to investigate self-regulation mechanisms in the HPA axis under acute and chronic stress. In this regard, a four-dimensional stoichiometric model of the HPA axis was used. Acute stress was modeled by inducing an abrupt change in cortisol level during the course of numerical integration, whereas chronic stress was modeled by changing the mean stationary state concentrations of CRH. Effects of acute stress intensity, duration and time of onset with respect to the ultradian amplitude, ultradian phase and the circadian phase of the perturbed oscillation were studied in detail. Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed.
Rutters, Femke; Nieuwenhuizen, Arie G; Lemmens, Sofie G T; Born, Jurriaan M; Westerterp-Plantenga, Margriet S
To relate hypothalamic-pituitary-adrenal (HPA) axis functioning and HPA feedback functioning to body fat distribution in normal weight to obese subjects. 91 men and 103 women [age 18-45 years, BMI 19-35 kg/m(2), waist-to-hip ratio (WHR) 0.6-1.1]. Anthropometry, body composition using hydrodensitometry and deuterium dilution method, cortisol variability by measuring 5-h cortisol concentrations, HPA axis feedback functioning using a dexamethasone suppression test, and HPA axis functioning under a challenged condition consisting of a standardized high-intensity test with ingestion of 4 mg dexamethasone. In men, an inverse relationship was observed between 5-h cortisol exposure (nmol/ml) and fat mass index (FMI) (kg/m(2)) (r = -0.55, P HPA axis functioning in a challenged condition expressed as percentage increase of cortisol concentrations after standardized high-intensity test with ingestion of 4 mg dexamethasone (%) and waist circumference (r = -0.21, P HPA axis functioning under basal and challenged conditions is related to visceral fat accumulation.
van Dalfsen, Jens H; Markus, C Rob
Inadequate sleep is highly prevalent and known to decline both physical- and mental health. Literature suggests that altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis might underlie this association. This assumption is mainly based on changes in basal neuroendocrine activity and it is of equal importance to elucidate whether sleep may also influence HPA stress responsiveness. The present review provides a complete outline of recent human studies that have investigated how different aspects of sleep influence cortisol reactivity to laboratory stress. From the available data it can be concluded that both objective and subjective decrements in sleep quality potentiate the stress reactivity of the HPA axis. On the contrary, normal variations in sleep duration do not seem to influence cortisol stress responsiveness whereas excessive daytime sleepiness is associated with a blunting of the cortisol response. Given its well-established health consequences, sensitization of the HPA axis might well be a crucial component linking inadequate sleep to stress-related pathology. Copyright © 2017 Elsevier Ltd. All rights reserved.
Fischer, Susanne; Macare, Christine; Cleare, Anthony J
Although antidepressants are effective, around 50% of depressed patients are non-responsive. At the same time, some patients show alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Due to interactions with central monoaminergic systems, these may profit less from antidepressants. To determine whether non-responders and responders differed in pre-treatment HPA axis functioning, the Cochrane Library, EMBASE, MEDLINE, and PsycINFO were searched. Studies using patients with depression being treated with antidepressants, and including both a pre-treatment HPA and a post-treatment response measure were included. Standardised mean differences were calculated for meta-analysis. Thirty-nine studies were included. Non-responders and responders did not differ in pre-treatment corticotropin-releasing hormone or adrenocorticotropic hormone. Meta-regression showed non-responders had comparably higher pre-treatment cortisol in studies measuring cortisol non-invasively, not reporting sample storage, failing to control for age, and excluding patients with comorbidities. Only studies with a specific methodological profile seem to be able to show that the more marked depressed patients' alterations in the HPA axis, the less likely they are to profit from antidepressants. Copyright © 2017 Elsevier Ltd. All rights reserved.
Marković, Vladimir M; Čupić, Željko; Maćešić, Stevan; Stanojević, Ana; Vukojević, Vladana; Kolar-Anić, Ljiljana
A mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis with cholesterol as a dynamical variable was derived to investigate the effects of cholesterol, the primary precursor of all steroid hormones, on the ultradian and circadian HPA axis activity. To develop the model, the parameter space was systematically examined by stoichiometric network analysis to identify conditions for ultradian oscillations, determine conditions under which dynamic transitions, i.e. bifurcations occur and identify bifurcation types. The bifurcations were further characterized using numerical simulations. Model predictions agree well with empirical findings reported in the literature, indicating that cholesterol levels may critically affect the global dynamics of the HPA axis. The proposed model provides a base for better understanding of experimental observations, it may be used as a tool for designing experiments and offers useful insights into the characteristics of basic dynamic regulatory mechanisms that, when impaired, may lead to the development of some modern-lifestyle-associated diseases. © The Authors 2014. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.
Evans, Brittany E; Greaves-Lord, Kirstin; Euser, Anja S; Franken, Ingmar H A; Huizink, Anja C
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. Adolescents' diurnal cortisol levels on a normal day and cortisol levels during a stress procedure were examined in relation to the age of onset of alcohol use. All adolescents (aged 14-20 years) were part of a general population study in the Netherlands (n = 2286). Ten assessments of salivary cortisol taken on a normal day (diurnal cortisol), as well as during a social stress procedure (stress cortisol) were used as indicators of HPA axis activity. The age at which the first alcoholic drink was consumed varied as a function of cortisol levels at the onset of as well as during the stress procedure. Those who began drinking at an earlier age showed lower cortisol levels at the onset of the stressful tasks (r(2) = 0.14, P hypothalamic-pituitary-adrenal axis at the onset of and during a stress procedure is present in adolescents who begin drinking at an early age. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.
N.S. Saridjan (Nathalie)
markdownabstractDysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity can be determined by studying patterns of the diurnal cortisol rhythm. Cortisol, the end-product of the HPA axis, is important for an adequate stress reaction, but also for the daily bodily functions in humans. In
van der Werf-Eldering, MJ; Riemersma-van der Lek, RF; Burger, H.; Holthausen, E.A.E.; Aleman, A.; Nolen, W.A.
Background: 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.
Jozic, Ivan; Stojadinovic, Olivera; Kirsner, Robert S F; Tomic-Canic, Marjana
UV radiation is among the most prevalent stressors in humans and diurnal rodents, exerting direct and indirect DNA damage, free-radical production, and interaction with specific chromophores that affects numerous biological processes. In addition to its panoply of effects, UVB (290-320 nm) radiation can specifically affect various local neuroendocrine activities by stimulating the expression of corticotropin-releasing hormone (CRH), urocortin, proopiomelanocortin (POMC), and POMC-derived peptides. Although very little is known about the interplay between the central hypothalamic-pituitary-adrenal (HPA) axis and the skin HPA axis analog, in the current issue Skobowiat and Slominski propose a novel mechanism by which exposure to UVB activates a local HPA axis in skin, which in turn activates the central HPA axis, with the requirement of a functional pituitary gland. This is the first evidence of the local HPA axis in skin contributing to the central neuroendocrine response. This raises intriguing possibilities regarding how local production of cortisol and other HPA axis molecules in skin influence overall systemic levels of cortisol and help regulate local and central HPA axes in the context of homeostasis, skin injury, and inflammatory skin disorders.
Damian Gabriel Zuloaga; Jason eJacobskind; Jacob eRaber
Psychostimulants such as methamphetamine (MA) induce significant alterations in the function of the hypothalamic-pituitary-adrenal (HPA) axis. These changes in HPA axis function are associated with altered stress-related behaviors and might contribute to addictive processes such as relapse. In this mini-review we discuss acute and chronic effects of MA (adult and developmental exposure) on the HPA axis, including effects on HPA axis associated genes/proteins, brain regions, and behaviors suc...
Johnston, Philip C; Lansang, M Cecilia; Chatterjee, Soumya; Kennedy, Laurence
The use of intra-articular (IA) glucocorticoids for reducing pain and inflammation in patients with osteoarthritis, rheumatoid arthritis, and other inflammatory arthropathies is widespread among primary care physicians, specialists, and non-specialists in the United States. Injectable glucocorticoids have anti-inflammatory and analgesic properties which can be effective in improving clinical parameters such as pain, range of motion, and quality of life. After injection into the IA space, glucocorticoids may be systemically absorbed; the degree of absorption can depend on the size of the joint injected, the injectable glucocorticoid preparation used, the dosage, and the frequency of the injection. The adverse effects of intra-articular glucocorticoid injections (IAGC) can often be overlooked by both the patient and physicians who administer them, in particular the potential deleterious effect on the hypothalamic-pituitary-adrenal (HPA)-axis which can result in adrenal suppression and/or iatrogenic Cushing syndrome. In this paper we provide an overview on the often under-recognized effects of IAGC on HPA-axis function.
Fortier, Marie-Ève; Sengupta, Sarojini M; Grizenko, Natalie; Choudhry, Zia; Thakur, Geeta; Joober, Ridha
Exposure to stressors results in a spectrum of autonomic, endocrine, and behavioral responses. A key pathway in this response to stress is the hypothalamic-pituitary-adrenal (HPA) axis, which results in a transient increase in circulating cortisol, which exerts its effects through the two related ligand-activated transcription factors: the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Genetic polymorphisms in these receptors have been shown to influence HPA axis reactivity, and chronic dysregulation of the HPA axis has been associated with the development of several psychiatric disorders. The objective of the study was to test the association between four functional polymorphisms in NR3C1 (encoding GR: ER22/23EK-rs6189, N363S-rs6195, BclI-rs41423247, A3669G-rs6198) and two in NR3C2 (encoding MR: 215G/C-rs2070951, I180 V-rs5522) with childhood ADHD. Family-based association tests (FBAT) were conducted with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, as well as with treatment response assessed in a 2-week, double-blind, placebo-controlled trial with methylphenidate. A specific haplotype (G:A:G:G; ER22/23EK- N363S- BclI- A3669G) of NR3C1 showed a significant association with behaviors related to ADHD (particularly thought and attention problems, aggressive behavior), comorbidity with oppositional defiant disorder, and executive function domains. An association was also observed with treatment response (assessed by the Conners'-Teachers and Restricted Academic Situation Scale). In contrast, MR gene polymorphisms were not associated with any of the variables tested. To the best of our knowledge, this is the first report showing an association between functional polymorphisms in NR3C1 and ADHD, providing genetic evidence for involvement of the HPA axis in the disorder and treatment response.
Karamouzis, Ioannis; Berardelli, Rita; Marinazzo, Elisa; D'Angelo, Valentina; Zinnà, Domenico; Minetto, Marco Alessandro; Zichi, Clizia; Fussotto, Beatrice; Giordano, Roberta; Ghigo, Ezio; Arvat, Emanuela
Mineralocorticoid receptors (MR) in the hippocampus display an important role in the control of hypothalamic-pituitary-adrenal (HPA)-axis, mediating the "proactive"-feedback of glucocorticoids. Fludrocortisone (FC), a potent MR agonist, has been shown to decrease HPA activity through a mechanism placed at hippocampal level. In order to clarify the effects of MR agonism on HPA function in humans, we studied the effects of FC, in a dose-related manner, on both basal and CRH-stimulated HPA axis during the quiescent phase. 8 young women were studied. ACTH, cortisol and aldosterone levels were evaluated every 15', from 1600 to 2000 hours, in randomized sessions: (1) placebo p.o. + placebo i.v., (2) 0.3 mg FC p.o. + placebo, (3) 0.1 mg FC. + placebo, (4) 0.075 mg FC + placebo, (5) 0.05 mg FC + placebo, (6) placebo + hCRH (2.0 μg/kg iv-bolus), (7) 0.3 mg FC + hCRH, (8) 0.1 mg FC + hCRH, (9) 0.075 mg FC + hCRH, (10) 0.05 mg FC + hCRH. FC induced a dose-related trend toward a further decrease of the ACTH and cortisol levels, while it showed a significant and dose-dependent inhibition of the hormonal response to hCRH (p HPA activity. These data suggest a possible hypophysial MR-mediated inhibiting effect of FC, although its pituitary glucocorticoid-mediated effect cannot be excluded. The interplay between fludrocortisone and hypophysial glucocorticoid receptors needs to be clarified in order to define better the clinical consequences of the hormonal replacement therapy of patients with primary adrenal insufficiency.
Damian Gabriel Zuloaga
Full Text Available Psychostimulants such as methamphetamine (MA induce significant alterations in the function of the hypothalamic-pituitary-adrenal (HPA axis. These changes in HPA axis function are associated with altered stress-related behaviors and might contribute to addictive processes such as relapse. In this mini-review we discuss acute and chronic effects of MA (adult and developmental exposure on the HPA axis, including effects on HPA axis associated genes/proteins, brain regions, and behaviors such as anxiety and depression. A better understanding of the mechanisms through which MA affects the HPA axis may lead to more effective treatment strategies for MA addiction.
Zuloaga, Damian G; Jacobskind, Jason S; Jacosbskind, Jason S; Raber, Jacob
Psychostimulants such as methamphetamine (MA) induce significant alterations in the function of the hypothalamic-pituitary-adrenal (HPA) axis. These changes in HPA axis function are associated with altered stress-related behaviors and might contribute to addictive processes such as relapse. In this mini-review we discuss acute and chronic effects of MA (adult and developmental exposure) on the HPA axis, including effects on HPA axis associated genes/proteins, brain regions, and behaviors such as anxiety and depression. A better understanding of the mechanisms through which MA affects the HPA axis may lead to more effective treatment strategies for MA addiction.
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.
Andersen, Morten; Vinther, Frank; Ottesen, Johnny T
This paper presents a mathematical model of the HPA axis. The HPA axis consists of the hypothalamus, the pituitary and the adrenal glands in which the three hormones CRH, ACTH and cortisol interact through receptor dynamics. Furthermore, it has been suggested that receptors in the hippocampus have an influence on the axis. A model is presented with three coupled, non-linear differential equations, with the hormones CRH, ACTH and cortisol as variables. The model includes the known features of the HPA axis, and includes the effects from the hippocampus through its impact on CRH in the hypothalamus. The model is investigated both analytically and numerically for oscillating solutions, related to the ultradian rhythm seen in data, and for multiple fixed points related to hypercortisolemic and hypocortisolemic depression. The existence of an attracting trapping region guarantees that solution curves stay non-negative and bounded, which can be interpreted as a mathematical formulation of homeostasis. No oscillating solutions are present when using physiologically reasonable parameter values. This indicates that the ultradian rhythm originate from different mechanisms. Using physiologically reasonable parameters, the system has a unique fixed point, and the system is globally stable. Therefore, solutions converge to the fixed point for all initial conditions. This is in agreement with cortisol levels returning to normal, after periods of mild stress, in healthy individuals. Perturbing parameters lead to a bifurcation, where two additional fixed points emerge. Thus, the system changes from having a unique stable fixed point into having three fixed points. Of the three fixed points, two are stable and one is unstable. Further investigations show that solutions converge to one of the two stable fixed points depending on the initial conditions. This could explain why healthy people becoming depressed usually fall into one of two groups: a hypercortisolemic depressive group or
Bodera, Paweł; Stankiewicz, Wanda; Kocik, Janusz
Brain-immune system interactions and neurohormonal changes which are induced by psychophysiological factors are growing areas of scientific interest. Central (CNS) and autonomic nervous-endocrine-immune system pathways are connected with a number of behavioral and physiological factors which may be linked to disease susceptibility and progression. In this paper, influence of orphanin FQ/nociceptin receptor (OFQ/N) on the hypothalamic-pituitary-adrenal (HPA) axis and their influence on the immunological system was reviewed. The neuroendocrine system, in particular the hypothalamic-pituitary-adrenal (HPA) axis, is closely connected with the cytokines. HPA axis activation by cytokines, via the release of glucocorticoids has, in turn, been found to play a critical role in restraining and shaping immune responses. Investigation of the OFQ/N system and G-proteins suggests a role for this receptor as a down-regulator of cytokine, chemokine and chemokine receptor expression. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.
Chen, Ai-Ling; Sun, Xi; Wang, Wei; Liu, Jin-Feng; Zeng, Xin; Qiu, Jing-Fan; Liu, Xin-Jian; Wang, Yong
Immunosuppression has been described as a consequence of brain injury and infection by different mechanisms. Angiostrongylus cantonensis can cause injury to the central nervous system and eosinophilic meningitis to human. Both T cell and B cell immunity play an essential role in the resistance of the infection. However, whether brain injury caused by A. cantonensis infection can lead to immunosuppression is not clear. Therefore, the present study sought to observe the alteration of immune responses in mice infected with A. cantonensis. Mice were infected with 20 third-stage A. cantonensis larvae. The messenger RNA (mRNA) expression of inflammatory mediators in brain tissues was observed by qRT-PCR. Cell surface markers including CD3, CD4, CD8, CD19, B220, 7-AAD, annexin-V, IgM, AA4.1, and CD23 were evaluated by using flow cytometry. The immune functions of T and B lymphocytes were detected upon stimulation by ConA and antibody responses to a nonself antigen OVA, respectively. Activation of the hypothalamic-pituitary-adrenal axis was evaluated by analyzing the concentration of plasma corticosterone and levels of mRNA for corticotropin-releasing hormone, tyrosine hydroxylase, and c-fos. A. cantonensis infection results in obvious immunosuppression evidenced as progressive spleen and thymus atrophy and significant decrease in the number of lymphocyte subsets including B cells, CD3+ T cells, CD4+ T cells, and CD8+ T cells, as well as reduced T cell proliferation at 21 days post-infection and antibody reaction to exogenous protein after infection. However, the sharp decrease of splenic and thymic cells was not due to cell apoptosis but to B cell genesis cessation and impairing thymocyte development. In addition, helminthicide treatment with albendazole on infected mice at 7 days post-infection could prevent immunosuppressive symptoms. Importantly, infected mice displayed hypothalamic-pituitary-adrenal axis activation, with peak responses occurring at 16 days post
Rensen, Niki; Gemke, Reinoud Jbj; van Dalen, Elvira C; Rotteveel, Joost; Kaspers, Gertjan Jl
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 host defence against infection, which remain a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is the second update of a previously published Cochrane review. To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE/PubMed (from 1945 to December 2016), and Embase/Ovid (from 1980 to December 2016). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 up to and including 2016, and the American Society of Pediatric Hematology/Oncology from 2014 up to and including 2016), and ongoing trial databases (the International Standard Registered Clinical/Social Study Number (ISRCTN) register via http://www.controlled-trials.com, the National Institutes of Health (NIH) register via www.clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) via apps.who.int/trialsearch) on 27 December 2016. All study designs, except case reports and patient series with fewer than 10 children, examining effects of glucocorticoid therapy for childhood ALL on HPA axis function. Two review authors independently performed study selection. One review author extracted data and assessed 'Risk of bias'; another review author checked this information. We identified 10 studies (total of 298 children; we identified two studies
van der Werf-Eldering, Marieke J; Riemersma-van der Lek, Rixt F; Burger, Huibert; Holthausen, Esther A E; Aleman, André; Nolen, Willem A
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.
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
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…
Arnett, Melinda G; Muglia, Lisa M; Laryea, Gloria; Muglia, Louis J
The normal function of the hypothalamic-pituitary-adrenal (HPA) axis, and resultant glucocorticoid (GC) secretion, is essential for human health. Disruption of GC regulation is associated with pathologic, psychological, and physiological disease states such as depression, post-traumatic stress disorder, hypertension, diabetes, and osteopenia, among others. As such, understanding the mechanisms by which HPA output is tightly regulated in its responses to environmental stressors and circadian cues has been an active area of investigation for decades. Over the last 20 years, however, advances in gene targeting and genome modification in rodent models have allowed the detailed dissection of roles for key molecular mediators and brain regions responsible for this control in vivo to emerge. Here, we summarize work done to elucidate the function of critical neuropeptide systems, GC-signaling targets, and inflammation-associated pathways in HPA axis regulation and behavior, and highlight areas for future investigation. PMID:26189452
Rhebergen, D.; Korten, N. C. M.; Penninx, B. W. J. H.; Stek, M. L.; van der Mast, R. C.; Voshaar, R. Oude; Comijs, H. C.
Background: Altered functioning of the hypothalamic-pituitary-adrenal axis (HPA-axis) has been associated with depression, but findings have been inconsistent. Among older depressed persons, both hyperactivity and hypo-activity of the HPA-axis were demonstrated. However, most studies were
Rhebergen, D.; Korten, N.C.M.; Penninx, B.W.J.H.; Stek, M.L.; van der Mast, R.; Oude Voshaar, R.; Comijs, H.
Background: Altered functioning of the hypothalamic-pituitary-adrenal axis (HPA-axis) has been associated with depression, but findings have been inconsistent. Among older depressed persons, both hyperactivity and hypo-activity of the HPA-axis were demonstrated. However, most studies were
Rhebergen, D.; Korten, N.C.; Penninx, B.W.; Stek, M.L.; Mast, R.C. van der; Oude Voshaar, R.C.; Comijs, H.C.
BACKGROUND: Altered functioning of the hypothalamic-pituitary-adrenal axis (HPA-axis) has been associated with depression, but findings have been inconsistent. Among older depressed persons, both hyperactivity and hypo-activity of the HPA-axis were demonstrated. However, most studies were
Mocking, Roel J. T.; Ruhé, Henricus G.; Assies, Johanna; Lok, Anja; Koeter, Maarten W. J.; Visser, Ieke; Bockting, Claudi L. H.; Schene, Aart H.
Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity and fatty acid (FA)-metabolism have been observed in (recurrent) major depressive disorder (MDD). Through the pathophysiological roles of FAs in the brain and cardiovascular system, a hypothesized relationship between HPA-axis
Mocking, R. J. T.; Ruhe, E.; Assies, J.; Lok, A.; Koeter, M. W. J.; Visser, I.; Bockting, C. L. H.; Schene, A. H.
Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity and fatty acid (FA)-metabolism have been observed in (recurrent) major depressive disorder (MDD). Through the pathophysiological roles of FAs in the brain and cardiovascular system, a hypothesized relationship between HPA-axis
Schatzberg, Alan F
This Anna Monika Award Lecture updates the role of the hypothalamic-pituitary-adrenal (HPA) axis in the pathogenesis and treatment of psychotic major depression (PMD). Published reports from our group and others on the clinical phenomenology (including cognition), HPA axis activity, and genetics of PMD are reviewed as are published trials of the GR antagonist, mifepristone. Current prevalence of PMD is 0.4%. PMD patients demonstrate significant elevations in HPA activity (e.g., particularly high rates of dexamethasone non-suppression, high post-dexamethasone cortisol, etc.) as well as significant impairment in cognition (attention, executive function/response inhibition and verbal and visual memory). High cortisol levels correlate with a number of cognitive deficits (e.g., verbal memory). Allelic variants of the glucocorticoid receptor (GR) gene contribute significantly to both cortisol levels and to measures of psychosis; corticotropin-releasing hormone receptor 1 variants contribute to measures of depression and psychosis. GR antagonists have produced rapid improvement in psychotic symptoms, although failed trials indicate a therapeutic blood level that may require a dose of 1,200 mg/day that is much higher than the commonly tested 600 mg/day. HPA axis over-activity appears to play a major role in the pathogenesis of PMD and is a target of drug development.
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
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.
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…
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
Eijsbouts, A.M.M.; Hoogen, F.H.J. van den; Laan, R.F.J.M.; Hermus, A.R.M.M.; Sweep, C.G.J.; Putte, L.B.A. van de
OBJECTIVE: To study the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatoid arthritis (RA). METHODS: Fifty patients with RA participated in 3 groups: recent onset active RA (n = 20), longstanding active RA (n = 20) and long-standing RA in remission (n = 10), and were compared with
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
Depressive disorder can be viewed as an adaptive defense mechanism in response to excessive stress that has gone awry. The hypothalamic-pituitary-adrenal (HPA) axis is an important node in the brain's stress circuit and suggested to play a role in several subtypes of depression. While the
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
Pompili, Maurizio; Serafini, Gianluca; Palermo, Mario; Seretti, Maria Elena; Stefani, Henry; Angeletti, Gloria; Lester, David; Amore, Mario; Girardi, Paolo
Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity measured with the dexamethasone suppression test and the dexamethesone/CRH test may have some predictive power for suicidal behavior in patients with mood disorders. Increased prolactin (PRL) levels may be related both to physiological and pathological conditions. HPA-axis abnormalities and increased levels of PRL may coexist, and common neuroendocrine changes may activate both HPA axis and PRL release. HPA-axis hyperactivity is presumably present in a large subpopulation of depressed subjects. Suicidal behavior is considered to be a form of inward-directed aggression, and aggressive behavior has been connected to high androgen levels. However, lower plasma total testosterone levels have also been reported in subjects with depression and higher suicidality. Lipid/immune dysregulations, the increased ratio of blood fatty acids, and increased PRL levels may each be associated with the increased production of pro-inflammatory cytokines, which have been reported in patients with major depression and patients engaging in suicidal behavior. Although no studies have been done to determine whether ante-mortem physical stress may be detected by raised post-mortem PRL, this would be of great interest for physicians.
Hypothalamic-pituitary-adrenal (HPA) axis function in the California mouse (Peromyscus californicus): Changes in baseline activity, reactivity, and fecal excretion of glucocorticoids across the diurnal cycle.
Harris, Breanna N; Saltzman, Wendy; de Jong, Trynke R; Milnes, Matthew R
The California mouse, Peromyscus californicus, is an increasingly popular animal model in behavioral, neural, and endocrine studies, but little is known about its baseline hypothalamic-pituitary-adrenal (HPA) axis activity or HPA responses to stressors. We characterized plasma corticosterone (CORT) concentrations in P. californicus under baseline conditions across the diurnal cycle, in response to pharmacological manipulation of the HPA axis, and in response to a variety of stressors at different times of day. In addition, we explored the use of fecal samples to monitor adrenocortical activity non-invasively. California mice have very high baseline levels of circulating CORT that change markedly over 24h, but that do not differ between the sexes. This species may be somewhat glucocorticoid-resistant in comparison to other rodents as a relatively high dose of dexamethasone (5mg/kg, s.c.) was required to suppress plasma CORT for 8h post-injection. CORT responses to stressors and ACTH injection differed with time of day, as CORT concentrations were elevated more readily during the morning (inactive period) than in the evening (active period) when compared to time-matched control. Data from (3)H-CORT injection studies show that the time course for excretion of fecal CORT, or glucocorticoid metabolites, differs with time of injection. Mice injected in the evening excreted the majority of fecal radioactivity 2-4h post-injection whereas mice injected during the morning did so at 14-16h post-injection. Unfortunately, the antibody we used does not adequately bind the most prevalent fecal glucocorticoid metabolites and therefore we could not validate its use for fecal assays. Copyright © 2012 Elsevier Inc. All rights reserved.
Harris, Breanna N; Saltzman, Wendy
Life history theory posits that organisms face a trade-off between current and future reproductive attempts. The physiological mechanisms mediating such trade-offs are still largely unknown, but glucocorticoid hormones are likely candidates as elevated, post-stress glucocorticoid levels have been shown to suppress both reproductive physiology and reproductive behavior. Aged individuals have a decreasing window in which to reproduce, and are thus predicted to invest more heavily in current as opposed to future reproduction. Therefore, if glucocorticoids are important in mediating the trade-off between current and future reproduction, aged animals are expected to show decreased hypothalamic-pituitary-adrenal (HPA) axis responses to stressors and to stimulation by corticotropin-releasing hormone (CRH), and enhanced responses to glucocorticoid negative feedback, as compared to younger animals. We tested this hypothesis in the monogamous, biparental California mouse by comparing baseline and post-stress corticosterone levels, as well as corticosterone responses to dexamethasone (DEX) and CRH injections, between old (∼18-20months) and young (∼4months) virgin adults of both sexes. We also measured gonadal and uterine masses as a proxy for investment in potential current reproductive effort. Adrenal glands were weighed to determine if older animal had decreased adrenal mass. Old male mice had lower plasma corticosterone levels 8h after DEX injection than did young male mice, suggesting that the anterior pituitary of older males is more sensitive to DEX-induced negative feedback. Old female mice had higher body-mass-corrected uterine mass than did young females. No other differences in corticosterone levels or organ masses were found between age groups within either sex. In conclusion, we did not find strong evidence for age-related change in HPA activity or reactivity in virgin adult male or female California mice; however, future studies investigating HPA activity and
Evans, B.E.; Greaves-Lord, K.; Euser, A.S.; Franken, I.H.A.; Huizink, A.C.
Aims Hypothalamicpituitaryadrenal (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 Adolescents'
Spiers, Jereme G.; Hsiao-Jou Cortina eChen; Conrad eSernia; Lavidis, Nickolas A.
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 prese...
Erdos, Benedek; Clifton, Rebekah R.; Liu, Meng; Li, Hongwei; McCowan, Michael L.; Sumners, Colin; Scheuer, Deborah A.
Exaggerated activation of the sympathetic nervous system and/or the hypothalamic-pituitary-adrenal (HPA) axis increases cardiovascular disease risk. The present study demonstrates that macrophage migration inhibitory factor (MIF) in paraventricular nucleus (PVN) neurons is a novel mechanism mediating attenuation of both the sympathetic and HPA axis responses to acute stress.
Vinther, Frank; Andersen, Morten; Ottesen, Johnny T
This paper concerns ODE modeling of the hypothalamic-pituitary- adrenal axis (HPA axis) using an analytical and numerical approach, combined with biological knowledge regarding physiological mechanisms and parameters. The three hormones, CRH, ACTH, and cortisol, which interact in the HPA axis 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 that influence the dynamics of the HPA axis, i.e. a negative feedback from cortisol on CRH and ACTH. Therefore we term our model the minimal model. The minimal model, encompasses a wide class of different realizations, obeying only a few physiologically reasonable demands. The results include the existence of a trapping region guaranteeing that concentrations do not become negative or tend to infinity. Furthermore, this treatment guarantees the existence of a unique fixed point. A change in local stability of the fixed point, from stable to unstable, implies a Hopf bifurcation; thereby, oscillating solutions may emerge from the model. Sufficient criteria for local stability of the fixed point, and an easily applicable sufficient criteria guaranteeing global stability of the fixed point, is formulated. If the latter is fulfilled, ultradian rhythm is an impossible outcome of the minimal model and all realizations thereof. The second part of the paper concerns a specific realization of the minimal model in which feedback functions are built explicitly using receptor dynamics. Using
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.
Varghese, Femina P.; Brown, E. Sherwood
Background: One of the most enduring and replicated findings in biological psychiatry is activation of the hypothalamic-pituitary-adrenal (HPA) axis in a subset of patients with major depressive disorder. This review will discuss some of these findings and their pertinence to the assessment and treatment of depressed patients.
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.
Fan, Ying; Ma, Lian; Pippins, Jennifer; Limb, Susan; Xu, Yun; Sahajwalla, Chandrahas G
Inhaled and intranasal corticosteroids (ICS and INS) are among the mainstays of the treatment for asthma and allergic rhinitis, respectively, and also carry the potential to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Several important factors affect the interpretability of trials investigating the impact of ICS and INS on the HPA axis. This paper reviews 106 published clinical trials, peer-reviewed articles, and New Drug Application reviews of approved ICS and INS, using MEDLINE and Drugs@FDA database. The trials included in this review evaluated the potential impact on HPA axis function of eight approved single-ingredient ICS and INS (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, flucticasone propionate, mometasone furoate, and triamcinolone acetonide) and combination products containing these ingredients. The most commonly utilized design was blinded, placebo controlled, and short term (<6 weeks) for adult trials and blinded, placebo controlled, and long term (≥6 weeks) for pediatric trials. Factors potentially affecting trial results include the choice of dose, dosing duration, assay sensitivity, statistical methodology, and the study population evaluated (patients or healthy volunteers). All of these factors have the potential to affect the level of adrenal suppression detected. In conclusion, to be informative, a HPA axis study should be well designed and carefully implemented to minimize variability in results and improve the overall interpretability of data obtained. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.
Tang, Akaysha C; Reeb, Bethany C; Romeo, Russell D; McEwen, Bruce S
.... Using neonatal novelty exposure, a brief and transient early life stimulation method known to produce long-lasting changes in the hypothalamic-pituitary-adrenal axis, we found that social recognition...
Tomas, Cara; Newton, Julia; Watson, Stuart
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered. In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females. Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder. Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear. PMID:24959566
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
Karuri, A R; Engelking, L R; Kumar, M S
Effects of acute exposure (2 h) to either 1.5% halothane or 0.5% methoxyflurane on chemical mediators of the hypothalamic-pituitary-adrenal (HPA) axis were evaluated in male Sprague-Dawley rats immediately after exposure, after the righting reflex (4 h), or 24 h postexposure. Effects of these anesthetics on hippocampal corticotropin releasing factor (CRF) were also evaluated. Methoxyflurane caused significant elevations in pituitary adrenocorticotropin hormone (ACTH)-like immunoreactivities in all three of the experiment's time groups, yet halothane failed to cause the same response immediately after exposure. Serum ACTH-like immunoreactivities were significantly elevated immediately after exposure to both anesthetics, but were not elevated at 4 and 24 h postexposure. Corticosterone (CORT)-like immunoreactivities were significantly elevated by halothane in all experimental groups, and in the 2- and 24-h groups following methoxyflurane exposure. Hippocampal CRF-like immunoreactivities remained unaffected by either anesthetic. Results indicate that a 2-h exposure to either halothane or methoxyflurane results in significant activation of the rat hypothalamic-pituitary-adrenal axis, and that the activation appears to be sustained over a 24-h period.
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.
Generaal, E.; Vogelzangs, N.; MacFarlane, G.J.; Geenen, R.; Smit, J.H.; Penninx, B.W.J.H.; Dekker, J.
BACKGROUND: Studies on hypothalamic-pituitary-adrenal axis (HPA-axis) function amongst patients with chronic pain show equivocal results and well-controlled cohort studies are rare in this field. The goal of our study was to examine whether HPA-axis dysfunction is associated with the presence and
Logrip, Marian L.; Rivier, Catherine; Lau, Calvin; Im, Sarah; Vaughan, Joan; Lee, Soon
Exposure to alcohol during adolescence exerts long-term effects on the adult brain stress circuits, causing many changes that persist into adulthood. Here we examined the consequences of adolescent intermittent ethanol [AIE, administered from postnatal day (PND) 28–42] on the hypothalamic-pituitary-adrenal (HPA) axis-related brain circuitry of rats challenged with an intragastric administration of alcohol in adulthood (PND 70–71). Both male and female adolescent rats were exposed to alcohol v...
Ibrahimagic, Omer C; Jakubovic, Amra Cickusic; Smajlovic, Dzevdet; Dostovic, Zikrija; Kunic, Suljo; Iljazovic, Amra
Psychological stress and changes in hypothalamic-pituitary-adrenal (HPA) axis in period after diagnosis of "de novo" Parkinson disease (PD) could be a big problem for patients. We measured psychological stress and changes in hypothalamic-pituitary-adrenal axis (HPA) in thirty patients (15:15) with "de novo" Parkinson's disease, average age 64.17 ± 13.19 (28-82) years (Department of Neurology, University Clinical Center Tuzla). We used Impact of events scale (with 15 questions) to evaluate psychological stress. Normal level of morning cortisol was 201-681 nmol/l, and morning adrenocorticotropic hormone (ACTH) up to 50 pg/ml. Almost 55% patients suffered from mild or serious psychological stress according to IES testing (Horowitz et al.). Non-iatrogenic changes in HPA axis were noticed at 30% patients. The differences between female and male patients regarding to the age (p=0.561), value of cortisol (p=0.745), value of ACTH (p=0.886) and IES testing (p=0.318) were not noticed. The value of cortisol was the predictor of value of ACTH (r=0.427). Psychological stress and changes in hypothalamic-pituitary-adrenal axis are present in patients with "de novo" PD. There is significant relation between values of cortisol and ACTH. Psychological stress is frequent problem for "de novo" PD patients.
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,
Smith, Ryan W; Downey, Kim; Gordon, Michelle; Hudak, Alan; Meeder, Rob; Barker, Sarah; Smith, W Gary
To determine the prevalence of hypothalamic-pituitary-adrenal (HPA) axis suppression in asthmatic children on inhaled corticosteroids (ICS). Clinical and demographic variables were recorded on preconstructed, standardized forms. HPA axis suppression was measured by morning serum cortisol levels and confirmed by low-dose adrenocorticotropic hormone stimulation testing. In total, 214 children participated. Twenty children (9.3%, 95% CI 5.3% to 13.4%) had HPA axis suppression. Odds of HPA axis suppression increased with ICS dose (OR 1.005, 95% CI 1.003 to 1.009, PHPA axis suppression were on a medium or lower dose of ICS for their age (200 μg/day to 500 μg/day). HPA axis suppression was not predicted by drug type, dose duration, concomitant use of long-acting beta-agonist or nasal steroid, or clinical features. Laboratory evidence of HPA axis suppression exists in children taking ICS for asthma. Children should be regularly screened for the presence of HPA axis suppression when treated with high-dose ICS (>500 μg/day). Consideration should be given to screening children on medium-dose ICS.
Gifford, Robert M; Reynolds, Rebecca M
Increasing evidence supports fetal glucocorticoid exposure with associated altered offspring hypothalamic-pituitary-adrenal (HPA) axis activity as a key mechanism linking early life events with later life disease. Alterations in HPA axis activity are linked to a range of cardiometabolic and psychiatric diseases. As many of these diseases manifest sex differences in presentation we review the evidence for programmed sex-differences in the HPA axis. Available literature suggests vulnerability of the female HPA axis to prenatal stressors with female offspring demonstrating increased HPA axis reactivity. This may be due to changes in placental glucocorticoid metabolism leading to increased fetal glucocorticoid exposure. We discuss the potential consequences of increased vulnerability of the female HPA axis for later life health and consider the underlying mechanisms. Further studies are needed to determine whether sex-differences in early-life programming of the HPA axis represent a pathway underpinning the sex-differences in common cardiometabolic and psychiatric diseases. Copyright © 2017 Elsevier B.V. All rights reserved.
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
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 (ɳ2=0.029) and decreases in reaction to the stress task (ɳ2=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.
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.
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...
Cortés-Puch, Irene; Hicks, Caitlin W; Sun, Junfeng; Solomon, Steven B; Eichacker, Peter Q; Sweeney, Daniel A; Nieman, Lynnette K; Whitley, Elizabeth M; Behrend, Ellen N; Natanson, Charles; Danner, Robert L
The clinical significance and even existence of critical illness-related corticosteroid insufficiency is controversial. Here, hypothalamic-pituitary-adrenal (HPA) function was characterized in severe canine Staphylococcus aureus pneumonia. Animals received antibiotics and titrated life-supportive measures. Treatment with dexamethasone, a glucocorticoid, but not desoxycorticosterone, a mineralocorticoid, improves outcome in this model. Total and free cortisol, adrenocorticotropic hormone (ACTH). and aldosterone levels, as well as responses to exogenous ACTH were measured serially. At 10 h after the onset of infection, the acute HPA axis stress response, as measured by cortisol levels, exceeded that seen with high-dose ACTH stimulation but was not predictive of outcome. In contrast to cortisol, aldosterone was largely autonomous from HPA axis control, elevated longer, and more closely associated with survival in early septic shock. Importantly, dexamethasone suppressed cortisol and ACTH levels and restored ACTH responsiveness in survivors. Differing strikingly, nonsurvivors, sepsis-induced hypercortisolemia, and high ACTH levels as well as ACTH hyporesponsiveness were not influenced by dexamethasone. During septic shock, only serial measurements and provocative testing over a well-defined timeline were able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identify a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies.
Hicks, Caitlin W.; Sun, Junfeng; Solomon, Steven B.; Eichacker, Peter Q.; Sweeney, Daniel A.; Nieman, Lynnette K.; Whitley, Elizabeth M.; Behrend, Ellen N.; Natanson, Charles; Danner, Robert L.
The clinical significance and even existence of critical illness-related corticosteroid insufficiency is controversial. Here, hypothalamic-pituitary-adrenal (HPA) function was characterized in severe canine Staphylococcus aureus pneumonia. Animals received antibiotics and titrated life-supportive measures. Treatment with dexamethasone, a glucocorticoid, but not desoxycorticosterone, a mineralocorticoid, improves outcome in this model. Total and free cortisol, adrenocorticotropic hormone (ACTH). and aldosterone levels, as well as responses to exogenous ACTH were measured serially. At 10 h after the onset of infection, the acute HPA axis stress response, as measured by cortisol levels, exceeded that seen with high-dose ACTH stimulation but was not predictive of outcome. In contrast to cortisol, aldosterone was largely autonomous from HPA axis control, elevated longer, and more closely associated with survival in early septic shock. Importantly, dexamethasone suppressed cortisol and ACTH levels and restored ACTH responsiveness in survivors. Differing strikingly, nonsurvivors, sepsis-induced hypercortisolemia, and high ACTH levels as well as ACTH hyporesponsiveness were not influenced by dexamethasone. During septic shock, only serial measurements and provocative testing over a well-defined timeline were able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identify a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies. PMID:25294215
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.
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
Mocking, Roel J. T.; Verburg, Hanka F.; Westerink, Anne M.; Assies, Johanna; Vaz, Frederic M.; Koeter, Maarten W. J.; Ruhe, Henricus G.; Schene, Aart H.
Background: Metabolism of dietary fatty acids (FAs), and its relationship with the hypothalamic-pituitary-adrenal (HPA)-axis, have been found to be altered in major depressive disorder (MDD). Moreover, indications exist that these factors are associated with antidepressant-response. If we better
Mocking, Roel J. T.; Verburg, Hanka F.; Westerink, Anne M.; Assies, Johanna; Vaz, Frédéric M.; Koeter, Maarten W. J.; Ruhé, Henricus G.; Schene, Aart H.
Metabolism of dietary fatty acids (FAs), and its relationship with the hypothalamic-pituitary-adrenal (HPA)-axis, have been found to be altered in major depressive disorder (MDD). Moreover, indications exist that these factors are associated with antidepressant-response. If we better understand
Mocking, R.J.T.; Verburg, H.F.; Westerink, A.M.; Assies, J.; Vaz, F.M.; Koeter, M.W.; Ruhe, H.G.; Schene, A.H.
BACKGROUND: Metabolism of dietary fatty acids (FAs), and its relationship with the hypothalamic-pituitary-adrenal (HPA)-axis, have been found to be altered in major depressive disorder (MDD). Moreover, indications exist that these factors are associated with antidepressant-response. If we better
Hillman, JB; Dorn, LD; Loucks, TL; Berga, SL
Objective Stress and stress-related concomitants, including hypothalamic-pituitary-adrenal (HPA) axis activation, are implicated in obesity and its attendant co-morbidities. 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. We hypothesized that obesity would be correlated with increased HPA axis activity and reactivity. Methods Measures of HPA axis activity included 3 blood samples obtained mid-day (between 1300 and 1400) over the course of 40 minutes and overnight urine free cortisol (UFC), and cortisol levels 0, 20, and 40 min after venipuncture (cortisol reactivity). Measures of adiposity included BMI, BMI-Z, percent body fat, and fat distribution (central adiposity) assessed by dual energy X-ray absorptiometry. Results Daytime levels of serum cortisol were inversely associated with BMI-Z and central adiposity (p adolescent girls. The clinical implications of our findings require further investigation. PMID:21944263
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.
Jahng, Jeong Won; Lee, Jong-Ho
Intraperitoneal injections (ip) of lithium chloride at large doses induce c-Fos expression in the brain regions implicated in conditioned taste aversion (CTA) learning, and also activate the hypothalamic-pituitary-adrenal (HPA) axis and increase the plasma corticosterone levels in rats. A pharmacologic treatment blunting the lithium-induced c-Fos expression in the brain regions, but not the HPA axis activation, induced CTA formation. Synthetic glucocorticoids at conditioning, but not glucocorticoid antagonist, attenuated the lithium-induced CTA acquisition. The CTA acquisition by ip lithium was not affected by adrenalectomy regardless of basal corticosterone supplement, but the extinction was delayed in the absence of basal corticosterone. Glucocorticoids overloading delayed the extinction memory formation of lithium-induced CTA. ip lithium consistently induced the brain c-Fos expression, the HPA activation and CTA formation regardless of the circadian activation of the HPA axis. Intracerebroventricular (icv) injections of lithium at day time also increased the brain c-Fos expression, activated the HPA axis and induced CTA acquisition. However, icv lithium at night, when the HPA axis shows its circadian activation, did not induce CTA acquisition nor activate the HPA axis, although it increased the brain c-Fos expression. These results suggest that the circadian activation of the HPA axis may affect central, but not peripheral, effect of lithium in CTA learning in rats, and the HPA axis activation may be necessary for the central effect of lithium in CTA formation. Also, glucocorticoids may be required for a better extinction; however, increased glucocorticoids hinder both the acquisition and the extinction of lithium-induced CTA. Copyright © 2015. Published by Elsevier B.V.
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.
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. PMID:29035323
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.
Azzam, I; Gilad, S; Limor, R; Stern, N; Greenman, Y
Ghrelin plasma concentration increases in parallel to cortisol after a standardized psychological stress in humans, but the physiological basis of this interaction is unknown. We aimed to elucidate this question by studying the ghrelin response to pharmacological manipulation of the hypothalamic-pituitary-adrenal (HPA) axis. Six lean, healthy male volunteers were examined under four experimental conditions. Blood samples were collected every 30 min for two sequential periods of two hours. Initially, a baseline period was followed by intravenous injection of a synthetic analog of ACTH (250 μg). Subsequently, a single dose of metyrapone was administered at midnight and in the following morning, blood samples were collected for 2 h, followed by an intravenous injection of hydrocortisone (100 mg) with continued sampling. We show that increased cortisol serum levels secondary to ACTH stimulation or hydrocortisone administration are positively associated with plasma ghrelin levels, whereas central stimulation of the HPA axis by blocking cortisol synthesis with metyrapone is associated with decreased plasma ghrelin levels. Collectively, this suggests that HPA-axis-mediated elevations in ghrelin plasma concentration require increased peripheral cortisol levels, independent of central elevation of ACTH and possibly CRH levels. © 2017 The authors.
Doolin, Kelly; Farrell, Chloe; Tozzi, Leonardo; Harkin, Andrew; Frodl, Thomas; O'Keane, Veronica
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.
Tara K S Craft
Full Text Available Chronic stress is capable of exacerbating each major, modifiable, endogenous risk factor for cerebrovascular and cardiovascular disease. Indeed, exposure to stress can increase both the incidence and severity of stroke, presumably through activation of the hypothalamic-pituitary-adrenal (HPA axis. Now that characterization of the mechanisms underlying epigenetic programming of the HPA axis is well underway, there has been renewed interest in examining the role of early environment on the evolution of health conditions across the entire lifespan. Indeed, neonatal manipulations in rodents that reduce stress-responsivity, and subsequent life-time exposure to glucocorticoids, are associated with a reduction in the development of neuroendocrine, neuroanatomical, and cognitive dysfunctions that typically progress with age. Although improved day to day regulation of the HPA axis also may be accompanied by a decrease in stroke risk, evidence from rodent studies suggest that an associated cost could be increased susceptibility to inflammation and neuronal death in the event that a stroke does occur and the individual is exposed to persistently elevated corticosteroids. Given its importance in regulation of health and disease states, any long-term modulation of the HPA axis is likely to be associated with both benefits and potential risks. The goals of this review article are to examine 1 the clinical and experimental data suggesting that neonatal experiences can shape HPA axis regulation, 2 the influence of stress and the HPA axis on stroke incidence and severity, and 3 the potential for neonatal programming of the HPA axis to impact adult cerebrovascular health.
