Hypothalamic-pituitary-adrenal Axis Axis Activity Research Articles

Long-term cortisol stress response in depression and comorbid anxiety is linked with reduced N-acetylaspartate in the anterior cingulate cortex

Objectives Major Depression (MDD) and anxiety disorders are stress-related disorders that share pathophysiological mechanisms. There is evidence for alterations of glutamate-glutamine, N-acetylaspartate (NAA) and GABA in the anterior cingulate cortex (ACC), a stress-sensitive region affected by hypothalamic-pituitary-adrenal axis (HPA). The aim was to investigate metabolic alterations in the ACC and whether hair cortisol, current stress or early life adversity predict them. Methods We investigated 22 patients with MDD and comorbid anxiety disorder and 23 healthy controls. Proton magnetic resonance spectroscopy was performed with voxels placed in pregenual (pg) and dorsal (d) ACC in 3 T. Analysis of hair cortisol was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results The N-acetylaspartate/Creatin ratio (NAA/Cr) was reduced in patients in both pgACC (p = .040) and dACC (p = .016). A significant interactive effect of diagnosis and cortisol on both pg-NAA/Cr (F = 5.00, p = .033) and d-NAA/Cr (F = 7.86, p = .009) was detected, whereby in controls cortisol was positively correlated with d-NAA/Cr (r = 0.61, p = .004). Conclusions Our results suggest a relationship between NAA metabolism in ACC and HPA axis activity as represented by long-term cortisol output.

Examining stress: an investigation of stress, mood and exercise in medical students.

Stress is an event that threatens homoeostasis and thus causes physiological and behavioural responses to reinstate equilibrium. Excessive and/or chronic stress can be psychologically and physiologically detrimental. Examinations can represent a significant source of stress for students. The hypothalamic-pituitary-adrenal axis (HPA) is the core endocrine stress system. Investigations into the HPA response to examinations have yielded inconsistent results. The aim of this study is to further explore the relationship between examination stress, HPA axis activity, mood, sleep and exercise in students undergoing a naturalistic examination period stressor. In total, 16 medical students participated. Students completed self-reported stress, anxiety, mood, sleep and physical activity questionnaires, and provided saliva samples during an examination-free period and an examination period 1 month later. The cortisol awakening response, representative of HPA activity, was determined from saliva samples by enzyme-linked immunosorbent assay. Anxiety levels increased (p=0.04) and mood decreased (p=0.05) during the examination period. There was concomitant decease in physical activity levels (p=0.02). There was no significant increase in HPA activity during the examination period (p=0.29). Sleep quality did not significantly worsen (p=0.55) during the examination period. Examination periods are associated with increased anxiety levels, lower mood and decreased physical activity. Future studies incorporating examination results and cognitive function may help to identify potential protective interventional strategies, while optimising performance.

IL-2 is involved in immune response of prenatally stressed rats exposed to postnatally stimulation

Environmental cues influence growth and development of mammals during prenatal and particularly early postnatal life and can exert long-lasting effects in adult life. High circulating concentration of glucocorticoids during pregnancy (prenatal stress) affects the activity of the hypothalamic-pituitary-adrenal axis (HPA) of offspring and has been linked to alter immune system responses. Early postnatal stimulation (handling) of prenatally stressed animals generates long-term beneficial effects on the reactiveness of the HPA axis and immune system function. The aim of this study was to further investigate the effect of handling on immune response inprenatally stressed male rats and to elucidate a possible relationship with the HPA axis activity. Control and prenatally stressed (PS) offspring by immobilization (IMO) were handled during the first week of life. Animals from both treatments were subjected to acute stress by IMO. Corticosterone (COR) plasma concentration was measured by RIA assay, T lymphocyte proliferation by [3H] thymidine assay and IL-2 levels by direct ELISA technique. Chronic IMO prenatal stress caused an increase in mother plasma COR basal levels. Furthermore, prenatally stressed rats subjected to an acute stress session had lower T cell proliferation and decreased IL-2 release. Inaddition, early postnatal stimulation reversed the negative effects of prenatal stress on proliferation of T lymphocytes and IL-2 release.