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.
Naughton, Marie; Dinan, Timothy G; Scott, Lucinda V
Since the 1960s, both corticotropin-releasing hormone (CRH) and the hypothalamic-pituitary-adrenal (HPA) axis have been studied in detail across a range of psychiatric illnesses, leading to important contributions to our knowledge in this area. This research arose from the conceptualization of depression, in particular, as a stress-related disorder. However, stress is now regarded as an integral component of psychiatric illnesses in general, whether as an environmental trigger or in the initial pathogenesis, and there is evidence of altered HPA axis function across a range of mental disorders. The chapter will cover the extensive literature on HPA axis abnormalities in these disorders with a particular emphasis on the CRH system as it is very evident that this 41-amino acid-containing peptide is not only a major physiologic regulator of HPA axis activity but also important in the pathogenesis of mental disorders. In particular, we discuss the abundant reports pertaining to major depressive disorder, where hyperactivity of the HPA axis, of mild to moderate severity, has been demonstrated in 30-50% of cases. Also under consideration is the less extensively studied, but equally intriguing question of HPA axis integrity in bipolar affective disorder. In addition there will be a concise summary of recent findings in schizophrenia and anxiety disorders, with an emphasis on post-traumatic stress disorder (PTSD) in the latter case. Interestingly, in diametric opposition to the theory of HPA hyperactivity in depression, PTSD has features consistent with hypofunctioning of this system. Advances in animal and human studies have made it possible to synthesize these findings, and while much still remains unknown, we are gradually building up a clearer picture of this very important axis in health, at times of stress, and in chronic enduring mental illness. © 2014 Elsevier B.V. All rights reserved.
Hodyl, Nicolette A; Walker, Frederick R; Krivanek, Klara M; Clifton, Vicki; Hodgson, Deborah M
Prenatal exposure of animals to bacterial endotoxin is an experimental model of systemic maternal infection in the human pregnancy. Previous studies in the rat have demonstrated that such exposure is associated with long term alterations to hypothalamic pituitary adrenal (HPA) axis development. Typically, these animals display an elevated HPA response to stress in adulthood. As neural development is more similar in the human and the guinea pig than the rat, this study adopted a guinea pig model of pregnancy to explore the effects of endotoxin exposure on the HPA axis in the offspring. The offspring of dams exposed to endotoxin exhibited an attenuated cortisol response to the novel environment stress in the weaning period. The degree to which this cortisol response was both buffered by the mother's presence, and habituated to on repeated exposure, differed significantly between the prenatal treatment groups. In adulthood, a diminished cortisol response to the immune challenge was only evident in the female offspring, while both male and female offspring exhibited altered febrile responses. The results of the present study indicate that prenatal bacterial exposure in the guinea pig results in offspring with lower cortisol responses to stress in later life. These findings contrast past research that has used the rat to model pregnancy. As such, the use of the guinea pig to model infection may provide a useful alternative model of human pregnancy to explore programming effects.
Rhebergen, D; Korten, N C M; Penninx, B W J H; Stek, M L; van der Mast, R C; Oude Voshaar, R; Comijs, H C
Altered functioning of the hypothalamic-pituitary-adrenal axis (HPA-axis) has been associated with depression, but findings have been inconsistent. Among older depressed persons, both hyperactivity and hypo-activity of the HPA-axis were demonstrated. However, most studies were population-based studies, with single cortisol measurements, lacking insight into diurnal patterns of HPA-axis functioning. We aim to provide insight into functioning of the HPA-axis, assessed by various salivary cortisol samples, in depressed older adults and non-depressed controls. Data were derived from the Netherlands Study of Depression in Older Persons. Cortisol levels of older persons without a lifetime diagnosis of depression and/or anxiety (n=109) were compared with older persons with a 6-month major depression diagnosis (n=311). ANCOVA analyses and random coefficient analysis on the four morning cortisol samples were performed. A possible U-shaped association between cortisol and depression status was examined. Depressed older persons showed higher morning cortisol levels at awakening (T1) and a less dynamic awakening response compared to non-depressed older persons. Dexamethasone suppression did not differ across groups. No U-shaped association between HPA-axis activity and depression was observed. We demonstrated a hypercortisolemic state and a diminished ability to respond to the stress of awakening among depressed older persons. Previously it was shown, that hypercortisolemic states may indicate a lifelong biological vulnerability for depression. Our findings expand on previous literature by demonstrating that in older persons the HPA-axis may become less responsive to stress, culminating in a further dysregulation of the diurnal cortisol-rhythm, superimposed on - possibly lifelong - hypercortisolemic states. Copyright © 2014 Elsevier Ltd. All rights reserved.
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.
Labad, Javier; Gutiérrez-Zotes, Alfonso; Creus, Marta; Montalvo, Itziar; Cabezas, Ángel; Solé, Montse; Ortega, Laura; Algora, Maria José; Sánchez-Gistau, Vanessa; Vilella, Elisabet
Measures of hypothalamic-pituitary-adrenal (HPA) axis activity such as increased diurnal cortisol levels or a blunted cortisol awakening response (CAR) have been associated with cognitive impairments in people with psychotic disorders. We aimed to explore whether there are sex differences in the relationship between HPA axis measures and cognition in early psychosis (EP). 60 EP outpatients and 50 healthy subjects (HS) were assessed with the MATRICS Consensus Cognitive Battery. Saliva cortisol levels were determined at the neuropsychological assessment and on another day at 6 sampling times: awakening; 30' and 60' post-awakening; and 10:00h, 23:00h and 10:00h the day after the administration of 0.25mg of dexamethasone, which occurred at 23:00h. Three HPA axis measures were calculated: CAR, cortisol diurnal slope and cortisol suppression ratio of the dexamethasone suppression test (DST). Multiple linear regression analyses were conducted to explore the relationship between HPA axis measures and cognitive tasks while adjusting for covariates (education level, smoking, cannabis use, and cortisol levels at the cognitive assessment). Interactions between female sex, EP diagnosis and HPA axis measures were examined. An increased CAR was associated with a poorer cognitive performance in EP women in processing speed and verbal memory. In contrast, a more flattened diurnal cortisol slope was associated with poorer functioning in the spatial working memory of EP women. DST suppression ratio was associated with better visual memory, without sex differences. Our study suggests that there are sex differences in the relationship between HPA axis measures and cognitive abilities in EP. Copyright © 2016. Published by Elsevier Ltd.
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.
Full Text Available Background: Most of the research on atopic dermatitis (AD has focused on the pathophysiological role of the immune system in AD, and the role of endocrine signals in the pathology of AD has not been explored. Current research has shown a link between the neuroendocrine and immune functions. Aim: The aim was to measure the serum basal cortisol levels and cortisol levels following a low-dose ACTH stimulation test in patients with AD before and after treatment with corticosteroids. Methods: Three groups of patients with AD were evaluated: mild, moderate, and severe. Basal cortisol levels following an ACTH stimulation test were measured before and after treatment with topical steroids when an improvement in the disease activity by 75% as determined by the SCORAD index was observed. Results: Eighteen patients of the severe group at baseline showed an impaired hypothalamic-pituitary-adrenal (HPA axis with cortisol levels <250 nmol/l during their first visit. A total of 13 of 18 patients regained their HPA axis activity when the baseline cortisol was measured after using topical corticosteroids which resulted in 75% improvement in the disease activity. Conclusions: The disease activity rather than the use of topical costicosteroids is responsible for the low basal levels in patients with severe AD.
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.
Vaillancourt, Tracy; Duku, Eric; Decatanzaro, Denys; Macmillan, Harriet; Muir, Cameron; Schmidt, Louis A
We examined the relationship between being bullied during childhood and activity of the hypothalamic-pituitary-adrenal (HPA) axis as assessed through repeated measures of salivary cortisol. A non-clinical sample of 154 (74 boys) predominantly Caucasian middle-class 12-year-olds each provided detailed information about their experiences with bullying and six saliva samples were standardized across time and day. Children with a history of child maltreatment, diagnosed psychiatric illness, foster care placement, medication use (psychotropic and oral contraception) and aggression directed toward peers and/or family members were excluded. Using multilevel regression and applying orthogonal polynomial contrasts to model the observed circadian pattern in the data, we found that occasional and frequent verbal peer victimization was associated with hyposecretion of cortisol when controlling for sex, pubertal status, age, depression and anxiety. This relation, however, was moderated by sex. For boys, occasional exposure was associated with higher cortisol levels, whereas for girls exposure was associated with lower cortisol levels. The present study highlights the need to consider the plight of peer-victimized children seriously, as it is associated with alterations to the HPA axis that affect males and females differently, and likely diminishes a person's ability to cope with stress, possibly placing them at risk for psychopathology and ill health. Copyright 2007 Wiley-Liss, Inc.
Maguire, Jamie; Salpekar, Jay A.
Epilepsy is a heterogeneous condition with multiple etiologies including genetics, infection, trauma, vascular, neoplasms, and toxic exposures. The overlap of psychiatric comorbidity adds to the challenge of optimal treatment for people with epilepsy. Seizure episodes themselves may have varying triggers; however, for decades, stress has been commonly and consistently suspected to be a trigger for seizure events. This paper explores the relationship between stress and seizures and reviews clinical data as well as animal studies that increasingly corroborate the impact of stress hormones on neuronal excitability and seizure susceptibility. The basis for enthusiasm for targeting glucocorticoid receptors for the treatment of epilepsy and the mixed results of such treatment efforts are reviewed. In addition, this paper will highlight recent findings identifying a regulatory pathway controlling the body’s physiologic response to stress which represents a novel therapeutic target for modulation of the hypothalamic-pituitary-adrenal (HPA) axis. Thus, the HPA axis may have important clinical implications for seizure control and imply use of anticonvulsants that influence this neuronal pathway. PMID:23200771
Gerald F Giesbrecht; Maede Ejaredar; Jiaying Liu; Jenna Thomas; Nicole Letourneau; Tavis Campbell; Jonathan W Martin; Deborah Dewey
Background 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...
Le-Ha, Chi; Herbison, Carly E; Beilin, Lawrence J; Burrows, Sally; Henley, David E; Lye, Stephen J; Matthews, Stephen G; Pennell, Craig E; Mori, Trevor A
Activation of the hypothalamic-pituitary-adrenal (HPA) axis has been associated with higher levels of cardiovascular (CVD) risk factors in adults. This study aimed to assess the relation between measures of HPA axis activity under resting conditions and CVD risk factors in a general population of adolescents at 17 years. A total of 1134 adolescents from the Western Australian Pregnancy Cohort (Raine) Study had phenotypic and socio-demographic data. The associations between HPA axis measures (plasma ACTH, total cortisol, calculated free cortisol, corticosteroid binding globulin (CBG), and salivary cortisol) and a range of cardiovascular risk factors were examined using multivariable linear regression models, with adjustment for gender, adiposity, birth weight, gestational age, and socio-behavioural factors. Plasma total cortisol was positively associated with systolic blood pressure (SBP) (p=0.011), total cholesterol, HDL-cholesterol, and triglycerides (all pLDL-cholesterol (p=0.016); plasma calculated free cortisol was positively associated with triglycerides (p=0.006); plasma CBG was positively associated with total cholesterol and HDL-cholesterol (both pLDL-cholesterol (p=0.022), and hs-CRP (p=0.001). After correction for multiple comparisons, significant associations remained for total cortisol with total cholesterol, HDL-C, and triglycerides; for calculated free cortisol with triglycerides; and for CBG with HDL-C, total cholesterol, and hs-CRP. Plasma ACTH was not associated with any cardiovascular risk factor. There was no association between BMI and any measure of HPA axis activity. In an adolescent population, HPA axis measures under resting conditions are associated with a range of CVD risk factors. Clarification of the mechanisms underlying these associations in adolescence would be an important step in understanding the evolution of adult CVD. Copyright © 2016 Elsevier Ltd. All rights reserved.
Salvat-Pujol, Neus; Labad, Javier; Urretavizcaya, Mikel; de Arriba-Arnau, Aida; Segalàs, Cinto; Real, Eva; Ferrer, Alex; Crespo, José M; Jiménez-Murcia, Susana; Soriano-Mas, Carles; Menchón, José M; Soria, Virginia
Neuropsychological deficits and hypothalamic-pituitary-adrenal (HPA) axis dysfunction have been described in major depressive disorder (MDD). We conducted an exploratory study to investigate the role of remission status in the relationship between HPA axis and cognition in MDD. Ninety-seven MDD patients (44 remitted, 53 non-remitted) and 97 healthy controls (HC) were evaluated. We measured verbal and visual memory, working memory, processing speed, attention, and executive function. Three HPA axis measures were assessed: cortisol awakening response (CAR), diurnal cortisol slope, and cortisol suppression ratio with 0.25mg of dexamethasone (DSTR). Multiple linear regression analyses were performed to study the relationship between cortisol measures and cognition while controlling for potential confounders. We conducted an overall analysis in all participants to compare both MDD-remitted and MDD non-remitted groups with respect to HC. Another analysis including MDD patients only was used to explore a moderating effect by remission status. MDD patients showed poorer cognitive performance compared with HC, without significant differences between remitters and non-remitters. Cortisol measures did not differ between remitters and non-remitters. Although most HPA axis measures were not associated with cognitive dysfunction, we found significant associations between cognitive performance in MDD-remitters and cortisol measures for visual memory, processing speed and executive function. A significant moderating effect for remission status was found between cortisol diurnal slope (but neither CAR nor DSTR) and performance in processing speed or executive function. Remission status in MDD appears to moderate the association between some cognitive domains (processing speed and executive function) and HPA axis activity. Copyright © 2016 Elsevier Ltd. All rights reserved.
Moidel, Melissa A; Belz, Emily E; Czambel, R Kenneth; Rubin, Robert T; Rhodes, Michael E
The hypothalamic-pituitary-adrenal (HPA) axis is a three-gland component of the endocrine system and a key modulator of the stress response. We have developed a novel in vitro perfusion system to enable the study of pharmacological and hormonal challenges to tissue components of the HPA axis. In vivo studies have shown functional sex differences (sexual diergism) in HPA responses to cholinergic drugs, and in the present in vitro study, we examine these differences at several levels of the HPA axis. Hypothalami, pituitaries, and adrenal glands were collected from male and female rats (n=3 per sex). One-half hypothalamus, one-half pituitary, and one adrenal gland were placed individually into three Erlenmeyer flasks connected by tubing. Flasks were perfused with medium (pH 7.4) at 37 degrees C. Sampling ports between the flasks were used to collect buffer for determination of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosterone (CORT) release from the hypothalamus, pituitary, and adrenal flasks, respectively, over an extended baseline period, to determine stability of the system, and after nicotine administration. The perfusion system produced steady CRH, ACTH, and CORT baselines, the ACTH and CORT values being comparable to in vivo basal ACTH and CORT values in jugular-vein-cannulated rats. In vitro CRH, ACTH, and CORT responses to nicotine were significantly increased at 10 min and returned to baseline by 30 min, the CRH and ACTH responses from female tissues being greater than responses from male tissues. These sex differences were similar to those following nicotine administration in vivo. The ability of this novel, dynamic in vitro system to replicate in vivo HPA axis responses supports its potential as a new method for pharmacological and toxicological studies.
Fan, Ying; Ma, Lian; Pippins, Jennifer; Limb, Susan; Xu, Yun; Sahajwalla, Chandrahas G
In part I of this review, an overview of the designs of hypothalamic-pituitary-adrenal (HPA) axis studies in the setting of inhaled corticosteroids (ICS) or intranasal corticosteroids (INS) use was discussed. Part II provides detailed discussion on the HPA axis evaluation results for each common ICS and INS, and how these results are possibly affected by the factors of study design. Significant adrenal suppression at conventional ICS/INS doses appears to be rare in clinical settings. The magnitude of cortisol suppression varies widely among different study designs. Factors potentially impacting this variability include: the choice of dose, dosing duration, assay sensitivity, statistical methodology, study population, and compliance. All of these factors have the potential to affect the extent of HPA axis effects detected and should be considered when designing or interpreting the results of a HPA axis study. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.
Vinther, Frank; Andersen, Morten; Ottesen, Johnny T.
This paper concerns ODE modeling of the hypothalamic-pituitary-adrenalaxis (HPA axis) using an analytical and numerical approach, combined with biological knowledge regarding physiological mechanisms and parameters. The three hormones, CRH, ACTH, and cortisol, which interact in the HPA axis are m...... thereof. The second part of the paper concerns a specific realization of the minimal model in which feedback functions are built explicitly using receptor dynamics. Using physiologically reasonable parameter values, along with the results of the general case, it is demonstrated that un......-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...
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-axis hyper
Easter, A; Taborelli, E; Bye, A; Zunszain, P A; Pariante, C M; Treasure, J; Schmidt, U; Micali, N
Psychiatric illness is associated with heightened hypothalamic-pituitary-adrenal (HPA) axis activity during pregnancy which may have long term effects on infant stress regulation. HPA axis regulation has not previously been investigated in women with eating disorders (ED) or their infants during the perinatal period. Women were recruited to a prospective longitudinal study in three groups: 1) current or active ED (C-ED=31), 2) past ED (P-ED=29) and healthy control (HC=57). Maternal psychopathology, diurnal cortisol levels, corticotropin-releasing hormone (CRH) and CRH binding protein (CRH-BP) were measured during the third trimester of pregnancy. At eight weeks postpartum infant cortisol was obtained before and after routine immunisations to determine infant hormonal response to a stressful situation. Women with current ED had a significantly lower cortisol decline throughout the day compared to HC, in both adjusted and unadjusted analyses. Lower cortisol decline among women with a current ED were associated with higher levels of psychopathology during pregnancy. Women's cortisol awakening response, CRH and CRH-BP levels did not differ across the three groups. Infants' stress response was also significantly higher among those in the C-ED group, although this effect was attenuated after controlling for confounders. During pregnancy women with ED have lower cortisol declines, suggestive of blunted diurnal cortisol rhythms. Postnatally, their infants also have a heightened response to stress. This is the first study to identify HPA axis dysfunction in pregnancy in women with ED, and to show an intergenerational effect. Since dysfunctions in HPA activity during childhood may represent a risk factor for psychological and physical health problems later in life, further investigation of the potential long-term implications of these findings is crucial. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.
Goncharova, Nadezhda D.; Marenin, Victor Y.; Oganyan, Tamara E.
We have investigated aging of the hypothalamic-pituitary-adrenal (HPA) axis in female rhesus monkeys that differ in adaptive behavior. Plasma cortisol (F) and dehydroepiandrosterone sulfate (DHEA-S) concentrations under basal conditions and under acute psycho-emotional stress were evaluated in blood plasma of young (6-8 years) and old (20-27 years) female rhesus monkeys with various types of adaptive behavior (aggressive, depression-like, and average). We have found that the age-related changes in the HPA axis of monkeys with depression-like behavior were accompanied by the maximal absolute and relative hypercortisolemia under both basal conditions and stress. Moreover, young aggressive monkeys, in comparison with young monkeys of other behavior groups, demonstrated the highest plasma levels of DHEA-S and the lowest molar ratios between F and DHEA-S. Thus, age-related dysfunctions of the HPA axis are associated with adaptive behavior of animals. PMID:21098884
Carr, Warner W; Szefler, Stanley J
Inhaled corticosteroids (ICSs) effectively deliver corticosteroids to target sites in the lungs and reduce systemic effects compared with oral corticosteroids, but long-term systemic exposure from inhaled corticosteroids remains a concern. To discuss ICS systemic effects on the eye and the hypothalamic-pituitary-adrenal (HPA) axis. Relevant publications were used to augment discussion. The most common adverse effects of exogenous corticosteroids on the eye are secondary open-angle glaucoma and posterior subcapsular cataracts. Study findings conflict about whether ICS use is associated with increased risk of glaucoma or elevated intraocular pressure, but studies might not have addressed the question in the right population. Increased risk of glaucoma may be limited to a few susceptible individuals, such as individuals with a family history of glaucoma. Large population-based studies reveal that high daily doses or high lifetime exposure of ICSs is associated with a higher risk of posterior subcapsular cataracts. More research is needed to determine the risk from low to moderate doses during long periods. For the HPA axis, there are several measures for detecting systemic effects. Short-term measures are more sensitive for detecting the systemic effects of ICSs but have less predictive value in identifying clinically important adverse effects. Several studies have found that ICSs have a dose-dependent effects on cortisol suppression that can be used to estimate equivalent dosages among ICSs. Because of systemic effects on the HPA axis, high doses of ICS should be avoided where possible. Adult patients undergoing high-dose or long-term ICS therapy should be monitored for cataracts. Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Couture, Sophie; Brown, Thomas G; Ouimet, Marie Claude; Gianoulakis, Christina; Tremblay, Jacques; Carbonneau, René
Cortisol is a stress hormone mediated by the hypothalamic-pituitary-adrenal (HPA) axis and a psychobiological marker of genetic risk for alcoholism and other high-risk behavioural characteristics. In previous work with driving under the influence of alcohol (DUI) recidivists, we uncovered a significant inverse relationship between the frequency of past DUI convictions and salivary cortisol, whose strength surpassed those observed between DUI frequency and measures of alcohol abuse and other DUI-related characteristics. This finding emerged using a methodology not specifically contrived to test this relationship. The goals of this follow-up study were to (a) examine if a standardized stress-induction protocol would produce a significant inverse relationship between cortisol response and number of DUI offences; and (b) clarify whether HPA axis dysregulation could be linked to particular DUI-related behavioural correlates, such as alcohol use severity, sensation seeking, and antisocial features. Thirty male DUI recidivists were recruited as well as 11 male non-DUI drivers as a comparison group. Results indicated an inverse relationship between DUI frequency and cortisol response (r(39)=-0.36, p=0.021), as well as a lower cortisol response in DUI offenders than the comparison group (F(1,39)=5.71, p=0.022). Finally, for recidivists, hierarchical regression analyses indicated that experience seeking (R(2)=0.23, p=0.008), followed by number of cigarettes smoked daily ((Delta)R(2)=0.12, p=0.031), combined to explain 35% of the variance in cortisol (F(2,29)=7.26, p=0.003). These findings indicate that severe recidivism may have psychobiological underpinnings, and that HPA axis dysregulation appears to be a mechanism common to high-risk behaviours including DUI recidivism, sensation seeking, and cigarette smoking.
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.
Uchoa, Ernane Torres; Aguilera, Greti; Herman, James P.; Fiedler, Jenny L.; Deak, Terrence; Cordeiro de Sousa, Maria Bernardete
Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to rhythmic and episodic release of adrenal glucocorticoids is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, glucocorticoids regulate behavior, metabolic, cardiovascular, immune, and neuroendocrine activities. In contrast to chronic elevated levels, circadian and acute stress-induced increases in glucocorticoids are necessary for hippocampal neuronal survival and memory acquisition and consolidation, through inhibiting apoptosis, facilitating glutamate transmission and inducing immediate early genes and spine formation. In addition to its metabolic actions leading to increasing energy availability, glucocorticoids have profound effects on feeding behavior, mainly through modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that in addition to the recognized immune suppressive actions of glucocorticoids by counteracting adrenergic proinflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative feedback by glucocorticoids involves multiple mechanisms leading to limiting HPA axis activation and preventing deleterious effects of excessive glucocorticoid production. Adequate glucocorticoid secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin releasing hormone (CRH) and vasopressin secretion, the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving non-genomic actions of glucocorticoids, mediate immediate inhibition of hypothalamic CRH and ACTH secretion, while intermediate and delayed mechanisms mediated by genomic actions involve modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily
Volpi, Simona; Rabadan-Diehl, Cristina; Aguilera, Greti
Vasopressin (VP) stimulates pituitary ACTH secretion through interaction with receptors of the V1b subtype (V1bR, V3R), located in the plasma membrane of the pituitary corticotroph, mainly by potentiating the stimulatory effects of corticotropin releasing hormone (CRH). Chronic stress paradigms associated with corticotroph hyperresponsiveness lead to preferential expression of hypothalamic VP over CRH and upregulation of pituitary V1bR, suggesting an important role for VP during adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to stress. Vasopressinergic regulation of ACTH secretion depends on the number of V1bRs as well as coupling of the receptor to phospholipase C (PLC) in the pituitary. Regulation of V1bR gene transcription may involve a number of regulatory elements in the promoter region, of which a GAGA box was shown to be essential. Although V1bR gene transcription is necessary to maintain V1bR mRNA levels, the lack of correlation between VP binding and V1bR mRNA suggests that regulation of mRNA translation is a major regulatory step of the number of V1bRs. V1bR translation appears to be under tonic inhibition by upstream minicistrons and positive regulation through protein kinase C (PKC) activation of an internal ribosome entry site (IRES) in the 5' untranslated region (5'UTR) of the mRNA. The data provide mechanisms by which regulation of hypothalamic VP and pituitary V1bR content contribute to controlling HPA axis activity during chronic stress.
Zhang, Guo-Fu; Ren, Yan-Ping; Sheng, Li-Xia; Chi, Yong; Du, Wan-Jun; Guo, Song; Jiang, Zuo-Ning; Xiao, Le; Luo, Xiao-Nian; Tang, Yi-Lang; Smith, Alicia K; Liu, Zhen-Qi; Zhang, Hong-Xi
The function of the Hypothalamic-Pituitary-Adrenal (HPA) axis during opioid dependence has been inconsistent. We compared HPA axis measures between subjects during methadone stabilization and drug-free detoxification with healthy controls. Sixty heroin dependent patients received either non-opiate treatment (NOT) with benzodiazepines and clonidine (n = 30) or methadone stabilization treatment (MT, n = 30), and their serum levels of corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (COR) were measured and compared to those of healthy, nondependent controls. Compared with healthy controls, CRH was significantly lower (p withdrawal in the NOT group. CRH and COR was lower (p withdrawal may decrease the response of the pituitary to CRH and increase the adrenal response to ACTH.
Hardiman, Rebecca Lyndsey; Bratt, Alison
Fragile X Syndrome (FXS) is characterised by features including anxiety and autistic-like behaviour, which led to early hypotheses that aberrant physiological arousal may underlie the behavioural phenotype. In line with this, several lines of evidence suggest that the hypothalamic-pituitary-adrenal (HPA) axis may be altered in the syndrome. This review collates evidence to determine the nature of HPA axis baseline activity and reactivity (as measured by glucocorticoid levels) differences in FXS, and its relationship to behaviour. Through a search of electronic databases, 15 papers were identified which provided data on humans with FXS or the FMR1 knockout mouse model. The findings across studies are mixed, though trends in the findings can be seen, including elevations in cortisol levels, particularly in males. Preliminary findings also highlight associations between cortisol levels and key behaviours associated with the syndrome, such as gaze avoidance. Areas for future research are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.
Švob Štrac, Dubravka; Muck-Šeler, Dorotea; Pivac, Nela
Aim To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity. Methods Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), ...
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
Diana C. Castañeda Cortés
Full Text Available Besides the well-known function of thyroid hormones (THs for regulating metabolism, it has recently been discovered that THs are also involved in testicular development in mammalian and non-mammalian species. THs, in combination with follicle stimulating hormone (FSH, lead to androgen synthesis in Denio rerio, which results in the onset of spermatogenesis in the testis, potentially relating the hypothalamic-pituitary-thyroid gland (HPT to the hypothalamic-pituitary-gonadal (HPG axes. Furthermore, studies in non-mammalian species have suggested that by stimulating the thyroid-stimulating hormone (TSH, THs can be induced by corticotropin-releasing hormone (CRH. This suggests that the hypothalamic-pituitary-adrenal/interrenal gland (HPA axis might influence the HPT axis. Additionally, it was shown that hormones pertaining to both HPT and HPA could also influence the HPG endocrine axis. For example, high levels of androgens were observed in the testis in Odonthestes bonariensis during a period of stress-induced sex determination, which suggests that stress hormones influence the gonadal fate towards masculinization. Thus, this review highlights the hormonal interactions observed between the HPT, HPA and HPG axes using a comparative approach in order to better understand how these endocrine systems could interact with each other to influence the development of testes.
Green, Matthew R; McCormick, Cheryl M
This review provides an overview of the current understanding of the role of the hypothalamic-pituitary-gonadal (HPG) axis in regulating the hypothalamic-pituitary-adrenal (HPA) axis response to stressors. HPA function is influenced by both organizational (programming) and activational effects of gonadal hormones. Typically, in adult rats, estradiol increases and androgens decrease the HPA response to stressors, thereby contributing to sex differences in HPA function, and sensitivity of the HPA axis to gonadal steroids is in part determined by exposure to these hormones in early development. Although developmental differences in HPA function are well characterized, the extent to which gonadal steroids contribute to age differences in HPA function is not well understood. Deficits in the understanding of the relationships between the HPA and HPG axes are greatest for the adolescent period of development. The critical outstanding questions are, when do gonadal hormones begin to regulate HPA function in adolescence, and what mechanisms precipitate change in sensitivity of the HPA axis to the HPG axis at this stage of life. Copyright © 2016 Elsevier Inc. All rights reserved.
Walker, Sophie E; Papilloud, Aurélie; Huzard, Damien; Sandi, Carmen
Aggressive behavior is not uniform, including proactive and reactive forms of aggression. Aberrant functioning of the hypothalamic-pituitary-adrenal (HPA) axis is frequently associated with abnormal aggression. Here, we review the rodent literature in order to assess whether developmental abnormalities in the HPA axis can be causally linked with the emergence of abnormal aggression. We examine studies that involve genetic models and life challenges (e.g., early life stress, drug exposure) that course with developmental alterations in the HPA axis. Although the lack of systematic studies hinders development of an integrated model, existing evidence supports a U-shaped function regarding differences in HPA axis functioning during development and the emergence of aggressive phenotypes. Thus, developmentally low or high HPA axis reactivity are typically found to be aligned with the emergence of aggressive phenotypes; however, existing information is insufficient to causally link divergent HPA axis aberration with specific types of aggression. Progress in this field is needed to support interventions in children aimed at ameliorating social dysfunctions associated with aberrations in HPA axis function. Copyright © 2016 Elsevier Ltd. All rights reserved.
Background To date, the relationships between childhood neglect, hypothalamic-pituitary-adrenal (HPA) axis functioning and dysfunctional attitude in depressed patients are still obscure. Methods The Childhood Trauma Questionnaire (CTQ) was used to assess childhood emotional neglect and physical neglect. Twenty-eight depressed patients with childhood neglect and 30 depressed patients without childhood neglect from Guangzhou Psychiatric Hospital were compared with 29 age- and gender-matched control subjects without childhood neglect and 22 control subjects with childhood neglect. Cortisol awakening response, the difference between the cortisol concentrations at awakening and 30 minutes later, provided a measure of HPA axis functioning. The Dysfunctional Attitude Scale measured cognitive schema. Results HPA axis functioning was significantly increased in depressed patients with childhood neglect compared with depressed patients without childhood neglect (p HPA axis activity in the control group with childhood neglect was significantly higher than in the depressed group without childhood neglect (p HPA axis functioning and dysfunctional attitude scores, but not with severity of depression. We did not find correlations with HPA axis functioning and dysfunctional attitude or with the Hamilton Rating Scale for Depression scores. Conclusions Childhood neglect may cause hyperactivity of the HPA axis functioning and dysfunctional attitude, but does not affect depression severity. PMID:24548345
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.
Hasiec, M; Herman, A P; Misztal, T
The most well-known physiological action of salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is the stimulation of prolactin secretion, especially during lactation. In addition, our recent work demonstrated that salsolinol inhibits the stress-induced activity of the hypothalamic-pituitary-adrenal (HPA) axis in lactating sheep. Here, we investigated whether salsolinol regulates the basal activity of the HPA axis in lactating sheep and whether its inhibitory action on the stress-induced activity of the HPA axis is present during the postweaning period. The first experiment was performed during the fifth week of lactation, in which unstressed sheep received an intracerebroventricular infusion of an antagonistic analogue of salsolinol, 1-MeDIQ (1-methyl-3,4-dihydroisoquinoline). Simultaneously, the infundibular nucleus and/or median eminence was perfused using the push-pull method. Sheep that received 1-MeDIQ infusion showed significantly higher concentration of plasma ACTH during the second, third, and fourth hour (P HPA axis in lactating sheep. In addition, the HPA axis of postweaning females is more sensitive to stressors associated with the experimental procedures, and salsolinol attenuates ACTH and cortisol release in this phenomenon. Copyright © 2015 Elsevier Inc. All rights reserved.
Nederhof, E.; van Oort, F. V. A.; Bouma, E. M. C.; Laceulle, O. M.; Oldehinkel, A. J.; Ormel, J.
Background. 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
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.
Kenny, Rachel; Dinan, Tara; Cai, Guohui; Spencer, Sarah J
Abstract Chronic calorie restriction (CR) is one of the few interventions to improve longevity and quality of life in a variety of species. It also reduces behavioral indices of anxiety and influences some stress hormones under basal conditions. However, it is not known how CR influences hypothalamic-pituitary-adrenal (HPA) axis function or if those on a CR diet have heightened HPA axis responses to stress. We hypothesized elevated basal glucocorticoid levels induced by CR would lead to exacerbated HPA axis responses to the psychological stress, restraint, in the male rat. We first confirmed rats fed 75% of their normal calorie intake for 3 weeks were less anxious than ad libitum-fed (AD) rats in the elevated plus maze test for anxiety. The anxiolytic effect was mild, with only grooming significantly attenuated in the open field and no measured behavior affected in the light/dark box. Despite elevated basal glucocorticoids, CR rats had very similar hormonal and central responses to 15-min restraint to the AD rats. Both CR and AD rats responded to restraint stress with a robust increase in glucocorticoids that was resolved by 60 min. Both groups also showed robust neuronal activation in the paraventricular nucleus of the hypothalamus and in other stress- and feeding-sensitive brain regions that was not substantially affected by calorie intake. Our findings thus demonstrate chronic mild CR is subtly anxiolytic and is not likely to affect HPA axis responses to psychological stress. These findings support research suggesting a beneficial effect of mild CR.
Full Text Available Our previous studies have demonstrated that the total flavonoids (XBXT-2 isolated from the extract of Xiaobuxin-Tang (XBXT, a traditional Chinese herbal decoction, ameliorated behavioral alterations and hippocampal dysfunctions in chronically stressed rats. Studies over the last decades have suggested that the hyperactivity of hypothalamic-pituitary-adrenal (HPA axis is one of the most consistent findings in stress-related depression. Herein, we used the same chronic mild stress model of rats as before to further investigate the effect of XBXT-2 on the hyperactivity of HPA axis, including the stress hormones levels and glucocorticoid receptors (GRs expression. Our ELISA results showed that chronic administration of XBXT-2 (25, 50 mg kg−1, p.o., 28 days, the effective doses for behavioral responses significantly decreased serum corticosterone level and its upstream stress hormone adrenocorticotropic hormone (ACTH level in chronically stressed rats. Furthermore, western blotting result demonstrated XBXT-2 treatment ameliorated stress-induced decrease of GRs expression in hippocampus, an important target involved in the hyperactivity of HPA axis. These results were similar to that of classic antidepressant imipramine treatment (10 mg kg−1, p.o.. In conclusion, the modulation of HPA axis produced by XBXT-2, including the inhibition of stress hormones levels and up-regulation of hippocampal GRs expression, may be an important mechanism underlying its antidepressant-like effect in chronically stressed rats.
Uzturk, Belkis Gizem; Jin, Shan-xue; Rubin, Beverly; Bartolome, Christopher; Feig, Larry A.
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the induction and prolongation of a variety of psychiatric disorders. As such, much effort has been made to understand the molecular mechanisms involved in its control. However, the vast majority of the studies on the HPA axis have used adult animals, and among these the majority has used males. Here we show that in knockout mice lacking the guanine nucleotide exchange factor, RasGRF1, habituation to 30 minutes a day of restraint stress is markedly accelerated, such that these mice do not display elevated corticosterone levels or enhanced locomotion after 7 days of stress exposure, like WT mice do. Strikingly, this phenotype is present in early-adolescent female RasGRF1 knockout mice, but not in their early-adolescent male, mid-adolescent female, adult female or adult male counterparts. Moreover, not only is there a clear response to restraint stress in early-adolescent female RasGRF1 knockout mice, their response after 1, 3, and 5 exposures is magnified ~3-fold compared to WT mice. These findings imply that distinct mechanisms exist to regulate the HPA axis in early-adolescent females that involves RasGRF1. A full understanding of how RasGRF1 controls the HPA axis response to stress may be required to design effective strategies to combat stress-associated psychiatric disorders initiated in young females. PMID:26246084
Montero-López, Eva; Santos-Ruiz, Ana; González, Raquel; Navarrete-Navarrete, Nuria; Ortego-Centeno, Norberto; Martínez-Augustín, Olga; Rodríguez-Blázquez, Manuel; Peralta-Ramírez, María Isabel
Although many studies have shown that patients with autoimmune disease present a hypoactive hypothalamic-pituitary-adrenal axis (HPA), controversial results have been described. Our objective was to study HPA axis activity in women with autoimmune disease compared to healthy women. Therefore, we analyzed salivary cortisol over the course of a day, and hair cortisol concentrations from the three preceding months, from 65 women divided into two groups: healthy women (n = 30), with a mean age of 44.70 ± 11.65 years; and women with autoimmune disease (n = 35), with a mean age of 48.26 ± 9.04 years. The latter group comprises women with systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and systemic sclerosis (SSc). Perceived stress and psychopathological symptomatology were also evaluated. Autoimmune disease group scored higher on the somatization subscale SCL-90-R and lower on the anxiety subscale than the control group. Regarding HPA axis activation, the area under curve for cortisol levels during the day was higher for the autoimmune disease group. In addition, higher cortisol levels in hair were found in the group with autoimmune disease. Our findings show greater short and long-term HPA axis activity in women with autoimmune disease than in healthy women.
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. PMID:27511270
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.
Hubers, A A M; van der Mast, R C; Pereira, A M; Roos, R A C; Veen, L J; Cobbaert, C M; van Duijn, E; Giltay, E J
Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in Huntington's disease (HD). In non-HD populations, alterations in HPA axis activity have been associated with depression and suicidality. The present study aims to compare HPA axis activity between HD mutation carriers and controls, and examine its association with depressive symptoms and suicidality. To this end, salivary cortisol concentrations at seven time points, as well as depressive symptoms and suicidality, were assessed in 49 pre-motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow-up combined. Differences in parameters of HPA axis activity between these three groups, and their associations with depressive symptoms and suicidality in HD mutation carriers, were analysed using multilevel regression analyses. There were no differences in parameters of HPA axis activity between mutation carriers and controls, whereas pre-motor symptomatic mutation carriers had a significantly higher area under the curve to the increase (AUCi ) compared to motor symptomatic mutation carriers. In the entire HD cohort, HPA axis activity was not associated with depressive symptoms or suicidality. After stratifying mutation carriers into pre-motor, early and advanced disease stages, β values differed between these groups. Remarkably, a higher AUCi was significantly associated with depressive symptoms in pre-motor and early disease stage mutation carriers, with a reverse nonsignificant association in advanced disease stage mutation carriers. The lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre-motor, early and advanced disease stages could possibly be explained by exhaustion of the HPA axis after prolonged stress-induced HPA axis hyperactivity and deserves further longitudinal study. © 2015 British Society for Neuroendocrinology.
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.
Basharat, Saadia; Parker, Jennifer A; Murphy, Kevin G; Bloom, Stephen R; Buckingham, Julia C; John, Christopher D
Obesity is a risk factor for sepsis morbidity and mortality, whereas the hypothalamic-pituitary-adrenal (HPA) axis plays a protective role in the body's defence against sepsis. Sepsis induces a profound systemic immune response and cytokines serve as excellent markers for sepsis as they act as mediators of the immune response. Evidence suggests that the adipokine leptin may play a pathogenic role in sepsis. Mouse endotoxaemic models present with elevated leptin levels and exogenously added leptin increased mortality whereas human septic patients have elevated circulating levels of the soluble leptin receptor (Ob-Re). Evidence suggests that leptin can inhibit the regulation of the HPA axis. Thus, leptin may suppress the HPA axis, impairing its protective role in sepsis. We hypothesised that leptin would attenuate the HPA axis response to sepsis. We investigated the direct effects of an i.p. injection of 2 mg/kg leptin on the HPA axis response to intraperitoneally injected 25 μg/kg lipopolysaccharide (LPS) in the male Wistar rat. We found that LPS potently activated the HPA axis, as shown by significantly increased plasma stress hormones, ACTH and corticosterone, and increased plasma interleukin 1β (IL1β) levels, 2 h after administration. Pre-treatment with leptin, 2 h before LPS administration, did not influence the HPA axis response to LPS. In turn, LPS did not affect plasma leptin levels. Our findings suggest that leptin does not influence HPA function or IL1β secretion in a rat model of LPS-induced sepsis, and thus that leptin is unlikely to be involved in the acute-phase endocrine response to bacterial infection in rats.
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.
Goncharova, Nadezhda D
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 adrenocorticotropic hormone (ACTH) release through specific G-protein-coupled membrane receptors on pituitary corticotrophs, CRHR1 for CRH and V1b for AVP; the adrenal gland cortex secretes glucocorticoids in response to 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.
Ullah, Rahim; Batool, Aalia; Wazir, Madiha; Naz, Rabia; Rahman, Tanzil Ur; Wahab, Fazal; Shahab, Muhammad; Fu, Junfen
Stress activates gonadotropin inhibitory hormone (GnIH), hypothalamic-pituitary-adrenal axis (HPA-axis) and represses hypothalamic-pituitary-gonadal axis (HPG-axis) but RF9 administration relieves stress-induced repression of the HPG-axis. Importantly, it was not known whether GnIH signaling and RF9 synthetic peptide modulate the HPA axis. To assess this, mammalian orthologs of GnIH (RFRP-1 and RFRP-3) and RF9 were administered to intact adult male rhesus monkeys. RFRP-1 (125μg/animal), RFRP-3 (250μg/animal) and RF9 (0.1mg/kg BW) were intravenously (iv) injected into normal fed (n=4) monkeys. Additionally, a single bolus iv injection of RF9 (0.1mg/kg BW) was also administered to 48h fasted monkeys (n=4) to check the effects of RF9 signaling on an activated HPA-axis. Serial blood samples were collected, centrifuged and the obtained plasma was used for the analysis of cortisol by specific enzyme immunoassay. RFRP-1 treatment significantly increased cortisol levels while RFRP-3 increased the plasma cortisol, but the effect was non-significant. RF9 treatment significantly increased cortisol levels in normal fed animals. In contrast, RF9 injection did not significantly alter circulating cortisol in fasted monkeys. In conclusion, our results suggest stimulatory action of RFRPs and RF9 on the HPA axis in the adult male monkeys. However, the mechanism and site of action of RFRP-1 and RF9 along the HPA-axis is still unknown. Therefore, further studies are needed to decipher the mechanism and site of action of RFRPs and RF9 on the HPA axis in primates. Copyright © 2017 Elsevier Ltd. All rights reserved.
Rao, Rohit T; Androulakis, Ioannis P
Significant sex differences exist in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. These differences are thought to contribute to the disparity in the prevalence of various autoimmune and infectious diseases between males and females. We used a mathematical model of the HPA axis to evaluate the hypothesis that differential sensitivity and negative feedback of the HPA axis network are causal factors for the observed sex differences in its activity. In doing so, we implicitly accounted for the differential influence of gonadal hormones on the HPA axis. Furthermore, we determined whether the putative mechanisms responsible for differences in basal HPA axis activity might also contribute to the observed differences in its stimulus-driven response. Model simulations predicted that the female HPA axis has greater adrenal sensitivity and weaker negative feedback. We identified two distinct sex-specific parameter spaces that generate corticosterone profiles in qualitative agreement with experimental results. We propose that these parameter subspaces indicate the interindividual variability in the regulatory mechanisms of the HPA axis. Furthermore, the model predicts that the maintenance of homeostatic rhythms in response to chronic stress requires specific regulatory adaptations resulting in a phenotype of allostatically driven chronic stress-sensitization. We propose that these adaptations indicate a physiological cost of adaptation to chronic stress. Model simulations suggest that individuals with high adrenal sensitivity are more vulnerable to chronic stress sensitization and might be more susceptible to the development of neuropsychiatric disorders. These results contribute to the study of sex differences in physiological feedback systems within a quantitative framework. Copyright © 2017 Endocrine Society.
Kong, Lingwen; Wu, Jingfeng; Lin, Yanhua; Wang, Genfa; Wang, Jia; Liu, Jiaqi; Chen, Meixia; Du, Xin; Sun, Jing; Lin, Jinpei; Dong, Jingcheng
Background Dysfunction of central and skin Hypothalamic-Pituitary-Adrenal (HPA) axis play important roles in pathogenesis of atopic dermatitis (AD). Our previous studies showed that several Chinese herbs could improve HPA axis function. In this study, we evaluated the anti-inflammatory effects of BuShenYiQi granule (BSYQ), a Chinese herbs formula, in AD mice and explored the effective mechanism from regulation of HPA axis. Methods The ovalbumin (OVA) induced AD mice model were established and treated with BSYQ. We evaluated dermatitis score and histology analysis of dorsal skin lesions, meanwhile, serum corticosterone (CORT), adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH) and inflammatory cytokines were determined by ELISA. The changes of CRH/proopiomelanocortin(POMC) axis elements, corresponding functional receptors and crucial genes of glucocorticosteroidogenesis in the skin were measured by quantitative real-time PCR and western blot, respectively. Results The symptoms and pathological changes in skin of AD mice were significantly improved and several markers of inflammation and allergy descended obviously after BSYQ treatment. We found that AD mice had insufficient central HPA tone, but these conditions were markedly improved after BSYQ treatment. The AD mice also showed a disturbed expression of skin HPA. In lesion skin of AD mice, the mRNA and protein expressions of CRH decreased significantly, on the contrary, POMC and cytochrome P450 side-chain cleavage enzyme (CYP11A1) increased markedly, meanwhile, NR3C1 (mouse GR), CRHR2 and 11-hydroxylase type 1(CYP11B1) were reduced locally. Most of these tested indexes were improved after BSYQ treatment. Conclusions AD mice displayed the differential expression pattern of central and skin HPA axis and BSYQ treatment significantly alleviated the symptoms of AD mice and presented anti-inflammatory and anti-allergic effects via regulating the expression of central and skin HPA axis. PMID
Kong, Lingwen; Wu, Jinfeng; Wu, Jingfeng; Lin, Yanhua; Wang, Genfa; Wang, Jia; Liu, Jiaqi; Chen, Meixia; Du, Xin; Sun, Jing; Lin, Jinpei; Dong, Jingcheng
Dysfunction of central and skin Hypothalamic-Pituitary-Adrenal (HPA) axis play important roles in pathogenesis of atopic dermatitis (AD). Our previous studies showed that several Chinese herbs could improve HPA axis function. In this study, we evaluated the anti-inflammatory effects of BuShenYiQi granule (BSYQ), a Chinese herbs formula, in AD mice and explored the effective mechanism from regulation of HPA axis. The ovalbumin (OVA) induced AD mice model were established and treated with BSYQ. We evaluated dermatitis score and histology analysis of dorsal skin lesions, meanwhile, serum corticosterone (CORT), adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH) and inflammatory cytokines were determined by ELISA. The changes of CRH/proopiomelanocortin(POMC) axis elements, corresponding functional receptors and crucial genes of glucocorticosteroidogenesis in the skin were measured by quantitative real-time PCR and western blot, respectively. The symptoms and pathological changes in skin of AD mice were significantly improved and several markers of inflammation and allergy descended obviously after BSYQ treatment. We found that AD mice had insufficient central HPA tone, but these conditions were markedly improved after BSYQ treatment. The AD mice also showed a disturbed expression of skin HPA. In lesion skin of AD mice, the mRNA and protein expressions of CRH decreased significantly, on the contrary, POMC and cytochrome P450 side-chain cleavage enzyme (CYP11A1) increased markedly, meanwhile, NR3C1 (mouse GR), CRHR2 and 11-hydroxylase type 1(CYP11B1) were reduced locally. Most of these tested indexes were improved after BSYQ treatment. AD mice displayed the differential expression pattern of central and skin HPA axis and BSYQ treatment significantly alleviated the symptoms of AD mice and presented anti-inflammatory and anti-allergic effects via regulating the expression of central and skin HPA axis.
Radley, Jason J; Sawchenko, Paul E
Emotional stressors activate a stereotyped set of limbic forebrain cell groups implicated in constraining stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation by inhibiting hypophysiotropic neurons in the paraventricular hypothalamic nucleus (PVH). We previously identified a circumscribed, anterior part of the bed nuclei of the stria terminalis (aBST) that houses stress-sensitive, PVH-projecting, γ-aminobutyric acid (GABA)-ergic neurons as representing a site of convergence of stress-inhibitory influences originating from medial prefrontal and hippocampal cortices. Here we investigate whether exaggerated HPA axis responses associated with chronic variable stress (CVS; daily exposure to different stressors at unpredictable times over 14 days, followed by restraint stress on day 15) and diminished HPA output seen following repeated (14 days) restraint-stress exposure are associated with differential engagement of the limbic modulatory network. Relative to acutely restrained rats, animals subjected to CVS showed the expected increase (sensitization) in HPA responses and diminished levels of activation (Fos) of GABAergic neurons and glutamic acid decarboxylase (GAD) mRNA expression in the aBST. By contrast, repeated restraint stress produced habituation in HPA responses, maintained levels of activation of GABAergic neurons, and increased GAD expression in the aBST. aBST-projecting neurons in limbic sites implicated in HPA axis inhibition tended to show diminished activational responses in both repeated-stress paradigms, with the exception of the paraventricular thalamic nucleus, in which responsiveness was maintained in repeatedly restrained animals. The results are consistent with the view that differential engagement of HPA inhibitory mechanisms in the aBST may contribute to alterations in HPA axis responses to emotional stress in sensitization and habituation paradigms. © 2015 Wiley Periodicals, Inc.
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.
Ozsoy, Saliha; Esel, Ertugrul
The study aims at investigating the relationship between hypothalamic-pituitary-adrenal (HPA) axis alterations and aggression level in alcoholic patients during early and late alcohol withdrawal. Serum levels of basal cortisol and dehydroepiandrosterone sulphate (DHEAS) were measured three times, and cortisol and DHEAS response to dexamethasone twice during the early and late withdrawal periods in alcohol dependent males (n=30) and once in healthy control males (n=20). Abnormal cortisol non-suppression response to dexamethasone in dexamethasone suppression test (DST) was observed in some proportion of the patients in early withdrawal, which normalized in late withdrawal. The study revealed reduced basal DHEAS levels and reduced DHEAS response to dexamethasone in late withdrawal. When the patients were assessed in two separate groups as high- and low-aggressives, in the high-aggression group abnormality in DST was observed during both early and late withdrawal periods, in the low-aggression group it was observed only in early withdrawal. While basal DHEAS levels were low in the high-aggression group only in early withdrawal, it was reduced in the low-aggression group during late withdrawal period. Some alterations of the HPA axis during alcohol withdrawal might be associated not only with alcohol use per se but also with aggressivity tendency of alcoholic patients.
McGirr, Alexander; Diaconu, Gabriel; Berlim, Marcelo T; Pruessner, Jens C; Sablé, Rebecca; Cabot, Sophie; Turecki, Gustavo
Suicidal behaviour aggregates in families, and the hypothalamic-pituitary-adrenal (HPA) axis and noradrenergic dysregulation may play a role in suicide risk. It is unclear whether stress dysregulation is a heritable trait of suicide or how it might increase risk. We investigated stress reactivity of the autonomic nervous system and the HPA axis in suicide predisposition and characterized the effect of this dysregulation on neuropsychologic function. In this family-based study of first-degree relatives (n = 14) of suicide completers and matched controls with no family or personal history of suicidal behaviour (n = 14), participants underwent the Trier Social Stress Test (TSST). We used salivary α-amylase and cortisol levels to characterize stress reactivity and diurnal variation. We administered a series of neuropsychologic and executive function tests before and after the TSST. Despite normal diurnal variation, relatives of suicide completers exhibited blunted cortisol and α-amylase TSST reactivity. Although there were no baseline differences in conceptual reasoning, sustained attention or executive function, the relatives of suicide completers did not improve on measures of inhibition upon repeated testing after TSST. Secondary analyses suggested that these effects were related to suicide vulnerability independent of major depression. The sample size was small, and the design prevents us from disentangling our findings from the possible traumatic consequences of losing a relative by suicide. Blunted stress response may be a trait of suicide risk, and impairment of stress-induced executive function may contribute to suicide vulnerability.
De Bucy, Charlotte; Guignat, Laurence; Niati, Tanya; Bertherat, Jérôme; Coste, Joel
Health-related quality of life (HrQoL) is increasingly considered to be an important outcome of care for hypothalamic-pituitary-adrenal (HPA) axis dysregulation. The objective of this study was to assess the influence of type of HPA axis dysregulation and cortisol status on HrQOL and its evolution with time and treatment. Prospective cohort study. Between September 2007 and April 2014, HrQoL questionnaires were administered during routine management to all patients with HPA axis dysregulation hospitalized in a single department, and this was repeated after 6- 12-, 24- and 36-month during standard follow-up. The Medical Outcomes Study 36-item short-form health survey (SF-36) and the General Health Questionnaire 12 (GHQ-12) were used simultaneously, with a common time schedule to measure the impact of HPA axis dysregulation on HrQoL. Multivariate mixed linear regression models were constructed to adjust for potential confounders. 343 patients (206 with Cushing's syndrome of pituitary origin, 91 with Cushing's syndrome of adrenal origin and 46 with Addison's disease) responded to the questionnaires. Overall, HrQoL scores were well below population values. Cushing syndrome of pituitary origin was associated with worse HrQoL, especially in physical dimensions. More than half of the patients, of all diagnoses and cortisol status, had psychological distress requiring attention according to the GHQ-12. Hypercortisolism had the greatest negative influence on HrQoL. HRQoL appears significantly altered by all forms of HPA axis dysregulation, and most substantially and broadly by Cushing's syndrome, notably during periods of hypercortisolism. These effects on HRQoL deserve further consideration both in clinical practice and research. © 2017 European Society of Endocrinology.
Full Text Available Objective To evaluate the association between objective short sleep duration in patients with insomnia and changes in blood parameters related to hypothalamic-pituitary-adrenal (HPA axis activity.Method A cross-sectional pilot study was conducted in 30 middle-aged adults with chronic insomnia who were divided into 2 groups according to polysomnography (PSG total sleep time (TST (TST > 5h and < 5h. All patients underwent subjective analysis of sleep quality, anthropometric measurements, PSG, and determination off asting blood parameters.Results The results revealed lower sleep efficiency and higher sleep latency for those with a TST < 5h. The subjective sleep quality was worse in the TST < 5h. Significantly, higher glucose and cortisol levels were observed with a TST < 5h. Glucose, cortisol and ACTH levels were inversely correlated with the PSG total sleep time.Conclusion Patients with insomnia with objective short sleep duration had HPA-associated endocrine and metabolic imbalances chronically linked to increases in cardiovascular risk observed with this more severe insomnia phenotype.
Pajer, Kathleen A
Negative emotions such as depression and hostility/anger are important risk factors for cardiovascular disease in adults, but are often neglected in treatment or prevention programs. Adolescence is a stage of life when negative emotions often first become problematic and is also a time when the pathogenesis of cardiovascular disease appears to accelerate. The literature on negative emotions and cardiovascular disease risk factors in adolescents is reviewed here. Research indicates that negative emotions are associated with cardiovascular disease risk factors in adolescence. Negative emotions are also associated with several types of hypothalamic-pituitary-adrenal axis dysregulation. Such dysregulation appears to have a facilitatory effect on cardiovascular disease development and progression in adults. Thus, it is possible that negative emotions in adolescents may be risk factors for the development of cardiovascular disease via dysregulation of the hypothalamic-pituitary-adrenal axis. Although this hypothesis has not been directly tested, some studies indirectly support the hypothesis. Negative emotions are associated with cardiovascular disease risk factors in adolescents; it is possible that hypothalamic-pituitary-adrenal axis dysregulation is an important mechanism. This hypothesis merits further research. If the hypothesis is valid, it has significant implications for early prevention of cardiovascular disease.
Wieczorek, Lindsay; Fish, Eric W; O'Leary-Moore, Shonagh K; Parnell, Scott E; Sulik, Kathleen K
The range of defects that fall within fetal alcohol spectrum disorder (FASD) includes persistent behavioral problems, with anxiety and depression being two of the more commonly reported issues. Previous studies of rodent FASD models suggest that interference with hypothalamic-pituitary-adrenal (HPA) axis structure and/or function may be the basis for some of the prenatal alcohol (ethanol) exposure (PAE)-induced behavioral abnormalities. Included among the previous investigations are those illustrating that maternal alcohol treatment limited to very early stages of pregnancy (i.e., gestational day [GD]7 in mice; equivalent to the third week post-fertilization in humans) can cause structural abnormalities in areas such as the hypothalamus, pituitary gland, and other forebrain regions integral to controlling stress and behavioral responses. The current investigation was designed to further examine the sequelae of prenatal alcohol insult at this early time period, with particular attention to HPA axis-associated functional changes in adult mice. The results of this study reveal that GD7 PAE in mice causes HPA axis dysfunction, with males and females showing elevated corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, respectively, following a 15-min restraint stress exposure. Males also showed elevated CORT levels following an acute alcohol injection of 2.0 g/kg, while females displayed blunted ACTH levels. Furthermore, analysis showed that anxiety-like behavior was decreased after GD7 PAE in female mice, but was increased in male mice. Collectively, the results of this study show that early gestational alcohol exposure in mice alters long-term HPA axis activity and behavior in a sexually dimorphic manner. Copyright © 2015 Elsevier Inc. All rights reserved.
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.
Full Text Available Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR and cholesterol side-chain cleavage enzyme (P450scc, as well as the level of fetal adrenal endogenous corticosterone (CORT, were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2. Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR, and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be
Le, Jing-jing; Yi, Tao; Qi, Li; Li, Ji; Shao, Lei; Dong, Jing-cheng
Hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathogenesis of depression. Dysfunction of the hippocampal serotonin (5-hydroxytryptamine, 5-HT) system has been shown to be a key factor in depression. There is growing evidence that electro-acupuncture (EA) has antidepressant-like effect. However, the effect of EA on HPA axis and hippocampal serotonin system remains unknown. In our study, we investigated the antidepressant-like effect and mechanism of EA for depression rat models. Depression in rats was induced by chronic unpredictable mild stress (CUMS). EA treatment was administered once daily to CUMS rats for 14 days. The acupoints (ST36, bilateral and CV4) were selected. Untreated CUMS rats and normal rats were used as controls. Behavioral tests including forced swim test and open-field test were performed to evaluate the antidepressant effects of EA treatment. Hypothalamic corticotropin-releasing hormone (CRH) mRNA, plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were estimated as indices of HPA axis activity. Enzyme linked immunosorbent assay (ELISA) was performed to determine the concentrations of 5-HT in the hippocampus. Real-time PCR(RT-PCR)and Western blot were respectively used to detect the mRNA and protein levels of 5-hydroxytryptamine 1A receptor (5-HT1AR) in the hippocampus. Our results showed that EA treatment reversed the behavioral deficiency induced by CUMS in rats. EA treatment decreased CRH mRNA expression in the hypothalamic, and ACTH and CORT level in plasma, and markedly increased 5-HT concentration, 5-HT1AR (mRNA and protein) expression in the hippocampus. These results indicated that EA treatment could act on depression by modulating HPA axis and enhancing hippocampal 5-HT/5-HT1AR in CUMS Rats. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Cavkaytar, Ozlem; Vuralli, Dogus; Arik Yilmaz, Ebru; Buyuktiryaki, Betul; Soyer, Ozge; Sahiner, Umit M; Kandemir, Nurgun; Sekerel, Bulent E
The possible risk of adverse effects due to regular use of inhaled corticosteroids (ICS) is a real concern. Our aim was to describe the factors that have an impact on hypothalamic-pituitary-adrenal axis suppression (HPA-AS) in children and adolescents taking ICS regularly. The HPA axis status of patients who were on moderate-to-high-dose ICS [>176 and >264 μg/day fluticasone propionate-hydrofluoroalkane (FP-HFA) for patients 0-11 and ≥12 years, respectively] was investigated. Various types of ICS were converted to FP-HFA equivalent according to National Asthma Education and Prevention Program (NAEPP) guidelines. Participants with a baseline (8 a.m.) serum cortisol HPA-AS. Among 91 patients, 60 (75.9 %) participants underwent LDAT, and seven (7.7, 95 % CI 3.5-15.3 %) were diagnosed with HPA-AS. Ciclesonide was more frequently used by the participants with HPA-AS compared to patients with a normal HPA axis (42.9 vs. 4.8 %, p = 0.009). Use of ICS at moderate-to-high doses for at least 7 months distinguished participants with HPA-AS from those with a normal HPA axis. Among the duration, type, and dose of ICS, solely the use of ICS with a body mass index (BMI)-adjusted daily dose of ≥22 μg FP was found to increase the risk for HPA-AS (odds ratio (OR) 7.22, 95 % confidence interval (CI) 1.23-42.26, p = 0.028). The receiver operating characteristics (ROC) curve analysis revealed a cutoff value of 291 μg/day FP (area under the curve (AUC) = 0.840, p = 0.003) for predicting HPA-AS Conclusion: The prevalence of HPA-AS was found to be 7.7 % in children taking not only high-dose ICS but also moderate-dose ICS. Dose alone was found to be an actual risk factor for HPA-AS.
Tsartsali, Lemonia; Papadopoulos, Marios; Lagona, Evagelia; Papadimitriou, Anastasios; Kanaka-Gantenbein, Christina; Louizou, Eirini; Kastania, Anastasia; Priftis, Kostas N; Chrousos, George
Long-term treatment of asthmatic children with low and moderate doses of inhaled corticosteroids (ICS) may result in mild adrenal suppression. Various associations have been shown between adrenal reactivity and single nucleotide polymorphisms (SNPs) related to the hypothalamic-pituitary-adrenal (HPA) axis. We aimed to investigate the genetic contribution of four HPA axis-related SNPs to the individual stress response when on ICS. The low dose Synacthen test was performed in 62 asthmatic children (43 males, median age 7.9 years) before and after 3 months of treatment with inhaled fluticasone (200 μg/day) or budesonide (400 μg/day). The SNPs determined were: rs1876828 and rs242941 in the corticotropin-releasing hormone receptor 1 (CRHR1) gene, T(-2C) in the promoter region of the melanocortin receptor 2 (MC2R) gene and BclI restriction fragment length polymorphsism in the glucocorticoid receptor (GR) gene. Homozygotes for the variant rs242941 (TT) demonstrated a delayed cortisol response after treatment with ICS compared to heterozygotes (GT) (p = 0.033) and those with the wild-type (GG) genotype (p = 0.018). Homozygotes for the variant rs1876828 (AA) manifested lower baseline cortisol levels before treatment (p = 0.009) compared to the GG genotype and delayed cortisol response after treatment compared to the GA genotype (p = 0.05). BclI heterozygotes for the G allele (GC) demonstrated higher basal cortisol levels before and after treatment with ICS compared to homozygotes (CC) (p = 0.024, p = 0.018). Three SNP interactions were associated with serum cortisol levels. There is evidence of a contribution of HPA axis-related genetic variation to the stress response of asthmatic children on ICS. The clinical importance of this finding needs further elucidation. Copyright © 2012 S. Karger AG, Basel.
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.
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
Stamper, Christopher E; Hennessey, Patrick A; Hale, Matthew W; Lukkes, Jodi L; Donner, Nina C; Lowe, Kenneth R; Paul, Evan D; Spencer, Robert L; Renner, Kenneth J; Orchinik, Miles; Lowry, Christopher A
Previous studies suggest that multiple corticolimbic and hypothalamic structures are involved in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, including the dorsomedial hypothalamus (DMH), but a potential role of the DMH has not been directly tested. To investigate the role of the DMH in glucocorticoid-mediated negative feedback, adult male Sprague Dawley rats were implanted with jugular cannulae and bilateral guide cannulae directed at the DMH, and finally were either adrenalectomized (ADX) or were subjected to sham-ADX. ADX rats received corticosterone (CORT) replacement in the drinking water (25 μg/mL), which, based on initial studies, restored a rhythm of plasma CORT concentrations in ADX rats that was similar in period and amplitude to the diurnal rhythm of plasma CORT concentrations in sham-ADX rats, but with a significant phase delay. Following recovery from surgery, rats received microinjections of either CORT (10 ng, 0.5 μL, 0.25 μL/min, per side) or vehicle (aCSF containing 0.2% EtOH), bilaterally, directly into the DMH, prior to a 40-min period of restraint stress. In sham-ADX rats, bilateral intra-DMH microinjections of CORT, relative to bilateral intra-DMH microinjections of vehicle, decreased restraint stress-induced elevation of endogenous plasma CORT concentrations 60 min after the onset of intra-DMH injections. Intra-DMH CORT decreased the overall area under the curve for plasma CORT concentrations during the intermediate time frame of glucocorticoid negative feedback, from 0.5 to 2 h following injection. These data are consistent with the hypothesis that the DMH is involved in feedback inhibition of HPA axis activity at the intermediate time frame.
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.
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.
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
Kim, Young-Sang; Yoo, Sang Bae; Ryu, Vitaly; Kim, Kyu-Nam; Kim, Bom-Taeck; Lee, Jong-Ho; Jahng, Jeong Won
Activation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in conditioned taste aversion (CTA) learning induced by lithium chloride. This study investigated if circadian activation of the HPA axis affects the lithium-induced CTA formation. The pairing of conditioned stimulus (sucrose) and unconditioned stimulus (lithium chloride) was performed at night (shortly after light-off) when the HPA activity shows its circadian increase. Intraperitoenal injection of lithium chloride (0.15M, 3ml/kg or 12ml/kg) at night induced CTA formation and the HPA axis activation and increased c-Fos expression in both the parabrachial nucleus (PBN) and the nucleus tractus of solitarius (NTS) in a dose dependent manner. However, intracerebroventricular lithium (0.6M, 5µl) at night failed to induce CTA or the HPA axis activation, although it increased c-Fos expression in the PBN and NTS. Results suggest that circadian activation of the HPA axis may affect central, but not peripheral, effect of lithium in CTA formation, and the lithium-induced c-Fos expression in brain regions may not be effective to induce CTA unless it is coupled with the HPA axis activation. It is concluded that the HPA axis activation may play an important role mediating not only peripheral but also central effect of lithium in CTA formation. Copyright © 2015 Elsevier B.V. All rights reserved.
Gangisetty, Omkaram; Bekdash, Rola; Maglakelidze, George; Sarkar, Dipak K
Proopiomelanocortin (POMC) is a precursor gene of the neuropeptide β-endorphin in the hypothalamus and is known to regulate various physiological functions including stress response. Several recent reports showed that fetal alcohol exposure programs the hypothalamus to produce lower levels of POMC gene transcripts and to elevate the hypothalamic-pituitary-adrenal (HPA) axis response to stressful stimuli. We investigated the role of methyl CpG binding protein (MeCP2) in the effects of prenatal ethanol on POMC gene expression and hypothalamic-pituitary-adrenal (HPA) axis function. Pregnant Sprague Dawley rats were fed between GD 7 and 21 with a liquid diet containing 6.7% alcohol, pair-fed with isocaloric liquid diet, or fed ad libitum with rat chow, and their male offsprings were used at 60 days after birth in this study. Fetal alcohol exposure reduced the level of POMC mRNA, but increased the level of DNA methylation of this gene in the arcuate nucleus (ARC) of the hypothalamus where the POMC neuronal cell bodies are located. Fetal alcohol exposed rats showed a significant increase in MeCP2 protein levels in POMC cells, MeCP2 gene transcript levels as well as increased MeCP2 protein binding on the POMC promoter in the arcuate nucleus. Lentiviral delivery of MeCP2 shRNA into the third ventricle efficiently reduced MeCP2 expression and prevented the effect of prenatal ethanol on POMC gene expression in the arcuate nucleus. MeCP2-shRNA treatment also normalized the prenatal ethanol-induced increase in corticotropin releasing hormone (CRH) gene expression in the hypothalamus and elevated plasma adrenocorticotrophic hormone (ACTH) and corticosterone hormone responses to lipopolysaccharide (LPS) challenge. These results suggest that fetal alcohol programming of POMC gene may involve recruitment of MeCP2 on to the methylated promoter of the POMC gene to suppress POMC transcript levels and contribute to HPA axis dysregulation.
Guyon, A; Balbo, M; Morselli, L L; Tasali, E; Leproult, R; L'Hermite-Balériaux, M; Van Cauter, E; Spiegel, K
Insufficient sleep is associated with increased cardiometabolic risk. Alterations in hypothalamic-pituitary-adrenal axis may underlie this link. Our objective was to examine the impact of restricted sleep on daytime profiles of ACTH and cortisol concentrations. Thirteen subjects participated in 2 laboratory sessions (2 nights of 10 hours in bed versus 2 nights of 4 hours in bed) in a randomized crossover design. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 9:00 am to midnight to measure ACTH and total cortisol. Saliva was collected every 20 minutes from 2:00 pm to midnight to measure free cortisol. Perceived stress, hunger, and appetite were assessed at hourly intervals by validated scales. Sleep restriction was associated with a 19% increase in overall ACTH levels (P sleep loss (rSp = 0.63, P sleep restriction (P sleep restriction (-21%; P Sleep restriction was not associated with higher perceived stress but resulted in an increase in appetite that was correlated with the increase in total cortisol. The impact of sleep loss on hypothalamic-pituitary-adrenal activity is dependent on time of day. Insufficient sleep dampens the circadian rhythm of cortisol, a major internal synchronizer of central and peripheral clocks.
Stamper, Christopher E; Hassell, James E; Kapitz, Adam J; Renner, Kenneth J; Orchinik, Miles; Lowry, Christopher A
Acute activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of corticosteroid hormones into the circulation, is an adaptive response to perceived threats. Persistent activation of the HPA axis can lead to impaired physiological or behavioral function with maladaptive consequences. Thus, efficient control and termination of stress responses is essential for well-being. However, inhibitory control mechanisms governing the HPA axis are poorly understood. Previous studies suggest that serotonergic systems, acting within the medial hypothalamus, play an important role in inhibitory control of stress-induced HPA axis activity. To test this hypothesis, we surgically implanted chronic jugular cannulae in adult male rats and conducted bilateral microinjection of vehicle or the 5-HT 1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT; 8 nmol, 0.2 μL, 0.1 μL/min, per side) into the dorsomedial hypothalamus (DMH) immediately prior to a 40 min period of restraint stress. Repeated blood sampling was conducted using an automated blood sampling system and plasma corticosterone concentrations were determined using enzyme-linked immunosorbent assay. Bilateral intra-DMH microinjections of 8-OH-DPAT suppressed stress-induced increases in plasma corticosterone within 10 min of the onset of handling prior to restraint and, as measured by area-under-the-curve analysis of plasma corticosterone concentrations, during the 40 min period of restraint. These data support an inhibitory role for serotonergic systems, acting within the DMH, on stress-induced activation of the HPA axis. Lay summary: Inhibitory control of the hypothalamic-pituitary-adrenal (HPA) stress hormone response is important for well-being. One neurochemical implicated in inhibitory control of the HPA axis is serotonin. In this study we show that activation of serotonin receptors, specifically inhibitory 5-HT 1A receptors in the dorsomedial
Švob Štrac, Dubravka; Muck-Šeler, Dorotea; Pivac, Nela
To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity. Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α(2)-adrenoreceptor agonist), yohimbine (α(2)-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine. Diazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity. The results suggest that α(2)-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity.
Švob Štrac, Dubravka; Muck-Šeler, Dorotea; Pivac, Nela
Aim To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity. Methods Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine. Results Diazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity. Conclusion The results suggest that α2-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity. PMID:22661134
Sorgdrager, F J H; Doornbos, B; Penninx, B W J H; de Jonge, P; Kema, I P
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 the HPA axis. We investigated tryptophan metabolism and its association with HPA axis functioning in single episode MDD, recurrent MDD and non-depressed individuals. We included depressed individuals (n = 1320) and controls (n = 406) from the Netherlands Study of Depression and Anxiety (NESDA). The kynurenine to tryptophan ratio (kyn/trp ratio) was established using serum kynurenine and tryptophan levels. Several HPA axis parameters were calculated using salivary cortisol samples. We adjusted the regression analyses for a wide range of potential confounders and differentiated between single episode MDD, recurrent MDD and control. Tryptophan, kynurenine and the kyn/trp ratio did not differ between controls and depressed individuals. Increased evening cortisol levels were associated with a decreased kyn/trp ratio in the total sample (Crude: β = -.102, p depressed individuals (Crude: β = -.196, p depression. Copyright © 2017 Elsevier B.V. All rights reserved.
Carvalho, Carolina M; Coimbra, Bruno M; Ota, Vanessa K; Mello, Marcelo F; Belangero, Sintia I
Posttraumatic stress disorder (PTSD) is a common psychiatric disorder. The etiology of PTSD is multifactorial, depending on many environmental and genetic risk factors, and the exposure to life or physical integrity-threatening events. Several studies have shown significant correlations of many neurobiological findings with PTSD. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is strongly correlated with this disorder. One hypothesis is that HPA axis dysfunction may precede the traumatic event, suggesting that genes expressed in the HPA axis may be involved in the development of PTSD. This article reviews molecular genetic studies related to PTSD collected through a literature search performed in PubMed, MEDLINE, ScienceDirect, and Scientific Electronic Library Online (SciELO). The results of these studies suggest that several polymorphisms in the HPA axis genes, including FKBP5, NR3C1, CRHR1, and CRHR2, may be risk factors for PTSD development or may be associated with the severity of PTSD symptoms. © 2017 Wiley Periodicals, Inc.
Cai, Guohui; Ziko, Ilvana; Barwood, Joanne; Soch, Alita; Sominsky, Luba; Molero, Juan C.; Spencer, Sarah J.
Early life diet can critically program hypothalamic-pituitary-adrenal (HPA) axis function. We have previously shown rats that are overfed as neonates have exacerbated pro-inflammatory responses to immune challenge with lipopolysaccharide (LPS), in part by altering HPA axis responses, but how this occurs is unknown. Here we examined neonatal overfeeding-induced changes in gene expression in each step of the HPA axis. We saw no differences in glucocorticoid or mineralocorticoid receptor expression in key regions responsible for glucocorticoid negative feedback to the brain and no differences in expression of key HPA axis regulatory genes in the paraventricular nucleus of the hypothalamus or pituitary. On the other hand, expression of the adrenal melanocortin 2 receptor (MC2R) is elevated after LPS in control rats, but significantly less so in the neonatally overfed. The in vitro adrenal response to ACTH is also dampened in these rats, while the in vivo response to ACTH does not resolve as efficiently as it does in controls. These data suggest neonatal diet affects the efficiency of the adrenally-mediated response to LPS, potentially influencing how neonatally overfed rats combat bacterial infection. PMID:26868281
Wei, Ying; Dong, Ming; Zhong, Ling; Liu, Jiaqi; Luo, Qingli; Lv, Yubao; Mo, Shuming; Sun, Jing; Liu, Feng; Xu, Fei; Yan, Chen; Dong, Jingcheng
Asthma is a complex inflammatory disease of the airways and acupuncture is one of the effective therapies widely used to treat asthma in China. The aim of the study was to evaluate the regulatory role of acupuncture in airway inflammation and the hypothalamic-pituitary-adrenal (HPA) axis activity in OVA-induced murine asthma model. Our results demonstrated that acupuncture was effective in suppression of AHR, inhibition of total leukocyte, neutrophil, lymphocyte and eosinophil counts in BALF, attenuation of airway inflammation and TNF-α, IL-1β, IL-5 and eotaxin secretion. Furthermore, the HPA axis activity was also regulated by acupuncture, which included promotion of adrenocorticotropic hormone and cortisol secretion in the plasma. Our findings revealed that acupuncture could attenuate airway inflammation and regulate HPA axis and immunologic function in the OVA-induced murine asthma model, which may provide support to better understand the contribution of acupuncture to the regulation of airway inflammation and HPA axis activity in asthma. Copyright Â© 2016 Elsevier Ireland Ltd. All rights reserved.
Besnier, Emmanuel; Clavier, Thomas; Tonon, Marie-Christine; Selim, Jean; Lefevre-Scelles, Antoine; Morin, Fabrice; Tamion, Fabienne; Dureuil, Bertrand; Castel, Hélène; Compere, Vincent
We compared the effects of etomidate and ketamine on the hypothalamic-pituitary-adrenal axis during sepsis. Mice (n = 5/group) were injected intraperitoneally with lipopolysaccharide (10 mg/kg) and 6 h later randomized to receive ketamine (100 mg/kg), etomidate (30 mg/kg), or saline. At two time points (12 and 48 h), messenger RNA levels of hypothalamic corticotropin-releasing hormone, pituitary proopiomelanocortin, and four adrenal enzymes (P450 side-chain cleavage, 3β-hydroxysteroid deshydrogenase, 21-hydroxylase, and 11β-hydroxylase) were measured by in situ hybridization (results are presented as optical density), and plasma levels of corticosterone and adrenocorticotropin hormones were measured by enzyme-linked immunosorbent assay (mean ± SD). At 12 h, lipopolysaccharide induced an overexpression of corticotropin-releasing hormone (32 ± 5 vs. 18 ± 6, P ketamine reduced P450 side-chain cleavage (19 ± 7 and 19 ± 3 vs. 32 ± 4, P Ketamine also inhibited adrenocorticotropin hormone production (2.5 ± 3.6 vs. 36 ± 15 pg/ml, P Ketamine and etomidate did not modify corticosterone plasma levels. Our endotoxemic model induces an initial activation of the hypothalamic-pituitary-adrenal axis, followed by a secondary inhibition of adrenal steroidogenesis processes. Ketamine and etomidate inhibit the enzyme expression and activity of the adrenal gland at the early stage.
Hamilton, Bradford S; Schoelch, Corinna; Schuler-Metz, Annette; Krosky, Paula; Lala, Deepak S; Claremon, David A; McGeehan, Gerard M
Inhibition of local cortisol regeneration from circulating cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. Chronic modulation of glucocorticoid homeostasis may result in hypothalamic-pituitary-adrenal (HPA) axis stimulation. HPA axis over-activation leading androgen excess would be undesirable in a therapeutic intervention designed to treat a chronic condition such as the metabolic syndrome. To address whether 11β-HSD1 inhibition would lead to excess androgens, we treated female cynomolgus monkeys with a selective inhibitor, BI 135558, for 4 weeks. Continual action of the compound over the dosing period was confirmed by constant plasma exposure, and a maintained change in urinary glucocorticoid metabolites consistent with 11β-HSD1 inhibition. No significant changes in adrenal function, as evidenced by an adrenocorticotropic hormone (ATCH) challenge, were observed. An examination of androgenic hormones revealed a slight increase in dehydroepiandrosterone sulfate (DHEA-S), while other hormones such as testosterone remained within reference values. Overall, treatment with BI 135558 in monkeys did not result in obvious over-activation of the HPA axis. Copyright © 2016 Elsevier B.V. All rights reserved.
Carpenter, T; Grecian, S M; Reynolds, R M
Fetal glucocorticoid overexposure is a key mechanism linking early development with later-life disease. In humans, low birth weight associates with increased fasting cortisol, hypothalamic-pituitary-adrenal (HPA) axis reactivity, and with cardiovascular risk and cognitive decline. As there are sex differences in these adult diseases, we hypothesized that there may be sex differences in programming of the HPA axis in response to prenatal stressors. We conducted a systematic review following Meta-Analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We searched Embase, MEDLINE and Web of Science from inception to 31 October 2016. We included studies related to sex differences, prenatal exposures and HPA axis. We excluded studies investigating specific disease states. The 23 included studies investigated the consequences of low birth weight, preterm birth and maternal stressors of asthma, psychosocial stress and glucocorticoid medications on HPA axis outcomes of placental glucocorticoid biology and offspring HPA axis function in early life and later life. Female offspring exposed to stressors had increased HPA axis reactivity compared with males. Furthermore, the female placenta increased its permeability to maternal glucocorticoids following maternal stress with changes in the expression of 11β-hydroxysteroid dehydrogenase enzymes in response to maternal glucocorticoid exposure or asthma. Among males there was some evidence of altered diurnal cortisol secretion. We conclude that although there is some evidence of male vulnerability leading to altered diurnal cortisol secretion, the female HPA axis is more vulnerable to programming, particularly in terms of its reactivity; this suggests a mechanism underlying sex differences in later-life diseases.
The Nutrient and Energy Sensor Sirt1 Regulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis by Altering the Production of the Prohormone Convertase 2 (PC2) Essential in the Maturation of Corticotropin-releasing Hormone (CRH) from Its Prohormone in Male Rats.
Toorie, Anika M; Cyr, Nicole E; Steger, Jennifer S; Beckman, Ross; Farah, George; Nillni, Eduardo A
Understanding the role of hypothalamic neuropeptides and hormones in energy balance is paramount in the search for approaches to mitigate the obese state. Increased hypothalamic-pituitary-adrenal axis activity leads to increased levels of glucocorticoids (GC) that are known to regulate body weight. The axis initiates the production and release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. Levels of active CRH peptide are dependent on the processing of its precursor pro-CRH by the action of two members of the family of prohormone convertases 1 and 2 (PC1 and PC2). Here, we propose that the nutrient sensor sirtuin 1 (Sirt1) regulates the production of CRH post-translationally by affecting PC2. Data suggest that Sirt1 may alter the preproPC2 gene directly or via deacetylation of the transcription factor Forkhead box protein O1 (FoxO1). Data also suggest that Sirt1 may alter PC2 via a post-translational mechanism. Our results show that Sirt1 levels in the PVN increase in rats fed a high fat diet for 12 weeks. Furthermore, elevated Sirt1 increased PC2 levels, which in turn increased the production of active CRH and GC. Collectively, this study provides the first evidence supporting the hypothesis that PVN Sirt1 activates the hypothalamic-pituitary-adrenal axis and basal GC levels by enhancing the production of CRH through an increase in the biosynthesis of PC2, which is essential in the maturation of CRH from its prohormone, pro-CRH. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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
Full Text Available Permanent brain injury is a complication of recurrent hypoglycemia during development. Recurrent hypoglycemia also has adverse consequences on the neuroendocrine system. Hypoglycemia-associated autonomic failure, characterized by ineffective glucose counterregulation during hypoglycemia, is well described in children and adults on insulin therapy for diabetes mellitus. Whether recurrent hypoglycemia also has a programming effect on the hypothalamus-pituitary-adrenal cortex (HPA axis has not been well studied. Hypoglycemia is a potent stress that leads to increased glucocorticoid secretion in all age groups, including the perinatal period. Other conditions associated with exposure to excess glucocorticoid in the perinatal period have a programming effect on the HPA axis activity. Limited animal data suggest the possibility of similar programming effect after recurrent hypoglycemia in the postnatal period. The age at exposure to hypoglycemia likely determines the HPA axis response in adulthood. Recurrent hypoglycemia in the early postnatal period likely leads to a hyperresponsive HPA axis, whereas recurrent hypoglycemia in the late postnatal period lead to a hyporesponsive HPA axis in adulthood. The age-specific programming effects may determine the neuroendocrine response during hypoglycemia and other stressful events in individuals with history of recurrent hypoglycemia during development.
Coplan, Jeremy D; Gupta, Nishant K; Karim, Asif; Rozenboym, Anna; Smith, Eric L P; Kral, John G; Rosenblum, Leonard A
Food insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term "social allostasis." We postulate that maternal food insecurity induces a "superorganism" state through coordination of individual HPA axis response. Twenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments. Despite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our "dyadic vulnerability" index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p < 0.0001) whereas relatively "advantaged" dyads exhibited maternal cortisol increases in response to VFD exposure. In response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a "superorganism" version of HPA axis homeostasis, provisionally termed "social allostasis."
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.
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.
Full Text Available Our previous studies demonstrated that the epimedium herb, when simultaneously used with GCs, counteracted suppressive effects of GCs on the HPA axis without adverse influence on the therapeutic action of GCs. Here, total flavones were extracted from the epimedium flavonoids (EFs and then used to investigate whether EFs provide protective effects on the HPA axis. We found that GCs induced a significant decrease in body weight gain, adrenal gland weight gain, and plasma adrenocorticotropin (ACTH and corticosterone levels. After treatment with EFs, body weight gain, adrenal gland weight gain, and plasma corticosterone level were significantly restored, whilst plasma ACTH level was partially elevated. EFs were also shown to promote cell proliferation in the outer layer of adrenal cortex and to enhance the migration of newly divided cells toward the inner layer. To elucidate the underlying mechanisms, the mRNA expression of insulin-like growth factor II (IGF-II was measured, and EFs significantly upregulated IGF-II expression. Our results indicated that EFs counteract the suppression of the HPA axis induced by GCs. This may involve both the ACTH and IGF-II pathways and thereby promote regeneration of the adrenal cortex suggesting a potential clinical application of EFs against the suppressive effects of GCs on the HPA axis.
Depressive disorder can be viewed as an adaptive defense mechanism in response to excessive stress that has gone awry. The hypothalamic–pituitary–adrenal (HPA) axis is an important node in the brain’s stress circuit and suggested to play a role in several subtypes of depression. While the
Basappa, Johnvesly; Graham, Christine E.; Turcan, Sevin; Vetter, Douglas E.
A key property possessed by the mammalian cochlea is its ability to dynamically alter its own sensitivity. Because hair cells and ganglion cells are prone to damage following exposure to loud sound, extant mechanisms limiting cochlear damage include modulation involving both the mechanical (via outer hair cell motility) and neural signaling (via inner hair cell-ganglion cell synapses) steps of peripheral auditory processing. Feedback systems such as that embodied by the olivocochlear system can alter sensitivity, but respond only after stimulus encoding, allowing potentially damaging sounds to impact the inner ear before sensitivity is adjusted. Less well characterized are potential cellular signaling systems involved in protection against metabolic stress and resultant damage. Although pharmacological manipulation of the olivocochlear system may hold some promise for attenuating cochlear damage, targeting this system may still allow damage to occur that does not depend on a fully functional feedback loop for its mitigation. Thus, understanding endogenous cell signaling systems involved in cochlear protection may lead to new strategies and therapies for prevention of cochlear damage and consequent hearing loss. We have recently discovered a novel cochlear signaling system that is molecularly equivalent to the classic hypothalamic-pituitary-adrenal (HPA) axis. This cochlear HPA-equivalent system functions to balance auditory sensitivity and susceptibility to noise-induced hearing loss, and also protects against cellular metabolic insults resulting from exposures to ototoxic drugs. This system may represent a local cellular response system designed to mitigate damage arising from various types of insult. PMID:22484018
Stroth, Nikolas; Liu, Ying; Aguilera, Greti; Eiden, Lee E.
External and internal stimuli that threaten homeostasis trigger coordinated stress responses through activation of specialised neuroendocrine circuits. In mammals, the hypothalamic-pituitary-adrenal (HPA) axis mediates responses to stressors such as restraint, ultimately enhancing adrenocortical hormone secretion. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in central control of the HPA axis, and we have recently shown PACAP-dependent expression of corticotropin-releasing hormone (CRH) and secretion of corticosterone in response to restraint. We now provide a more detailed analysis of PACAP-dependent HPA axis stimulation in the mouse, indicating that the hypothalamic paraventricular nucleus (PVN) is the primary site of action. We demonstrate by quantitative PCR and in situ hybridisation that upregulation of mRNAs encoding CRH and inducible transcription factors from the Nr4a family (Nur77, Nor1) in the PVN is PACAP-dependent. Furthermore, CRH hnRNA is rapidly upregulated in cultured hypothalamic neurones after treatment with PACAP. Induction of Nr4a factors (Nur77, Nurr1) in response to restraint is attenuated in the pituitary gland of PACAP-deficient mice. In the adrenal glands, restraint elicits a marked PACAP-dependent increase in adrenocortical mRNA levels of all three Nr4a transcription factors, SF-1 (steroidogenic factor 1; Nr5a1), steroidogenic acute regulatory protein (StAR) and steroid 21-hydroxylase. Taken together, our results show that PACAP controls HPA responses to restraint primarily at the level of the hypothalamus by upregulating CRH, possibly involving transcription factors such as Nur77 and Nor1. Subsequent adrenocortical steroidogenesis also appears to involve PACAP-dependent stimulus-transcription coupling, suggesting a mechanism by which PACAP exerts control over HPA axis function during stress. PMID:21824204
ALLEN, Camryn D.; LEE, Soon; KOOB, George F.; RIVIER, Catherine
Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Part of this influence is likely exerted directly at the level of the corticotropin-releasing factor (CRF) gene, but intermediates may also play a role. Here we review the effect of alcohol on this axis, provide new data on the effects of binge drinking during adolescence, and argue for a role of catecholaminergic circuits. Indeed, acute injection of this drug activates brain stem adrenergic and noradrenergic circuits, and their lesion, or blockade of α1 adrenergic receptors significantly blunts alcohol-induced ACTH release. As alcohol can influence the HPA axis even once discontinued, and alcohol consumption in young people is associated with increased adult drug abuse (a phenomenon possibly mediated by the HPA axis), we determined whether alcohol consumption during adolescence modified this axis. The number of CRF-immunoreactive (ir) cells/section was significantly decreased in the central nucleus of the amygdala of adolescent self-administering binge-drinking animals, compared to controls. When another group of adolescent binge-drinking rats was administered alcohol in adulthood, the number of colocalized c-fos-ir and PNMT-ir cells/brain stem section in the C3 area was significantly decreased, compared to controls. As the HPA axis response to alcohol is blunted in adult rats exposed to alcohol vapors during adolescence, a phenomenon which was not observed in our model of self-administration, it is possible that the blood alcohol levels achieved in various models play a role in the long-term consequences of exposure to alcohol early in life. Collectively, these results suggest an important role of brain catecholamines in modulating the short- and long-term consequences of alcohol administration. PMID:21300146
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
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…
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
McGauran, Monica; Jordan, Brigid; Beijers, Roseriet; Janssen, Irma; Franich-Ray, Candice; de Weerth, Carolina; Cheung, Michael
Children with congenital heart disease (CHD) have poorer neurodevelopmental and psychological outcomes. The mechanisms underlying this remain unclear. One mechanism could be that the stressful experience of cardiac surgery early in life influences long-term hypothalamic-pituitary-adrenal (HPA) axis regulation. Dysregulation of the HPA axis has been linked to poorer neurocognitive and psychological outcomes in other study populations. This case-control study aims to compare HPA-axis regulation (circadian rhythm and reactivity) using salivary cortisol in 3- to 5-year-olds with CHD who did and did not have cardiac surgery prior to 6 months of age. Saliva samples for cortisol analysis were collected from preschoolers with CHD (N = 28, Males = 18, Females = 10) over two weekend days, and before and after an echocardiogram. Caregiver education, child age, sex, and cardiac disease severity score were included as confounders. Multilevel analysis (hierarchical linear modeling) was used to analyze the data. The analysis for the cortisol circadian rhythm shows that the early surgery group has a flatter diurnal slope secondary to lower mean weekend morning waking cortisol levels than controls but similar mean bed time values. Multilevel analysis of the stress response to an echocardiogram indicates that the early surgery group has an increased response when compared to the control group. This is the first study to show that cardiac surgery prior to 6 months of age is associated with a different pattern of HPA-axis regulation at 3-5 years of age.
Zöllner, Ekkehard Werner; Lombard, Carl; Galal, Ushma; Hough, Stephen; Irusen, Elvis; Weinberg, Eugene
Hypothalamic pituitary adrenal axis suppression (HPAS) when treating asthmatic children with inhaled corticosteroids (ICS) is thought to be rare. To determine the prevalence of HPAS in asthmatic children treated with ICS and nasal steroids (NS). Twenty-six asthmatic children were recruited. Clinical features of HPAS, height, weight, height and weight velocity, steroid dose, adherence, symptom control and lung functions were documented. Metyrapone test was performed if the serum cortisol was > 83 nmol/L (> 3 microg/dL). No child had a serum cortisol < 83 nmol/L (< 3 microg/dL). Prevalence of HPAS was 35 (CI = 17%-56%). Daily NS dose/ m2 and cumulative NS dose/m2 were significantly (p = 0.03) inversely correlated with the post-metyrapone ACTH (r = -0.42 for both). Current ICS dose was not associated with the post-metyrapone ACTH (r = 0). There was a weak correlation with the daily ICS dose/m2 (r = -0.12) and cumulative ICS dose/m2 (r = -0.26). A third of asthmatic children on ICS and NS develop HPAS. Contributing factors are the use of NS, body size and cumulative dose of ICS.
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.
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.
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.
Koenig, Julian; Rinnewitz, Lena; Warth, Marco; Kaess, Michael
Adolescent non-suicidal self-injury (NSSI) is associated with altered sensitivity to experimentally induced pain. Adolescents engaging in NSSI report greater pain threshold and pain tolerance, as well as lower pain intensity and pain unpleasantness compared to healthy controls. The experience of pain is associated with reactivity of both the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. However, previous research has not yet systematically addressed differences in the physiological response to experimentally induced pain comparing adolescents with NSSI and age- and sex-matched healthy controls. Adolescents with NSSI and healthy controls undergo repeated painful stimulation with the cold pressor task. ANS activity is continuously recorded throughout the procedure to assess changes in heart rate and heart rate variability. Blood pressure is monitored and saliva is collected prior to and after nociceptive stimulation to assess levels of saliva cortisol. The study will provide evidence whether lower pain sensitivity in adolescents with NSSI is associated with blunted physiological and endocrinological responses to experimentally induced pain compared to healthy controls. Extending on the existing evidence on altered pain sensitivity in NSSI, measured by self-reports and behavioural assessments, this is the first study to take a systematic approach in evaluating the physiological response to experimentally induced pain in adolescent NSSI. Deutsche Register Klinischer Studien, Study ID: DRKS00007807; Trial Registration Date: 13.02.2015.
Johnson, Elizabeth O; Calogero, Aldo E; Konstandi, Mary; Kamilaris, Themis C; La Vignera, Sandro; Chrousos, George P
The purpose of this study is to assess the effects of hypothyroidism on the hypothalamic-pituitary-adrenal (HPA) axis; the functional integrity of each component of the HPA axis was examined in short-term and long-term hypothyroidism. Neuropeptide synthesis, release, and content were evaluated in vitro both in the hypothalamus and anterior pituitary, and corticosterone release was assessed in primary adrenal cell cultures at 7 (short-term) and 60 days (long-term hypothyroidism) after thyroidectomy in male rats. Hypothyroid rats showed adrenal insufficiency in several parameters, which were associated with the duration of hypothyroidism. Cerebrospinal (CSF) ACTH was decreased in all hypothyroid animals, while CSF corticosterone levels were significantly decreased only in long-term hypothyroidism. Long-term hypothyroid animals showed decreased corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus under both basal and stress conditions, decreased CRH release from hypothalamic organ cultures after KCL and arginine vasopressin stimulation, as well as an increased number of anterior pituitary CRH receptors. In contrast, short-term hypothyroid rats showed changes in anterior pituitary function with an increased responsiveness to CRH that was associated with an increase in CRH receptors. Although both short- and long-term hypothyroidism was associated with significant decreases in adrenal weights, only long-term hypothyroid rats showed changes in adrenal function with a significant decrease of ACTH-induced corticosterone release from cultured adrenal cells. The data suggest that long-term hypothyroidism is associated with adrenal insufficiency with abnormalities in all three components of the HPA axis. Short-term hypothyroidism, on the other hand, is associated with increased pituitary corticotroph responsiveness to CRH.
Liu, Lian; Yang, Junqiang; Qian, Feng; Lu, Chengbiao
A high-fat diet (HFD) is highly correlated to obesity, metabolic diseases and certain behavioral changes. However, the effects of post-weaning HFD in rats during puberty and the role of the hypothalamic-pituitary-adrenal (HPA) axis in this process have remained elusive. The present study hypothesized that the HPA axis mediates the behavioral alterations induced by a post-weaning HFD. To investigate this, female rats were divided into two groups, one of which was fed a HFD from postnatal weeks (PWs) 4-12, while the other group received standard chow. Rats in each group were then subdivided into two subgroups each, and from PW 9-12, animals from one of the two subgroups were subjected to chronic mild stress (CMS), while the other subgroup received no stress. At PW 12, the body weight of rats receiving a HFD but no DMS was significantly higher than that in the control group. The frequency of crossing and rearing in the open field test and the time in the center of the Y-maze were decreased following CMS. Total time to escape was decreased in rats receiving HFD and after CMS. The serum levels of adrenocorticotropic hormone and corticosterone were increased in rats receiving an HFD and after CMS, and the mRNA levels of corticotropin-releasing hormone and arginine vasopressin in the hypothalamus were increased in the HFD + CMS group compared to that in the control group. The mRNA expression of glucocorticoid receptor (GR) in the hippocampi of rats in the HFD + CMS group was significantly decreased and the mineralocorticoid receptor/GR ratio was increased compared to that in the groups receiving either CMS or a HFD. In conclusion, these results indicated that female rats fed a post-weaning HFD showed HPA axis hypersensitivity under CMS, which may mediate behavioral alterations.
Jansen, Steffy W; Roelfsema, Ferdinand; Akintola, Abimbola A
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......). METHODS: During 24 h, venous blood was sampled every 10 minutes for determination of circulatory ACTH and cortisol concentrations. Deconvolution analysis, cross approximate entropy analysis and ACTH-cortisol-dose response modeling were used to assess, respectively, ACTH and cortisol secretion parameters......, feedforward and feedback synchrony and adrenal gland ACTH responsivity. RESULTS: Mean (95% Confidence Interval) basal ACTH secretion was higher in male offspring compared to male controls (645 (324-1286) ngl/L/24 h versus 240 (120-477) ng/L/24 h, P = 0.05). Other ACTH and cortisol secretion parameters did...
Hee Kyung Kim
Full Text Available BackgroundIn subclinical Cushing syndrome (SC, it is assumed that glucocorticoid production is insufficient to cause a clinically recognizable syndrome. Differences in hormonal levels or recovery time of the hypothalamic-pituitary-adrenocortical (HPA axis after adrenalectomy between patients with overt Cushing syndrome (OC and SC remain unknown.MethodsThirty-six patients (10 with OC and 26 with SC with adrenal Cushing syndrome who underwent adrenalectomy from 2004 to 2014 were reviewed retrospectively. Patients were treated with glucocorticoid after adrenalectomy and were reevaluated every 1 to 6 months using a rapid adrenocorticotropic hormone (ACTH stimulation test.ResultsLevels of basal 24-hour urine free cortisol (UFC, serum cortisol after an overnight dexamethasone suppression test (DST, and serum cortisol and 24-hour UFC after low-dose DST and high-dose DST were all significantly lower in patients with SC compared with OC. Basal ACTH levels showed significantly higher in patients with SC compared with OC. The probability of recovering adrenal function during follow-up differed significantly between patients with OC and SC (P=0.001, with significant correlations with the degree of preoperative cortisol excess. Patients with OC required a longer duration of glucocorticoid replacement to recover a normal ACTH stimulation test compared with patients with SC (median 17.0 months vs. 4.0 months, P<0.001.ConclusionThe HPA axis recovery time after adrenalectomy in patients with SC is rapid and is dependent on the degree of cortisol excess. More precise definition of SC is necessary to achieve a better management of patients and to avoid the risk of under- or over-treatment of SC patients.
Kim, Hee Kyung; Yoon, Jee Hee; Jeong, Yun Ah; Kang, Ho Cheol
In subclinical Cushing syndrome (SC), it is assumed that glucocorticoid production is insufficient to cause a clinically recognizable syndrome. Differences in hormonal levels or recovery time of the hypothalamic-pituitary-adrenocortical (HPA) axis after adrenalectomy between patients with overt Cushing syndrome (OC) and SC remain unknown. Thirty-six patients (10 with OC and 26 with SC) with adrenal Cushing syndrome who underwent adrenalectomy from 2004 to 2014 were reviewed retrospectively. Patients were treated with glucocorticoid after adrenalectomy and were reevaluated every 1 to 6 months using a rapid adrenocorticotropic hormone (ACTH) stimulation test. Levels of basal 24-hour urine free cortisol (UFC), serum cortisol after an overnight dexamethasone suppression test (DST), and serum cortisol and 24-hour UFC after low-dose DST and high-dose DST were all significantly lower in patients with SC compared with OC. Basal ACTH levels showed significantly higher in patients with SC compared with OC. The probability of recovering adrenal function during follow-up differed significantly between patients with OC and SC (P=0.001), with significant correlations with the degree of preoperative cortisol excess. Patients with OC required a longer duration of glucocorticoid replacement to recover a normal ACTH stimulation test compared with patients with SC (median 17.0 months vs. 4.0 months, P<0.001). The HPA axis recovery time after adrenalectomy in patients with SC is rapid and is dependent on the degree of cortisol excess. More precise definition of SC is necessary to achieve a better management of patients and to avoid the risk of under- or over-treatment of SC patients.
Thiagarajan, A B; Mefford, I N; Eskay, R L
Activation of the hypothalamic-pituitary-adrenal axis (HPAA) by single-dose ethanol administration, which achieved moderately high blood ethanol levels, was explored in naive rats in order to determine the mechanism of ethanol's activation of the stress axis. Adult male rats received a single dose (3.2 g/kg body weight-1 of a 12% solution of ethanol in physiological saline. The plasma concentration of immunoreactive (ir) adrenocorticotropic hormone (ACTH), beta-endorphin (BE) and corticosterone (CS) was determined by radioimmunoassay, whereas, plasma concentrations of epinephrine (E) and norepinephrine (NE) were quantified following reverse-phase liquid chromatographic separation and amperometric detection. Ethanol induced maximal plasma ACTH levels within minutes, which declined toward basal levels by 60 min, whereas, plasma concentration of CS rose rapidly and remained elevated at 60 min. Plasma ACTH and CS levels in saline-treated control animals did not vary significantly at any time point. Consistent with co-release of ACTH from corticotrophs, the plasma concentration of ir-BE increased 5-fold at 15 min and declined towards basal levels at 60 min after-ethanol challenge. Plasma E increased 10- to 20-fold as compared to saline controls or preinjection levels and returned to preinjection levels by 90 min, in a manner similar to ethanol-induced changes in proopiomelanocortin-derived peptides and CS. Removal of the adrenal medulla and thus the source of E prior to ethanol administration, did not attenuate activation of the HPAA. Passive immunoneutralization of arginine vasopressin (AVP), using a high-titer AVP antiserum and a protocol which was found to block ether-induced ACTH secretion by 40% in adult male rats, failed to even partially block ethanol-induced ACTH or CS secretion. The results of this study indicate that neither adrenal medulla-derived E nor AVP are significant regulators or coregulators of corticotroph secretions following a moderately high
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.
Li, Chuting; Liu, Yuan; Yin, Shiping; Lu, Cuiyan; Liu, Dexiang; Jiang, Hong; Pan, Fang
Post-traumatic stress disorder (PTSD) is a stress-related mental disorder caused by traumatic experiences. Studies have found that exposure to early stressful events is a risk factor for developing PTSD. However, a limited number of studies have explored the effects of traumatic stress in early adolescence on behavior, hypothalamic-pituitary-adrenal (HPA) axis function, central corticotropin releasing factor receptor 1 (CRFR1) expression and the relative vulnerability of PTSD in adulthood. The current study aims to explore these issues using inescapable electric foot shock to induce a PTSD model in early adolescent rats. Meanwhile, running on a treadmill for six weeks and administration of the antagonist with 3.2mg/kg/day of CP-154, 526 for 14 consecutive days were used as therapeutic measures. Presently, the stress (S) group showed more anxiety and depression in the open field (OF) test and elevated plus maze (EPM) test, memory damage in the Y maze test, decreased basal CORT level, increased DEX negative feedback inhibition and exacerbated and longer-lasting reaction to CRH challenge in the DEX/CRH test compared with the control group. Central CRFR1 expression was also changed in the S group, as evidenced by the increased CRFR1 expression in the hypothalamus, amygdala and the prefrontal cortex (PFC). However, treadmill exercise alleviated early adolescent stress-induced behavior abnormalities and improved the functional state of the HPA axis, performing a more powerful effect than the CRFR1 antagonist CP-154, 526. Additionally, this study revealed that the alteration of central CRFR1 expression might play an important role in etiology of PTSD in adulthood. Copyright © 2015 Elsevier B.V. All rights reserved.
Conclusion: Normal age- and gender-specific DHEA-S level or a DHEA-S ratio of more than 1.78 are valuable markers of HPA integrity. Serum DHEA-S may be a candidate for a less costly approach where ACTH stimulation is unavailable.
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.
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.
Vore, Andrew S; Doremus-Fitzwater, Tamara; Gano, Anny; Deak, Terrence
Adolescent alcohol use comprises a significant public health concern and is often characterized by binge-like consumption patterns. While ethanol exposure in adulthood has been shown to alter the stress response, including the Hypothalamic-Pituitary-Adrenal (HPA) axis, few studies have examined whether binge-like ethanol exposure during adolescence results in enduring changes in HPA axis sensitivity in adulthood. In the present studies, adolescent Sprague-Dawley rats were given intragastric (i.g.) intubations of ethanol (4 g/kg) or vehicle once per day for three consecutive days, beginning on postnatal day (P) 30 (±1). This exposure was followed by a 2-day period of rest/withdrawal. Rats received a total of either two (Experiments 1, 2 and 3) or four (Experiment 4) cycles of ethanol exposure and were subsequently allowed to age normally until adulthood. In Experiment 1, adult, (P71-75), ethanol- or vehicle-exposed rats received a 60 min restraint stress challenge. In Experiment 2, rats received a 50 μg/kg injection of lipopolysaccharide (LPS). In Experiment 3, rats received a challenge of 2.5 g/kg ethanol (intraperitoneally; i.p.). In Experiment 4, male and female ethanol- or vehicle- exposed rats received a 50 μg/kg injection of LPS. In all experiments, blood samples were collected for later assessment of corticosterone (CORT), blood ethanol concentrations (BECs), and the cellular fraction of blood was analyzed for cytokine gene expression. As expected, all three challenges led to a time-dependent surge in CORT. Gene expression analyses of cytokines (Interleukin [IL]-6, IL-1β, and Tumor necrosis factor alpha [TNFα]) from the cellular fraction of blood revealed unique, time-dependent patterns of cytokine expression depending upon the nature of the adult challenge incurred (restraint, LPS, or EtOH). Importantly, adolescent ethanol exposure led to attenuated restraint and LPS-induced cytokine expression in males, whereas female rats displayed an absence of
Lodish, Maya; Dunn, Somya Verma; Sinaii, Ninet; Keil, Margaret F; Stratakis, Constantine A
Recovery of the hypothalamic-pituitary-adrenal axis (HPAA) after transsphenoidal surgery (TSS) for Cushing's disease (CD) in children has not been adequately studied. Our objective was to assess time to recovery of the HPAA after TSS in children with CD. This was a case series at the National Institutes of Health Clinical Center. Fifty-seven patients with CD (6-18 yr, mean 13.0 ± 3.1 yr) given a standard regimen of glucocorticoid tapering after TSS were studied out of a total of 73 recruited. ACTH (250 μg) stimulation tests were administered at approximately 6-month intervals for up to 36 months. Age, sex, pubertal status, body mass index, length of disease, midnight cortisol, and urinary free cortisol at diagnosis were analyzed for effects on recovery. The main outcome measure was complete recovery of the HPAA as defined by a cortisol level of at least 18 μg/dl in response to 250 μg ACTH. Full recovery was reached by 43 (75.4%) of 57 patients, with 29 of the 43 (67.4%) and 41 of the 43 (95.3%) recovering by 12 and 18 months, respectively. The overall mean time to recovery was 12.6 ± 3.3 months. Kaplan-Meier survivor function estimated a 50% chance of recovering by 12 months after TSS and 75% chance of recovering within 14 months. By receiver operating characteristic curve assessment, the cutoff of at least 10-11 μg/dl of cortisol as the peak of ACTH stimulation testing at 6 months after TSS yielded the highest sensitivity (70-80%) and specificity (64-73%) to predict full recovery of the HPAA at 12 months. Two of the four patients that recovered fully within 6 months had recurrent CD. Although this is not a randomized study, we present our standardized tapering regimen for glucocorticoid replacement after TSS that led to recovery of the HPAA in most patients within the first postoperative year. Multiple factors may affect this process, but an early recovery may indicate disease recurrence.
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
Frederico G Graeff
Full Text Available OBJETIVO: Este artigo discute a ativação diferencial do eixo hipotálamo-pituitária-adrenal no transtorno de ansiedade generalizada e no transtorno de pânico. MÉTODO: Resultados de recentes revisões da literatura são resumidos e discutidos. RESULTADOS: Os resultados de estudos experimentais que dosaram o hormônio adrenocorticotrópico, o cortisol e a prolactina mostram que ataques de pânico naturais, bem como os provocados por agentes panicogênicos seletivos - como lactato de sódio e dióxido de carbono -, não ativam o eixo hipotálamo-pituitária-adrenal. Agonistas do receptor de colecistocinina do tipo B, como o peptídeo colecistocinina-4 e a pentagastrina, elevam os hormônios de estresse, independentemente da ocorrência de um ataque de pânico, parecendo ativar diretamente o eixo hipotálamo-pituitária-adrenal. O antagonista benzodiazepínico flumazenil não eleva o nível dos hormônios de estresse; porém, este agente farmacológico não induz ataques de pânico de modo consistente. Agentes farmacológicos que aumentam a ansiedade em pacientes de pânico (cafeína, ioimbina, agonistas serotonérgicos, assim como em pessoas saudáveis, elevam o nível dos hormônios de estresse. CONCLUSÕES: Além das diferenças na sintomatologia e na resposta farmacológica, o transtorno de ansiedade generalizada e o transtorno de pânico afetam os hormônios de estresse de modo distinto. Enquanto a ansiedade antecipatória e o transtorno de ansiedade generalizada ativam tanto o eixo hipotálamo-pituitária-adrenal como o simpático-adrenal, o ataque de pânico causa acentuada ativação simpática; porém, afeta pouco o eixo hipotálamo-pituitária-adrenal.OBJECTIVE: This article focuses on the differential activation of the hypothalamic-pituitary-adrenal axis in generalized anxiety disorder and panic disorder. METHOD: The results of recently reported reviews of the literature are summarized and discussed. RESULTS: The results of
Mick, Inge; Spring, Konstanze; Uhr, Manfred; Zimmermann, Ulrich S
Acute alcohol challenge studies in rodents and naturalistic observations in drinking alcoholics suggest that alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) system. The literature on respective studies in healthy volunteers is more inconsistent, suggesting differential alcohol effects depending on dosage, recent drinking history, family history of alcoholism and alcohol-induced side effects. These papers and the putative pharmacologic mechanisms underlying alcohol effects on the HPA system are reviewed here and compared with a new study, in which we investigated how secretion of adrenocorticotrophin (ACTH) and cortisol is affected by ingestion of 0.6 g/kg ethanol in 33 young healthy socially drinking males with a paternal history of alcoholism (PHP) versus 30 family history negative (FHN) males. Alcohol and placebo were administered in a 2-day, double-blind, placebo controlled crossover design with randomized administration sequence. After administration of placebo, ACTH and cortisol decreased steadily over 130 minutes. In FHN subjects, secretion of both hormones was even more attenuated after alcohol, resulting in significantly lower levels compared with placebo. In PHP subjects, no alcohol effect on hormone secretion could be detected. The ratio of cortisol to ACTH secretion, each expressed as area under the secretion curve, was significantly increased by alcohol in FHN and PHP participants. These results argue against HPA stimulation being a mechanism that promotes the transition from moderate to dependent drinking. The fact that alcohol-induced HPA suppression was not detected in PHP males is consistent with the general concept that subjects at high risk for alcoholism exhibit less-pronounced alcohol effects. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.
Melhem, Nadine M; Keilp, John G; Porta, Giovanna; Oquendo, Maria A; Burke, Ainsley; Stanley, Barbara; Cooper, Thomas B; Mann, J John; Brent, David A
Studies looking at the relationship of the hypothalamic-pituitary-adrenal (HPA) axis to suicidal behavior and its risk factors, such as depression, childhood abuse, and impulsive aggression, report inconsistent results...
Porzezińska-Furtak, Joanna; Krzyżanowska-Świniarska, Barbara; Miazgowski, Tomasz; Safranow, Krzysztof; Kamiński, Ryszard
We sought associations among metabolic profiles, copeptin levels, emotional control, personality traits, and hypothalamic-pituitary-adrenal axis activity in metabolically obese normal-weight young women (MONW). We assessed body composition, including fat-free mass; body fat (BF) and android and gynoid fat depots; fasting blood glucose, insulin, copeptin, cortisol (baseline and after dexamethasone), adrenocorticotropin (ACTH), triglycerides, total cholesterol, low- (LDL) and high-density (HDL) lipoproteins; and the BCL1 and N363S polymorphisms of the glucocorticoid receptor gene in 59 MONW and 71 healthy women aged 20-40 years. We also evaluated personality traits using the NEO-Five Factor Inventory and the subjective extent of emotional suppression by the Courtauld Emotional Control Scale. Compared to the controls, MONW had significantly higher insulin, cholesterol, LDL, triglycerides, and waist circumference, but lower HDL. MONW also had increased BF (>30 % of weight) and unfavorable regional fat distribution with excess android fat. The android/BF ratio was 8.29 % (MONW) versus 7.89 % (controls) (p = 0.005), while the gynoid/BF ratio was 31.99 versus 34.1 %, respectively (p = 0.008). Despite similar ACTH levels in both groups, MONW had higher cortisol levels both at the baseline (p < 0.001) and in the dexamethasone suppression test (p = 0.003). Copeptin levels and the distribution of glucocorticoid receptor polymorphisms were similar in both groups. There were also no significant differences in psychological features between MONW and controls. In conclusion, the MONW phenotype was associated with hypothalamic-pituitary-adrenal axis dysregulation, unfavorable metabolic profiles, and fat accumulation, but normal distribution of glucocorticoid receptor gene polymorphisms and copeptin levels, and no significant differences in psychological features between MONW and controls.
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.
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.
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.
Cianfarani, Stefano; Geremia, Caterina; Scott, Carolyn D; Germani, Daniela
Intrauterine growth retardation (IUGR) is one of the major causes of short stature in childhood. Although postnatal catch-up growth occurs in the majority of IUGR children, approximately 20% of them remain permanently short. The mechanisms that allow catch-up growth or, on the contrary, prevent IUGR children from achieving a normal height are still unknown. Our aim was to investigate whether intrauterine reprogramming of hypothalamic-pituitary-adrenal axis may be involved in postnatal growth retardation of IUGR children through a modulation of the function of the IGF system. Anthropometry, IGF system assessment, cortisol measurement, and lipid profile evaluation were performed in 49 IUGR children. Children were subdivided into two groups according to their actual height corrected for midparental height: CG (catch-up growth) group, 19 children with corrected height >or=0 z-score; and NCG (noncatch-up growth) group, 30 subjects with corrected height weight (p cortisol (p cortisol levels resulted inversely to birth weigh (r = -0.34, p 3.4 mM (130 mg/dL). LDL cholesterol was inversely related to birth weight (r = -0.31, p cortisol levels and first trimester length gain (r = -0.54, p cortisol (r = -0.67, p stress: children with increased cortisol secretion may be at higher risk of growth failure. During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and, therefore, reducing IGF bioavailability.
Investigation of Genetic Variants, Birthweight and Hypothalamic-Pituitary-Adrenal Axis Function Suggests a Genetic Variant in the SERPINA6 Gene Is Associated with Corticosteroid Binding Globulin in the Western Australia Pregnancy Cohort (Raine) Study
Anderson, Laura N.; Briollais, Laurent; Atkinson, Helen C.; Marsh, Julie A.; Xu, Jingxiong; Connor, Kristin L.; Matthews, Stephen G.; Pennell, Craig E.; Lye, Stephen J.
Background The hypothalamic-pituitary-adrenal (HPA) axis regulates stress responses and HPA dysfunction has been associated with several chronic diseases. Low birthweight may be associated with HPA dysfunction in later life, yet human studies are inconclusive. The primary study aim was to identify genetic variants associated with HPA axis function. A secondary aim was to evaluate if these variants modify the association between birthweight and HPA axis function in adolescents. Methods Morning fasted blood samples were collected from children of the Western Australia Pregnancy Cohort (Raine) at age 17 (n = 1077). Basal HPA axis function was assessed by total cortisol, corticosteroid binding globulin (CBG), and adrenocorticotropic hormone (ACTH). The associations between 124 tag single nucleotide polymorphisms (SNPs) within 16 HPA pathway candidate genes and each hormone were evaluated using multivariate linear regression and penalized linear regression analysis using the HyperLasso method. Results The penalized regression analysis revealed one candidate gene SNP, rs11621961 in the CBG encoding gene (SERPINA6), significantly associated with total cortisol and CBG. No other candidate gene SNPs were significant after applying the penalty or adjusting for multiple comparisons; however, several SNPs approached significance. For example, rs907621 (p = 0.002) and rs3846326 (p = 0.003) in the mineralocorticoid receptor gene (NR3C2) were associated with ACTH and SERPINA6 SNPs rs941601 (p = 0.004) and rs11622665 (p = 0.008), were associated with CBG. To further investigate our findings for SERPINA6, rare and common SNPs in the gene were imputed from the 1,000 genomes data and 8 SNPs across the gene were significantly associated with CBG levels after adjustment for multiple comparisons. Birthweight was not associated with any HPA outcome, and none of the gene-birthweight interactions were significant after adjustment for multiple comparisons. Conclusions
Kryski, Katie R.; Dougherty, Lea R.; Dyson, Margaret W.; Olino, Thomas M.; Laptook, Rebecca S.; Klein, Daniel N.; Hayden, Elizabeth P.
While activation of the hypothalamic-pituitary-adrenal (HPA) axis is an adaptive response to stress, excessive HPA axis reactivity may be an important marker of childhood vulnerability to psychopathology. Parenting, including parent affect during parent-child interactions, may play an important role in shaping the developing HPA system; however,…
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.
Zöllner, Ekkehard W; Lombard, Carl; Galal, Ushma; Hough, Stephen; Irusen, Elvis; Weinberg, Eugene
Hypothalamic-pituitary-adrenal axis suppression (HPAS) in asthmatic children treated with inhaled corticosteroids (ICS), with or without nasal steroids (NS), may be more common than previously thought. Only dynamic testing will identify children at risk of adrenal crisis. It is impractical to test all asthmatic children for HPAS with a gold standard adrenal function test, i.e. the metyrapone or insulin tolerance test. To determine which clinical or biochemical parameter is the most useful screening test for HPAS in asthmatic children. Twenty-six asthmatic children, 5-18 yr old, on ICS ± NS, not treated with oral or topical steroids in the preceding year were recruited. Height, weight, height velocity, weight velocity and a change in systolic blood pressure from the recumbent to the standing position (ΔSBP) were recorded. Early-morning urine for urinary free cortisol (UFC) and urinary cortisol metabolites (UCM) was collected. UFC was analysed by both a chemiluminescent assay and gas chromatography/mass spectrometry (GC-MS). Morning serum cortisol and adrenocorticotropic hormone (ACTH) levels were measured. The overnight metyrapone test was performed if the fasting morning serum cortisol was >83 nmol/l. HPAS was diagnosed if the ACTH failed to rise >100 pg/ml after metyrapone. Spearman correlation coefficients (r) were calculated between the post-metyrapone ACTH and each variable. A receiver-operating characteristics (ROC) curve was drawn for the most promising test, and the diagnostic performance was calculated. All clinical and biochemical parameters investigated were weakly and non-significantly correlated with the post-metyrapone ACTH, except for the morning serum ACTH (r = 0.68; p <0.001). The best discrimination between those who have and those who do not have HPAS is a morning serum ACTH level of 11.7 pg/ml. This corresponds to a sensitivity of 0.89 (0.57-0.98), a specificity of 0.77 (0.53-0.90), a positive predictive value of 0.67 (0.39-0.87), a negative
Reducing treatments in cattle superovulation protocols by combining a pituitary extract with a 5% hyaluronan solution: Is it able to diminish activation of the hypothalamic pituitary adrenal axis compared to the traditional protocol?
Biancucci, Andrea; Sbaragli, Tatiana; Comin, Antonella; Sylla, Lakamy; Monaci, Maurizio; Peric, Tanja; Stradaioli, Giuseppe
Traditional superovulation protocols that include multiple gonadotropin treatments are time-consuming and labor intensive. These protocols require multiple handling and restraining of embryo donors. This will likely increase the risks of injuries in both animals and humans and induce stress that may lead to a reduced superovulatory response. These are more evident when working with cattle that are rarely handled or raised on extensive grazing. The objectives of this experiment were to compare the efficacy of a split-injection protocol of porcine pituitary-derived porcine FSH (pFSH) preparation (slow release [SR] group) to the traditional 4-day treatment with pFSH administered twice daily (C group) and to determine the concentrations of cortisol in the hair as a marker of activation of the hypothalamic-pituitary-adrenal (HPA) axis during the two superovulatory treatments. Thirty-two heifers were stimulated twice in a 2 × 2 crossover design and compared for ovarian response and numbers and characteristics of recovered ova-embryo among treatments. No differences between SR and C groups were found in terms of percentage of responsive animals (100% vs. 93.8%) and ovulation rate (83.7 ± 1.1 vs. 79.5 ± 1.0%). A positive correlation was found between the number of follicles responsive to pFSH (2-8 mm) at the beginning of treatments and the superovulatory response, and no differences were found in these follicular populations between the two treatment groups. The numbers of CLs, ova-embryos, fertilized ova, transferable and freezable embryos recovered per cow were found to be significantly higher in SR compared with C group (14.0 ± 1.6 vs. 10.6 ± 1.0, 12.1 ± 1.6 vs. 7.6 ± 1.0, 11.1 ± 1.1 vs. 7.3 ± 1.0, 9.6 ± 1.4 vs. 6.6 ± 1.0, and 9.4 ± 1.4 vs. 6.0 ± 1.0 for SR and C group, respectively). The SR group produced also a significantly greater number of excellent- and/or good-quality embryos compared with the C group. The concentrations of cortisol in the hair at
Smith, Justin A; Wang, Lei; Hiller, Helmut; Taylor, Christopher T; de Kloet, Annette D; Krause, Eric G
Previous investigation by our laboratory found that acute hypernatremia potentiates an oxytocinergic tone that inhibits parvocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus (PVN), attenuates restraint-induced surges in corticosterone (CORT), and reduces anxiety-like behavior in male rats. To investigate the neural mechanisms mediating these effects and extend our findings to a more versatile species, we repeated our studies using laboratory mice. In response to 2.0M NaCl injections, mice had increased plasma sodium concentrations which were associated with a blunted rise in CORT subsequent to restraint challenge relative to 0.15M NaCl injected controls. Immunofluorescent identification of the immediate early gene product Fos found that 2.0M NaCl treatment increased the number of activated neurons producing oxytocin in the PVN. To evaluate the effect of acute hypernatremia on PVN neurons producing corticotropin-releasing hormone (CRH), we used the Cre-lox system to generate mice that produced the red fluorescent protein, tdTomato, in cells that had Cre-recombinase activity driven by CRH gene expression. Analysis of brain tissue from these CRH-reporter mice revealed that 2.0M NaCl treatment caused a dramatic reduction in Fos-positive nuclei specifically in CRH-producing PVN neurons. This altered pattern of activity was predictive of alleviated anxiety-like behavior as mice administered 2.0M NaCl spent more time exploring the open arms of an elevated-plus maze than 0.15M NaCl treated controls. Taken together, these results further implicate an oxytocin-dependent inhibition of CRH neurons in the PVN and demonstrate the impact that slight elevations in plasma sodium have on hypothalamic-pituitary-adrenocortical axis output and anxiety-like behavior. Copyright © 2014 Elsevier Inc. All rights reserved.
Smith, Justin A.; Wang, Lei; Hiller, Helmut; Taylor, Christopher T.; de Kloet, Annette D.; Krause, Eric G.
Previous investigation by our laboratory found that acute hypernatremia potentiates an oxytocinergic tone that inhibits parvocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus (PVN), attenuates restraint-induced surges in corticosterone (CORT), and reduces anxiety-like behavior in male rats. To investigate the neural mechanisms mediating these effects and extend our findings to a more versatile species, we repeated our studies using laboratory mice. In response to 2.0 M NaCl injections, mice had increased plasma sodium concentrations which were associated with a blunted rise in CORT subsequent to restraint challenge relative to 0.15 M NaCl injected controls. Immunofluorescent identification of the immediate early gene product Fos found that 2.0 M NaCl treatment increased the number of activated neurons producing oxytocin in the PVN. To evaluate the effect of acute hypernatremia on PVN neurons producing corticotropin-releasing hormone (CRH), we used the Cre-lox system to generate mice that produced the red fluorescent protein, tdTomato, in cells that had Cre-recombinase activity driven by CRH gene expression. Analysis of brain tissue from these CRH-reporter mice revealed 2.0 M NaCl treatment caused a dramatic reduction in Fos-positive nuclei specifically in CRH-producing PVN neurons. This altered pattern of activity was predictive of alleviated anxiety-like behavior as mice administered 2.0 M NaCl spent more time exploring the open arms of an elevated-plus maze than 0.15 M NaCl treated controls. Taken together, these results further implicate an oxytocin-dependent inhibition of CRH neurons in the PVN and demonstrate the impact that slight elevations in plasma sodium have on hypothalamic-pituitary-adrenocortical axis output and anxiety-like behavior. PMID:24704193
Mastorakos, George; Pavlatou, Maria G; Mizamtsidi, Maria
Vertebrates respond to stress with activation of the hypothalamic-pituitary-adrenal (HPA) axis, the adrenergic and the autonomic nervous systems. The principal central nervous system regulators of the HPA axis are corticotropin releasing hormone (CRH) and antidiuretic hormone (AVP). Apart from in the central nervous system, CRH has been found in the adrenal medulla, ovaries, myometrium, endometrium, placenta, testis and elsewhere. The activation of the HPA axis during stress affects all body systems. The reproductive axis is inhibited by the HPA axis for the sake of saving energy. The changes to the hypothalamic-pituitary-gonadal (HPG) axis during stress are species-specific, and depend on the type and duration of the stimulus. Several conditions may be associated with altered regulation of the HPA axis. Polycystic ovary syndrome, anorexia nervosa and pregnancy in the third trimester are all characterized by HPA axis activation. In contrast, during the postpartum period, HPA axis suppression is implicated in the "postpartum blues". The actions of CRH are also essential in fetal development and neonatal survival.
Guerry, John D.; Hastings, Paul D.
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative…
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...... follow changes in plasma. In conclusion, the positive correlation between saliva and plasma cortisol concentration in response to ACTH and inflammation suggests the suitability of saliva cortisol measurement for the HPA axis activation assessment. However, changes in saliva cortisol concentration occur......One of the most prominent physiological responses to stressors is the activation of the hypothalamic–pituitary–adrenocortical (HPA) axis, currently assessed by measuring cortisol concentration in blood plasma. To reduce animal discomfort during sampling, which negatively affects stress biomarkers...
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.
Baes,Cristiane Von Werne; Martins, Camila Maria Severi; Tofoli, Sandra Márcia de Carvalho; Juruena, Mário Francisco
Background: Evidence indicates that early life stress (ELS) can induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis to respond to stress in the adult life that leads to depression. These appear to be related to the impairment of HPA hormones through binding to glucocorticoid (GR) and mineralocorticoid receptors (MR). The aim of this study was to evaluate the impact of ELS in HPA axis response to challenges with GR and MR agonists in depressed patients. Methods: We in...
Di, Tingting; Zhang, Suyun; Hong, Juan; Zhang, Tingting; Chen, Ling
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.
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.
Cutolo, M; Villaggio, B; Foppiani, L; Briata, M; Sulli, A; Pizzorni, C; Faelli, F; Prete, C; Felli, L; Seriolo, B; Giusti, M
The hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes involvement or response to immune activation seems crucial for the control of excessive inflammatory and immune conditions such as autoimmune rheumatic diseases, including rheumatoid arthritis (RA). However, female patients seem to depend more on the HPA axis, whereas male patients seem to depend more on the HPG axis. In particular, hypoandrogenism may play a pathogenetic role in male RA patients because adrenal and gonadal androgens, both products of the HPA and HPG axes, are considered natural immunosuppressors. A significantly altered steroidogenesis of adrenal androgens (i.e., dehydroepiandrosterone sulfate, DHEAS and DHEA) in nonglucocorticoid-treated premenopausal RA patients has been described. The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also play a role in the disease, and many data indicate that estrogens suppress cellular immunity, but stimulate humoral immunity (i.e., deficiency promotes cellular Th1-type immunity). A range of physical and psychosocial stressors are also implicated in the activation of the HPA axis and related HPG changes. Chronic and acute stressors appear to have different actions on immune mechanisms with experimental and human studies indicating that acute severe stressors may be even immunosuppressive, while chronic stress may enhance immune responses. The interactions between the immunological and neuroendocrine circuits is the subject of active and extensive ongoing research and might in the near future offer highly promising strategies for hormone-replacement therapies in RA.
Andrew S. Vore
Full Text Available Adolescent alcohol use comprises a significant public health concern and is often characterized by binge-like consumption patterns. While ethanol exposure in adulthood has been shown to alter the stress response, including the Hypothalamic–Pituitary–Adrenal (HPA axis, few studies have examined whether binge-like ethanol exposure during adolescence results in enduring changes in HPA axis sensitivity in adulthood. In the present studies, adolescent Sprague-Dawley rats were given intragastric (i.g. intubations of ethanol (4 g/kg or vehicle once per day for three consecutive days, beginning on postnatal day (P 30 (±1. This exposure was followed by a 2-day period of rest/withdrawal. Rats received a total of either two (Experiments 1, 2 and 3 or four (Experiment 4 cycles of ethanol exposure and were subsequently allowed to age normally until adulthood. In Experiment 1, adult, (P71–75, ethanol- or vehicle-exposed rats received a 60 min restraint stress challenge. In Experiment 2, rats received a 50 μg/kg injection of lipopolysaccharide (LPS. In Experiment 3, rats received a challenge of 2.5 g/kg ethanol (intraperitoneally; i.p.. In Experiment 4, male and female ethanol- or vehicle- exposed rats received a 50 μg/kg injection of LPS. In all experiments, blood samples were collected for later assessment of corticosterone (CORT, blood ethanol concentrations (BECs, and the cellular fraction of blood was analyzed for cytokine gene expression. As expected, all three challenges led to a time-dependent surge in CORT. Gene expression analyses of cytokines (Interleukin [IL]-6, IL-1β, and Tumor necrosis factor alpha [TNFα] from the cellular fraction of blood revealed unique, time-dependent patterns of cytokine expression depending upon the nature of the adult challenge incurred (restraint, LPS, or EtOH. Importantly, adolescent ethanol exposure led to attenuated restraint and LPS-induced cytokine expression in males, whereas female rats displayed an
Lengua, Liliana J.; Zalewski, Maureen; Fisher, Phil; Moran, Lyndsey
The effects of low income on children's adjustment might be accounted for by disruptions to hypothalamic-pituitary-adrenal (HPA)-axis activity and to the development of effortful control. Using longitudinal data and a community sample of preschool-age children (N?=?306, 36-39?months) and their mothers, recruited to over-represent low-income…
Castañeda Cortés, Diana C; Langlois, Valerie S; Fernandino, Juan I
Besides the well-known function of thyroid hormones (THs) for regulating metabolism, it has recently been discovered that THs are also involved in testicular development in mammalian and non-mammalian species. THs, in combination with follicle stimulating hormone, lead to androgen synthesis in Danio rerio, which results in the onset of spermatogenesis in the testis, potentially relating the hypothalamic-pituitary-thyroid (HPT) gland to the hypothalamic-pituitary-gonadal (HPG) axes. Furthermore, studies in non-mammalian species have suggested that by stimulating the thyroid-stimulating hormone (TSH), THs can be induced by corticotropin-releasing hormone. This suggests that the hypothalamic-pituitary-adrenal/interrenal gland (HPA) axis might influence the HPT axis. Additionally, it was shown that hormones pertaining to both HPT and HPA could also influence the HPG endocrine axis. For example, high levels of androgens were observed in the testis in Odonthestes bonariensis during a period of stress-induced sex-determination, which suggests that stress hormones influence the gonadal fate toward masculinization. Thus, this review highlights the hormonal interactions observed between the HPT, HPA, and HPG axes using a comparative approach in order to better understand how these endocrine systems could interact with each other to influence the development of testes.
Debonne, M.; Baarendse, P.J.J.; Brand, van den H.; Kemp, B.; Bruggeman, V.; Decuypere, E.
The emergence of thermoregulation in avian species is a complex matter in which neural as well as hormonal processes are involved. In a previous paper, the neural aspects of primary avian thermoregulation were discussed. In this paper the role of the hypothalamus-pituitary-thyroid axis (HPT-axis)
Topic, Bianca; Oitzl, Melly S; Meijer, Onno C; Huston, Joseph P; de Souza Silva, Maria A
Clinical studies point to structural differences in the neurobiological mechanisms underlying early versus late onset of depression. However, studies examining the neuropathology of depressive-like behavior induced in the aged rodent are sparse. Extinction of learned behavior induces be- havioral 'despair', and is held to provide a conceptual and empirical model of human depression resulting from the withdrawal of reinforcement. We tested whether the neuroendocrinological and chemical concomitants of susceptibility to extinction-induced despair in aged animals differed from adult ones. Following the withholding of reinforcement (extinction of escape from a water maze), a number of aged and adult rats are prone to develop depressive-like behavior, i.e. immobility. Analysis of hypothalamus-pituitary-adrenal (HPA) axis markers revealed an increase in the mineralocorticoid/glucocorticoid receptor (MR/GR) mRNA ratio in the CA1 region of the hippocampus in aged and adult despair animals; however, in dependence on age, divergent changes contributed to the enhanced ratio. While aged despair rats had less GR mRNA, adult despair rats had more MR mRNA. Furthermore, age- and despair-related interactions with hippocampal and cortical steroid receptor co-activators and neurotransmitter contents in diverse brain areas were found. For instance, adult despair rats had an increased, and aged despair rats a decreased, DOPAC/dopamine turnover compared to the respective non-despair group. These results show that neurobiological underpinnings of depression in the aged differ from those of adults, and underline the importance of investigating age-related alterations in HPA axis dynamics in conjunction with neurotransmitter systems to advance our knowledge about neuronal mechanisms of late-life and/or late-onset depression. 2008 S. Karger AG, Basel.
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
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…
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.
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
Rao Bondugulapati, L N; Rees, D A
Inhaled corticosteroids (ICS) are established as a cornerstone of management for patients with bronchoconstrictive lung disease. However, systemic absorption may lead to suppression of the hypothalamic-pituitary-adrenal (HPA) axis in a significant minority of patients. This is more likely in 'higher risk' patients exposed to high cumulative ICS doses, and in those treated with frequent oral corticosteroids or drugs which inhibit cytochrome p450 3A4. Hypothalamic-pituitary-adrenal axis suppression is frequently unrecognized, such that some patients, notably children, only come to light when an adrenal crisis is precipitated by physical stress. To minimize this risk, 'higher risk' patients and those with previously identified suppressed cortisol responses to Synacthen testing should undergo an education programme to inform them about sick day rules. A review of ICS therapy should also be undertaken to ensure that the dose administered is the minimum required to control symptoms. © 2016 John Wiley & Sons Ltd.
Johnson, Megan M.; Dismukes, Andrew R.; Vitacco, Michael J.; Breiman, Chelsea; Fleury, Donald; Shirtcliff, Elizabeth A.
Conduct disorder (CD) is a heterogeneous diagnosis, leading researchers to initiate research into the neurobiological mechanisms underlying this disorder. One specifier of CD currently considered for inclusion in the DSM-V is callous-unemotional (CU) traits. CU traits are thought to have neuroendocrine underpinnings, yet little is known about Hypothalamic-Pituitary-Adrenal (HPA) and –Gonadal (HPG) hormones in the context of psychopathic traits. The current study sought to identify daily coupl...
Conrad, Cheryl D; Bimonte-Nelson, Heather A
Life expectancies have increased substantially in the last century, dramatically amplifying the proportion of individuals who will reach old age. As individuals age, cognitive ability declines, although the rate of decline differs amongst the forms of memory domains and for different individuals. Memory domains especially impacted by aging are declarative and spatial memories. The hippocampus facilitates the formation of declarative and spatial memories. Notably, the hippocampus is particularly vulnerable to aging. Genetic predisposition and lifetime experiences and exposures contribute to the aging process, brain changes and subsequent cognitive outcomes. In this review, two factors to which an individual is exposed, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, will be considered regarding the impact of age on hippocampal-dependent function. Spatial memory can be affected by cumulative exposure to chronic stress via glucocorticoids, released from the HPA axis, and from gonadal steroids (estrogens, progesterone and androgens) and gonadotrophins, released from the HPG axis. Additionally, this review will discuss how these hormones impact age-related hippocampal function. We hypothesize that lifetime experiences and exposure to these hormones contribute to the cognitive makeup of the aged individual, and contribute to the heterogeneous aged population that includes individuals with cognitive abilities as astute as their younger counterparts, as well as individuals with severe cognitive decline or neurodegenerative disease. Copyright 2010 Elsevier B.V. All rights reserved.
Influence of environmental enrichment on hypothalamic-pituitary-adrenal (HPA) responses to single-dose nicotine, continuous nicotine by osmotic mini-pumps, and nicotine withdrawal by mecamylamine in male and female rats
Skwara, Amanda J.; Karwoski, Tracy E.; Czambel, R. Kenneth; Rubin, Robert T.; Rhodes, Michael E.
In the present study, we determined the effects of environmental enrichment (EE; Kong Toys® and Nestlets®) on sexually diergic HPA axis responses to single-dose nicotine (NIC), single-dose NIC following continuous NIC administration for two weeks, and NIC withdrawal by single-dose mecamylamine (MEC) in male and female rats. Blood sampling occurred before and after MEC and NIC administrations for the determination of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Supporting and extending our previous findings, EE appeared to produce anxiolytic effects by reducing hormone responses: Male and female rats housed with EE had lower baseline ACTH and significantly lower HPA axis responses to the mild stress of saline (SAL) injection than did those housed without EE. The sexually diergic responses to single dose NIC, continuous NIC, and MEC-induced NIC withdrawal were reduced by EE in many male and female groups. ACTH responses to continuous NIC and MEC-induced NIC withdrawal were blunted to a greater extent in female EE groups than in male EE groups, suggesting that females are more sensitive to the anxiolytic effects of EE. Because EE lowered stress-responsive hormones of the HPA axis in most groups, EE may be a useful intervention for stress reduction in animal models of NIC addiction. As well, the effectiveness of EE in animal studies of NIC withdrawal may enlighten human studies addressing coping styles and tobacco cessation in men and women. PMID:22705101
Joseph, Dana N; Whirledge, Shannon
An organism's reproductive fitness is sensitive to the environment, integrating cues of resource availability, ecological factors, and hazards within its habitat. Events that challenge the environment of an organism activate the central stress response system, which is primarily mediated by the hypothalamic-pituitary-adrenal (HPA) axis. The regulatory functions of the HPA axis govern the cardiovascular and metabolic system, immune functions, behavior, and reproduction. Activation of the HPA axis by various stressors primarily inhibits reproductive function and is able to alter fetal development, imparting a biological record of stress experienced in utero. Clinical studies and experimental data indicate that stress signaling can mediate these effects through direct actions in the brain, gonads, and embryonic tissues. This review focuses on the mechanisms by which stress activation of the HPA axis impacts fertility and fetal development.
Crofford, L J; Jacobson, J; Young, E
Autoimmune and stress-related rheumatic diseases are significantly more common in women than in men. Our group has focused on the role of two principal neuroendocrine axes, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, in this increased susceptibility to rheumatic disease. We review the physiology of the HPA and HPG axes and discuss their reciprocal interactions. Mechanisms by which hormones of the HPA and HPG axes influence the immune system and modulate the course of autoimmune inflammatory diseases in animal models of rheumatic disease are described. In addition, we review the data suggesting the importance of these neurohormonal systems in rheumatic diseases. These data provide insights into why women may be at increased risk and how we might better understand the mechanisms that provoke expression of rheumatic diseases in women. To advance research in this area, it is critical to develop methods to evaluate the function of the neuroendocrine axes. Secretion of both HPA and HPG axis hormones, particularly the hormones of the hypothalamus and anterior pituitary, is largely by intermittent pulses. In addition, the HPA axis exhibits a profound circadian, or near 24-hour, variation, and HPG axis hormones fluctuate over the monthly cycle. These factors make meaningful analysis of these axes quite complex. We discuss models used in the analyses of neuroendocrine axes and the use of challenge testing to assess the integrity of neuroendocrine axes.
Repercussões imunológicas dos distúrbios do sono: o eixo hipotálamo-pituitária-adrenal como fator modulador Immune outcomes of sleep disorders: the hypothalamic-pituitary-adrenal axis as a modulatory factor
Beatriz Duarte Palma
Full Text Available OBJETIVO: Revisar a literatura a respeito da interação entre sono e sistema imunológico. MÉTODO: Busca no Web of Science e no PubMed com os descritores: sono, privação de sono, estresse, eixo hipotálamo-pituitária-adrenal, sistema imunológico e doenças auto-imunes. RESULTADOS: Foram encontrados 588 artigos no Web of Science. As 61 referências mais significativas e mais relacionadas aos objetivos do estudo foram utilizadas. Foram incluídos artigos originais e de revisão. CONCLUSÃO: A privação de sono e o sistema imunológico exercem e sofrem influências mútuas. A privação de sono é considerada um estressor, uma vez que induz a elevação do cortisol em seres humanos - ou da corticosterona em roedores. Os glicocorticóides, por sua vez, exercem um efeito imunossupressor. Por essas razões, foi proposto que o aumento da ativação do eixo hipotálamo-pituitária-adrenal seja um importante mediador das alterações imunológicas observadas em pacientes com insônia ou privados de sono.OBJECTIVE: To review the literature on the interaction between sleep and the immune system. METHOD: A search on Web of Science and Pubmed database including the keywords sleep, sleep deprivation, stress, hypothalamic-pituitary-adrenal axis, immune system, and autoimmune diseases. RESULTS: On Web of Science, 588 publications were retrieved; 61 references, more significant and closer to our objective, were used, including original articles and review papers. CONCLUSION: Sleep deprivation and immune system exert a bidirectional influence on each other. Since sleep deprivation is considered a stressor, inasmuch as it induces elevation of cortisol or corticosterone levels in humans and rodents, respectively, and given the well-known immunosuppressive effect of glucocorticoids, we propose that increased activation of the hypothalamic-pituitary-adrenal axis is a major mediator of the immune alterations observed in patients with insomnia or in sleep
White-Welkley, J E; Bunnell, B N; Mougey, E H; Meyerhoff, J L; Dishman, R K
It is generally believed that physical fitness promotes health by attenuating responsiveness to other stressors. The experimental evidence for this belief is limited and does not extend to interactions between the hypothalamic-pituitary-adrenal cortical (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. We tested the hypothesis that treadmill exercise training would lead to an estrogen-dependent hyporesponsiveness of the HPA axis that would generalize to immobilization stress. Ovariectomized female Sprague-Dawley rats (N = 74) that had been treadmill trained (TT) or sedentary for 6 weeks received intramuscular injections of estradiol benzoate (Eb) or sesame oil on each of 3 days prior to 15 min of acute treadmill running or immobilization. Plasma (adrenocorticotrophin) (ACTH), (corticosterone) (B) and (prolactin) (PRL) were determined from trunk blood by radioimmunoassay and compared in a 2 group (TT vs. sedentary)-by-2 treatment (Eb vs. oil)-by-2 acute stressor (running vs. immobilization) design. Home-cage (HC) animals (N = 24) provided baseline hormone levels. ACTH and B levels were elevated after stressors in animals treated with either Eb or oil compared to HC, but increases in PRL after stressors were dependent on Eb. Treadmill exercise training led to an attenuation of ACTH and prolactin to running, but the attenuation did not generalize to immobilization. In contrast, treadmill exercise training led to a hyperresponsiveness of ACTH. Treadmill training did not modulate prolactin responses to immobilization. The modulating effects of the estradiol treatment are consistent with an interaction of the HPA and HPG axes in response to stress.(ABSTRACT TRUNCATED AT 250 WORDS)
Lawson, Elizabeth A.; Holsen, Laura M.; DeSanti, Rebecca; Santin, McKale; Meenaghan, Erinne; Herzog, David B.; Goldstein, Jill M.; Klibanski, Anne
Objective Corticotropin releasing hormone (CRH)-mediated hypercortisolemia has been demonstrated in anorexia nervosa (anorexia), a psychiatric disorder characterized by food restriction despite low body weight. While CRH is anorexigenic, downstream cortisol stimulates hunger. Using a food-related fMRI paradigm, we have demonstrated hypoactivation of brain regions involved in food motivation in women with anorexia, even after weight-recovery. The relationship between hypothalamic-pituitary-adrenal (HPA) axis dysregulation and appetite, and the association with food motivation neurocircuitry hypoactivation is unknown in anorexia. We investigated the relationship between HPA activity, appetite and food motivation neurocircuitry hypoactivation in anorexia. Design Cross-sectional study of 36 women [13 anorexia (AN), 10 weight-recovered AN (ANWR), 13 healthy controls (HC)]. Methods Peripheral cortisol and ACTH levels were measured fasting and 30, 60, and 120min after a standardized mixed meal. The Visual Analogue Scale was used to assess homeostatic and hedonic appetite. fMRI was performed during visual processing of food and non-food stimuli to measure brain activation pre- and post-meal. Results In each group, serum cortisol levels decreased following the meal. Mean fasting, 120min post-meal, and nadir cortisol levels were high in AN vs. HC. Mean postprandial ACTH levels were high in ANWR compared to HC and AN. Cortisol levels were associated with lower fasting homeostatic and hedonic appetite, independent of BMI and depressive symptoms. Cortisol levels were also associated with between-group variance in activation in food-motivation brain regions (e.g., hypothalamus, amygdala, hippocampus, OFC and insula). Conclusions HPA activation may contribute to the maintenance of anorexia by suppression of appetitive drive. PMID:23946275
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 (PHPA 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.
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.
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.…
Johnson, Megan M; Dismukes, Andrew R; Vitacco, Michael J; Breiman, Chelsea; Fleury, Donald; Shirtcliff, Elizabeth A
Conduct disorder (CD) is a heterogeneous diagnosis, leading researchers to initiate studies focused on neurobiological mechanisms underlying this disorder. One specifier of CD currently considered for inclusion in the DSM-V is callous-unemotional (CU) traits, a key component of psychopathy. CU traits are thought to have neuroendocrine underpinnings, yet little is known about hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) hormones in the context of psychopathic traits. The current study sought to identify daily coupling patterns between HPA and HPG hormones in order to clarify distinct neurobiological underpinning associated with psychopathic/CU traits. Fifty incarcerated adolescent males who met criteria for CD were recruited and provided 10 saliva samples across 2 days. Participants completed the Psychopathy Checklist Youth Version (PCL:YV) and Inventory of Callous Unemotional Traits (ICU) on a third day. Diurnal cortisol, testosterone, and DHEA functioning was modeled via hierarchical linear modeling. Psychopathy subscales from the measures administered were used as predictors of daily coupling patterns between these hormones. Results indicated all three hormones were tightly coupled. Further, higher PCL-YV interpersonal scores related to greater coupling between all three hormones, whereas higher ICU callousness scores related to greater uncoupling of testosterone with cortisol and DHEA. The current study is novel in its emphasis on testing the coupling of HPA and HPG hormones among incarcerated adolescent males. Results suggest that affective and interpersonal psychopathic traits are marked by unique HPA- and HPG coupling. © 2013 Wiley Periodicals, Inc.
Spencer, Robert L; Deak, Terrence
Glucocorticoid hormones (cortisol and corticosterone - CORT) are the effector hormones of the hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system. CORT is a systemic intercellular signal whose level predictably varies with time of day and dynamically increases with environmental and psychological stressors. This hormonal signal is utilized by virtually every cell and physiological system of the body to optimize performance according to circadian, environmental and physiological demands. Disturbances in normal HPA axis activity profiles are associated with a wide variety of physiological and mental health disorders. Despite numerous studies to date that have identified molecular, cellular and systems-level glucocorticoid actions, new glucocorticoid actions and clinical status associations continue to be revealed at a brisk pace in the scientific literature. However, the breadth of investigators working in this area poses distinct challenges in ensuring common practices across investigators, and a full appreciation for the complexity of a system that is often reduced to a single dependent measure. This Users Guide is intended to provide a fundamental overview of conceptual, technical and practical knowledge that will assist individuals who engage in and evaluate HPA axis research. We begin with examination of the anatomical and hormonal components of the HPA axis and their physiological range of operation. We then examine strategies and best practices for systematic manipulation and accurate measurement of HPA axis activity. We feature use of experimental methods that will assist with better understanding of CORT's physiological actions, especially as those actions impact subsequent brain function. This research approach is instrumental for determining the mechanisms by which alterations of HPA axis function may contribute to pathophysiology. Copyright © 2016 Elsevier Inc. All rights reserved.
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.
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.
Lago, Natalia; Quintana, Albert; Carrasco, Javier; Giralt, Mercedes; Hidalgo, Juan; Molinero, Amalia
Metallothioneins (MTs) are multipurpose proteins with clear antioxidant, anti-inflammatory and metal homeostasis properties. The roles of brain MT-1 and MT-2 are similar to those described in the periphery, and are inducible by metals, inflammatory and stress stimuli. MT-3, originally named growth inhibitory factor, exists mainly in the central nervous system, is hardly ever inducible and its functional role and regulation are poorly understood and controversial. In the present study we examined how absence of MT-3 affects phenotypic characteristics and its effects on MT1/2 expression in basal situation and after induction. Hyperactive behavior was found only in young male Mt-3 KO mice and disappeared in the older ones. Absence of MT-3 was associated with a significant increase of MT-1/2 protein levels in several brain areas but decreased MT-1 mRNA levels, which might be related to lower corticosterone levels. The response to stress or inflammation on corticosterone plasma levels was similar in wild type and Mt-3 KO mice, suggesting that the relevant MT-3 role as MT-1/2 regulator in basal conditions is lost when other important regulatory factors such as glucocorticoids or cytokines appear. Copyright © 2014 Elsevier Ltd. All rights reserved.
Michopoulos, Vasiliki; Reding, Katherine M; Wilson, Mark E; Toufexis, Donna
Linear dominance hierarchies organize and maintain stability in female rhesus macaque (Macaca mulatta) social groups regardless of group size. As a consequence of their low social status, subordinate females suffer from an array of adverse outcomes including reproductive compromise, impaired immune function, and poor cardiovascular health. However, data that differentiate limbic-hypothalamic-pituitary-adrenal axis (LHPA) parameters between dominant from subordinate female monkeys are inconsistent, bringing into question whether social subordination alters the LHPA axis in female macaques. One difficulty in examining LHPA function in macaques may be the confounding effects of cycling ovarian steroids that are known to modulate LHPA activity. The current study used ovariectomized dominant and subordinate female rhesus monkeys to examine the effect that social subordination has on LHPA function by measuring morning and diurnal serum cortisol levels, dexamethasone (Dex) suppression of cortisol, metabolic clearance of Dex, and ACTH stimulation of adrenal cortisol release and cortisol response following exposure to acute social isolation. Compared to dominant females, subordinate females showed diminished morning peak cortisol secretion, weakened glucocorticoid negative feedback, and decreased adrenal cortisol response to an ACTH challenge as well as a restrained cortisol response following social isolation. However, the metabolism of Dex did not account for differences in Dex suppression between dominant and subordinate females. These results indicate that the ability to mount and limit glucocorticoid release is significantly reduced by psychosocial stress in female rhesus macaques, suggesting a hyporesponsive LHPA phenotype which resembles that observed in several human psychopathologies. Copyright © 2012 Elsevier Inc. All rights reserved.
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Quinn, Matthew; Ueno, Yoshiyuki; Pae, Hae Yong; Huang, Li; Frampton, Gabriel; Galindo, Cheryl; Francis, Heather; Horvat, Darijana; McMillin, Matthew
Cholestatic patients often present with clinical features suggestive of adrenal insufficiency. In the bile duct-ligated (BDL) model of cholestasis, the hypothalamic-pituitary-adrenal (HPA) axis is suppressed. The consequences of this suppression on cholangiocyte proliferation are unknown. We evaluated 1) HPA axis activity in various rat models of cholestasis and 2) effects of HPA axis modulation on cholangiocyte proliferation. Expression of regulatory molecules of the HPA axis was determined after BDL, partial BDL, and α-naphthylisothiocyanate (ANIT) intoxication. The HPA axis was suppressed by inhibition of hypothalamic corticotropin-releasing hormone (CRH) expression by central administration of CRH-specific Vivo-morpholinos or by adrenalectomy. After BDL, the HPA axis was reactivated by 1) central administration of CRH, 2) systemic ACTH treatment, or 3) treatment with cortisol or corticosterone for 7 days postsurgery. There was decreased expression of 1) hypothalamic CRH, 2) pituitary ACTH, and 3) key glucocorticoid synthesis enzymes in the adrenal glands. Serum corticosterone and cortisol remained low after BDL (but not partial BDL) compared with sham surgery and after 2 wk of ANIT feeding. Experimental suppression of the HPA axis increased cholangiocyte proliferation, shown by increased cytokeratin-19- and proliferating cell nuclear antigen-positive cholangiocytes. Conversely, restoration of HPA axis activity inhibited BDL-induced cholangiocyte proliferation. Suppression of the HPA axis is an early event following BDL and induces cholangiocyte proliferation. Knowledge of the role of the HPA axis during cholestasis may lead to development of innovative treatment paradigms for chronic liver disease. PMID:21979757
Lan, N; Yamashita, F; Halpert, A G; Ellis, L; Yu, W K; Viau, V; Weinberg, J
Prenatal ethanol exposure has marked effects on development of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes. In adulthood, ethanol-treated rats show altered gonadal hormone responses and reproductive function, and increased HPA responsiveness to stressors. Importantly, prenatal ethanol differentially alters stress responsiveness in adult males and females, raising the possibility that the gonadal hormones play a role in mediating prenatal ethanol effects on HPA function. To examine a possible testicular influence on HPA activity in males, we compared the effects of gonadectomy on HPA stress responses of adult male offspring from ethanol, pair-fed (PF) and ad libitum-fed control dams. Intact ethanol-treated rats showed increased adrenocorticotrophic hormone (ACTH) but blunted testosterone and luteinising hormone (LH) responses to restraint stress, and no stress-induced elevation in arginine vasopressin (AVP) mRNA levels compared to those observed in PF and/or control rats. Gonadectomy: (i) significantly increased ACTH responses to stress in control but not ethanol-treated and PF males; (ii) eliminated differences among groups in plasma ACTH and AVP mRNA levels; and (iii) altered LH and gonadotrophin-releasing hormone responses in ethanol-treated males. Taken together, these findings suggest that central regulation of both the HPA and HPG axes are altered by prenatal ethanol exposure, with normal testicular influences on HPA function markedly reduced in ethanol-treated animals. A decreased sensitivity to inhibitory effects of androgens could contribute to the HPA hyperresponsiveness typically observed in ethanol-treated males.
Lawson, Elizabeth A; Holsen, Laura M; Desanti, Rebecca; Santin, McKale; Meenaghan, Erinne; Herzog, David B; Goldstein, Jill M; Klibanski, Anne
Corticotrophin-releasing hormone (CRH)-mediated hypercortisolemia has been demonstrated in anorexia nervosa (AN), a psychiatric disorder characterized by food restriction despite low body weight. While CRH is anorexigenic, downstream cortisol stimulates hunger. Using a food-related functional magnetic resonance imaging (fMRI) paradigm, we have demonstrated hypoactivation of brain regions involved in food motivation in women with AN, even after weight recovery. The relationship between hypothalamic-pituitary-adrenal (HPA) axis dysregulation and appetite and the association with food-motivation neurocircuitry hypoactivation are unknown in AN. We investigated the relationship between HPA activity, appetite, and food-motivation neurocircuitry hypoactivation in AN. Cross-sectional study of 36 women (13 AN, ten weight-recovered AN (ANWR), and 13 healthy controls (HC)). Peripheral cortisol and ACTH levels were measured in a fasting state and 30, 60, and 120 min after a standardized mixed meal. The visual analog scale was used to assess homeostatic and hedonic appetite. fMRI was performed during visual processing of food and non-food stimuli to measure the brain activation pre- and post-meal. In each group, serum cortisol levels decreased following the meal. Mean fasting, 120 min post-meal, and nadir cortisol levels were high in AN vs HC. Mean postprandial ACTH levels were high in ANWR compared with HC and AN subjects. Cortisol levels were associated with lower fasting homeostatic and hedonic appetite, independent of BMI and depressive symptoms. Cortisol levels were also associated with between-group variance in activation in the food-motivation brain regions (e.g. hypothalamus, amygdala, hippocampus, orbitofrontal cortex, and insula). HPA activation may contribute to the maintenance of AN by the suppression of appetitive drive.
Chiang, Jessica J.; Tsai, Kim M.; Park, Heejung; Bower, Julienne E.; Almeida, David M.; Dahl, Ronald E.; Irwin, Michael R.; Seeman, Teresa E.; Fuligni, Andrew J.
The present study examined the moderating role of sleep in the association between family demands and conflict and hypothalamic-pituitary-adrenal (HPA) axis functioning in a sample of ethnically diverse adolescents (n = 316). Adolescents completed daily diary reports of family demands and conflict for 15 days, and wore actigraph watches during the first 8 nights to assess sleep. Participants also provided five saliva samples for 3 consecutive days to assess diurnal cortisol rhythms. Regression analyses indicated that sleep latency and efficiency moderated the link between family demands and the cortisol awakening response. Specifically, family demands were related to a smaller cortisol awakening response only among adolescents with longer sleep latency and lower sleep efficiency. These results suggest that certain aspects of HPA axis functioning may be sensitive to family demands primarily in the context of longer sleep latency and lower sleep efficiency. PMID:27235639
Johnson, Megan M.; Dismukes, Andrew R.; Vitacco, Michael J.; Breiman, Chelsea; Fleury, Donald; Shirtcliff, Elizabeth A.
Conduct disorder (CD) is a heterogeneous diagnosis, leading researchers to initiate research into the neurobiological mechanisms underlying this disorder. One specifier of CD currently considered for inclusion in the DSM-V is callous-unemotional (CU) traits. CU traits are thought to have neuroendocrine underpinnings, yet little is known about Hypothalamic-Pituitary-Adrenal (HPA) and –Gonadal (HPG) hormones in the context of psychopathic traits. The current study sought to identify daily coupling patterns between HPA and HPG hormones in order to clarify distinct neurobiological underpinning associated with psychopathic/CU traits. Fifty incarcerated adolescent males who met criteria for CD were recruited and provided 10 saliva samples across two days. Participants completed the Psychopathy Checklist Youth Version (PCL:YV) and Inventory of Callous Unemotional Traits (ICU) on a third day. Diurnal cortisol, testosterone, and DHEA functioning was modeled via hierarchical linear modeling. Psychopathy subscales from the measures administered were used as predictors of daily coupling patterns between these hormones. Results indicated that all three hormones were tightly coupled. Further, higher PCL-YV interpersonal scores related to greater coupling between all three hormones, whereas higher ICU callousness scores related to greater uncoupling of testosterone with cortisol and DHEA. The current study is novel in its emphasis on testing the coupling of HPA and HPG hormones among incarcerated adolescent males. Results suggest that affective and interpersonal psychopathic traits are marked by unique HPA- and HPG- coupling. PMID:23852424
Hill, M. N.; Tasker, J. G.
The hypothalamic-pituitary-adrenal (HPA) axis regulates the outflow of glucocorticoid hormones under basal conditions and in response to stress. Within the last decade, a large body of evidence has mounted indicating that the endocannabinoid system is involved in the central regulation of the stress response; however, the specific role endocannabinoid signalling plays in phases of HPA axis regulation, or the neural sites of action mediating this regulation, was not mapped out until recently. This review aims to collapse the current state of knowledge regarding the role of the endocannabinoid system in the regulation of the HPA axis to put together a working model of how and where endocannabinoids act within the brain to regulate outflow of the HPA axis. Specifically, we discuss the role of the endocannabinoid system in the regulation of the HPA axis under basal conditions, activation in response to acute stress and glucocorticoid-mediated negative feedback. Interestingly, there appears to be some anatomical specificity to the role of the endocannabinoid system in each phase of HPA axis regulation, as well as distinct roles of both anandamide and 2-arachidonoylglycerol in these phases. Ultimately, the current level of information indicates that endocannabinoid signalling acts to suppress HPA axis activity through concerted actions within the prefrontal cortex, amygdala and hypothalamus. PMID:22214537
Shah, Jai L; Malla, Ashok K
In the context of a stress-vulnerability framework, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is thought contribute to the risk, onset and course of psychotic illness. However, recent reports regarding static and dynamic features of the HPA axis suggest a more complex set of phenomena at play in the early phases of psychosis. We review literature regarding structural and functional aspects of the HPA axis in subjects at risk for or experiencing the first episode of psychosis, including evidence favoring as well as that which contradicts a model of HPA axis hyperactivation. Static measures of diurnal cortisol and hippocampal/pituitary volumes suggest that the HPA axis is in a hyperactivated state in early phases of psychosis. In contrast, the dynamic cortisol response to encountered or anticipated stress is blunted in the same populations. These incongruent findings need to be better understood. We consider potential explanations for the seemingly contradictory elevation and blunting of HPA biomarkers in the early course of psychosis. Finally, we propose and explore implications of a conceptual model of tonic HPA hyperactivation and phasic HPA blunting that integrates and reconciles these data. Copyright © 2015 Elsevier B.V. All rights reserved.
Lin, Tzu-Kai; Zhong, Lily; Santiago, Juan Luis
The hypothalamic-pituitary-adrenal (HPA) axis is one of the body's neuroendocrine networks that responds to psychological stress (PS). In the skin, there exists a peripheral HPA axis similar to the central axis. Glucocorticoids (GCs) are key effector molecules of the HPA axis and are essential for cutaneous homeostasis. Atopic dermatitis (AD) is a condition typically characterized by a chronic relapsing course that often results in PS. HPA dysfunction is present in AD patients by the decreased response of GCs elevation to stress as compared to those unaffected by AD. Nevertheless, in skin, acute PS activates several metabolic responses that are of immediate benefit to the host. During the acute phase of PS, increased endogenous GCs have been shown to provide benefit rather than by aggravating cutaneous inflammatory dermatoses. However, a chronic T helper cell type 2 (Th2) predominant cytokine profile acts as a negative feedback loop to blunt the HPA axis response in AD. In this article, we reviewed the role of CRF, pro-opiomelanocortin (POMC)-derived peptides, GCs of the HPA, and 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in AD, with a discussion of the pathogenetic mechanisms of inflammation and skin barrier functions, including antimicrobial defense, and their association with PS.
Otten, W; Kanitz, E; Couret, D; Veissier, I; Prunier, A; Merlot, E
Maternal stress in pregnant sows may induce long-lasting alterations in the behavior, physiology, and immunity of their offspring. The aim of the present study was to investigate the consequences of repeated social stress during late gestation on determinants of the hypothalamic-pituitary-adrenal axis and on hippocampal neurotransmitter profiles in pig offspring. All pregnant gilts were housed in pairs. Each Stress gilt was mixed with an unfamiliar gilt twice a week between days 77 and 105 of gestation (n=18). Control gilts were housed in stable pairs over the same period (n=18). Plasma cortisol and corticosteroid binding globulin (CBG) were measured in 1 male and 1 female per litter in a basal situation on postnatal days (PND) 4, 26, and 60 and in a stressful situation at PND 28 (2 d after weaning) and 62 (2 d after relocation to a new building). Prenatal stress had no effect on plasma cortisol, but it decreased CBG at PND 26. Brain and adrenals were collected from 1 female per litter after weaning or relocation at PND 28 and PND 62. Adrenals were additionally collected at PND 4. Glucocorticoid receptor binding in the hippocampus and hypothalamus was not affected by prenatal treatment. However, prenatal stress increased the expression of 11beta-hydroxysteroid dehydrogenase type 1 mRNA in the hippocampus after weaning (P<0.05) and after relocation (P=0.08). In addition, prenatally stressed piglets showed an increased 5-hydroxyindole-3-acetic acid to 5-hydroxytryptamine ratio in the hippocampus after weaning and increased hippocampal c-fos mRNA expression and noradrenaline concentration after relocation (P<0.05). Prenatal stress also increased the relative adrenal weight at PND 4 and the cell density in the cortex and the medulla at PND 28, whereas no difference was found for activities of catecholamine-synthesising enzymes in the medulla. Overall, our data indicate that repeated social stress during pregnancy has long-lasting consequences on hypothalamic-pituitary-adrenal
Čupić, Željko; Stanojević, Ana; Marković, Vladimir M; Kolar-Anić, Ljiljana; Terenius, Lars; Vukojević, Vladana
Stress and alcohol use are interrelated-stress contributes to the initiation and upholding of alcohol use and alcohol use alters the way we perceive and respond to stress. Intricate mechanisms through which ethanol alters the organism's response to stress remain elusive. We have developed a stoichiometric network model to succinctly describe neurochemical transformations underlying the stress response axis and use numerical simulations to model ethanol effects on complex daily changes of blood levels of cholesterol, 6 peptide and 8 steroid hormones. Modelling suggests that ethanol alters the dynamical regulation of hypothalamic-pituitary-adrenal (HPA) axis activity by affecting the amplitude of ultradian oscillations of HPA axis hormones, which defines the threshold with respect to which the response to stress is being set. These effects are complex-low/moderate acute ethanol challenge (8 mM) increases instantaneous CORT levels and the amplitude of ultradian CORT oscillations in a dose-dependent manner, affecting the HPA axis activity also during the following day(s). Chronic exposure to ethanol qualitatively changes the HPA axis dynamics, whereas ethanol at intoxicating levels shuts down this dynamic regulation mechanism. Mathematical modelling gives a quantitative biology-based framework that can be used for predicting how the integral HPA axis response is perturbed by alcohol. © 2016 Society for the Study of Addiction.
Azuma, Kagaku; Zhou, Qian; Niwa, Masami; Kubo, Kin-ya
Mastication is mainly involved in food intake and nutrient digestion with the aid of teeth. Mastication is also important for preserving and promoting general health, including hippocampus-dependent cognition. Both animal and human studies indicate that mastication influences hippocampal functions through the end product of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoid (GC). Epidemiologic studies suggest that masticatory dysfunction in aged individuals, such as that resulting from tooth loss and periodontitis, acting as a source of chronic stress, activates the HPA axis, leading to increases in circulating GCs and eventually inducing various physical and psychological diseases, such as cognitive impairment, cardiovascular disorders, and osteoporosis. Recent studies demonstrated that masticatory stimulation or chewing during stressful conditions suppresses the hyperactivity of the HPA axis via GCs and GC receptors within the hippocampus, and ameliorates chronic stress-induced hippocampus-dependent cognitive deficits. Here, we provide a comprehensive overview of current research regarding the association between mastication, the hippocampus, and HPA axis activity. We also discuss several potential molecular mechanisms involved in the interactions between mastication, hippocampal function, and HPA axis activity. PMID:28771175
Azuma, Kagaku; Zhou, Qian; Niwa, Masami; Kubo, Kin-Ya
Mastication is mainly involved in food intake and nutrient digestion with the aid of teeth. Mastication is also important for preserving and promoting general health, including hippocampus-dependent cognition. Both animal and human studies indicate that mastication influences hippocampal functions through the end product of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoid (GC). Epidemiologic studies suggest that masticatory dysfunction in aged individuals, such as that resulting from tooth loss and periodontitis, acting as a source of chronic stress, activates the HPA axis, leading to increases in circulating GCs and eventually inducing various physical and psychological diseases, such as cognitive impairment, cardiovascular disorders, and osteoporosis. Recent studies demonstrated that masticatory stimulation or chewing during stressful conditions suppresses the hyperactivity of the HPA axis via GCs and GC receptors within the hippocampus, and ameliorates chronic stress-induced hippocampus-dependent cognitive deficits. Here, we provide a comprehensive overview of current research regarding the association between mastication, the hippocampus, and HPA axis activity. We also discuss several potential molecular mechanisms involved in the interactions between mastication, hippocampal function, and HPA axis activity.
Lin, Ya-Tin; Yu, Yu-Lian; Hong, Wei-Chen; Yeh, Ting-Shiuan; Chen, Ting-Chun; Chen, Jin-Chung
Neuropeptide FF (NPFF) belongs to the RFamide family and is known as a morphine-modulating peptide. NPFF regulates various hypothalamic functions through two receptors, NPFFR1 and NPFFR2. The hypothalamic-pituitary-adrenal (HPA) axis participates in physiological stress response by increasing circulating glucocorticoid levels and modulating emotional responses. Other RFamide peptides, including neuropeptide AF, neuropeptide SF and RFamide related peptide also target NPFFR1 or NPFFR2, and have been reported to activate the HPA axis and induce anxiety- or depression-like behaviors. However, little is known about the action of NPFF on HPA axis activity and anxiety-like behaviors, and the role of the individual receptors remains unclear. In this study, NPFFR2 agonists were used to examine the role of NPFFR2 in activating the HPA axis in rodents. Administration of NPFFR2 agonists, dNPA (intracerebroventricular, ICV) and AC-263093 (intraperitoneal, IP), time-dependently (in rats) and dose-dependently (in mice) increased serum corticosteroid levels and the effects were counteracted by the NPFF receptor antagonist, RF9 (ICV), as well as corticotropin-releasing factor (CRF) antagonist, α-helical CRF(9-41) (intravenous, IV). Treatment with NPFFR2 agonist (AC-263093, IP) increased c-Fos protein expression in the hypothalamic paraventricular nucleus and induced an anxiogenic effect, which was evaluated in mice using an elevated plus maze. These findings reveal, for the first time, that the direct action of hypothalamic NPFFR2 stimulates the HPA axis and triggers anxiety-like behaviors.
Saxbe, Darby; Del Piero, Larissa; Margolin, Gayla
Parents and children have been found to show coordination or coregulation of the hypothalamic-pituitary-adrenal (HPA) axis. This coordination may be reflected in adolescents' neural activation to parent stimuli, particularly in regions of the brain associated with social information processing. This study reports on 22 adolescents (13 males, mean age 17years), recruited from a longitudinal study to participate in a functional MRI (fMRI) scanning protocol. Approximately 1.5years before the scan, these same adolescents participated in a family conflict discussion in the lab with both parents, and all three family members provided samples of salivary cortisol five times, before and after the discussion. Multilevel models found positive cross-sectional and time-lagged associations between parents' and youth cortisol. Empirical Bayes (EB) coefficients, extracted from these models to reflect the strength of the relationship between parent and adolescent cortisol, were tested in conjunction with adolescents' neural activation to video clips of their parents taken from the conflict discussion. For both mothers and fathers, youth who showed stronger cortisol coregulation with each parent (both in cross-sectional and time-lagged analyses) showed more activation to that same parent in posteromedial regions (precuneus, posterior cingulate, and retrosplenial cortex) that have been linked with social cognition, e.g. mentalizing about others' emotions. Youths' adrenocortical coregulation with their parents may be reflected in their neural processing of stimuli featuring those same parents. Copyright © 2015 Elsevier Inc. All rights reserved.
Malek, Hamed; Ebadzadeh, Mohammad Mehdi; Safabakhsh, Reza; Razavi, Alireza; Zaringhalam, Jalal
In the work presented here, a novel mathematical model was developed to explore the bi-directional communication between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory cytokines in acute inflammation. The dynamic model consists of five delay differential equations 5D for two main pro-inflammatory cytokines (TNF-α and IL-6) and two hormones of the HPA axis (ACTH and cortisol) and LPS endotoxin. The model is an attempt to increase the understanding of the role of primary hormones and cytokines in this complex relationship by demonstrating the influence of different organs and hormones in the regulation of the inflammatory response. The model captures the main qualitative features of cytokine and hormone dynamics when a toxic challenge is introduced. Moreover, in this work a new simple delayed model of the HPA axis is introduced which supports the understanding of the ultradian rhythm of HPA hormones both in normal and infection conditions. Through simulations using the model, the role of key inflammatory cytokines and cortisol in transition from acute to persistent inflammation through stability analysis is investigated. Also, by employing a Markov chain Monte Carlo (MCMC) method, parameter uncertainty and the effects of parameter variations on each other are analyzed. This model confirms the important role of the HPA axis in acute and prolonged inflammation and can be a useful tool in further investigation of the role of stress on the immune response to infectious diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.
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.
Raff, Hershel; Bruder, Eric D; Cullinan, William E; Ziegler, Dana R; Cohen, Eric P
Although loud noise and intense vibration are known to alter the behavior and phenotype of laboratory animals, little is known about the effects of nearby construction. We studied the effect of a nearby construction project on the classic stress hormones ACTH, corticosterone, renin, and aldosterone in rats residing in a barrier animal facility before, for the first 3 months of a construction project, and at 1 month after all construction was completed. During some of the construction, noise and vibrations were not obvious to investigators inside the animal rooms. Body weight matched for age was not altered by nearby construction. During nearby construction, plasma ACTH, corticosterone, and aldosterone were approximately doubled compared with those of pre- and postconstruction levels. Expression of CRH mRNA in the paraventricular nucleus of the hypothalamus, CRH receptor and POMC mRNA in the anterior pituitary, and most mRNAs for steroidogenic genes in the adrenal gland were not significantly changed during construction. We conclude that nearby construction can cause a stress response without long-term effects on hypothalamic-pituitary-adrenal axis gene expression and body weight.
Hampel, Frank C; Nayak, Nicholas A; Segall, Nathan; Small, Calvin J; Li, Jiang; Tantry, Sudeesh K
Intranasal corticosteroids are the mainstay of allergic rhinitis (AR) treatment. Their potential to suppress the hypothalamic-pituitary-adrenal axis should be evaluated, especially after long-term daily use in children. To evaluate the effects of treatment with non-aqueous beclomethasone dipropionate (BDP) nasal aerosol on hypothalamic-pituitary-adrenal axis function in children with perennial AR. In this double-blinded, placebo-controlled, parallel-group study, patients (6-11 years old) with perennial AR were randomized (2:1) to BDP nasal aerosol at 80 μg/day (n = 67) or placebo (n = 32). The primary end point was change from baseline in 24-hour serum cortisol (SC) weighted mean for BDP nasal aerosol and placebo after 6 weeks of treatment, which was analyzed in the per-protocol population. The per-protocol population included 97 patients (BDP nasal aerosol, n = 66; placebo, n = 31). Baseline geometric mean SC weighted mean values were similar in the 80-μg/day BDP nasal aerosol and placebo groups (5.97 and 6.47 μg/dL, respectively). After 6 weeks' treatment, geometric mean values were 6.19 and 7.13 μg/dL, respectively, with no decrease from baseline in either group. Geometric mean SC ratio of BDP nasal aerosol at 80 μg/day to placebo was 0.91 (95% confidence interval 0.81-1.03), indicating predefined noninferiority. SC concentration-time profiles were similar for the placebo and 80-μg/day BDP nasal aerosol groups at baseline and week 6. BDP nasal aerosol at 80 μg/day was generally well tolerated. In pediatric patients with perennial AR, 24-hour SC profiles were comparable for BDP nasal aerosol and placebo, indicating that once-daily BDP nasal aerosol treatment did not significantly affect hypothalamic-pituitary-adrenal axis function. ClinicalTrials.gov; NCT01697956. Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Lan, Ni; Hellemans, Kim G C; Ellis, Linda; Viau, Victor; Weinberg, Joanne
Prenatal ethanol (E) exposure programs the fetal hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes such that E rats show HPA hyperresponsiveness to stressors and altered HPG and reproductive function in adulthood. Importantly, prenatal ethanol may differentially alter stress responsiveness in adult male and female offspring compared to their control counterparts. To test the hypothesis that alterations in HPA activity in E males are mediated, at least in part, by ethanol-induced changes in the capacity of testosterone to regulate HPA activity, we explored dose-related effects of testosterone on HPA and HPG function in adult male offspring from prenatal E, pair-fed (PF) and ad libitum-fed control (C) dams. Our data suggest that E males show changes in both HPA and HPG regulation, as well as altered sensitivity to the inhibitory effects of testosterone. While gonadectomy (GDX) reduced weight gain in all animals, low testosterone replacement restored body weights in PF and C but not E males. Further, sensitivity of the thymus and adrenal to circulating testosterone was reduced in E rats. In addition, stress-induced corticosterone (CORT) levels were increased in PF and C but not E males following GDX, and while low dose testosterone replacement restored CORT levels for PF and C, high testosterone levels were needed to normalize CORT levels for E males. A negative correlation between pre-stress testosterone and post-stress CORT levels in C but not in E and PF males further supports the finding of reduced sensitivity to testosterone. Importantly, testosterone appeared to have reduced effects on central corticotrophin releasing hormone (CRH) pathways in E, but greater effects on central arginine vasopressin (AVP) pathways in E and/or PF compared to C males. Testosterone also had less of an inhibitory effect on stress-induced luteinizing hormone increases in E than in PF and C males following GDX. In addition, androgen receptor mRNA levels in the medial preoptic
Lozovaya, Natalya; Miller, Andrew D
Stress is a ubiquitous and pervasive part of modern life that is frequently blamed for causing a plethora of diseases and other discomforting medical conditions. All higher organisms, including humans, experience stress in the form of a wide variety of stressors that range from environmental pollutants and drugs to traumatic events or self-induced trauma. Stressors registered by the central nervous system (CNS) generate physiological stress responses in the body (periphery) by means of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis. This LHPA axis operates through the use of chemical messengers such as the stress hormones corticotropin-releasing hormone (CRH) and glucocorticoids (GCs). Under conditions of frequent exposure to acute stress and/or chronic, long-term exposure to stress, the LHPA axis becomes dysfunctional and in the process frequently overproduces both CRH and GCs, which results in many mild to severely toxic side effects. Bidirectional communication between the LHPA axis and immune/inflammatory systems can dramatically potentiate these side effects and create environments in the CNS and periphery ripe for the triggering and/or promotion of tissue degeneration and disease. This review aims to present as far as possible a molecular view of the processes involved so as to provide a bridge from the diffuse range of studies on molecular structure and receptor interactions to the burgeoning biological and medical literature that describes the empirical interplay between stress and disease. We hope that our review of this fast-growing field, which we christen chemical neuroimmunology, will give a clear indication of the striking range and depth of current molecular, cellular and medical evidence linking stress hormones to degeneration and disease. In so doing, we hope to provide encouragement for others to become interested in this critical and far-reaching field of research, which is very much at the heart of many important disease processes and
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.
Švob Štrac, Dubravka; Muck-Šeler, Dorotea
Aim To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity. Methods Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methylp- tyrosine (α-MPT, an inhibitor of ca...
Belvederi Murri, Martino; Prestia, Davide; Mondelli, Valeria; Pariante, Carmine; Patti, Sara; Olivieri, Benedetta; Arzani, Costanza; Masotti, Mattia; Respino, Matteo; Antonioli, Marco; Vassallo, Linda; Serafini, Gianluca; Perna, Giampaolo; Pompili, Maurizio; Amore, Mario
To provide a quantitative and qualitative synthesis of the available evidence on the role of Hypothalamic-Pituitary-Adrenal (HPA) axis in the pathophysiology of Bipolar Disorder (BD). Meta-analysis and meta-regression of case-control studies examining the levels of cortisol, ACTH, CRH levels. Systematic review of stress reactivity, genetic, molecular and neuroimaging studies related to HPA axis activity in BD. Forty-one studies were included in the meta-analyses. BD was associated with significantly increased levels of cortisol (basal and post-dexamethasone) and ACTH, but not of CRH. In the meta-regression, case-control differences in cortisol levels were positively associated with the manic phase (p=0.005) and participants' age (p=0.08), and negatively with antipsychotics use (p=0.001). Reviewed studies suggest that BD is associated with abnormalities of stress-related molecular pathways in several brain areas. Variants of HPA axis-related genes seem not associated with a direct risk of developing BD, but with different clinical presentations. Also, studies on unaffected relatives suggest that HPA axis dysregulation is not an endophenotype of BD, but seems related to environmental risk factors, such as childhood trauma. Progressive HPA axis dysfunction is a putative mechanism that might underlie the clinical and cognitive deterioration of patients with BD. BD is associated with dysfunction of HPA axis activity, with important pathophysiological implications. Targeting HPA axis dysfunctions might be a novel strategy to improve the outcomes of BD. Copyright © 2015 Elsevier Ltd. All rights reserved.
Keller, J; Gomez, R; Williams, G; Lembke, A; Lazzeroni, L; Murphy, G M; Schatzberg, A F
The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance and a potential role of HPA axis genetic variation in cognition. The present study investigated the simultaneous roles HPA axis activity, clinical symptomatology and HPA genetic variation play in cognitive performance. Patients with major depression with psychotic major depression (PMD) and with nonpsychotic major depression (NPMD) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, overnight hourly blood sampling for cortisol and genetic assessment. Cognitive performance differed as a function of depression subtype. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher cortisol than did NPMDs and HCs. Cortisol, clinical symptoms and variation in genes, NR3C1 (glucocorticoid receptor; GR) and NR3C2 (mineralocorticoid receptor; MR) that encode for GRs and MRs, predicted cognitive performance. Beyond the effects of cortisol, demographics and clinical symptoms, NR3C1 variation predicted attention and working memory, whereas NR3C2 polymorphisms predicted memory performance. These findings parallel the distribution of GR and MR in primate brain and their putative roles in specific cognitive tasks. HPA axis genetic variation and activity were important predictors of cognition across the entire sample of depressed subjects and HR. GR and MR genetic variation predicted unique cognitive functions, beyond the influence of cortisol and clinical symptoms. GR genetic variation was implicated in attention and working memory, whereas MR was implicated in verbal memory.
O'Toole, Kate K; Hooper, Andrew; Wakefield, Seth; Maguire, Jamie
Stress is the most commonly reported precipitating factor for seizures. The proconvulsant actions of stress hormones are thought to mediate the effects of stress on seizure susceptibility. Interestingly, epileptic patients have increased basal levels of stress hormones, including corticotropin-releasing hormone (CRH) and corticosterone, which are further increased following seizures. Given the proconvulsant actions of stress hormones, we proposed that seizure-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to future seizure susceptibility. Consistent with this hypothesis, our data demonstrate that pharmacological induction of seizures in mice with kainic acid or pilocarpine increases circulating levels of the stress hormone, corticosterone, and exogenous corticosterone administration is sufficient to increase seizure susceptibility. However, the mechanism(s) whereby seizures activate the HPA axis remain unknown. Here we demonstrate that seizure-induced activation of the HPA axis involves compromised GABAergic control of CRH neurons, which govern HPA axis function. Following seizure activity, there is a collapse of the chloride gradient due to changes in NKCC1 and KCC2 expression, resulting in reduced amplitude of sIPSPs and even depolarizing effects of GABA on CRH neurons. Seizure-induced activation of the HPA axis results in future seizure susceptibility which can be blocked by treatment with an NKCC1 inhibitor, bumetanide, or blocking the CRH signaling with Antalarmin. These data suggest that compromised GABAergic control of CRH neurons following an initial seizure event may cause hyperexcitability of the HPA axis and increase future seizure susceptibility. Copyright © 2013 Elsevier B.V. All rights reserved.
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
Juruena, Mario F; Bocharova, Mariia; Agustini, Bruno; Young, Allan H
The link between the abnormalities of the Hypothalamic-pituitary-adrenal (HPA) axis and depression has been one of the most consistently reported findings in psychiatry. At the same time, multiple studies have demonstrated a stronger association between the increased activation of HPA-axis and melancholic, or endogenous depression subtype. This association has not been confirmed for the atypical subtype, and some researchers have suggested that as an antinomic depressive subtype, it may be associated with the opposite type, i.e. hypo-function, of the HPA-axis, similarly to PTSD. The purpose of this systematic review is to summarise existing studies addressing the abnormalities of the HPA-axis in melancholic and/or atypical depression. We conducted a systematic review in the literature by searching MEDLINE, PsycINFO, OvidSP and Embase databases until June 2017. The following search items were used: "hypothalamic-pituitary-adrenal" OR "HPA" OR "cortisol" OR "corticotropin releasing hormone" OR "corticotropin releasing factor" OR "glucocorticoid*" OR "adrenocorticotropic hormone" OR "ACTH" AND "atypical depression" OR "non-atypical depression" OR "melancholic depression" OR "non-melancholic depression" OR "endogenous depression" OR "endogenomorphic depression" OR "non-endogenous depression". Search limits were set to include papers in English or German language published in peer-reviewed journals at any period. All studies were scrutinized to determine the main methodological characteristics, and particularly possible sources of bias influencing the results reported. We selected 48 relevant studies. Detailed analysis of the methodologies used in the studies revealed significant variability especially regarding the samples' definition comparing the HPA axis activity of melancholic patients to atypical depression, including healthy controls. The results were subdivided into 4 sections: (1) 27 studies which compared melancholic OR endogenous depression vs. non
Straub, Rainer H; Detert, Jaqueline; Dziurla, René; Fietze, Ingo; Loeschmann, Peter-Andreas; Burmester, Gerd R; Buttgereit, Frank
Rheumatoid arthritis (RA) patients have sleep problems, and inflammation influences sleep. We demonstrated that sleep quality improves during intensified treatment with methotrexate (MTX) or etanercept (ETA). Since the hypothalamic-pituitary-adrenal (HPA) axis is involved in sleep regulation, this study investigated the interrelation between sleep parameters, inflammation as objectified by C-reactive protein (CRP), and serum cortisol and adrenocorticotropic hormone (ACTH) levels. Thirty-one eligible patients (disease activity score, DAS28CRP ≥3.2) participated in a 16-week, open, prospective study of HPA axis outcomes. MTX was initiated in 15 patients (female-to-male ratio 9/6) and ETA in 16 patients (14/2). Clinical, laboratory (after polysomnography [PSG] between 8 and 9 a.m.), sleep (PSG), and HPA axis outcome parameters (after PSG between 8 and 9 a.m.) were recorded at baseline and week 16. Clinical characteristics of patients markedly improved throughout the study (e.g., DAS28CRP: p HPA axis. © 2017 S. Karger AG, Basel.
Fisher, Philip A.; Van Ryzin, Mark J.; Gunnar, Megan R.
Summary Maltreated foster children often exhibit alterations in diurnal hypothalamic-pituitary-adrenal (HPA) axis activity that are characterized by lower cortisol levels upon waking and smaller declines in morning-to-evening cortisol levels. Previous research has shown that this dysregulated pattern is associated with high caregiver stress levels over the course of foster care placements. In contrast, therapeutic interventions that emphasize consistent and responsive caregiving have been associated with more regulated cortisol rhythms. In this paper, two related issues were explored: whether placement changes (i.e., moving between foster homes or from a foster home to a permanent placement) were associated with more blunted daily cortisol rhythms and whether a caregiver-based intervention exerted a protective effect in this context. Because the intervention program has components specifically designed to prepare foster children for placement changes and to maintain consistent parenting techniques despite them, a prevention effect on HPA axis dysregulation during placement changes was hypothesized. The results of linear mixed modeling analyses showed that placement changes predicted dysregulation in cortisol rhythms in the regular foster care group but not in the intervention foster care group. These findings are discussed in terms of implications for child welfare policy and practice. PMID:20888698
Smith, Alicia K; White, Peter D; Aslakson, Eric; Vollmer-Conna, Ute; Rajeevan, Mangalathu S
Chronic fatigue syndrome (CFS) is characterized by persistent or relapsing fatigue that is not alleviated by rest, causes substantial reduction in activities and is accompanied by a variety of symptoms. Its unknown etiology may reflect that CFS is heterogeneous. Latent class analyses of symptoms and physiological systems were used to delineate subgroups within a population-based sample of fatigued and nonfatigued subjects  . This study examined whether genetic differences underlie the individual subgroups of the latent class solution. Polymorphisms in 11 candidate genes related to both hypothalamic-pituitary-adrenal (HPA) axis function and mood-related neurotransmitter systems were evaluated by comparing each of the five ill classes (Class 1, n = 33; Class 3, n = 22; Class 4, n = 22; Class 5, n = 17; Class 6, n = 11) of fatigued subjects with subjects defined as well (Class 2, n = 35). Of the five classes of subjects with unexplained fatigue, three classes were distinguished by gene polymorphsims involved in either HPA axis function or neurotransmitter systems, including proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2). These data support the hypothesis that medically unexplained chronic fatigue is heterogeneous and presents preliminary evidence of the genetic mechanisms underlying some of the putative conditions.
Full Text Available In response to physiological and psychogenic stressors, the hypothalamic-pituitary adrenal (HPA axis orchestrates the systemic release of glucocorticoids (GCs. By virtue of nearly ubiquitous expression of the GC receptor (GR and the multifaceted metabolic, cardiovascular, cognitive and immunologic functions of GCs, this system plays an essential role in the response to stress and restoration of an homeostatic state. GCs act on almost all types of immune cells and were long recognized to perform salient immunosuppressive and anti-inflammatory functions through various genomic and non-genomic mechanisms. These renowned effects of the steroid hormone have been exploited in the clinic for the past 70 years and synthetic GC derivatives are commonly used for the therapy of various allergic, autoimmune, inflammatory and haematological disorders. The role of the HPA axis and GCs in restraining immune responses across the organism is however still debated in light of accumulating evidence suggesting that GCs can also have both permissive and stimulatory effects on the immune system under specific conditions. Such paradoxical actions of GCs are particularly evident in the brain, where substantial data support either a beneficial or detrimental role of the steroid hormone. In this review, we examine the roles of GCs on the innate immune system with a particular focus on the CNS compartment. We also dissect the numerous molecular mechanisms through which GCs exert their effects and discuss the various parameters influencing the paradoxical immunomodulatory functions of GCs in the brain.
Gaffey, Allison E.; Bergeman, C.S.; Clark, Lee Anna; Wirth, Michelle M.
Hypothalamic-pituitary-adrenal (HPA) axis function may change over the course of aging, and altered diurnal or stress-induced secretion of the hormone cortisol could predispose older adults to negative health outcomes. We propose that psychological resilience may interact with diurnal cortisol to affect health outcomes later in life. Emotion regulation and social support are two constructs that contribute to resilience and exhibit age-specific patterns in older adults. Determining how the use of resilience resources interacts with age-related diurnal cortisol will improve our understanding of the pathways between stress, resilience, and well-being. In this review, we assess published studies evaluating diurnal cortisol in older adults to better understand differences in their HPA axis functioning. Evidence thus far suggests that diurnal cortisol may increase with age, although cross-sectional studies limit the conclusions that can be drawn. We also review extant evidence connecting age-specific signatures of emotion regulation and social support with diurnal cortisol. Conclusions are used to propose a preliminary model demonstrating how resilience resources may modulate the effects of cortisol on health in aging. PMID:27377692
Ma, S; Mifflin, S W; Cunningham, J T; Morilak, D A
Obstructive sleep apnea (OSA) is associated with several pathophysiological conditions, including hypertension, obesity, insulin resistance, hypothalamic-pituitary-adrenal (HPA) dysregulation, and other endocrine and metabolic disturbances comprising the "metabolic syndrome." Repeated episodes of hypoxia in OSA may represent a chronic intermittent stress, leading to HPA dysregulation. Alterations in HPA reactivity could then contribute to or exacerbate other pathophysiological processes. We showed previously that another metabolic stressor, chronic intermittent cold stress, enhanced noradrenergic facilitation of acute HPA stress reactivity. In this study, we investigated whether chronic intermittent hypoxia (CIH), a rat model for the arterial hypoxemia that accompanies OSA, similarly sensitizes the HPA response to novel acute stress. Rats were exposed to CIH (alternating cycles of normoxia [3 min at 21% O(2)] and hypoxia [3 min at 10% O(2)], repeated continuously for 8 h/day during the light portion of the cycle for 7 days). On the day after the final CIH exposure, there were no differences in baseline plasma adrenocorticotropic hormone (ACTH), but the peak ACTH response to 30 min acute immobilization stress was greater in CIH-stressed rats than in controls. Induction of Fos expression by acute immobilization stress was comparable following CIH in several HPA-modulatory brain regions, including the paraventricular nucleus, bed nucleus of the stria terminalis, and amygdala. Fos induction was attenuated in lateral hypothalamus, an HPA-inhibitory region. By contrast, acute Fos induction was enhanced in noradrenergic neurons in the locus coeruleus following CIH exposure. Thus, similar to chronic cold stress, CIH sensitized acute HPA and noradrenergic stress reactivity. Plasticity in the acute stress response is important for long-term adaptation, but may also contribute to pathophysiological conditions associated with states of chronic or repeated stress, such as OSA
Liang, Yan-Qiu; Huang, Guo-Yong; Ying, Guang-Guo; Liu, Shuang-Shuang; Jiang, Yu-Xia; Liu, Shan; Peng, Feng-Jiao
The objective of the present study was to investigate the effects of norgestrel on the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes in zebrafish eleutheroembryos. Zebrafish embryos were exposed to different concentrations of norgestrel (0 ng L(-1) , 5 ng L(-1) , 50 ng L(-1) , and 100 ng L(-1) ) for 144 h post fertilization (hpf), and the transcriptional profiles of the HPG and HPA axes were examined every day. Norgestrel modulated the expression of Pgr and Vtg1 messenger (m)RNAs mainly at 96 hpf for all treatment groups. In addition, norgestrel strongly altered the expression of Cyp11a1 mRNA above 5 ng L(-1) (significant upregulation from 48 hpf to 120 hpf and significant downregulation for 144 hpf). Norgestrel treatment could significantly induce expression of Cyp19a1a, Cyp11b, Gnrh2, Gnrh3, and Lhb mRNAs but inhibit transcripts of Hsd11b2 and Crh genes above 5 ng L(-1) at different time points. The transcriptional expression levels of Esr1, Ar, Star, Hsd17b3, Fshb, and Pomc were also mediated by 5 ng L(-1) norgestrel or higher during different exposure periods. Taken together, the overall results imply that the transcriptional changes in zebrafish eleutheroembryos may pose a potential effect on embryonic development, in particular in the brain and gonadogenesis. © 2014 SETAC.
Lin, Ya-Tin; Liu, Tzu-Yu; Yang, Ching-Yao; Yu, Yu-Lian; Chen, Ting-Chun; Day, Yuan-Ji; Chang, Che-Chien; Huang, Guo-Jen; Chen, Jin-Chung
Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra-paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder. Copyright © 2016 Elsevier Ltd. All rights reserved.
Full Text Available Neuropeptide FF (NPFF belongs to the RFamide family and is known as a morphine-modulating peptide. NPFF regulates various hypothalamic functions through two receptors, NPFFR1 and NPFFR2. The hypothalamic-pituitary-adrenal (HPA axis participates in physiological stress response by increasing circulating glucocorticoid levels and modulating emotional responses. Other RFamide peptides, including neuropeptide AF, neuropeptide SF and RFamide related peptide also target NPFFR1 or NPFFR2, and have been reported to activate the HPA axis and induce anxiety- or depression-like behaviors. However, little is known about the action of NPFF on HPA axis activity and anxiety-like behaviors, and the role of the individual receptors remains unclear. In this study, NPFFR2 agonists were used to examine the role of NPFFR2 in activating the HPA axis in rodents. Administration of NPFFR2 agonists, dNPA (intracerebroventricular, ICV and AC-263093 (intraperitoneal, IP, time-dependently (in rats and dose-dependently (in mice increased serum corticosteroid levels and the effects were counteracted by the NPFF receptor antagonist, RF9 (ICV, as well as corticotropin-releasing factor (CRF antagonist, α-helical CRF(9-41 (intravenous, IV. Treatment with NPFFR2 agonist (AC-263093, IP increased c-Fos protein expression in the hypothalamic paraventricular nucleus and induced an anxiogenic effect, which was evaluated in mice using an elevated plus maze. These findings reveal, for the first time, that the direct action of hypothalamic NPFFR2 stimulates the HPA axis and triggers anxiety-like behaviors.
Maripuu, Martin; Wikgren, Mikael; Karling, Pontus; Adolfsson, Rolf; Norrback, Karl-Fredrik
A hyperactive hypothalamic-pituitary-adrenal axis (HPA-axis) is a well-known phenomenon in bipolar disorder (BD). However, hypocortisolism has also been described and found associated with depression, low quality of life and cardiovascular risk factors in BD patients. Although the pathophysiology related to hypocortisolism in BD is largely unknown, hypocortisolism is associated with chronic stress exposure and after inducing an initial rise in cortisol long-term stress may result in a transition to hypocortisolism. BD patients are throughout life often exposed to chronic stress. We therefore hypothesized that higher age would be associated with lower HPA-axis activity especially among patients without previous mood stabilizing treatment. This cross-sectional study consisted of 159 bipolar outpatients and 258 controls. A low-dose-dexamethasone-suppression-test (DST) was used to measure HPA-axis activity. Patients with BD showed a negative association between post DST cortisol and age (-3.0 nmol/l per year; p=0.007). This association gradually increased in subgroups that were naïve to lithium (-7.7 nmol/l per year; p=0.001) and "all mood stabilizers" (-11.4 nmol/l per year; p=0.004). Patients exhibiting hypercortisolism were characterized by younger age and female gender, whereas patients exhibiting hypocortisolism were characterized by long disease duration without prophylactic lithium treatment as well as absence of current lithium medication. Cross sectional study design. There was a negative association between HPA-axis activity and age in BD, rendering BD patients at risk for developing hypocortisolism. This association was most pronounced among patients without previous or current lithium prophylaxis. Copyright © 2017 Elsevier B.V. All rights reserved.
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
Sondeijker, Frouke E P L; Ferdinand, Robert F; Oldehinkel, Albertine J; Veenstra, R; Tiemeier, H; Ormel, Johan; Verhulst, Frank C
It is important to investigate associations between biological factors and disruptive behaviors in children and adolescents. Antisocial, aggressive, and criminal behaviors in adults often begin early in life. Disruptive behaviors are often thought to be associated with low activity of the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol, the end-product of this axis, can be measured to investigate HPA-axis activity. Previous studies on this topic concerned clinical or high risk samples. The aim of the present study was to investigate to which extent HPA-axis functioning plays a role in disruptive behaviors in pre-adolescents from the general population. One thousand seven hundred and sixty eight 10- to 12-year-olds from the Dutch general population were investigated. Disruptive behaviors were assessed with the Child Behavior Checklist, the Youth Self-Report, and the Antisocial Behavior Questionnaire. Baseline morning and evening salivary cortisol levels were assessed. Unexpectedly, small associations were found between disruptive behaviors, including attention problems, and higher cortisol levels. However, all effect sizes of significant effects were very small. Our study indicated that HPA-axis functioning may be more relevant in clinical or high risk samples than at the general population level. The association between HPA-axis functioning and attention problems, that has gotten less attention than that with aggressive or delinquent behaviors, requires further research. Furthermore, because effect sizes were relatively small, it can be concluded that, in pre-adolescence, the measures of baseline HPA-axis functioning that were used for the present study can not be used as biological markers for disruptive behaviors.
Mormede, P.; Andanson, S.; Auperin, B.; Beerda, B.; Guemene, D.; Malmkvist, J.; Manteca, X.; Manteuffel, G.; Prunet, P.; Reenen, van C.G.; Richard, S.; Veissier, I.
Measuring HPA axis activity is the standard approach to the study of stress and welfare in farm animals. Although the reference technique is the use of blood plasma to measure glucocorticoid hormones (cortisol or corticosterone), several alternative methods such as the measurement of corticosteroids
Chojnowska, Katarzyna; Czerwinska, Joanna; Kaminski, Tadeusz; Kaminska, Barbara; Kurzynska, Aleksandra; Bogacka, Iwona
The European beaver (Castor fiber) is the largest seasonal free-living rodent in Eurasia. Since the physiology and endocrine system of this species remains unknown, the present study aimed to determine plasma leptin concentrations and the expression of the leptin gene and protein in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal (HPG and HPA) axes of beavers during breeding (April), postbreeding (July), and prebreeding (November) seasons. Leptin plasma concentrations did not change in females, whereas in males, leptin plasma concentrations were higher in July than those in April. The presence of leptin mRNA and protein was found in all examined tissues. In females, leptin mRNA expression in the hypothalamus, pituitary, ovaries, and myometrium was markedly higher in July than that in April. In males, leptin mRNA levels varied across the examined tissues of the HPG and HPA. Leptin synthesis increased in the hypothalamus during breeding and postbreeding seasons, but seasonal changes were not observed in the pituitary. In turn, testicular leptin levels were higher during breeding and prebreeding stages. Seasonal differences in the concentrations of leptin mRNA were also observed in the adrenal cortex. In males, leptin mRNA levels were higher in November than those in April or July. In females, leptin synthesis increased in the adrenal cortex during pregnancy relative to other seasons. This is the first ever study to demonstrate seasonal differences in leptin expression in beaver tissues, and our results could suggest that leptin is involved in the regulation of the HPG and HPA axes during various stages of the reproductive cycle in beavers. Copyright © 2016 Elsevier Inc. All rights reserved.
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.
Lee, Tiffany T-Y; Gorzalka, Boris B
Adolescence is a period characterized by many distinct physical, behavioral, and neural changes during the transition from child- to adulthood. In particular, adolescent neural changes often confer greater plasticity and flexibility, yet with this comes the potential for heightened vulnerability to external perturbations such as stress exposure or recreational drug use. There is substantial evidence to suggest that factors such as adolescent stress exposure have longer lasting and sometimes more deleterious effects on an organism than stress exposure during adulthood. Moreover, the adolescent neuroendocrine response to stress exposure is different from that of adults, suggesting that further maturation of the adolescent hypothalamic-pituitary-adrenal (HPA) axis is required. The endocannabinoid (eCB) system is a potential candidate underlying these age-dependent differences given that it is an important regulator of the adult HPA axis and neuronal development. Therefore, this review will focus on (1) the functionality of the adolescent HPA axis, (2) eCB regulation of the adult HPA axis, (3) dynamic changes in eCB signaling during the adolescent period, (4) the effects of adolescent stress exposure on the eCB system, and (5) modulation of HPA axis activity and emotional behavior by adolescent cannabinoid treatment. Collectively, the emerging picture suggests that the eCB system mediates interactions between HPA axis stress responsivity, emotionality, and maturational stage. These findings may be particularly relevant to our understanding of the development of affective disorders and the risks of adolescent cannabis consumption on emotional health and stress responsivity. © 2015 Elsevier Inc. All rights reserved.
Dahmen, Brigitte; Puetz, Vanessa B; Scharke, Wolfgang; von Polier, Georg G; Herpertz-Dahlmann, Beate; Konrad, Kerstin
Early-life adversity (ELA) is one of the major risk factors for serious mental and physical health risks later in life. ELA has been associated with dysfunctional neurodevelopment, especially in brain structures such as the hippocampus, and with dysfunction of the stress system, including the hypothalamic-pituitary-adrenal (HPA) axis. Children who have experienced ELA are also more likely to suffer from mental health disorders such as depression later in life. The exact interplay of aberrant neurodevelopment and HPA axis dysfunction as risks for psychopathology is not yet clear. We investigated volume differences in the bilateral hippocampus and in stress-sensitive hippocampal subfields, behavior problems, and diurnal cortisol activity in 24 children who had experienced documented ELA (including out-of-home placement) in a circumscribed duration of adversity only in their first 3 years of life in comparison to data on 25 control children raised by their biological parents. Hippocampal volumes and stress-sensitive hippocampal subfields (Cornu ammonis [CA]1, CA3, and the granule-cell layer of the dentate gyrus [GCL-DG]) were significantly smaller in children who had experienced ELA, taking psychiatric diagnoses and dimensional psychopathological symptoms into account. ELA moderated the relationship between left hippocampal volume and cortisol: in the control group, hippocampal volumes were not related to diurnal cortisol, while in ELA children, a positive linear relationship between left hippocampal volume and diurnal cortisol was present. Our findings show that ELA is associated with altered development of the hippocampus, and an altered relationship between hippocampal volume and HPA axis activity in youth in care, even after they have lived in stable and caring foster family environments for years. Altered hippocampal development after ELA could thus be associated with a risk phenotype for the development of psychiatric disorders later in life. © 2017 S. Karger
Melhem, Nadine M; Keilp, John G; Porta, Giovanna; Oquendo, Maria A; Burke, Ainsley; Stanley, Barbara; Cooper, Thomas B; Mann, J John; Brent, David A
Studies looking at the relationship of the hypothalamic-pituitary-adrenal (HPA) axis to suicidal behavior and its risk factors, such as depression, childhood abuse, and impulsive aggression, report inconsistent results. These studies also do not always differentiate between subjects who go on to attempt suicide, suicidal subjects who never attempted suicide, and non-suicidal subjects with psychiatric disorders. In this study, we examined cortisol responses to an experimental stressor, the Trier Social Stress Test (TSST), in 208 offspring of parents with mood disorder. Offspring suicide attempters showed lower total cortisol output (β=-0.47, 95% CI (-0.83, -0.11), p=0.01) compared with offspring with suicide-related behavior (SRB) but never attempted, non-suicidal offspring, and a healthy control group. The result remained significant even after controlling for sex, age, race, ethnicity, site, socio-economic status, and hour of the day when the TSST was conducted. Suicide attempters also showed lower baseline cortisol before the TSST (β=-0.45, 95% CI (-0.74, -0.17), p=0.002). However, there were no significant differences between the groups on cortisol reactivity to stress (β=4.5, 95% CI (-12.9, 22), p=0.61). Although subjects with suicide attempt and SRB have similar clinical and psychosocial characteristics, this is the first study to differentiate them biologically on HPA axis indices. Blunted HPA axis activity may increase risk for suicide attempt among individuals with psychopathology by reducing their ability to respond adaptively to ongoing stressors. These results may help better identify subjects at high risk for suicidal behavior for targeted prevention and intervention efforts.
Schreuder, Merel M; Vinkers, Christiaan H; Mesman, Esther; Claes, Stephan; Nolen, Willem A; Hillegers, Manon H J
Children of a parent with bipolar disorder (bipolar offspring) have an increased risk for mood disorders. While genetic factors play a significant role in this population, susceptibility to environmental stress may also significantly contribute to this vulnerability for mood disorders. Childhood trauma has consistently been found to increase the risk for mood disorders, with persisting consequences for hypothalamic-pituitary-adrenal (HPA) axis functionality. However, it is currently unknown whether childhood trauma specifically affects HPA axis activity in individuals with a familial risk for bipolar disorder. Therefore, we investigated the effects of childhood trauma on daytime and evening cortisol levels and dexamethasone suppression in bipolar offspring (N=70) and healthy controls (N=44). In our study we found no significant differences in daytime and evening cortisol levels as well as dexamethasone suppression between bipolar offspring and healthy controls (all p-values>0.43). In contrast, childhood trauma differentially affected daytime cortisol levels in the bipolar offspring compared to healthy controls (childhood trauma X bipolar offspring interaction, β=-7.310, p=0.0414) with an effect of childhood trauma on daytime cortisol in bipolar offspring at trend level (p=0.058). In the bipolar offspring group, lifetime or current psychiatric diagnoses, and stressful life events separately did not affect cortisol levels or dexamethasone suppression (all p-values>p=0.50). These findings were independent of current or lifetime psychiatric diagnosis. In conclusion, trauma-related changes in daytime HPA axis activity appear to be a specific trait in bipolar offspring who have increased risk for mood disorders compared to healthy individuals. Copyright © 2016. Published by Elsevier Ltd.
Apter-Levi, Yael; Pratt, Maayan; Vakart, Adam; Feldman, Michal; Zagoory-Sharon, Orna; Feldman, Ruth
Maternal depression across the first years of life negatively impacts children's development. One pathway of vulnerability may involve functioning of the hypothalamic-pituitary-adrenal (HPA) axis. We utilize a community cohort of 1983 women with no comorbid risk repeatedly assessed for depression from birth to six years to form two groups; chronically depressed (N=40) and non-depressed (N=91) women. At six years, mother and child underwent psychiatric diagnosis, child salivary cortisol (CT) was assessed three times during a home-visit, mother-child interaction was videotaped, and child empathy was coded from behavioral paradigms. Latent Growth curve Model using Structural Equation Modeling (SEM) estimated the links between maternal depression and mother's negative parenting and three child outcomes; psychopathology, social withdrawal, and empathy as related to child CT baseline and variability. Depressed mothers displayed more negative parenting and their children showed more Axis-I psychopathology and social withdrawal. SEM analysis revealed that maternal depression was associated with reduced CT variability, which predicted higher child psychopathology and social withdrawal. Whereas all children exhibited similar initial levels of CT, children of controls reduced CT levels over time while children of depressed mothers maintained high, non-flexible levels. Mother negativity was related to lower initial CT levels, which predicted decreased empathy. Findings suggest that chronic maternal depression may compromise children's social-emotional adjustment by diminishing HPA-system flexibility as well as limiting the mother's capacity to provide attuned and predictable caregiving. Copyright © 2015 Elsevier Ltd. All rights reserved.
Baes, Cristiane von Werne; Martins, Camila Maria Severi; Tofoli, Sandra Márcia de Carvalho; Juruena, Mário Francisco
Evidence indicates that early life stress (ELS) can induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis to respond to stress in the adult life that leads to depression. These appear to be related to the impairment of HPA hormones through binding to glucocorticoid (GR) and mineralocorticoid receptors (MR). The aim of this study was to evaluate the impact of ELS in HPA axis response to challenges with GR and MR agonists in depressed patients. We included 30 subjects, 20 patients with current major depression (HAM-D21 ≥ 17). Patients were recruited into two groups according to ELS history assessed by the Childhood Trauma Questionnaire (CTQ). The cortisol measures in the saliva and plasma were evaluated after using (at 10:00 p.m.) placebo, fludrocortisone (MR agonist), or dexamethasone (GR agonist). Depressed patients showed a significantly lower salivary cortisol upon waking after placebo compared with controls. Moreover, cortisol awakening responses (CAR) after MR agonist were found to be lower in depressed patients than in controls. With CTQ scores, HAM-D21, body mass index and CAR after placebo, GR agonist, MR agonist we found in a Linear Regression model that depressive patients with ELS (p = 0.028) show differences between placebo vs. MR agonist (R = 0.51; p depressive patients, without ELS the data show differences between placebo vs. MR agonist (R = 0.69; p depressed patients compared with controls. Furthermore, in spite of the previous limitations described, in depressed patients with ELS, there was suppression by MR agonist, indicating that patients with ELS are sensitive to MR agonists. In contrast with depressed patients without ELS, we find suppression after both MR and GR agonist. These data suggested that in ELS an imbalance exists between MR and GR with MR dysfunction.
Ferguson, Elizabeth H; Di Florio, Arianna; Pearson, Brenda; Putnam, Karen T; Girdler, Susan; Rubinow, David R; Meltzer-Brody, Samantha
It is unclear whether women with a history of postpartum depression (PPD) have residual, abnormal hypothalamic-pituitary-adrenal (HPA) axis reactivity, as has been reported in major depression (MDD). Further unclear is whether the abnormalities in HPA axis reactivity associated with MDD represent a stable, underlying predisposition or a state-dependent phenomenon. This study sought the following: (1) to determine if euthymic postpartum women with a history of depression have an abnormal HPA axis reactivity to pharmacologic and psychological challenges and (2) to compare HPA reactivity in women with histories of PPD versus MDD. As a secondary objective, we wanted to determine the influence of trauma history on HPA axis function. Forty-five parous (12-24 months postpartum), euthymic women with history of MDD (n = 15), PPD (n = 15), and controls (n = 15) completed pharmacologic (dexamethasone/corticotropin-releasing hormone (CRH) test [DEX/CRH]) and psychological (Trier social stress test [TSST]) challenges during the luteal phase. Outcome measures were cortisol and adrenocorticotropic hormone (ACTH) response after DEX/CRH, and blood pressure, heart rate, epinephrine, norepinephrine, and cortisol response during the TSST. All groups had robust cortisol and ACTH response to DEX/CRH and cortisol response to TSST. Groups did not differ significantly in cortisol or ACTH response to DEX/CRH or in blood pressure, heart rate, epinephrine, norepinephrine, or cortisol response to TSST. Cortisol/ACTH ratio did not differ significantly between groups. Trauma history was associated with decreased cortisol response to DEX/CRH in women with histories of MDD, which was not significant after correction (F 8,125, p = 0.02, Greenhouse-Geisser corrected p = 0.11). Currently euthymic women with histories of MDD or PPD did not demonstrate residual abnormal stress responsivity following administration of either a pharmacologic or psychological stressor.
Jimenez, Vanessa A; Allen, Daicia C; McClintick, Megan N; Grant, Kathleen A
Hypothalamic-pituitary-adrenal (HPA) axis activity under different social settings in non-human primates is understudied. The aim of this study is to evaluate the response of pituitary-adrenal hormones (adrenocorticotropic hormone (ACTH) and cortisol) to pharmacological challenges of the HPA axis in male cynomolgus macaques under different social settings. Male cynomolgus macaques (Macaca fascicularis, n = 11) were individually (A) and socially housed (B) in alternation, over consecutive months, in an ABA design. During each experimental phase, plasma ACTH and cortisol were measured in response to low- and mild-intensity psychological stressors and following administration of saline, naloxone, ovine-corticotropin-releasing factor (oCRF), and dexamethasone. These data demonstrate that cortisol measured under low stress conditions is sensitive to social rank (dominance hierarchy) and distinguishes dominant from non-dominant animals during both individual and social settings. Administration of naloxone resulted in elevated circulating ACTH and cortisol, while oCRF only increased circulating cortisol. During social housing, the cortisol response to naloxone and oCRF was increased, whereas dexamethasone suppression of ACTH and cortisol remained consistent across all social settings. Circulating ACTH and cortisol are differentially sensitive to changes in social settings in non-human primates. Cortisol response increased during social housing and could be stimulated by both naloxone and oCRF, whereas ACTH response was generally not influenced by social setting or oCRF but was increased by naloxone. These data show differential adrenal and pituitary response to changes in social settings and a small, but consistent, effect of social dominance.
Juruena, Mario F
It is now broadly accepted that psychological stress may change the internal homeostatic state of an individual. During acute stress, adaptive physiological responses occur, which include hyperactivity of the HPA axis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behavior, and they influence the process of adaptation or 'allostasis'. It is correct to state that at the same time that our experiences change our brain and thoughts, namely, changing our mind, we are changing our neurobiology. Increased adrenocortical secretion of hormones, primarily cortisol in major depression, is one of the most consistent findings in neuropsychiatry. A significant percentage of patients with major depression have been shown to exhibit increased concentrations of cortisol, an exaggerated cortisol response to adrenocorticotropic hormone, and an enlargement of both the pituitary and adrenal glands. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of hypothalamic-pituitary-adrenal (HPA) hormones through binding to mineralocorticoid (MR) and glucocorticoid (GR) receptors limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals. The HPA axis response to stress can be thought of as a mirror of the organism's response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. Evidence indicates that early-life stress can induce persistent changes in the ability of the HPA axis to respond to stress in adulthood. These abnormalities appear to be related to changes in the ability of hormones to bind to GR and MR receptors. First episodes may begin with an environmental stressor, but if the cycles continue or occur unchecked, the brain
Full Text Available There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression, and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic-pituitary-adrenal (HPA axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioural deficits and/or mood disorders. Dysregulation of the HPA axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, anti-depressant drugs such as the selective serotonin reuptake inhibitors (SSRI have been shown to alter HPA axis activity. In this review, we will summarize the current state of knowledge regarding HPA axis pathology in Alzheimer’s, Parkinson’s and Huntington’s diseases, differentiating between prodromal and later stages of disease progression where possible. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the pre-clinical evidence to better inform prospective, intervention studies.
Videlock, Elizabeth J.; Shih, Wendy; Adeyemo, Mopelola; Mahurkar-Joshi, Swapna; Presson, Angela P.; Polytarchou, Christos; Alberto, Melissa; Iliopoulos, Dimitrios; Mayer, Emeran A.; Chang, Lin
Background and aims Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in irritable bowel syndrome (IBS). Enhanced HPA axis response has been associated with reduced glucocorticoid receptor (GR) mediated negative feedback inhibition. We aimed to study the effects of IBS status, sex, or presence of early adverse life events (EAL) on the cortisol response to corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and on GR mRNA expression in peripheral blood mononuclear cells (PBMCs). Methods Rome III+ IBS patients and healthy controls underwent CRF (1 μg/kg ovine) and ACTH (250 μg) stimulation tests with serial plasma ACTH and cortisol levels measured (n = 116). GR mRNA levels were measured using quantitative PCR (n = 143). Area under the curve (AUC) and linear mixed effects models were used to compare ACTH and cortisol response measured across time between groups. Results There were divergent effects of IBS on the cortisol response to ACTH by sex. In men, IBS was associated with an increased AUC (p = 0.009), but in women AUC was blunted in IBS (p = 0.006). Men also had reduced GR mRNA expression (p = 0.007). Cumulative exposure to EALs was associated with an increased HPA response. Lower GR mRNA was associated with increased pituitary HPA response and increased severity of overall symptoms and abdominal pain in IBS. Conclusion This study highlights the importance of considering sex in studies of IBS and the stress response in general. Our findings also provide support for PBMC GR mRNA expression as a peripheral marker of central HPA response. PMID:27038676
Jothie Richard, Edwin; Illuri, Ramanaiah; Bethapudi, Bharathi; Anandhakumar, Senthilkumar; Bhaskar, Anirban; Chinampudur Velusami, Chandrasekaran; Mundkinajeddu, Deepak; Agarwal, Amit
The present study investigated anti-stress potential of Ocimum sanctum in chronic variable stress (CVS) paradigm. Further, the possible mechanism of anti-stress was explored in vitro using cell and cell-free assays. Rats were administered O. sanctum followed by CVS regimen for a period of 16 days. On days 4, 8, 12, and 16, body weight and immobility time in forced swim test were measured. In addition, the possible inhibitory effect of O. sanctum and ursolic acid on cortisol release and CRHR1 receptor activity were studied in cell-based assays, while inhibitory effects on 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and catechol-O-methyltransferase (COMT) were studied in cell-free assays. CVS group demonstrated less body weight gain and higher immobility time than O. sanctum administered groups, while oral administration of O. sanctum significantly increased body weight gain and decreased the immobility time. Further, O. sanctum and its constituents inhibited cortisol release and exhibited a significant CRHR1 receptor antagonist activity. Also, they had specific inhibitory activity towards 11β-HSD1 and COMT activity. Thus, O. sanctum was found to be effective in the management of stress effects, and anti-stress activity could be due to inhibition of cortisol release, blocking CRHR1 receptor, and inhibiting 11β-HSD1 and COMT activities. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.
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.
Madsen, Kathrine Skak; Jernigan, Terry L; Iversen, Pernille
healthy adults aged 19 to 86 years were included in the analyses. Diffusion-weighted imaging was acquired from all subjects. Hippocampal mean diffusivity (MD) and volume was extracted. Cortisol measures were based on 5 morning and 3 afternoon/evening saliva samples. Higher left relative to right...
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.
Full Text Available The supra-chiasmatic nucleus (SCN is the primarily biological clock determining thecircadian rhythm. The neurons of the nucleus making this clock have inherent rhythmand set in biological day and night. These periods usually corresponds to day/night, andindirectly to sleep-wakefulness cycle, in most individuals. Retino-hypothalamic tractcarrying photic information from the retina provides the most important input tomaintain the inherent rhythm of the SCN. The rhythmic discharges from the SCN tovarious neurons of the central nervous system, including pineal gland andhypothalamus, translate into circadian rhythm characteristic of several hormones andmetabolites such as glucose. As a result there is a pattern of hormonal changesoccurring during cycle of sleep wakefulness. Most characteristic of these changes aresurge of melatonin with biological night, surge of growth hormone-releasing hormone(GHRHat onset of sleep and surge of corticotropin-releasinghormone(CRHduring late part of the sleep. The cause and effect relationship of the hypothalamicreleasing hormones and their target hormones on various phases of sleep includinginitial non rapid eye movement (NREM phase at onset of sleep, and rapid eyemovement (REM phase near awakening, is an upcoming research area. Sleepelectroencephalogram (EEG determining the onset of NREM and REM sleep is animportant tool complimenting the studies assessing relationship between varioushormones and phases of sleep. The slow wave activity (SWA corresponds to theintensity of sleep at its onset during the biological night of an individual. Besides,GHRH and CRH, several other peptide and steroid hormones such as growthhormone (GH, its secretagogues, ghrelin, neuropeptide Y, estrogen anddehydroepiandrosterone sulfate are associated or have the potential to change phases ofsleep including initial slow wave-NREM sleep.
Spencer, S.J.; Emmerzaal, T.L.; Kozicz, L.T.; Andrews, Z.B.
Ghrelin is a stomach hormone normally associated with feeding behavior and energy homeostasis. Recent studies highlight that ghrelin targets the brain to regulate a diverse number of functions, including learning, memory, motivation, stress responses, anxiety, and mood. In this review, we discuss
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…
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
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...
Buller, K M; Crane, J W; Spencer, S J; Day, T A
Apomorphine is a dopamine receptor agonist that was recently licensed for the treatment of erectile dysfunction. However, although sexual activity can be stressful, there has been little investigation into whether treatments for erectile dysfunction affect stress responses. We have examined whether a single dose of apomorphine, sufficient to produce penile erections (50 microg/kg, i.a.), can alter basal or stress-induced plasma ACTH levels, or activity of central pathways thought to control the hypothalamic-pituitary-adrenal axis in rats. An immune challenge (interleukin-1 beta, 1 microg/kg, i.a.) was used as a physical stressor while sound stress (100 dB white noise, 30 min) was used as a psychological stressor. Intravascular administration of apomorphine had no effect on basal ACTH levels but did substantially increase the number of Fos-positive amygdala and nucleus tractus solitarius catecholamine cells. Administration of apomorphine prior to immune challenge augmented the normal ACTH response to this stressor at 90 min and there was a corresponding increase in the number of Fos-positive paraventricular nucleus corticotropin-releasing factor cells, paraventricular nucleus oxytocin cells and nucleus tractus solitarius catecholamine cells. However, apomorphine treatment did not alter ACTH or Fos responses to sound stress. These data suggest that erection-inducing levels of apomorphine interfere with hypothalamic-pituitary-adrenal axis inhibitory feedback mechanisms in response to a physical stressor, but have no effect on the response to a psychological stressor. Consequently, it is likely that apomorphine acts on a hypothalamic-pituitary-adrenal axis control pathway that is unique to physical stressors. A candidate for this site of action is the nucleus tractus solitarius catecholamine cell population and, in particular, A2 noradrenergic neurons.
Zhao, Xiao-Jie; Zhao, Zhan; Yang, Dan-Dan; Cao, Lu-Lu; Zhang, Ling; Ji, Juan; Gu, Jun; Huang, Ji-Ye; Sun, Xiu-Lan
Stress-induced disturbance of the hypothalamic-pituitary-adrenal (HPA) axis is strongly implicated in incidence of mood disorders. A heightened neuroinflammatory response and oxidative stress play a fundamental role in the dysfunction of the HPA axis. We have previously demonstrated that iptakalim (Ipt), a new ATP-sensitive potassium (K-ATP) channel opener, could prevent oxidative injury and neuroinflammation against multiple stimuli-induced brain injury. The present study was to demonstrate the impacts of Ipt in stress-induced HPA axis disorder and depressive behavior. We employed 2 stress paradigms: 8 weeks of continuous restraint stress (chronic restraint stress, CRS) and 2h of restraint stress (acute restraint stress, ARS), to mimic both chronic stress and severe acute stress. Prolonged (4 weeks) and short-term (a single injection) Ipt treatment was administered 30min before each stress paradigm. We found that HPA axis was altered after stress, with different responses to CRS (lower ACTH and CORT, higher AVP, but normal CRH) and ARS (higher CRH, ACTH and CORT, but normal AVP). Both prolonged and short-term Ipt treatment normalized stress-induced HPA axis disorders and abnormal behaviors in mice. CRS and ARS up-regulated mRNA levels of inflammation-related molecules (TNFα, IL-1β, IL-6 and TLR4) and oxidative stress molecules (gp91phox, iNOS and Nrf2) in the mouse hypothalamus. Double immunofluorescence showed CRS and ARS increased microglia activation (CD11b and TNFα) and oxidative stress in neurons (NeuN and gp91phox), which were alleviated by Ipt. Therefore, the present study reveals that Ipt could prevent against stress-induced HPA axis disorders and depressive behavior by alleviating inflammation and oxidative stress in the hypothalamus. Copyright © 2017 Elsevier Inc. All rights reserved.
Daughters, Stacey B; Richards, Jessica M; Gorka, Stephanie M; Sinha, Rajita
Substance abuse treatment programs are often characterized by high rates of premature treatment dropout, which increases the likelihood of relapse to drug use. Negative reinforcement models of addiction emphasize an individual's inability to tolerate stress as a key factor for understanding poor substance use treatment outcomes, and evidence indicates that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis contributes to an individual's inability to respond adaptively to stress. The aim of the current study was to examine whether HPA axis response to stress is predictive of treatment retention among a sample of drug users in residential substance abuse treatment. Prospective study assessing treatment retention among 102 individuals enrolled in residential substance abuse treatment. Participants completed two computerized stress tasks, and HPA axis response to stress was measured via salivary cortisol at five time points from baseline (pre-stress) to 30 min post-stress exposure. The main outcome measures were treatment dropout (categorical) and total number of days in treatment (continuous). A significantly higher salivary cortisol response to stress was observed in treatment dropouts compared to treatment completers. Further, Cox proportional hazards survival analyses indicated that a higher peak cortisol response to stress was associated with a shorter number of days to treatment dropout. Results indicate that a higher salivary cortisol level in response to stress is associated with an inability to remain in substance abuse treatment. These findings are the first to document a biological marker of stress as a predictor of substance abuse treatment dropout, and support the development and implementation of treatments targeting this vulnerability.
Daughters, Stacey B.; Richards, Jessica M.; Gorka, Stephanie M.; Sinha, Rajita
Introduction Substance abuse treatment programs are often characterized by high rates of premature treatment dropout, which increases the likelihood of relapse to drug use. Negative reinforcement models of addiction emphasize an individual’s inability to tolerate stress as a key factor for understanding poor substance use treatment outcomes, and evidence indicates that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis contributes to an individual’s inability to respond adaptively to stress. The aim of the current study was to examine whether HPA axis response to stress is predictive of treatment retention among a sample of drug users in residential substance abuse treatment. Method Prospective study assessing treatment retention among 102 individuals enrolled in residential substance abuse treatment. Participants completed two computerized stress tasks, and HPA axis response to stress was measured via salivary cortisol at five time points from baseline (pre-stress) to 30 min post-stress exposure. Results The main outcome measures were treatment dropout (categorical) and total number of days in treatment (continuous). A significantly higher salivary cortisol response to stress was observed in treatment dropouts compared to treatment completers. Further, Cox proportional hazards survival analyses indicated that a higher peak cortisol response to stress was associated with a shorter number of days to treatment dropout. Conclusions Results indicate that a higher salivary cortisol level in response to stress is associated with an inability to remain in substance abuse treatment. These findings are the first to document a biological marker of stress as a predictor of substance abuse treatment dropout, and support the development and implementation of treatments targeting this vulnerability. PMID:19713052
Schinke, Christian; Hesse, Swen; Stoppe, Muriel; Meyer, Klara; Schmidt, Elisa; Orthgiess, Johannes; Bechmann, Lukas; Bresch, Anke; Rullmann, Michael; Luthardt, Julia; Sabri, Osama; Blüher, Matthias; Kratzsch, Jürgen; Then Bergh, Florian
Increased activities of the arginine-vasopressin (AVP) system and the hypothalamic-pituitary-adrenal (HPA) axis were shown to be associated with human obesity, but relationships between these systems in obesity remain unclear. To assess HPA axis responsiveness and its relation to serum concentrations of the AVP-surrogate copeptin in subjects with obesity (OB) in comparison to non-obesity controls (NOC). In a cross-sectional monocentric study, thirty-nine OB (f/m 25/14; age 36.5±10.0years; body mass index, BMI, 41.5±4.7kg/m2) were compared to twenty-two NOC (f/m 12/10; age 35.3±8.5years; BMI 23.1±2.4kg/m2), matched for age and sex. All individuals underwent the combined dexamethasone/CRH test. Plasma ACTH and cortisol curve indicators derived from the dex/CRH test (post-CRH concentrations 30min after 100μg CRH; maximum concentration, MAX; area-under-the-curve, AUC; ACTH/cortisol ratios). Copeptin was assessed in 1500h samples of the dex/CRH test (after 1.5mg of oral dexamethasone, prior to CRH administration). Copeptin serum concentrations were higher in OB (median [IQR]: OB 4.62 [2.60-5.88] vs. NOC 3.04 [2.52-4.29] pmol/l, P=0.04). Correspondingly, OB showed higher post-CRH cortisol concentrations (OB: 51.5 [25.9-159.3] vs. NOC: 28.6 [20.0-41.6] nmol/l, P=0.01) and a lower post-CRH ACTH/cortisol ratio (OB: 0.028 [0.016-0.053] vs. NOC: 0.048 [0.034-0.070] pmol/nmol, Pcopeptin was significantly associated with HPA responsiveness in OB (post-CRH ACTH: R=0.42, Pcopeptin with ACTH and cortisol release suggests a potential mechanistic interaction of the AVP system with HPA activation in human obesity. The relation of copeptin and HPA responsiveness should be further validated in situations with pronounced HPA activation, such as depression or multiple sclerosis. Copyright © 2017 Elsevier Ltd. All rights reserved.
Martinson, Amber; Craner, Julia; Sigmon, Sandra
Sexual trauma can lead to longstanding effects on individuals' intimacy functioning. The current study aimed to assess hypothalamic pituitary adrenal (HPA) axis functioning (i.e., cortisol reactivity) prior to (-5min), during (+15, +30, +45min), and following (+60min) an experimental manipulation of emotional closeness in a sample of women survivors of sexual trauma with varying levels of posttraumatic stress disorder (PTSD) symptomatology versus controls. Participants included 50 women, which were divided into 2 groups on the basis of a structured clinical interview: 26 women with a history of sexual trauma with and without PTSD (sexual trauma group), and 24 women without a history of sexual trauma or PTSD (controls). Participants came into the lab and participated in a 45min emotional closeness exercise with a male confederate and completed self-report questionnaires of closeness, state anxiety/depression, and cortisol assays at the aforementioned time points. Women with a history of sexual trauma exhibited a blunted cortisol response and greater anxious mood in reaction to the intimacy induction task compared to controls. Results also demonstrated that, unexpectedly, PTSD symptom severity scores among sexual trauma survivors were not associated with differential cortisol responding to the task compared to controls. Adaptive responses to stress are characterized by a relatively rapid cortisol increase followed by a steady decline. The results of this study demonstrated that women with a history of sexual trauma, in contrast, displayed a blunted cortisol response to an intimacy induction task. Both controls and women with a history of sexual trauma reported increased feelings of closeness to the male confederate in response to the intimacy induction task, suggesting that survivors were able to achieve similar adaptive feelings of intimacy when provided with the right conditions. Published by Elsevier Ltd.
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...... method for diagnosing depression and suggesting individual treatment protocols. Finally, the method may inspire pharmaceutical companies to develop target specific psychopharmaca for more effective and individual treatment.......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...
Burke, Andrew R.; Miczek, Klaus A.
Rationale Research on adolescence and drug abuse increased substantially in the past decade. However, drug-addiction related behaviors following stressful experiences during adolescence are less studied. We focus on rodent models of adolescent stress cross-sensitization to drugs of abuse. Objectives Review the ontogeny of behavior, dopamine, corticotropin-releasing factor (CRF), and the hypothalamic pituitary adrenal (HPA) axis in adolescent rodents. We evaluate evidence that stressful experiences during adolescence engender hypersensitivity to drugs of abuse and offer potential neural mechanisms. Results and Conclusions Much evidence suggests that final maturation of behavior, dopamine systems, and HPA axis occurs during adolescence. Stress during adolescence increases amphetamine- and ethanol-stimulated locomotion, preference, and self-administration under many conditions. The influence of adolescent stress on subsequent cocaine- and nicotine-stimulated locomotion and preference is less clear. The type of adolescent stress, temporal interval between stress and testing, species, sex, and the drug tested are key methodological determinants for successful cross-sensitization procedures. The sensitization of the mesolimbic dopamine system is proposed to underlie stress cross-sensitization to drugs of abuse in both adolescents and adults through modulation by CRF. Reduced levels of mesocortical dopamine appear to be a unique consequence of social stress during adolescence. Adolescent stress may reduce the final maturation of cortical dopamine through D2 dopamine receptor regulation of dopamine synthesis or glucocorticoid-facilitated pruning of cortical dopamine fibers. Certain rodent models of adolescent adversity are useful for determining neural mechanisms underlying the cross-sensitization to drugs of abuse. PMID:24370534
Xu, Ying; Ku, Baoshan; Tie, Lu; Yao, Haiyan; Jiang, Wengao; Ma, Xing; Li, Xuejun
Curcuma longa is a major constituent of the traditional Chinese medicine Xiaoyao-san, which has been used to effectively manage stress and depression-related disorders in China. Curcumin is the active component of curcuma longa, and its antidepressant effects were described in our prior studies in mouse models of behavioral despair. We hypothesized that curcumin may also alleviate stress-induced depressive-like behaviors and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Thus in present study we assessed whether curcumin treatment (2.5, 5 and 10 mg/kg, p.o.) affects behavior in a chronic unpredictable stress model of depression in rats and examined what its molecular targets may be. We found that subjecting animals to the chronic stress protocol for 20days resulted in performance deficits in the shuttle-box task and several physiological effects, such as an abnormal adrenal gland weight to body weight (AG/B) ratio and increased thickness of the adrenal cortex as well as elevated serum corticosterone levels and reduced glucocorticoid receptor (GR) mRNA expression. These changes were reversed by chronic curcumin administration (5 or 10 mg/kg, p.o.). In addition, we also found that the chronic stress procedure induced a down-regulation of brain-derived neurotrophic factor (BDNF) protein levels and reduced the ratio of phosphorylated cAMP response element-binding protein (pCREB) to CREB levels (pCREB/CREB) in the hippocampus and frontal cortex of stressed rats. Furthermore, these stress-induced decreases in BDNF and pCREB/CREB were also blocked by chronic curcumin administration (5 or 10 mg/kg, p.o.). These results provide compelling evidence that the behavioral effects of curcumin in chronically stressed animals, and by extension humans, may be related to their modulating effects on the HPA axis and neurotrophin factor expressions.
Melhem, Nadine M; Munroe, Sara; Marsland, Anna; Gray, Katarina; Brent, David; Porta, Giovanna; Douaihy, Antoine; Laudenslager, Mark L; DePietro, Frank; Diler, Rasim; Driscoll, Henry; Gopalan, Priya
Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation is associated with increased risk for suicidal behavior. However, it is not clear whether such dysregulation exists prior to or is a consequence of attempt. Studies also show an activation of inflammatory responses in suicidal behavior but often combine attempters with those with ideation. The sample consisted of psychiatric inpatients, aged 15-30 years, admitted for suicide attempt (SA, n=38), inpatients admitted for suicidal ideation with no prior history of attempts (SI, n=40), and healthy controls (n=37). We compared SA, SI, and controls on hair cortisol concentrations (HCC), which provides retrospective levels of cortisol and thus prior to the attempt in SA. We also compared them on the expression of genes in the HPA axis and inflammatory pathways previously implicated in suicidal behavior (GR or NR3C1, SKA2, FKBP5, IL-1β, TNF-α); plasma C-Reactive Protein (CRP); and cellular measures of glucocorticoid receptor (GR) sensitivity and stimulated production of IL-6. We found lower HCC [β=-0.55, 95% CI (-0.96, -0.13), p=0.01, ES=-0.54] in first-time SA compared to SI and controls. In addition, SA showed lower GR or NR3C1 (α isoform) mRNA [β=-5.11, 95% CI (-10.9, 0.73), p=0.09, ES=-0.46], higher CRP [β=0.94, 95% CI (-0.004, 1.9), p=0.05, ES=0.60], and higher TNF-α mRNA [β=26.4, 95% CI (7.7, 45.2), p=0.006, ES=0.73]. This is the first study to differentiate youth who attempt suicide from those with suicidal ideation on HCC and to show that low HCC precedes suicide attempt. Suicide attempters also showed a distinct biological profile on several markers in both the HPA axis and inflammatory pathways. Future longitudinal studies are needed to examine the ability of these biomarkers to predict suicidal behavior. Copyright © 2017 Elsevier Ltd. All rights reserved.
Mustoe, Aaryn C; Taylor, Jack H; Birnie, Andrew K; Huffman, Michelle C; French, Jeffrey A
Both gestational cortisol exposure (GCE) and variability in postnatal environments can shape the later-life behavioral and endocrine outcomes of the hypothalamic-pituitary-adrenal (HPA) axis. We examined the influence of GCE and social play on HPA functioning in developing marmosets. Maternal urinary cortisol samples were collected across pregnancy to determine GCE for 28 marmoset offspring (19 litters). We administered a social separation stressor to offspring at 6, 12, and 18 months of age, during which we collected urinary cortisol samples and behavioral observations. Increased GCE was associated with increased basal cortisol levels and cortisol reactivity, but the strength of this relationship decreased across age. Increased social play was associated with decreased basal cortisol levels and a marginally greater reduction in cortisol reactivity as offspring aged, regardless of offspring GCE. Thus, GCE is associated with HPA functioning, but socially enriching postnatal environments can alter the effects associated with increased fetal exposure to glucocorticoids. © 2014 Wiley Periodicals, Inc.
Daskalakis, Nikolaos P; Enthoven, Leo; Schoonheere, Edwige; de Kloet, Edo Ronald; Oitzl, Melly S
The postnatal development of the mouse is characterized by a period of hypo-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to mild stressors. Maternal deprivation (MD) during this period can disrupt the quiescence of the HPA-axis. The present study examined the influence of strain (outbred CD1 vs. inbred C57BL/6J mice) on some central and peripheral components of the HPA-axis in neonatal mice (5-day-old) in the presence of their mother or after 24 h MD (on postnatal day 4) under basal or mild stressful conditions. In the presence of the dam, adrenal corticosterone (CORT) secretion was low in both mouse strains. Compared to CD1 mice, C57BL/6J had lower CORT levels associated with higher ACTH levels and ACTH/CORT ratio (i.e., lower adrenal sensitivity to ACTH), and higher glucocorticoid receptor (GR) mRNA expression in the paraventricular nucleus. Although MD disinhibited the HPA-axis in both strains as reflected by increased basal CORT and ACTH, we found a strain-dependent pattern. MD increased CORT more in C57BL/6J compared to CD1 mice together with a lower ACTH/CORT ratio (i.e., higher adrenal sensitivity to ACTH), while GR mRNA was no longer different in the two strains. However, this increased adrenal sensitivity in maternally deprived C57BL/6J mice was not reflected in their CORT response to a subsequent novelty stressor, possibly due to an MD-induced ceiling effect in their steroidogenic capacity. In conclusion, the immediate outcome of MD depends on the genetic background of the mother-infant dyad, suggesting that maybe also the outcome in later-life cannot be generalized.
Nikolaos P Daskalakis
Full Text Available The postnatal development of the mouse is characterised by a period of hypo-responsiveness of the hypothalamic-pituitary-adrenal (HPA axis to mild stressors. Maternal deprivation (MD during this period can disrupt the quiescence of the HPA-axis. The present study examined the influence of strain (outbred CD1 versus inbred C57BL/6J mice on some central and peripheral components of the HPA-axis in neonatal mice (5 day-old in the presence of their mother or after 24 h MD (on postnatal day 4 under basal or mild stressful conditions. In the presence of the dam, adrenal corticosterone (CORT secretion was low in both mouse strains. Compared to CD1 mice, C57BL/6J had lower CORT levels associated with higher ACTH levels and ACTH/CORT ratio (i.e., lower adrenal sensitivity to ACTH, and higher glucocorticoid receptor (GR mRNA expression in the paraventricular nucleus. Although MD disinhibited the HPA-axis in both strains as reflected by increased basal CORT and ACTH, we found a strain-dependent pattern. MD increased CORT more in C57BL/6J, compared to CD1 mice, together with a lower ACTH/CORT ratio (i.e., higher adrenal sensitivity to ACTH, while GR mRNA was no longer different in the two strains. However, this increased adrenal sensitivity in maternally deprived C57BL/6J mice was not reflected in their CORT response to a subsequent novelty stressor, possibly due to a MD-induced ceiling effect in their steroidogenic capacity.In conclusion, the immediate outcome of MD depends on the genetic background of the mother-infant dyad, suggesting that maybe also the outcome in later-life cannot be generalized. genetic background of the mother-infant dyad, predicting that the outcome in later-life cannot be generalized.
Majidi, Jafar; Kosari-Nasab, Morteza; Salari, Ali-Akbar
Neonatal infection is associated with increased lifetime risk for neuropsychiatric disorders including anxiety and depression, with evidence showing that dysregulation of the hypothalamic-pituitary-adrenal-(HPA)-axis system may be partly responsible. Preclinical and clinical studies demonstrate that minocycline exhibits antidepressant effects through inhibition of microglial activation and anti-inflammatory actions, and of interest is that recent studies suggest that minocycline alleviates the behavioral abnormalities induced by early-life insults. The current study was designed to determine if developmental minocycline treatment attenuates the neonatal immune activation-induced anxiety- and depression-like symptoms and HPA-axis-dysregulation later in life. To this end, neonatal mice were treated to either lipopolysaccharide or saline on postnatal days (PND) 3-5, then dams during lactation (PND 6-20) and male offspring during adolescence (PND 21-40) received oral administration of minocycline or water via regular drinking bottles. Anxiety- and depression-like behaviors, HPA-axis-reactivity (corticosterone), and hippocampal inflammation (TNF-α and IL-1β) after exposure to stress were evaluated. The results indicated that neonatal immune activation resulted in increased anxiety and depression-like symptoms, HPA-axis-hyperactivity, and elevated the levels of TNF-α and IL-1β in the hippocampus in response to stress in adulthood. Interestingly, developmental minocycline treatment significantly reduced the abnormalities induced by neonatal inflammation in adult mice. In addition, minocycline, regardless of postnatal inflammation, did not have any detrimental effects on the above measured parameters. Considering that minocycline is currently under exploration as an alternative or adjunctive therapy for reducing the symptoms of neurological disorders, our findings suggest that minocycline during development can decrease the behavioral abnormalities induced by early
Christiansen, A.M.; DeKloet, A.D; Ulrich-Lai, Y.M.; Herman, J.P.
A history of limited, intermittent intake of palatable food (sucrose drink) attenuates hypothalamic-pituitary-adrenal (HPA) axis stress responses and induces markers of neuronal plasticity in stress- and reward-regulatory brain regions. Synaptic plasticity could provide a mechanism for long-term changes in neuronal function, implying that sucrose stress-dampening may endure over long periods of time. The present study tests the persistence of HPA axis dampening and plasticity after cessation of palatable drinking. Adult, male Long-Evans rats (n = 10–13) with free access to water and chow were given additional twice-daily access to 4 ml sucrose (30%) or water for 14 days. Rats were subsequently tested for HPA responsiveness to an acute (20-minute) restraint stress at 1, 6 and 21 days after the cessation of sucrose. Brains were collected for immunohistochemical analysis of FosB/deltaFosB, a marker of long-term neuronal plasticity, in the basolateral amygdala and nucleus accumbens. Prior sucrose consumption significantly decreased the plasma corticosterone response to restraint at one day after the last palatable drink presentation, and also increased FosB/deltaFosB-positive cells in the basolateral amygdala and in the nucleus accumbens core. This HPA-dampening persisted through 21 days after the termination of the palatable drink, as did the increased FosB/deltaFosB immunoreactivity in both the BLA and the NuAc core. These data suggest that chronic palatable food intake causes lasting changes in stress/reward-modulatory circuitry and that the suppressed hormonal response to stress that can persist well beyond periods of palatable drink exposure. PMID:21262247
Castañeda Cortés, Diana C.; Langlois, Valerie S.; Juan I Fernandino
Besides the well-known function of thyroid hormones (THs) for regulating metabolism, it has recently been discovered that THs are also involved in testicular development in mammalian and non-mammalian species. THs, in combination with follicle stimulating hormone (FSH), lead to androgen synthesis in Denio rerio, which results in the onset of spermatogenesis in the testis, potentially relating the hypothalamic-pituitary-thyroid gland (HPT) to the hypothalamic-pituitary-gonadal (HPG) axes. Furt...
Laurent, Heidemarie; Powers, Sally
Difficulty managing the stress of conflict in close relationships can lead to mental and physical health problems, possibly through dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine stress response system. Temperament, an individual characteristic, and attachment, a dyadic characteristic, have both been implicated in emotion regulation processes and physiological reactivity, yet there is no clear consensus on how the two work together to influence the stress response, especially after childhood. The present study investigated the ways in which temperament and attachment together predict HPA response in emerging adult couples. Analyses using multilevel modeling (HLM) found that partners' dyadic fit on attachment avoidance impacted females' cortisol response patterns, and attachment avoidance further moderated the effect of males' emotionality on both their own and their partners' cortisol. Results are discussed in terms of emotional coregulation processes in romantic attachment. PMID:17681662
The effects of progesterone on transcriptional expression profiles of genes associated with hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes during the early development of zebrafish (Danio rerio).
Liang, Yan-Qiu; Huang, Guo-Yong; Ying, Guang-Guo; Liu, Shuang-Shuang; Jiang, Yu-Xia; Liu, Shan; Peng, Feng-Jiao
Progesterone (P4) has been reported in surface water, and it may have adverse effects on aquatic organisms. This study provided the transcriptional effects of P4 during the early development of zebrafish. Zebrafish embryos were exposed for 144 h post fertilization (hpf) to 0, 6, 45 and 90 ng L(-1) P4, and transcriptional expression profiles of the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes were assessed every day. For the receptor signaling pathways, P4 significantly induced the transcript of Pgr gene above 45 ng L(-1) at 72 and 144 hpf, but inhibited its transcript above 6 ng L(-1) at 96 and 120 hpf. A significant up-regulation of Vtg1 mRNA was observed at 6 ng L(-1) P4 or higher at 24, 96 and 144 hpf. For the steroidogenic pathways, the transcriptional expression of Cyp11a1 and Hsd17b3 mRNAs was mediated by 6 ng L(-1) P4 or higher according to different exposure time points. In addition, P4 resulted in a significant induction of Cyp19a1a and Cyp11b mRNA expression while it caused a significant inhibition of Hsd11b2 mRNA expression above 6 ng L(-1). For the other target genes related to hypothalamic and pituitary hormones, P4 mainly modulated the transcripts of Gnrh2, Fshb and Lhb genes at 6 ng L(-1) or higher. The overall results from the present study indicate that P4 at environmentally relevant concentrations could cause the potential effects on zebrafish reproductive and adrenal endocrine systems by interfering with the HPG and HPA axes. Copyright © 2015 Elsevier Ltd. All rights reserved.
Li, Qing; Qu, Fa-Lin; Gao, Yue; Jiang, Yi-Ping; Rahman, Khalid; Lee, Kuo-Hsiung; Han, Ting; Qin, Lu-Ping
There are many plants of genus Piper which have been reported to induce antidepressant-like effects, Piper sarmentosum (PS) is one of them. PS is a Chinese herbal medicine and a traditional edible vegetable. In the present study, the antidepressant-like effects of PS extracts and the ethyl acetate fraction of PS extracts (PSY) were assessed using the open field test (OFT), forced swimming test (FST), and tail suspension test (TST) in mice. Furthermore, we applied a 4 consecutive weeks of chronic unpredictable mild stress (CUMS) as a model of depression in rats, followed by a sucrose preference test. Then we examined the possible mechanisms of this action. The activity of the hypothalamic-pituitary-adrenal (HPA) axis was evaluated by detecting the serum corticosterone (CORT) concentrations, and the protein expression levels of brain-derived neurotrophic factor (BDNF), the phosphorylated form CREB and ERK1/2 were detected by qRT-PCR or Western blot. The results showed that PS extracts (100, 200mg/kg) and PSY (12.5, 25, 50mg/kg) treatment produced antidepressant-like effects in mice similar to fluoxetine (20mg/kg), indicated by the reduced immobility time in the FST and TST, while both had no influence on the locomotor activity in the OFT. PSY treatment significantly increased sucrose preference and reduced serum CORT levels in CUMS rats. Moreover, PSY up-regulated BDNF protein levels, and increased CREB and ERK phosphorylation levels in the hippocampus on CUMS rats. These findings suggest that the antidepressant-like effects of PS extracts and PSY are mediated, at least in part, by modulating HPA axis, BDNF, CREB and ERK phosphorylation and expression in the hippocampus. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
Laurent, Heidemarie K.; Leve, Leslie D.; Neiderhiser, Jenae M.; Natsuaki, Misaki N.; Shaw, Daniel S.; Harold, Gordon T.; Reiss, David
This study used a prospective adoption design to investigate effects of prenatal and postnatal parent depressive symptom exposure on child hypothalamic-pituitary-adrenal (HPA) activity and associated internalizing symptoms. Birth mother prenatal symptoms and adoptive mother/father postnatal (9-month, 27-month) symptoms were assessed with the Beck…
Buttenschøn, Henriette Nørmølle; Krogh, Jesper; Nielsen, Marit Nyholm
(ACE). METHODS: In total, 78 single nucleotide polymorphisms (SNPs) and one insertion/deletion polymorphism were genotyped. The study included 408 individuals with depression and 289 controls. In a subset of cases, the interaction between genetic variants and stressful life events (SLEs......) 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......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...
Full Text Available Abstract Background Basic and clinical studies suggest that hypothalamic-pituitary-adrenal (HPA axis is the neuroendocrine-immnue pathway that functionally regulates the chronic inflammatory disease including asthma. Our previous studies showed corresponding changes of cytokines and leukotriene B4 (LTB4 between brain and lung tissues in antigen-challenged asthmatic rats. Here, we investigated how the increased LTB4 level in brain interacts with HPA axis in regulating antigen-induced asthmatic response in sensitized rats. Methods Ovalbumin-sensitized rats were challenged by inhalation of antigen. Rats received vehicle, LTB4 or U75302 (a selective LTB4 BLT1 receptor inhibitor was given via intracerebroventricular injection (i.c.v 30 min before challenge. Lung resistance (RL and dynamic lung compliance (Cdyn were measured before and after antigen challenge. Inflammatory response in lung tissue was assessed 24 h after challenge. Expression of CRH mRNA and protein in hypothalamus were evaluated by RT-PCR and Western Blot, and plasma levels of adrenocorticotropic hormone (ACTH and corticosterone (CORT were measured using the ELISA kits. Results Antigen challenge decreased pulmonary function and induced airway inflammation, evoked HPA axis response in sensitized rats. Administration of LTB4 via i.c.v markedly attenuated airway contraction and inflammation. Meanwhile, LTB4 via i.c.v markedly increased CORT and ACTH level in plasma before antigen challenge, and followed by further increases in CORT and ACTH levels in plasma after antigen challenge in sensitized rats. Expression of CRH mRNA and protein in hypothalamus were also significantly increased by LTB4 via i.c.v in sensitized rats after antigen challenge. These effect were completely blocked by pre-treatment with BLT1 receptor antagonist U75302 (10 ng, but not by BLT2 antagonist LY255283. Conclusions LTB4 administered via i.c.v down-regulates the airway contraction response and inflammation through
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.
Webb, L E; van Reenen, C G; Engel, B; Berends, H; Gerrits, W J J; Bokkers, E A M
Stereotypies are used as indicators of poor animal welfare and it is, therefore, important to understand underlying factors mediating their development. In calves, two oral stereotypies, that is, tongue playing and object manipulation, result mostly from insufficient structure in the diet. Three hypotheses were studied: (1) oral stereotypies in calves are one of two alternative strategies, the alternative being hypo-activity; (2) stereotyping and non-stereotyping calves differ in terms of cortisol secretion; (3) oral stereotypy development in calves rests on a gene by environment interaction. Eight-week-old bull calves (n=48) were assigned to one of four solid feed allowances (0, 9, 18 or 27 g dry matter/kg metabolic weight per day) with the following composition: 50% concentrate, 25% maize silage and 25% straw on dry matter basis. The calves received milk replacer in buckets, the provision of which was adjusted to achieve equal growth rates. At 14 to 18 weeks of age, calves were exposed to a challenge, that is, tethering inside cages. Oral stereotypies and inactivity were recorded in the home pens in the 4 weeks before the challenge using instantaneous scan sampling. Salivary cortisol levels were measured at -120, +40, +80, +120 min and +48 h relative to the challenge. Individual differences in behaviour were recorded in the first 30 min after challenge implementation using focal animal sampling and continuous recording, and these elements were entered into a principal component (PC) analysis to extract PCs. Regression analyses were performed to find relationships between stereotypies and inactivity, stereotypies and cortisol, and stereotypies and PCs (individual differences, genes) and solid feed (environment). Relationships between PCs and cortisol were also investigated to help with the interpretation of PCs. Hypotheses 1 and 2 were rejected. Hypothesis 3, however, was supported: calves with a zero solid feed allowance, that is, in the most barren environment, showed links between stereotypies and two of the PCs. Calves that displayed high levels of idle and rapid locomotion and low levels of oral contact with the cage during the challenge also displayed high levels of object manipulation in the home pens. Calves that displayed low levels of stepping and turning attempts during the challenge also displayed high levels of tongue playing in the home pens. This study corroborates the gene by environment interaction on the development of oral stereotypies in calves.
Turner-Cobb, Julie M; Rixon, Lorna; Jessop, David S
We have previously reported an increase in salivary cortisol in a cohort of 4-year-old children transitioning to primary school. We hypothesised that increased cortisol in response to this acute naturalistic stress in early development may be immunostimulatory and associated with positive health outcomes. We tested this hypothesis by measuring upper respiratory tract infection (URI) across the first 6 months of school, in relation to salivary cortisol at the end of the second week following school transition Seventy children supplied morning and evening saliva samples for cortisol assay. Children were psychologically assessed for temperament and behavioural adaptation. Symptoms of URI were recorded in diary form, and variables relating to URI occurrence, duration and severity were assessed. Children with higher evening cortisol at school transition experienced significantly fewer episodes of URI over the following 6 months. Diurnal cortisol change was negatively correlated with number of illnesses across the 6 months, indicating an association between a greater decline in cortisol across the day and a greater number of colds. URI severity was associated with the greatest resistance to URI infection in children who were less socially isolated and who had a smaller diurnal change in cortisol across the day. Our results showing that higher cortisol is associated with lower URI may be explained by proposing that increased cortisol in response to the naturalistic stress of school transition may prime the immune system to develop resistance to URI at this critical stage of a child's development.
Malmkvist, J; Damgaard, B M; Pedersen, L J; Jørgensen, E; Thodberg, K; Chaloupková, H; Bruckmaier, R M
Provision of additional floor heating (33 to 34 degrees C) at birth and during the early postnatal hours is favorable for newborn piglets of domestic sows (Sus scrofa). We investigated whether this relatively high temperature influenced sow behavior and physiology around farrowing. One-half of 28 second-parity pregnant sows were randomly chosen to be exposed to floor heating 12 h after onset of nest building and until 48 h after birth of the first piglet (heat treatment), whereas the rest of the sows entered the control group (control treatment) with no floor heating. Hourly blood sampling from 8 h before and until 24 h after the birth of the first piglet was used for investigation of temporal changes in plasma concentrations of oxytocin, cortisol, and ACTH. In addition, occurrence and duration of sow postures were recorded -8 to +48 h relative to the birth of the first piglet. There was a clear temporal development in sow behavior and hormone concentrations (ACTH, cortisol, and oxytocin) across parturition (P heating increased the mean concentration of cortisol (P = 0.02; estimated as 29% greater than in controls) and tended to increase the mean concentration of ACTH (P = 0.08; estimated as 17% greater than in controls), but we did not find any treatment effect on mean oxytocin concentrations, the course of parturition, or the behavior of sows. Behavioral thermoregulation may, however, have lost some function for the sows because the floor was fully heated in our study. In addition, exposure to heat decreased the between-sow variation of plasma oxytocin (approximately 31% less relative to control) and ACTH (approximately 46% less relative to control). Whether this decreased variation may be indicative of acute stress or linked to other biological events is unclear. In conclusion, inescapable floor heating (around 33.5 degrees C) may be considered a stressor for sows around farrowing, giving rise to elevated plasma concentrations of cortisol, but without concurrent changes in oxytocin or behavioral activity.
Romero, L Michael
Recent evidence indicates that house sparrows (Passer domesticus) seasonally regulate corticosterone responses to capture, handling, and restraint. Responses during molt and in the fall are lower than responses in the winter and while breeding. This study tested whether changes in either adrenal tissue responsiveness to adrenocorticotropin (ACTH) or pituitary responsiveness to corticotropin releasing factor (CRF) or arginine vasotocin (AVT) could provide the mechanism regulating these seasonal changes. House sparrows were captured at two sites (Massachusetts and New Mexico, USA) and during the above four seasons and injected with exogenous ACTH, CRF, and AVT. ACTH stimulated further corticosterone release in all birds except Massachusetts birds in the winter, suggesting that reduced adrenal sensitivity to ACTH cannot explain reduced corticosterone release during fall and molt. However, exogenous ACTH was less effective during molt at both sites, implying that adrenal sensitivity does change. Pituitary sensitivity also changed seasonally, but these pituitary changes did not match the seasonal changes in corticosterone release. CRF and AVT only succeeded in elevating corticosterone in the spring in Massachusetts birds and in the winter in New Mexico birds, whereas CRF alone also stimulated corticosterone release in New Mexico birds in the fall. Taken together, these data indicate that house sparrows can alter the amount of corticosterone released from adrenal tissue, the amount of ACTH released from the pituitary, and the amount of CRF and AVT released from the hypothalamus, but that none of these changes correlate with seasonal changes in corticosterone release. Consequently, seasonal modulation of corticosterone release in house sparrows appear to result from a complicated mix of adrenal, pituitary, and hypothalamic changes that also vary seasonally.
Full Text Available Metabolic disease subclinical hypothyroidism (SCH is closely associated with depression-like behavior both in human and animal studies, and our previous studies have identified the antidepressant effect of resveratrol (RES in stressed rat model. The aim of this study was to investigate whether RES would manifest an antidepressant effect in SCH rat model and explore the possible mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization, after which the model rats in the RES and LT4 groups received a daily intragastric injection of RES at the dose of 15 mg/kg or LT4 at the dose of 60 μg/kg for 16 days, respectively. The rats’ plasma concentrations of thyroid hormones were measured. Behavioral performance and hypothalamic-pituitary-adrenal (HPA activity were evaluated. The protein expression levels of the Wnt/β-catenin in the hippocampus were detected by western blot. The results showed that RES treatment down-regulated the elevated plasma thyroid stimulating hormone (TSH concentration and the hypothalamic mRNA expression of thyrotropin releasing hormone (TRH in the SCH rats. RES-treated rats showed increased rearing frequency and distance in the OFT, increased sucrose preference in the SPT, and decreased immobility in the FST compared with SCH rats. The ratio of the adrenal gland weight to body weight, the plasma corticosterone levels and the hypothalamic CRH mRNA expression were reduced in the RES-treated rats. Moreover, RES treatment up-regulated the relative ratio of phosphorylated-GSK3β (p-GSK3β/GSK3β and protein levels of p-GSK3β, cyclinD1 and c-myc, while down-regulating the relative ratio of phosphorylated-β-catenin (p-β-catenin/β-catenin and expression of GSK3β in the hippocampus. These findings suggest that RES exerts anxiolytic- and antidepressant-like effect in SCH rats by down-regulating hyperactivity of the HPA axis and regulating both the HPT axis and the Wnt/β-catenin pathway.
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.
Camille Melón, Laverne; Maguire, Jamie
The hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes are regulated by GABAergic signaling at the level of corticotropin-releasing hormone (CRH) and gonadotropin-releasing hormone (GnRH) neurons, respectively. Under basal conditions, activity of CRH and GnRH neurons are controlled in part by both phasic and tonic GABAergic inhibition, mediated by synaptic and extrasynaptic GABAA receptors (GABAARs), respectively. For CRH neurons, this tonic GABAergic inhibition is mediated by extrasynaptic, δ subunit-containing GABAARs. Similarly, a THIP-sensitive tonic GABAergic current has been shown to regulate GnRH neurons, suggesting a role for δ subunit-containing GABAARs; however, this remains to be explicitly demonstrated. GABAARs incorporating the δ subunit confer neurosteroid sensitivity, suggesting a potential role for neurosteroid modulation in the regulation of the HPA and HPG axes. Thus, stress-derived neurosteroids may contribute to the impact of stress on reproductive function. Interestingly, excitatory actions of GABA have been demonstrated in both CRH neurons at the apex of control of the HPA axis and in GnRH neurons which mediate the HPG axis, adding to the complexity for the role of GABAergic signaling in the regulation of these systems. Here we review the effects that stress has on GnRH neurons and HPG axis function alongside evidence supporting GABAARs as a major interface between the stress and reproductive axes. Copyright © 2015 Elsevier Ltd. All rights reserved.
Muñoz-Abellán, C; Andero, R; Nadal, R; Armario, A
Exposure of rodents to cats or certain cat odors results in long-term behavioral effects reminiscent of enhanced anxiety that have been considered to model post-traumatic stress disorder. However, other severe stressors such as tail-shock or immobilization in wooden boards (IMO) appear to induce shorter lasting changes in anxiety. In addition, there are controversial results regarding the effects of urine/feces odors. In the present work, we studied in two experiments the relationship between the degree of stress experienced by the animals during exposure to IMO, urine odors or fur odors (as assessed by hypothalamic-pituitary-adrenal activation and plasma glucose) and the short- and long-term behavioral consequences. In the first experiment, rats were individually exposed for 15 min to a novel environment (white large cages) containing either clean cat litter (controls) or litter soiled by cats (urine odors). Half of the rats in each condition were left to freely explore the environment whereas the others were subjected to immobilization (IMO) within the cages. Although ACTH, corticosterone and glucose responses to IMO were much stronger than those to the white cages with clean litter or urine odors (which did not differ from each other), no effect of treatments on anxiety-like behavior in the elevated plus-maze (EPM) were found one week later. However, previous IMO exposure did cause sensitization of the ACTH response to the EPM. In the second experiment, the response to white large cages containing either no odor (controls), litter soiled by cats (urine odor) or a cloth impregnated with cat odor (fur odor) was compared. Urine and fur odors elicited similar ACTH and corticosterone responses that were higher than those of controls, but plasma glucose levels were slightly higher in rats exposed to fur odor. When compared to controls, activity was only diminished in the novel cages containing fur odor. Similarly, fur odor-exposed rats, but not those exposed to urine
Mel��n, Laverne Camille; Maguire, Jamie
The hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes are regulated by GABAergic signaling at the level of corticotropin-releasing hormone (CRH) and gonadotropin-releasing hormone (GnRH) neurons, respectively. Under basal conditions, activity of CRH and GnRH neurons are controlled in part by both phasic and tonic GABAergic inhibition, mediated by synaptic and extrasynaptic GABAA receptors (GABAARs), respectively. For CRH neurons, this tonic GABAergic inhibitio...
Dismukes, Andrew R; Johnson, Megan M; Vitacco, Michael J; Iturri, Florencia; Shirtcliff, Elizabeth A
The effects of early life adversity can be observed across the lifespan, and the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes could be mechanistic intermediaries underlying this phenomenon. The current study examined 50 adolescent males aged 12-18 in a maximum-security correctional and treatment setting. Saliva samples were collected five times a day for 2 days and assayed for cortisol, testosterone, and DHEA. Youth completed semi-structured life stress interviews and self-reports of child maltreatment to index adversity. When youth had higher testosterone levels, they had higher cortisol and DHEA levels, indicating positive "coupling" of the HPA-HPG axes. In addition, children experiencing greater life adversity had tighter coupling of the HPA-HPG axes. Additional analyses hint that coupling may be driven largely by HPG axis functioning. Results indicate that positive coupling of the HPA-HPG axis is observed within incarcerated adolescents, especially for those with the greatest life stress. © 2014 Wiley Periodicals, Inc.
Dismukes, Andrew R.; Johnson, Megan; Vitacco, Michael; Shirtcliff, Elizabeth A.
The effects of early life adversity can be observed across the lifespan, and the Hypothalamic-Pituitary-Adrenal (HPA) and Hypothalamic-Pituitary-Gonadal (HPG) axes could be mechanistic intermediaries underlying this phenomenon. The current study examined fifty adolescent males aged 12–18 in a maximum-security correctional and treatment setting. Saliva samples were collected five times a day for two day and assayed for cortisol, testosterone and DHEA. Youth completed semi-structured life stres...
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.
Tarter, Ralph E.; Kirisci, Levent; Kirillova, Galina; Reynolds, Maureen; Gavaler, Judy; Ridenour, Ty; Horner, Michelle; Clark, Duncan; Vanyukov, Michael
Background 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 also 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. Method 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. Results 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. Conclusion 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. PMID:22867990
Bandelow, B; Wedekind, D; Pauls, J; Broocks, A; Hajak, G; Ruther, E
Objective: Documentation of hypothalamic-pituitary-adrenal (HPA) axis disturbance in panic disorder has been inconsistent. Increased cortisol levels have been associated with altered HPA function due to stress. The authors examined salivary cortisol levels in spontaneously occurring, unprovoked
Zhang, Chong; Xu, Dan; Luo, Hanwen; Lu, Juan; Liu, Lian; Ping, Jie; Wang, Hui
The hypothalamic-pituitary-adrenal (HPA) axis is one of the most important neuroendocrine axes and plays an important role in stress defense responses before and after birth. Prenatal exposure to xenobiotics, including environmental toxins (such as smoke, sulfur dioxide and carbon monoxide), drugs (such as synthetic glucocorticoids), and foods and beverage categories (such as ethanol and caffeine), affects fetal development indirectly by changing the maternal status or damaging the placenta. Certain xenobiotics (such as caffeine, ethanol and dexamethasone) may also affect the fetus directly by crossing the placenta into the fetus due to their lipophilic properties and lower molecular weights. All of these factors probably result in intrauterine programming alteration of the HPA axis, which showed a low basal activity but hypersensitivity to chronic stress. These alterations will, therefore, increase the susceptibility to adult neuropsychiatric (such as depression and schizophrenia) and metabolic diseases (such as hypertension, diabetes and non-alcoholic fatty liver disease). The "over-exposure of fetuses to maternal glucocorticoids" may be the main initiation factor by which the fetal HPA axis programming is altered. Meantime, xenobiotics can directly induce abnormal epigenetic modifications and expression on the important fetal genes (such as hippocampal glucocorticoid receptor, adrenal steroidogenic acute regulatory protein, et al) or damage by in situ oxidative metabolism of fetal adrenals, which may also be contributed to the programming alteration of fetal HPA axis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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 (trait-like 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 3-level hierarchical linear model addressed questions regarding the influences of ELS on HPA functioning and its co-variation with mental health symptoms. ELS influenced trait-like cortisol level and slope, with both hyper- and hypo-arousal evident depending on type of ELS. Further, type(s) of ELS influenced co-variation 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. PMID:22018080
Dirven, B.C.J.; Homberg, J.R.; Kozicz, L.T.; Henckens, M.J.A.G.
The hypothalamic-pituitary-adrenal (HPA) axis is critically involved in the neuroendocrine regulation of stress adaptation, and the restoration of homeostasis following stress exposure. Dysregulation of this axis is associated with stress-related pathologies like major depressive disorder,
Schechter, Daniel S; Moser, Dominik A; Paoloni-Giacobino, Ariane; Stenz, Ludwig; Gex-Fabry, Marianne; Aue, Tatjana; Adouan, Wafae; Cordero, María I; Suardi, Francesca; Manini, Aurelia; Sancho Rossignol, Ana; Merminod, Gaëlle; Ansermet, Francois; Dayer, Alexandre G; Rusconi Serpa, Sandra
...) report greater difficulty in parenting their toddlers. Relative to their frequent early exposure to violence and maltreatment, these mothers display dysregulation of their hypothalamic pituitary adrenal axis (HPA-axis...
Pagliaccio, David; Luby, Joan L.; Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S.; Belden, Andrew C.; Botteron, Kelly N.; Harms, Michael P.; Barch, Deanna M.
Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9–14 year olds; N=120). Whole-brain regression analyses indicated that increasing genetic ‘risk’ predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic ‘risk’ and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology. PMID:26595470
Full Text Available ... About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain Brain ... called the hypothalamic-pituitary-adrenal (HPA) axis. Brain Basics in Real Life Brain Basics in Real Life— ...
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 ...
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
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. ...
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
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...
Licht, C.M.M.; Vreeburg, S.A.; van Reedt Dortland, A.K.B.; Giltay, E.J.; Hoogendijk, W.J.G.; DeRijk, R.H.; Vogelzangs, N.; Zitman, F.G.; de Geus, E.J.C.; Penninx, B.W.J.H.
Context: Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome, but the underlying biological mechanisms are not yet well understood. Objective: We examined the relationship between two main str systems, the autonomic nervous system and the
Licht, Carmilla M. M.; Vreeburg, Sophie A.; Dortland, Arianne K. B. van Reedt; Giltay, Erik J.; Hoogendijk, Witte J. G.; DeRijk, Roel H.; Vogelzangs, Nicole; Zitman, Frans G.; de Geus, Eco J. C.; Penninx, Brenda W. J. H.
Context: Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome, but the underlying biological mechanisms are not yet well understood. Objective: We examined the relationship between two main str systems, the autonomic nervous system and the
Matrisciano, Francesco; Modafferi, Antonella M E; Togna, Giuseppina I; Barone, Ylenia; Pinna, Graziano; Nicoletti, Ferdinando; Scaccianoce, Sergio
Abuse of anabolic androgenic steroids (AASs) is frequently associated with changes in mood, including depression. However, the nature of this association is still largely unexplored. As a model of AAS abuse, we used male adult rats injected for 4 weeks with either nandrolone or stanozolol at daily doses (5 mg/kg, s.c.) that are considered equivalent to those abused by humans on a milligram per kilogram of body weight basis. AAS treatment reduced levels of brain-derived neurotrophic factor in the hippocampus and prefrontal cortex, reduced the expression of low-affinity glucocorticoid receptors in the hippocampus, and increased morning trough basal plasma corticosterone levels. All these changes have been related to the pathophysiology of major depressive disorder. Accordingly, rats treated with nandrolone or stanozolol showed an increased immobility time in the forced swim test, which is widely used for the screening of antidepressant drugs. All effects produced by AASs were prevented by co-administration with the classical antidepressant, chlorimipramine. The evidence that supraphysiological doses of AASs induce changes indicative of a depressive state in normal rats, raises the concern that AAS abuse in humans may cause depression regardless of exposure to stress or other risk factors. (c) 2010 Elsevier Ltd. 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
Huizink, Anja; Greaves-Lord, K.; Oldehinkel, A.J.; Ormel, J.; Verhulst, F.C.
Aims We examined within a prospective longitudinal study whether cortisol levels were associated with smoking or drinking behaviours, taking parental substance use into account. Design The influence of parental substance use on cortisol levels of their adolescent offspring at age 10-12 years was
Huizink, A.C.; Greaves-Lord, K.; Oldehinkel, A.J.; Ormel, J.; Verhulst, F.C.
Aims We examined within a prospective longitudinal study whether cortisol levels were associated with smoking or drinking behaviours, taking parental substance use into account. Design The influence of parental substance use on cortisol levels of their adolescent offspring at age 10-12 years was
Yu, Guoliang; Chen, Hao; Wu, Xingjun; Matta, Shannon G.; Sharp, Burt M.
The Mechanisms by which chronic nicotine self-administration augments hypothalamo-pituitary-adrenal (HPA) responses to stress are only partially understood. Nicotine self-administration alters neuropeptide expression in corticotropin-releasing factor (CRF) neurons within paraventricular nucleus (PVN) and increases PVN responsiveness to norepinephrine during mild footshock stress. Glutamate and GABA also modulate CRF neurons, but their roles in enhanced HPA responsiveness to footshock during c...
Smith, Carli J; Emge, Jacob R; Berzins, Katrina; Lung, Lydia; Khamishon, Rebecca; Shah, Paarth; Rodrigues, David M; Sousa, Andrew J; Reardon, Colin; Sherman, Philip M; Barrett, Kim E; Gareau, Mélanie G
The gut-brain-microbiota axis is increasingly recognized as an important regulator of intestinal physiology. Exposure to psychological stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis and causes altered intestinal barrier function, intestinal dysbiosis, and behavioral changes. The primary aim of this study was to determine whether the effects of psychological stress on intestinal physiology and behavior, including anxiety and memory, are mediated by the adaptive immune system. Furthermore, we wanted to determine whether treatment with probiotics would normalize these effects. Here we demonstrate that B and T cell-deficient Rag1(-/-) mice displayed altered baseline behaviors, including memory and anxiety, accompanied by an overactive HPA axis, increased intestinal secretory state, dysbiosis, and decreased hippocampal c-Fos expression. Both local (intestinal physiology and microbiota) and central (behavioral and hippocampal c-Fos) changes were normalized by pretreatment with probiotics, indicating an overall benefit on health conferred by changes in the microbiota, independent of lymphocytes. Taken together, these findings indicate a role for adaptive immune cells in maintaining normal intestinal and brain health in mice and show that probiotics can overcome this immune-mediated deficit in the gut-brain-microbiota axis. Copyright © 2014 the American Physiological Society.
Lemaire, V; Taylor, G T; Mormède, P
Stress in males via the hypothalamic-pituitary-adrenal (HPA) axis may set into motion varied physiological alterations, including dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis. However, the influence of the HPA on the HPG axis may not always be inhibitory. Presence or absence of stimuli of sexual significance that typically activates the HPG axis may alter the influence of the adrenal axis on gonadal axes. In this project, we used male rats and chronic social stimulation that included brief or extended periods with female rats to examine HPA-HPG axes interactions. In experiment 1, we used intact males and a 'chronic social stress' paradigm developed in our previous research that induces social instability by daily changing the membership of group-housed males with females. Thymus weight was reduced and corticosterone levels were marginally increased by chronic social stress, indicating a HPA axis hyperactivity. The HPG axis was also activated as shown by the increased weight of the androgen-sensitive sex structures. These results indicate that when these two axes are stimulated together, neither interferes with nor suppresses activities of the other. Implants of corticosterone pellets to adrenalectomized animals that maintained constant, high corticosterone levels failed to reverse the gonadal hyperactivity induced by sexual stimulation. In a second experiment, we studied the influence of different intensity of sexual stimulations on HPA-HPG axes interactions. Increased corticosterone levels and adrenal weight, indicating a HPA hyperactivity, failed to inhibit HPG hyperactivity as measured by the increased sexual organs weight, whatever the sexual intensity of the stimulation. This work demonstrates that the gonadal axis is freed from suppression when sexual stimulation occurs together with stress. The general conclusion is that the nature of complex social settings is important in determining interactions between the two neuroendocrine axes.
Taylor, Jack H; Mustoe, Aaryn C; Hochfelder, Benjamin; French, Jeffrey A
The relationships that offspring develop with caregivers can exert a powerful influence on behavior and physiology, including the hypothalamic-pituitary-adrenal (HPA) axis. In many mammalian species, offspring-caregiver relationships are largely limited to interactions with mother. Marmoset monkeys receive care in early life from multiple classes of caregivers in addition to the mother, including fathers and siblings. We evaluated whether affiliative social interactions with family members in marmosets were associated with differences in cortisol reactivity to a short-term social separation stressor, and whether these variations in affiliative interactions upon reunion predicted how well marmosets subsequently regulated HPA axis function after cessation of the stressor. Marmosets were separated from the family for 8h at three developmental time points (6-, 12-, and 18-months of age), and interactions of the separated marmoset with the family group were recorded during reunion. Urinary cortisol was measured prior to social separation, every 2h during the separation, and on the morning after separation. Heightened cortisol reactivity during social separation did not predict affiliative social behavior upon reunion but higher rates of grooming and play behavior predicted enhanced HPA regulation. Marmosets with higher rates of grooming and play with family members upon reunion had post-stress cortisol levels closer to preseparation baseline than marmosets with lower rates of affiliative reunion behavior. Combined with previous research showing the early programming effects of social interactions with caregivers, as well as the buffering effect of a close social partner during stress, the current study highlights the high degree of behavioral and HPA adaptability to social stressors across development in marmoset monkeys. Copyright © 2015 Elsevier Ltd. All rights reserved.
Yu, Guoliang; Chen, Hao; Wu, Xingjun; Matta, Shannon G; Sharp, Burt M
The mechanisms by which chronic nicotine self-administration augments hypothalamo-pituitary-adrenal (HPA) responses to stress are only partially understood. Nicotine self-administration alters neuropeptide expression in corticotropin-releasing factor (CRF) neurons within paraventricular nucleus (PVN) and increases PVN responsiveness to norepinephrine during mild footshock stress. Glutamate and GABA also modulate CRF neurons, but their roles in enhanced HPA responsiveness to footshock during chronic self-administration are unknown. We show that nicotine self-administration augmented footshock-induced PVN glutamate release, but further decreased GABA release. In these rats, intra-PVN kynurenic acid, a glutamate receptor antagonist, blocked enhanced adrenocorticotropic hormone and corticosterone responses to footshock. In contrast, peri-PVN kynurenic acid, which decreases activity of GABA afferents to PVN, enhanced footshock-induced corticosterone secretion only in control rats self-administering saline. Additionally, in rats self-administering nicotine, footshock-induced elevation of corticosterone was significantly less than in controls after intra-PVN saclofen (GABA-B receptor antagonist). Therefore, the exaggerated reduction in GABA release by footshock during nicotine self-administration disinhibits CRF neurons. This disinhibition combined with enhanced glutamate input provides a new mechanism for HPA sensitization to stress by chronic nicotine self-administration. This mechanism, which does not preserve homeostatic plasticity, supports the concept that smoking functions as a chronic stressor that sensitizes the HPA to stress.
Femke M. van Haalen
Full Text Available ObjectiveCentral 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.DesignCross-sectional study.Patients86 cCSC patients and 24 controls.MeasurementsPrevalence of Cushing’s syndrome, HPA axis activity.ResultsNone 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.ConclusionNo 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.
Full Text Available Fetal development is a critical period in the life cycle which is why the placenta provides a structural and physiological barrier that protects the fetus from the outer fluctuations and inner disturbances. A variety of influences from the environment, however, might induce fetal overexposure to glucocorticoids that target the fetal hypothalamic-pituitary-adrenal (HPA axis and influence the fetal growth trajecto-r y. Development of the HPA axis starts in the early stages of pregnancy, but the timing of HPA axis maturation and the glucocorticoid receptor (GR expression in relation to birth is highly species-specific. The functional state of the fetal HPA axis plays a key role in the maturation of many organs necessary for intrauterine development and existence after birth. A functional HPA axis in near-term fetuses provides an adequate response to stress and also affects the timing of parturition. Due to their potent effect on the maturation of fetal tissues, synthetic glucocorticoids are used in human pregnancy at risk of preterm delivery. Dexamethasone and betamethasone, as the ones most commonly used, cross the placental enzymatic barrier (11b-hydroxysteroid dehydrogenase type 2 – 11b-HSD2 and have 25-fold higher affinity to the GR than endogenous glucocorticoids, stimulating many aspects of fetal maturation. Despite the numerous positive effects, exposure to synthetic glucocorticoids during fetal development may result in intrauterine growth retardation and fetal programming of the HPA axis function which is associated with cardiovascular, metabolic and psychiatric disorders manifested later in life. Long-term consequences indicate the need for the implementation of new studies that will provide a better understanding of the link between glucocorti-coid overexposure during fetal development and adverse outcomes in adulthood.
Dana N. Joseph
Full Text Available An organism’s reproductive fitness is sensitive to the environment, integrating cues of resource availability, ecological factors, and hazards within its habitat. Events that challenge the environment of an organism activate the central stress response system, which is primarily mediated by the hypothalamic–pituitary–adrenal (HPA axis. The regulatory functions of the HPA axis govern the cardiovascular and metabolic system, immune functions, behavior, and reproduction. Activation of the HPA axis by various stressors primarily inhibits reproductive function and is able to alter fetal development, imparting a biological record of stress experienced in utero. Clinical studies and experimental data indicate that stress signaling can mediate these effects through direct actions in the brain, gonads, and embryonic tissues. This review focuses on the mechanisms by which stress activation of the HPA axis impacts fertility and fetal development.
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 < .001). Relative cortisol VAR was decreased in depressed patients as compared with patients without depression (11.72% vs 60.6%, P = .037). A positive correlation between the depressive symptoms and IL-6 concentration was found (r = 0.469, P < .001). Negative correlations were found between cortisol VAR versus depressive symptoms and cortisol VAR versus IL-6 (r = -0.6, P < .001 and r = -0.52, P < .001, respectively). IL-6 (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 1.0-1.2; P = .006) and cortisol VAR (OR = 1.3; 95%CI = 1.0-1.4; P = .02) are independently associated with depression. Depression in cancer is associated with increased plasma IL-6 concentrations and dysfunction of the HPA axis.
Toufexis, D; Rivarola, M A; Lara, H; Viau, V
There exists a reciprocal relationship between the hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes, wherein the activation of one affects the function of the other and vice versa. For example, both testosterone and oestrogen modulate the response of the HPA axis, whereas activation of the stress axis, especially activation that is repeating or chronic, has an inhibitory effect upon oestrogen and testosterone secretion. Alterations in maternal care can produce significant effects on both HPG and HPA physiology, as well as behaviour in the offspring at adulthood. For example, changes in reproductive behaviour induced by altered maternal care may alter the expression of sex hormone receptors such as oestrogen receptor (ER)α that govern sexual behaviour, and may be particularly important in determining the sexual strategies utilised by females. Stress in adulthood continues to mediate HPG activity in females through activation of a sympathetic neural pathway originating in the hypothalamus and releasing norepinephrine into the ovary, which produces a noncyclic anovulatory ovary that develops cysts. In the opposite direction, sex differences and sex steroid hormones regulate the HPA axis. For example, although serotonin (5-HT) has a stimulatory effect on the HPA axis in humans and rodents that is mediated by the 5-HT1A receptor, only male rodents respond to 5-HT1A antagonism to show increased corticosterone responses to stress. Furthermore, oestrogen appears to decrease 5-HT1A receptor function at presynaptic sites, yet increases 5-HT1A receptor expression at postsynaptic sites. These mechanisms could explain the heightened stress HPA axis responses in females compared to males. Studies on female rhesus macaques show that chronic stress in socially subordinate female monkeys produces a distinct behavioural phenotype that is largely unaffected by oestrogen, a hyporesponsive HPA axis that is hypersensitive to the modulating effects
Rao, Yathindar S; Mott, Natasha N; Pak, Toni R
The hypothalamo-pituitary-adrenal (HPA) and hypothalamo-pituitary-gonadal (HPG) axes have an intricate cross talk that results in the inhibition of reproductive functions during periods of chronic physiological or psychological stress. Recent studies have shown that kisspeptin neurons have projections to many non-reproductive areas of the brain including the paraventricular nucleus (PVN) of the hypothalamus, thereby providing evidence of an anatomical framework for kisspeptin to regulate the HPA axis. In this study, we tested as to whether kisspeptin modulates the HPA axis at three potential levels of regulation: (1) transcription of stress-related genes CRH, AVP, and oxytocin (OXY); (2) release of neuropeptides from PVN-derived neuronal cells via mobilization of intracellular calcium stores; and (3) in vivo regulation of the HPA axis under basal and stress-induced conditions in adult male rats. Overall, our data showed that kisspeptin did not alter basal, or stress-induced HPA axis activity (plasma corticosterone (CORT) and adrenocorticotropin hormone (ACTH)) in adult male rats and had modest, yet significant effects on CRH, AVP, and OXY gene expressions.
D’Anna-Hernandez, Kimberly L.; Ross, Randal G.; Natvig, Crystal L.; Laudenslager, Mark L.
Maternal stress during pregnancy is associated with negative maternal/child outcomes. One potential biomarker of the maternal stress response is cortisol, a product of activity of the hypothalamic-pituitary-adrenal axis. This study evaluated cortisol levels in hair throughout pregnancy as a marker of total cortisol release. Cortisol levels in hair have been shown to be easily quantifiable and may be representative of total cortisol release more than single saliva or serum measures. Hair corti...
Schmidt, Kim L; Macdougall-Shackleton, Elizabeth A; Soma, Kiran K; Macdougall-Shackleton, Scott A
Variation in early environmental conditions can have long-term effects on physiology and behavior, a process referred to as developmental programming. In particular, exposure to early-life stressors can have long-term effects on regulation of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. Although these effects have been well documented in mammals, less is known about how early-life stress affects regulation of these endocrine systems in non-mammalian species. In the current study, we determined the long-term effects of early-life food restriction or corticosterone (CORT) treatment on the HPA axis of song sparrows (Melospiza melodia), including the responses to restraint stress, dexamethasone challenge, and ACTH challenge. In addition, we assessed long-term effects on the HPG axis by measuring sex steroid levels (testosterone in males and 17β-estradiol in females) before and after a gonadotropin-releasing hormone (GnRH) challenge. Subjects treated with CORT during development had larger increases in CORT in response to ACTH challenge than food-restricted or control subjects. Neither treatment affected the responses of CORT to restraint or dexamethasone. CORT-treated males also had higher initial testosterone levels, but neither treatment affected testosterone levels post-GnRH. Lastly, although GnRH challenge failed to increase circulating estradiol levels in females, females exposed to food restriction or CORT treatment had lower estradiol levels than control females. These results show that exposure to stress can developmentally program the endocrine system of songbirds and illustrate the importance of considering developmental conditions when determining the factors responsible for inter-individual variation in endocrine regulation. Copyright © 2013 Elsevier Inc. All rights reserved.
... on the hypothalamic-pituitary-adrenal (HPA) axis, immune system, prostate, brain, and the enzyme... human relevance, pharmacokinetics, neuroendocrinology (hormone-mediated health effects), HPA axis... susceptibility and linking a chemically-induced activation of the HPA axis to other health outcomes and possible...
homeostasis. Stress activates the hypothalamic-pituitary- adrenal (HPA) axis and the sympathetic nervous system. (SNS). The result of HPA activation is an increase of cortisol. The activation of the SNS results in an increase in norepinephrine levels. Both the HPA axis and the SNS are attempts the body makes to return to ...
Vangeel, Elise; Van Den Eede, Filip; Hompes, Titia; Izzi, Benedetta; Del Favero, Jurgen; Moorkens, Greta; Lambrechts, Diether; Freson, Kathleen; Claes, Stephan
Chronic fatigue syndrome (CFS) has been associated with hypothalamic-pituitary-adrenal axis hypofunction and enhanced glucocorticoid receptor (GR) sensitivity. In addition, childhood trauma is considered a major risk factor for the syndrome. This study examines DNA methylation of the GR gene (NR3C1) in CFS and associations with childhood sexual and physical trauma. Quantification of DNA methylation within the 1F promoter region of NR3C1 was performed in 76 female patients (46 with no/mild and 30 with moderate/severe childhood trauma) and 19 healthy controls by using Sequenom EpiTYPER. Further, we examined the association of NR3C1-1F promoter methylation with the outcomes of the low-dose (0.5 mg) dexamethasone/corticotropin-releasing factor test in a subset of the study population. Mann-Whitney U tests and Spearman correlations were used for statistical analyses. Overall NR3C1-1F DNA methylation was lower in patients with CFS than in controls. After cytosine guanine dinucleotide (CpG)-specific analysis, CpG_1.5 remained significant after Bonferroni correction (adjusted p = .0014). Within the CFS group, overall methylation (ρ = 0.477, p = .016) and selective CpG units (CpG_1.5: ρ = 0.538, p = .007; CpG_12.13: ρ = 0.448, p = .025) were positively correlated with salivary cortisol after dexamethasone administration. There was no significant difference in NR3C1-1F methylation between traumatized and nontraumatized patients. We found evidence of NR3C1 promoter hypomethylation in female patients with CFS and the functional relevance of these differences was consistent with the hypothalamic-pituitary-adrenalaxis hypofunction hypothesis (GR hypersuppression). However, we found no evidence of an additional effect of childhood trauma on CFS via alterations in NR3C1 methylation.
Beijers, R.; Riksen-Walraven, J.M.A.; Weerth, C. de
Experiences during early life are suggested to affect the physiological systems underlying stress responses, including the hypothalamic-pituitary-adrenal axis (HPA axis). While stressful early experiences have been associated with dysregulated HPA-axis functioning, positive early experiences, i.e.
Li, Jing; Bian, Weiliang; Dave, Vaidehi; Ye, Jiang-Hong
The paraventricular nucleus (PVN) in the hypothalamus is the main integration site that controls the hypothalamic-pituitary-adrenal (HPA) neuroendocrine stress system. Disruption of this system has been linked with alcoholism, but the specific role of the PVN has not been fully explored. Of particular interest is the ability of γ-aminobutyric acid type A receptors (GABA(A)Rs) in the PVN, to regulate ethanol self-administration behavior, as these receptors appear to play an essential role in mediating the effects of ethanol in the central nervous system and in the regulation of PVN activity. We observed that Long-Evans rats, in the intermittent access to 20% ethanol paradigm, consumed high amounts of ethanol and subsequently developed ethanol dependence. Microinjection of the GABA(A)R antagonist picrotoxin into the PVN, but not to the lateral ventricle of the brain, significantly reduced the intake of ethanol, but not the intake of sucrose. Picrotoxin-induced reduction was mimicked by another GABA(A)R antagonist bicuculline but was attenuated by the GABA(A)R agonist muscimol. Moreover, increased ethanol consumption was associated with lowered blood corticosterone levels, indicating a blunted HPA signaling, which was reversed by intra-PVN injection of picrotoxin, as indicated by the increased Fos immunostaining-positive cells in the PVN and the increased blood corticosterone levels. Taken together, our data provide evidence that in ethanol-dependent rats, the function of GABA(A)Rs in the PVN is upregulated, leading to a dampened HPA system. Moreover, it demonstrates that the GABA(A)R antagonists normalize HPA axis signaling and reduce excessive ethanol drinking. Therefore, drugs targeting GABA(A)Rs may be beneficial for alcoholics. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.
Full Text Available ... a major mood circuit called the hypothalamic-pituitary-adrenal (HPA) axis. Brain Basics in Real Life Brain ... in creating and filing new memories. hypothalmic-pituitary-adrenal (HPA) axis —A brain-body circuit which plays ...
Depression may be associated with hippocampal volume changes and HPA axis dysfunction: Is treatment to remission the answer? ume loss in depression include hyperactivity of the hypothalamic- pituitary-adrenal (HPA) axis and associated glucocorticoid neurotox- icity, decreased levels of brain-derived neurotrophic ...
Evers, A.W.M.; Verhoeven, E.W.M.; Kraaimaat, F.W.; Jong, E.M.G.J. de; Brouwer, S.J.M. de; Schalkwijk, J.; Sweep, F.C.; Kerkhof, P.C.M. van de
BACKGROUND: Psychological stressors might contribute to the severity of chronic inflammatory diseases such as psoriasis by dysregulating hypothalamic-pituitary-adrenal (HPA) axis activity. OBJECTIVES: To evaluate the role of cortisol, a key component of the HPA axis, in reaction to psychological
Luik, Annemarie I; Direk, Neşe; Zuurbier, Lisette A; Hofman, Albert; Van Someren, Eus J W; Tiemeier, Henning
The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in sleep. Nevertheless, the association of sleep and its 24-h organization with negative feedback control of the HPA axis has received limited attention in population-based studies. We explored this association in 493 middle-aged
Lopez-Duran, Nestor L.; Hajal, Nastassia J.; Olson, Sheryl L.; Felt, Barbara T.; Vazquez, Delia M.
The purpose of this study was to examine individual differences in the activation and regulation of the hypothalamic-pituitary-adrenal (HPA) axis in prepubertal children after exposure to two different stress modalities and to evaluate the utility of an individual differences approach to the examination of HPA axis functioning. After a 30-min…
Sandman, Curt A.; Touchette, Paul; Lenjavi, Mohammed; Marion, Sarah; Chicz-DeMet, Aleksandra
Relations between self-injurious behavior (SIB), the hypothalamic-pituitary-adrenal (HPA) stress axis, and response to an opiate antagonist were examined in 31 individuals with severe/profound neurodevelopmental disabilities. A significant number of subjects reduced SIB after receiving naltrexone supporting reports that the HPA axis is disturbed…
Vinberg, Maj; Bennike, Bente; Kyvik, Kirsten Ohm
Dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a biological endophenotype for affective disorders. In the present study the hypothesis that a high genetic liability to affective disorder is associated with higher cortisol levels was tested in a cross-sectional h......Dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a biological endophenotype for affective disorders. In the present study the hypothesis that a high genetic liability to affective disorder is associated with higher cortisol levels was tested in a cross...
Sondeijker, Frouke E. P. L.; Ferdinand, Robert F.; Oldehinkel, Albertine J.; Tiemeier, Henning; Ormel, Johan; Verhulst, Frank C.
Low HPA-axis activity has been proposed as a risk factor for disruptive behaviors. However longitudinal data on this topic are practically lacking. In the present study we investigated if low HPA-axis activity predicted future disruptive behaviors. We included 1,399 boys and girls from the Dutch
Jabben, Nienke; Nolen, Willem A.; Smit, Johannes H.; Vreeburg, Sophie A.; Beekman, Aartjan T. F.; Penninx, Brenda
Although dysfunctioning of the HPA axis is considered to be a core pathophysiological process in mood disorders, the evidence with regard to depression remains conflicting. This could partly be due to the large heterogeneity within mood disorders, since HPA axis abnormalities may also be associated
Ellen Renée Klaassens
Full Text Available Dysregulation of the hypothalamic–pituitary–adrenal (HPA-axis is thought to underlie stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD. Some studies have reported HPA-axis dysregulation in trauma-exposed (TE adults in the absence of psychiatric morbidity. In this dissertation we set out to unravel part of the mechanism that underlies the complex relations between trauma exposure, stress regulation, and psychopathology. Mentally healthy TE subjects were compared with non-trauma-exposed (NE healthy controls. To distinguish between the potential effects of childhood trauma and adulthood trauma, we included women exposed to childhood trauma as well as men who were exposed to trauma during adulthood. Basal HPA-axis functioning was assessed with salivary cortisol samples. HPA-axis reactivity was assessed with the dexamethasone/corticotropin-releasing hormone (Dex/CRH test. The results show that childhood trauma exposure is associated with an attenuated cortisol response after the Dex/CRH challenge test in women. In contrast, trauma exposure during adulthood was not associated with alterations in HPA-axis regulation after the Dex/CRH test. Neither childhood trauma nor adulthood trauma were associated with basal HPA-axis functioning. Childhood trauma rather than adulthood trauma may chronically affect HPA-axis functioning. Since the association between adulthood trauma and resilience to psychopathology cannot be explained by HPA-axis functioning alone, other factors must play a role.
Henckens, Marloes J. A. G.; van Wingen, Guido A.; Joëls, Marian; Fernández, Guillén
The amygdala is a key regulator of vigilance and heightens attention toward threat. Its activity is boosted upon threat exposure and contributes to a neuroendocrine stress response via the hypothalamic-pituitary-adrenal (HPA) axis. Corticosteroids are known to control brain activity as well as HPA
Henckens, M.J.A.G.; Wingen, G.A. van; Joëls, M.; Fernandez, G.S.E.
The amygdala is a key regulator of vigilance and heightens attention toward threat. Its activity is boosted upon threat exposure and contributes to a neuroendocrine stress response via the hypothalamic-pituitary-adrenal (HPA) axis. Corticosteroids are known to control brain activity as well as HPA
Hastings, Paul D.; Fortier, Isabel; Utendale, William T.; Simard, Louise R.; Robaey, Philippe
Disruptions to hypothalamic-pituitary-adrenal (HPA) axis function have been associated with varying forms of psychopathology in children. Studies suggesting children with ADHD have blunted HPA function have been complicated by the prevalence of comorbid diagnoses and heterogeneity of ADHD. The goals of this research were to assess the relations…
Pajer, Kathleen; Gardner, William
This study investigates the function of the hypothalamic-pituitary-adrenal (HPA) axis in adolescent antisocial girls. This question is important because disturbance of HPA functioning has been found in populations of violent adult males and antisocial adolescent males, suggesting that it may be a marker of a physiological disorder associated with…
Stress induces modification in both psychological and biological systems, which have been associated with the onset of illness. Many of these changes are mediated through the hypothalamic-pituitary-adrenal (HPA) axis and the effects of its hormones. This review describes how the HPA response to ps...
Booth, Alan; Granger, Douglas A.; Shirtcliff, Elizabeth A.
The majority of studies linking individual differences in the quality of social relationships and activity of the hypothalamic-pituitary-adrenal (HPA) axis have focused on the early development of attachment between infants and their caregivers. Later in development, during middle childhood and adolescence, the parallel HPA links to…
Puig Pérez, Sara
Sólo unos pocos estudios han investigado el papel protector o perjudicial de factores psicológicos sobre los principales sistemas fisiológicos involucrados en la respuesta de estrés en personas mayores. Considerando la importancia que éstos sistemas fisiológicos en la salud, el objetivo principal de esta tesis doctoral es investigar los posibles factores psicológicos que protegen o contribuyen a un mal funcionamiento del SNA y del eje HHA. Estudio 1 En el presente estudio nos hemos...
Effects of an exercise and hypocaloric healthy eating intervention on indices of psychological health status, hypothalamic-pituitary-adrenal axis regulation and immune function after early-stage breast cancer: a randomised controlled trial
Saxton, John M; Scott, Emma J; Daley, Amanda J; Woodroofe, M; Mutrie, Nanette; Crank, Helen; Powers, Hilary J; Coleman, Robert E
.... A total of 85 women treated for breast cancer 3 to 18 months previously were randomly allocated to a 6-month exercise and hypocaloric healthy eating program plus usual care or usual care alone (control group...
THE ASSESSMENT OF THE FUNCTIONAL-CAPACITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BY MEASUREMENT OF BASAL PLASMA AND URINARY CORTISOL IN COMPARISON WITH INSULIN-INDUCED HYPOGLYCEMIA AND METYRAPONE TESTS
DELANGE, WE; SLUITER, WJ
In 58 patients with a pituitary adenoma or hypothalamic-pituitary disease an insulin-induced hypoglycaemia test and a metyrapone test were performed. The results of these tests were compared with morning plasma cortisol levels and daily urinary cortisol excretion as indicators of insufficiency of
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 flexible operating characterisitics. Major drivers include two circadian drivers, two extra-hypothalamic networks controlling top-down (psychogenic) and bottom-up (systemic) threats, and two intra-hypothalamic networks coordinating behavioral, autonomic, and neuroendocrine outflows. These various networks jointly and flexibly control HPA axis output of periodic (oscillatory) functions and a range of adventitious systemic or psychological threats, including predictable daily cycles of energy flow, actual metabolic deficits over many time scales, predicted metabolic deficits, and the state-dependent management of post-prandial responses to feeding. Evidence is provided that reparation of metabolic derangement by either food or glucocorticoids results in a metabolic signal that inhibits HPA activity. In short, the HPA axis is intimately involved in managing and remodeling peripheral energy fluxes, which appear to provide an unidentified metabolic inhibitory feedback signal to the HPA axis via glucocorticoids. In a complementary and perhaps a less appreciated role, adrenocortical hormones also act on brain to provide not only feedback, but feedforward control over the HPA axis itself and its various drivers, as well as coordinating behavioral and autonomic outflows, and mounting central incentive and memorial networks that are adaptive in both appetitive and aversive motivational modes. By centrally remodeling the phenotype, the HPA axis provides ballistic and predictive control over motor outflows relevant to the type of stressor. Evidence is examined concerning the global hypothesis that the HPA axis comprehensively induces integrative phenotypic plasticity, thus
Zhu, Li-Juan; Liu, Meng-Ying; Li, Huan; Liu, Xiao; Chen, Chen; Han, Zhou; Wu, Hai-Yin; Jing, Xing; Zhou, Hai-Hui; Suh, Hoonkyo; Zhu, Dong-Ya; Zhou, Qi-Gang
Hypothalamus-pituitary-adrenal (HPA) hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR) - neuronal nitric oxide synthesis enzyme (nNOS) - nitric oxide (NO) pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.
Liu, Xiao; Chen, Chen; Han, Zhou; Wu, Hai-Yin; Jing, Xing; Zhou, Hai-Hui; Suh, Hoonkyo; Zhu, Dong-Ya; Zhou, Qi-Gang
Hypothalamus-pituitary-adrenal (HPA) hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR) - neuronal nitric oxide synthesis enzyme (nNOS) - nitric oxide (NO) pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression. PMID:24831808
Full Text Available Hypothalamus-pituitary-adrenal (HPA hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR - neuronal nitric oxide synthesis enzyme (nNOS - nitric oxide (NO pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.
Marsman, R.; Nederhof, E.; Rosmalen, J.G.; Oldehinkel, A.J.; Ormel, J.; Buitelaar, J.K.
The purpose of the present study was to investigate the developmental programming part of the theory of biological sensitivity to context using family environmental factors and hypothalamus-pituitary-adrenal (HPA) axis functioning. Specifically, we investigated whether perceived parenting (Rejection
Zhou, Rong; Chen, Fang; Feng, Xuejiao; Zhou, Libin; Li, Yingchun; Chen, Ling
The present study focuses on detecting anxiety-like behavior and associated neurochemical alterations in adolescent rats exposed perinatally to bisphenol A (BPA), an estrogen-mimicking endocrine disrupter and investigating the possible involvement of metabotropic glutamate 2/3 receptors (mGlu2/3 receptors) in BPA-induced anxiogenic effects. When female breeders were administered orally with BPA (40 μg/kg/d) during pregnancy and lactation, their pups (here named 'BPA-exposed offspring') developed an anxiety-like phenotype, characterized by the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, impaired glucocorticoid receptor (GR)-mediated negative feedback regulation of the HPA axis, altered hippocampal synaptic plasticity and increased anxiety-like behaviors. BPA-exposed offspring also showed a reduced expression of mGlu2/3 receptors in the hippocampus. BPA-exposed offspring further subjected to systemic administration of mGlu2/3 receptor agonist (LY379268, 0.5 mg/kg, i.p.) or antagonist (LY341495, 1.5 mg/kg, i.p.) twice per day for 6 days. The results indicated that chronic LY379268 treatment corrected the anxiety-like behaviors and associated neurochemical and endocrinological alterations in BPA-exposed offspring. Our data demonstrate for the first time that the perinatal BPA exposure induces an anxiety-like phenotype in behaviors and -related neuroendocrinology, and suggest that the changes in mGlu2/3 receptor might lie at the core of the pathological reprogramming triggered by early-life adversity. mGlu2/3 receptor may serve as a novel biomarker and potential therapeutic target for anxiety disorders associated with adverse early-life agents including perinatal BPA exposure. Copyright © 2015 Elsevier Ltd. All rights reserved.
Brand, Serge; Wilhelm, Frank H; Kossowsky, Joe; Holsboer-Trachsler, Edith; Schneider, Silvia
Separation anxiety disorder (SAD) is one of the most common mental disorders in childhood, and one of the earliest emerging. Little is known about the association between SAD and the hypothalamic-pituitary-adrenocortical (HPA) axis activity. Therefore, the present study aimed at investigating this association in children suffering from separation anxiety compared to healthy controls. A total of 31 children with diagnosed SAD (mean age: 8.45; 17 females, 14 males) and 25 healthy controls (HC; mean age: 9.74; 12 females, 13 males) took part in the study. All participants underwent psycho-physiological testing for HPA axis challenge. Testing consisted of a separation and a social exposure paradigm. Saliva samples to assess HPA axis-related cortisol secretion were gathered in parallel. Compared to healthy controls, children with SAD showed greatly increased HPA axis activity, as reflected by an increased cortisol secretion throughout the entire period of investigation. The rise of cortisol was already observed in anticipation of, but not following the separation paradigm. No gender-related differences of cortisol secretion were observed. Separation anxiety disorder (SAD) in children is reflected in greatly increased HPA axis activity. Compared to healthy controls, children with SAD showed increased cortisol values from the beginning of, and throughout, the entire investigation. This pattern of results suggests that both the anticipation of a separation and a persistent hyperactivity of the HPA axis system leads to an increased cortisol secretion. Copyright © 2010 Elsevier Ltd. All rights reserved.
Bos, P.A.; Montoya, E.R.; Terburg, D.; van Honk, J.
Animal studies show that exposure to parental neglect alters stress regulation and can lead to neural hyposensitivity or hypersensitivity in response to cortisol, most pronounced in the hippocampus. Cortisol, the end product of the hypothalamic-pituitary-adrenal (HPA) axis, has also been related to
Zipursky, Amy R.; Whittle, Sarah; Yucel, Murat; Lorenzetti, Valentina; Wood, Stephen J.; Lubman, Dan I.; Simmons, Julian G.; Allen, Nicholas B.
Background: Early adolescence is a critical time for the development of both internalizing and externalizing disorders. We aimed to investigate whether pituitary volume, an index of hypothalamic-pituitary-adrenal (HPA) axis function, represents a vulnerability factor for the emergence of internalizing and externalizing symptoms during adolescence…
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,
Witteveen, A.B.; Huizink, A.C.; Slottje, P.; Bramsen, I.; Smid, T.; van der Ploeg, H.M.
Given the inconsistent associations of cortisol with posttraumatic stress disorder (PTSD), analysis of basal functioning of the hypothalamic-pituitary-adrenal (HPA) axis in subjects frequently exposed to trauma and critical incidents with a range of PTSD symptomatology, may be valuable. In an
Witteveen, A.B.; Huizink, A.C.; Slottje, P.; Bramsen, I.; Smid, T.; Ploeg, H.M. van der
Given the inconsistent associations of cortisol with posttraumatic stress disorder (PTSD), analysis of basal functioning of the hypothalamic-pituitary-adrenal (HPA) axis in subjects frequently exposed to trauma and critical incidents with a range of PTSD symptomatology, may be valuable. In an
van der Pompe, G.; Bernards, N; Meijman, T.F.; Heijnen, C.J
The present study was designed to elucidate the effect of depressive symptomatology on the cortisol response to strenuous exercise. Thirteen healthy, post-menopausal women participated in this study. The results show that acute bicycle exercise activates the hypothalamic-pituitary-adrenal (HPA) axis
Nijhof, S.L.; Rutten, J.M.; Uiterwaal, C.S.; Bleijenberg, G.; Kimpen, J.L.L.; Putte, E.M. van de
BACKGROUND: There is accumulating evidence of hypothalamic-pituitary-adrenal (HPA) axis hypofunction in chronic fatigue syndrome (CFS). However, knowledge of this hypofunction has so far come exclusively from research in adulthood, and its clinical significance remains unclear. The objective of the
Nijhof, Sanne L.; Rutten, Juliette M. T. M.; Uiterwaal, Cuno S. P. M.; Bleijenberg, Gijs; Kimpen, Jan L. L.; Putte, Elise M. van de
There is accumulating evidence of hypothalamic-pituitary-adrenal (HPA) axis hypofunction in chronic fatigue syndrome (CFS). However, knowledge of this hypofunction has so far come exclusively from research in adulthood, and its clinical significance remains unclear. The objective of the current
In this thesis we investigated whether the experience of stressful life events and depression were related to early symptoms of Alzheimer’s disease and whether this relation could be explained by alterations in hypothalamic-pituitary adrenal (HPA) axis activity. To study this we used data from two
Platje, E.; Vermeiren, R.; Branje, S.T.J.; Doreleijers, Th.A.H.; Meeus, W.H.J.; Koot, H.M.; Frijns, T.; van Lier, P.A.C.; Jansen, L.M.C.
The cortisol awakening response (CAR) has been widely assessed as a measure of hypothalamic-pituitary-adrenal (HPA) axis activity. Short-term stability is high; however, little is known about the long-term stability of the CAR. Because there are indications that development in adolescence influences
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
Frokjaer, Vibe Gedsoe; Erritzoe, David; Holst, Klaus Kähler
Serotonergic signaling is considered critical for an appropriate adaptation to stress. We have previously observed that in healthy volunteers, prefrontal serotonin transporter (SERT) binding is positively associated with hypothalamic-pituitary-adrenal (HPA)-axis output in terms of the cortisol aw...
Lobato, E.; Merino, S.; Moreno, J.; Morales, J.; Tomás, G.; Martínez-de la Puente, J.; Osorno, J.L.; Kuchar, A.; Möstl, E.
The hypothalamic-pituitary-adrenal (HPA) axis of birds induces the secretion of corticosterone (CORT) as a response to different ecological variables. In this study we tested experimentally if manipulations of brood size or ectoparasitism led to subsequent differences in the concentration of
de Koning, Pelle P.; Figee, Martijn; Endert, Erik; Storosum, Jitschak G.; Fliers, Eric; Denys, Damiaan
Deep brain stimulation (DBS) is an effective treatment for obsessive-compulsive disorder (OCD), but its mechanism of action is largely unknown. Since DBS may induce rapid symptomatic changes and the pathophysiology of OCD has been linked to the hypothalamic-pituitary-adrenal (HPA) axis, we set out
Conclusion: JYAS-D had a significant antidepressant-like effect on rat model through regulating serum concentration of CORT, ACTH and CRH, increasing the content of hippocampus GR and regulating the equilibrium of amino acids neurotransmitter. Keywords: Hypothalamic-pituitary-adrenal (HPA) axis; Glucocorticoid/ ...
Rademaker, Arthur R.; Kleber, Rolf J.; Geuze, Elbert; Vermetten, Eric
To account for individual differences in vulnerability for stress-related disorders, studies have examined the relationship between hypothalamic-pituitary-adrenal (HPA) axis functioning and personality. The present study examined the relationship between the free fraction of cortisol in saliva after
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
Vries, G.J. de; Lok, A.; Mocking, R.; Assies, J.; Schene, A.H.; Olff, M.
BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with increased morbidity and mortality through somatic conditions, particularly cardiovascular disease. The one-carbon metabolism in connection with the hypothalamic-pituitary-adrenal (HPA)-axis may be an important mediator of this
Nygaard, Birte; Kristensen, Lars Østergaard
Objective: Graves' ophthalmopathy (GO) is an inflammatory disease in the orbital region. The first-line medical treatment is glucocorticoids. An important potential side effect of glucocorticoid treatment is suppression of the hypothalamic-pituitary-adrenal (HPA) axis with impairment of endogenous...
Simons, S.S.H.; Cillessen, A.H.N.; Weerth, C. de
Hypothalamic-pituitary-adrenal (HPA) axis functioning is characterized by the baseline production of cortisol following a circadian rhythm, as well as by the superimposed production of cortisol in response to a stressor. However, it is relatively unknown whether the basal cortisol circadian rhythm
Schechter, Julia C.; Brennan, Patricia A.; Cunningham, Phillippe B.; Foster, Sharon L.; Whitmore, Elizabeth
Stress and hypothalamic-pituitary-adrenal (HPA) axis dysregulation have been associated with externalizing behavior in adolescence, but few studies have examined these factors in a treatment context. This study investigated the relationship between stress, cortisol, and externalizing behavior among 120 adolescent males (mean age = 15) receiving…
Stress has been tied to changes in eating behavior and food choice. Previous studies in rodents have shown that chronic stress increases palatable food intake which, in turn, increases mesenteric fat and inhibits acute stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity. The effect of...
Spratt, Eve G.; Nicholas, Joyce S.; Brady, Kathleen T.; Carpenter, Laura A.; Hatcher, Charles R.; Meekins, Kirk A.; Furlanetto, Richard W.; Charles, Jane M.
Children with Autism often show difficulties in adapting to change. Previous studies of cortisol, a neurobiologic stress hormone reflecting hypothalamic-pituitary-adrenal (HPA) axis activity, in children with autism have demonstrated variable results. This study measured cortisol levels in children with and without Autism: (1) at rest; (2) in a…
) as well as hypothalamic-pituitary-adrenal (HPA) axis, which results in an increase of cortisol secretion. Very little is known however about adrenocortical response at basal state, just before the onset of exercise (pre-exercise) and immediately ...
Vreeburg, Sophie A.; Zitman, Frans G.; van Pelt, Johannes; DeRijk, Roel H.; Verhagen, Jolanda C. M.; van Dyck, Richard; Hoogendijk, Witte J. G.; Smit, Johannes H.; Penninx, Brenda
Objective: To examine the association between several subtypes of anxiety disorders and various cortisol indicators in a large cohort study. Anxiety disorders have been suggested to be linked to hypothalamic-pituitary-adrenal (HPA) axis activity, although results are scarce and inconsistent. No
Smit, M.P. (Maaike P.); E.H.G. van Leer (Eduard); G. Noppe (Gerard); Y.B. de Rijke (Yolanda); Kramer van Driel, D. (Dieneke); E.L.T. van den Akker (Erica)
textabstractIntroduction: Inhaled corticosteroids (ICS) can interfere with the hypothalamic-pituitary-adrenal (HPA) axis and may lead to adrenal insufficiency, resulting in a decrease of cortisol production. Cortisol levels measured in scalp hair provide a marker for long-term cortisol exposure.
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.
Tollenaar, M.S.; Beijers, R.; Jansen, J.; Riksen-Walraven, J.M.A.; Weerth, C. de
Early life factors can shape the development of hypothalamic pituitary adrenal (HPA) axis. Maternal prenatal stress might constitute such an early environmental factor. As little is known about the relation between maternal prenatal stress and cortisol reactivity in human offspring, we performed a
Bisschop, P. H.; Dekker, M. J. H. J.; Osterthun, W.; Kwakkel, J.; Anink, J. J.; Boelen, A.; Unmehopa, U. A.; Koper, J. W.; Lamberts, S. W. J.; Stewart, P. M.; Swaab, D. F.; Fliers, E.
The hypothalamus is a major target for glucocorticoids and a key structure for hypothalamic-pituitary-adrenal (HPA) axis setpoint regulation. The enzyme 11β hydroxysteroid dehydrogenase type 1 (11βHSD1) modulates glucocorticoid signalling in various tissues at the prereceptor level by converting
Chida, Yoichi; Hamer, Mark
This meta-analysis included 729 studies from 161 articles investigating how acute stress responsivity (including stress reactivity and recovery of hypothalamic-pituitary-adrenal [HPA] axis, autonomic, and cardiovascular systems) changes with various chronic psychosocial exposures (job stress; general life stress; depression or hopelessness;…
Hessl, David; Glaser, Bronwyn; Dyer-Friedman, Jennifer; Reiss, Allan L.
Objective: To examine the association between limbic-hypothalamic-pituitary-adrenal (L-HPA) axis reactivity and social behavior in children with fragile X syndrome (FXS). Method: Salivary cortisol changes and concurrent anxiety-related behaviors consistent with the behavioral phenotype of FXS were measured in 90 children with the fragile X full…
Hostinar, Camelia E.; Johnson, Anna E.; Gunnar, Megan R.
The goal of the present study was to investigate the role of early social deprivation in shaping the effectiveness of parent support to alleviate hypothalamic-pituitary-adrenal (HPA)-axis-stress responses of children (ages 8.9-11, M = 9.83 years, SD = 0.55). The sample was equally divided between children who had been adopted internationally from…
Lovell, Brian; Moss, Mark; Wetherell, Mark A.
Elevated psychological distress and concomitant dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated as one pathway that links the stress of caregiving with adverse health outcomes. This study assessed whether perceived social support might mitigate the psychological, endocrine and health consequences of caregiver…
Chronic stress and over-activity in the hypothalamic-pituitary-adrenal (HPA) axis may link breakfast skipping and poor cardiometabolic health. Missing the first major meal of the day in rodents prolongs elevated circulating corticosterone at a time when it’s normally decreasing. To extend these fi...
Lange, Claudia; Huber, Christian G; Fröhlich, Daniela; Borgwardt, Stefan; Lang, Undine E; Walter, Marc
HPA axis functioning plays an important role in the etiology of schizophrenia spectrum disorders (SSD). However, only few studies have examined HPA axis responsivity to psychosocial stress in SSD, and results are heterogeneous. Furthermore, childhood trauma is known to influence psychopathology and treatment outcome in SSD, but studies on the influence of childhood trauma on stress related HPA axis activity are missing. The purpose of this study was to investigate cortisol response to a psychosocial stress challenge in SSD patients, and to examine its association with severity of childhood trauma. The present study included 25 subacutely ill patients with a current episode of a chronic SSD and 25 healthy controls. Participants underwent the modified Trier Social Stress Test, and salivary cortisol levels were assessed. The childhood trauma questionnaire was used to assess severity of adverse life events. Overall, cortisol response was blunted in the patient group compared to the control group (pchildhood trauma experience: responders had experienced more emotional abuse in their past (pchildhood trauma might influence stress-related HPA axis activity in SSD. Our data contribute to the hypothesis that severity of childhood trauma may be of pathophysiological relevance in schizophrenia. In addition, it may be an overlooked factor contributing to inconsistent findings regarding HPA axis response to psychosocial stress in SSD. Copyright © 2017. Published by Elsevier Ltd.
Castro, Jorge E; Diessler, Shanaz; Varea, Emilio; Márquez, Cristina; Larsen, Marianne H; Cordero, M Isabel; Sandi, Carmen
Emerging evidence indicates that certain behavioral traits, such as anxiety, are associated with the development of depression-like behaviors after exposure to chronic stress. However, single traits do not explain the wide variability in vulnerability to stress observed in outbred populations. We hypothesized that a combination of behavioral traits might provide a better characterization of an individual's vulnerability to prolonged stress. Here, we sought to determine whether the characterization of relevant behavioral traits in rats could aid in identifying individuals with different vulnerabilities to developing stress-induced depression-like behavioral alterations. We also investigated whether behavioral traits would be related to the development of alterations in the hypothalamic-pituitary-adrenal axis and in brain activity - as measured through phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2)--in response to an acute stressor following either sub-chronic (2 weeks) or chronic (4 weeks) unpredictable stress (CUS). Sprague-Dawley rats were characterized using a battery of behavioral tasks, and three principal traits were identified: anxiety, exploration and activity. When combined, the first two traits were found to explain the variability in the stress responses. Our findings confirm the increased risk of animals with high anxiety developing certain depression-like behaviors (e.g., increased floating time in the forced swim test) when progressively exposed to stress. In contrast, the behavioral profile based on combined low anxiety and low exploration was resistant to alterations related to social behaviors, while the high anxiety and low exploration profile displayed a particularly vulnerable pattern of physiological and neurobiological responses after sub-chronic stress exposure. Our findings indicate important differences in animals' vulnerability and/or resilience to the effects of repeated stress, particularly during initial or
Sondeijker, Frouke E P L; Ferdinand, Robert F; Oldehinkel, Albertine J; Tiemeier, Henning; Ormel, Johan; Verhulst, Frank C
Low HPA-axis activity has been proposed as a risk factor for disruptive behaviors. However longitudinal data on this topic are practically lacking. In the present study we investigated if low HPA-axis activity predicted future disruptive behaviors. We included 1,399 boys and girls from the Dutch general population, initially aged 10-12 years. At the first assessment, basal cortisol levels were assessed. At the first assessment and at follow-up 2 years later disruptive behaviors were assessed with parent and self-report questionnaires. The results suggest that the association between low cortisol levels at 8.00 p.m. and future disruptive behaviors according to the parents was only present for boys. More importantly however, the results suggest that low HPA-axis activity is not a good predictor for disruptive behaviors, but could be valuable to identify those with a poor prognosis, once disruptive behaviors are present in preadolescence.
Moran-Santa Maria, Megan M; McRae-Clark, Aimee L; Back, Sudie E; DeSantis, Stacia M; Baker, Nathaniel L; Spratt, Eve G; Simpson, Annie N; Brady, Kathleen T
Long-term changes in the hypothalamic-pituitary-adrenal (HPA) axis as a result of early life stress could be related to the development of substance use disorders during adulthood. In this study, the neuroendocrine, physiologic (HR), and subjective responses to corticotropin releasing hormone (CRH) and the Trier Social Stress Task (TSST) in individuals with cocaine dependence, with (n=21)/without early life stress (n=21), non-dependent individuals with early life stress (n=22), and a control group were examined (n=21). CRH increased cortisol and ACTH levels in all groups. However, a significant effect of early life stress on ACTH was observed indicating that the increase in ACTH was greatest in subjects with a history of childhood stress. Post hoc analysis indicated the early life stress/non-cocaine dependent individuals exhibited significantly higher levels of ACTH as compared to the early life stress/cocaine-dependent group. Despite the elevated ACTH response there was no difference between the groups in the cortisol response to CRH. The TSST produced a significant elevation in ACTH and cortisol all study groups. No significant group differences were observed. The subjective stress and peak heart rate responses to the TSST were greatest in cocaine-dependent subjects without early life stress. In response to CRH, subjective stress and craving were positively correlated in cocaine-dependent subjects regardless of early life stress history, while stress and craving following the TSST were correlated only in cocaine-dependent subjects without a history of early life stress. Findings support previous studies demonstrating that subjects with a history of childhood adversity exhibit elevated ACTH and blunted cortisol levels in response to stress. In contrast, HR and subjective stress in response to the TSST were greatest in cocaine-dependent subjects without a history of early life stress, suggesting that childhood adversity may desensitize autonomic and subjective
Bloch, Miki; Peleg, Ido; Koren, Danny; Aner, Hamotal; Klein, Ehud
We investigated the long-term effects of divorce and early separation from one parent on HPA axis reactivity, in young adults without psychopathology. Participants were 44 young subjects, 22 whose parents divorced before they reached age 10, and 22 controls. Psychiatric symptomatology was measured with the Brief Symptom Inventory (BSI), family perceived stress by the Dyadic Adjustment Scale (DAS), and bonding by the Parental Bonding Instrument (PBI). Assessment of HPA axis function included baseline morning cortisol and ACTH and cortisol response to a CRH stimulation test. No baseline or stimulated group differences were observed for ACTH. Cortisol levels were consistently but insignificantly lower in the divorce group throughout the CRH stimulation reaching statistical significance only at 5 min (peffect reached a trend level (peffect for both family stress and child-parent bonding to stimulated ACTH levels. These preliminary findings suggest that even in the absence of adult psychopathology, a history of childhood separation from one parent due to divorce may lead to detectable, albeit mild, long-term alterations in HPA axis activity. Furthermore, they suggest that level of stress at home and parental bonding are important determinants of this effect. It is likely that divorce has significant and sustained effects on children's HPA axis only in the context of a traumatic separation.
Babb, Jessica A; Masini, Cher V; Day, Heidi E W; Campeau, Serge
Experiencing stress can be physically and psychologically debilitating to an organism. Women have a higher prevalence of some stress-related mental illnesses, the reasons for which are unknown. These experiments explore differential HPA axis hormone release in male and female rats following acute stress. Female rats had a similar threshold of HPA axis hormone release following low intensity noise stress as male rats. Sex did not affect the acute release, or the return of HPA axis hormones to baseline following moderate intensity noise stress. Sensitive indices of auditory functioning obtained by modulation of the acoustic startle reflex by weak pre-pulses did not reveal any sexual dimorphism. Furthermore, male and female rats exhibited similar c-fos mRNA expression in the brain following noise stress, including several sex-influenced stress-related regions. The HPA axis response to noise stress was not affected by stage of estrous cycle, and ovariectomy significantly increased hormone release. Direct comparison of HPA axis hormone release to two different stressors in the same animals revealed that although female rats exhibit robustly higher HPA axis hormone release after restraint stress, the same effect was not observed following moderate and high intensity loud noise stress. Finally, the differential effect of sex on HPA axis responses to noise and restraint stress cannot readily be explained by differential social cues or general pain processing. These studies suggest the effect of sex on acute stress-induced HPA axis hormone activity is highly dependent on the type of stressor.
Braun, Thorsten; Li, Shaofu; Sloboda, Deborah M; Li, Wei; Audette, Melanie C; Moss, Timothy J M; Matthews, Stephen G; Polglase, Graeme; Nitsos, Ilias; Newnham, John P; Challis, John R G
Fetal exposure to elevated levels of bioactive glucocorticoids early in gestation, as in suspected cases of congenital adrenal hyperplasia, may result in adverse neurological events. Fetal hypothalamic-pituitary-adrenal development and function may be involved. We investigated immediate and long-term effects of maternal dexamethasone (DEX) administration early in pregnancy on fetal growth and pituitary-adrenal activity in sheep. Pregnant ewes carrying singleton fetuses (total n = 119) were randomized to control (2 ml saline/ewe) or DEX-treated groups (im injections of 0.14 mg/kg ewe weight . 12 h) at 40-41 d gestation (dG). At 50, 100, 125, and 140 dG, fetal plasma and tissues were collected. DEX-exposed fetuses were lighter than controls at 100 dG (P patterns. DEX exposure reduced CBG only in males at 50 dG (P < 0.05). Placental mRNA levels of 11beta-HSD2 were increased after DEX in males (P < 0.05). Therefore, in sheep, early DEX may alter the developmental trajectory of the fetal hypothalamic-pituitary-adrenal axis, directly increasing fetal adrenal activation but not anterior pituitary function. In females, this effect may be attributed, in part, to increased fetal adrenal steroidogenic activity.