Lead exposure is related to hypercortisolemic profiles and allostatic load in Brazilian older adults

Lead levels (Pb) have been linked to both hyper- and hypo-reactivity of hypothalamic-pituitary-adrenal axis (HPA) axis to acute stress in animals and humans. Similarly, allostatic load (AL), the ‘wear and tear’ of chronic stress, is associated with inadequate HPA axis activity. We examined whether Pb levels would be associated with altered diurnal cortisol profile, as a primary mediator of AL, during aging. Pb levels were measured from blood samples (BPb) of 126 Brazilian individuals (105 women), between 50 and 82 years old. Six neuroendocrine, metabolic, and anthropometric biomarkers were analyzed and values were transformed into an AL index using clinical reference cut-offs. Salivary samples were collected at home over 2 days at awakening, 30-min after waking, afternoon, and evening periods to determine cortisol levels. A multiple linear regression model showed a positive association between BPb as the independent continuous variable and cortisol awakening response (R2=0.128; B=0.791; p=0.005) and overall cortisol concentration (R2=0.266; B=0.889; p<0.001) as the outcomes. Repeated measures ANOVA showed that individuals with high BPb levels showed higher cortisol at 30min after awakening (p=0.003), and in the afternoon (p=0.002) than those with low BPb values. Regarding AL, regression model showed that BPb was positively associated with AL index (R2=0.100; B=0.204; p=0.032). Correlation analyzes with individual biomarkers showed that BPb was positively correlated with HDL cholesterol (p=0.02) and negatively correlated with DHEA-S (p=0.049). These findings suggest that Pb exposure, even at levels below the reference blood lead level for adults recommended by the National Institute for Occupational Safety and Health and by the Center for Disease Control and Prevention, may contribute to AL and dysregulated cortisol functioning in older adults. Considering these findings were based on cross-sectional data future research is needed to confirm our exploratory results.

Concurrent and prospective associations between HPA axis activity and depression symptoms in newlywed women

We investigated the extent to which individual differences in activity of the hypothalamic pituitary adrenal axis (HPA) are associated with depressive symptoms among newlywed couples. Participants were 218 couples (M age 28.4 years; 94% White) who provided 5 saliva samples (later assayed for cortisol and DHEA-S) before and after participation in a discussion of a major area of disagreement in their relationship. Depressive symptoms were assessed initially, and approximately 19- and 37-months later. Results revealed an interactive effect suggesting that concordant levels of cortisol and DHEA-S (either both high or both low) were concurrently and prospectively associated with higher depression scores. Interestingly, this interactive effect was observed for wives only – not for husbands. These observations underscore contemporary theoretical assumptions that the expression of the association between HPA activity and depression is dependent on factors related to the interaction between characteristics of the person and features of the social environment, and moderated by co-occurring variation in endocrine milieu.

The role of estradiol in adrenal insufficiency and its interaction with corticosterone on hydromineral balance

Estradiol (E2) plays an important role in controlling the homeostasis of body fluids. Several studies have reported the involvement of the hypothalamic pituitary adrenal axis (HPA) in the homeostatic control of hydromineral balance and the influence of estrogens on the modulation of this system. Nevertheless, until now, the physiological relevance of HPA axis activity on the hydromineral balance in females has not yet been fully elucidated. Therefore, the objective of the present study was to evaluate the effects of E2 (20μg/animal) pretreatment on neuroendocrine and hydroelectrolyte changes induced by adrenalectomy (ADX) with or without glucocorticoid hormone replacement (corticosterone, CORT; 10mg/kg) in ovariectomized rats (OVX). The results show that sodium appetite, natriuresis and the elevated plasma angiotensin II (ANG II) concentration induced by ADX were attenuated by E2 pretreatment. Additionally, a reduction of AT1 mRNA expression in the subfornical organ (SFO) and an increase in plasma atrial natriuretic peptide (ANP) concentrations by E2 pretreatment were observed. E2 pretreatment reversed the reduction in water intake induced by ADX in ADX CORT-replaced rats. Moreover, E2 pretreatment attenuated corticotropin releasing factor (CRF) mRNA expression in the paraventricular nucleus (PVN) induced by ADX. In contrast, E2 pretreatment increased CRF mRNA expression in the PVN in ADX CORT-replaced rats. Taken together, these results suggest that E2 has an important role in the modulation of behavioral and neuroendocrine responses involved in the maintenance of body fluid homeostasis in ADX rats with or without glucocorticoid replacement therapy.

Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results

Major depressive disorder (MDD) has been related to both a dysfunctional gamma-amino butyric acid (GABA) system and to hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA). Although GABA has been suggested to inhibit HPA axis activity, their relationship has never been studied at the level of the central GABA(A)-benzodiazepine receptor in depressed patients or in relation to antidepressant treatment. Eleven depressed outpatients were compared, before and after treatment with citalopram, with nine age-matched healthy controls. The subjects were scanned using the positron emission tomography (PET) tracer [(11)C]flumazenil ([(11)C]FMZ). Parametric voxel-by-voxel Logan plots were compared with methods based on regions of interest (ROI), to provide volume of distribution (V(T)) and binding potential (BP(ND)) values. Plasma GABA levels were determined and a dexamethasone-corticotropin releasing hormone (DEX-CRH) test was performed. In MDD, parametric voxel-by-voxel Logan plots showed bilateral reduced [(11)C]FMZ binding in the parahippocampal gyrus and right lateral superior temporal gyrus (p uncorrected < or =0.001). In the temporal area, [(11)C]FMZ binding showed a strong inverse correlation with HPA axis activity. Plasma GABA did not discriminate MDD from controls, but correlated inversely with [(11)C]FMZ binding in the right insula. Following treatment with citalopram, voxel-based analysis revealed reduced binding in the right lateral temporal gyrus and dorsolateral prefrontal cortex. The bilateral reduction in limbic parahippocampal and right temporal [(11)C]FMZ binding found in MDD indicates decreased GABA(A)-benzodiazepine receptor complex affinity and/or number. The inverse relationship between GABA(A) binding in the temporal lobe and HPA axis activity, suggests that HPA axis hyperactivity is partly due to reduced GABA-ergic inhibition.

The Acute and Post-Discontinuation Effects of a Glucocorticoid Receptor (GR) Antagonist Probe on Sleep and the HPA Axis in Chronic Insomnia: A Pilot Study

Hypothalamic-pituitary-adrenal axis (HPA) hyperactivity has been reported in patients with chronic insomnia without depression. Aglucocorticoid receptor (GR) antagonist may re-regulate HPA axis activity even after discontinuation and may have clinical benefit. Ten subjects with chronic insomnia participated in a placebo controlled double-blinded prospective 30-day pilot study of the acute and post-discontinuation effects of a 5-day course of 600 mg of the glucocorticoid antagonist, mifepristone. Sleep outcome measures were polysomnogram and Insomnia Severity Index. Hormonal outcome measures were mean overnight cortisol and ACTH (23:00-07:00). We predicted sleep would improve and that overnight cortisol and ACTH would decrease at 2 weeks post-treatment discontinuation. At 2 weeks post-discontinuation, Insomnia Severity Index (ISI) decreased by 4.0 points (effect size = 0.97). Polysomnogram findings were limited. Mean cortisol (0.84 microg/dL, effect size = 0.91) and ACTH (5.50 pg/mL, effect size = 0.96) were still mildly increased (23:00 to 07:00). Post hoc analysis revealed that, the ratio of cortisol/ ACTH decreased (-0.21, effect size = 1.15) as did mean cortisol from 18:00 to 23:00 (-0.47 microg/dL, effect size = 0.56). This is the first study of a GR antagonist in chronic insomnia. Sleep improvement manifests in terms of decreased ISI post-treatment discontinuation. The decrease in cortisol in the early evening (18:00 to 23:00) in combination with the decrease in cortisol/ ACTH ratio may be an indicator of the longer-term biological mode of action of the drug.

Platelet serotonin and plasma prolactin and cortisol in healthy, depressed and schizophrenic women

Serotonin (5-hydroxytryptamine, 5-HT) is involved in the regulation of hypothalamic-pituitary-adrenal axis (HPA) activity and prolactin (PRL) secretion. The present study examined the relationship between platelet 5-HT and plasma cortisol and PRL concentrations in 20 schizophrenic, 25 depressed, and 25 healthy women. At the time of blood sampling, the schizophrenic and depressed patients had been drug-free for at least 7 days. Platelet 5-HT, plasma cortisol and PRL concentrations were determined by spectrofluorimetric, radioimmunoassay and immunoradiometric methods, respectively. Platelet 5-HT concentration was significantly higher in schizophrenic patients than in depressed patients or in healthy controls, while it was significantly lower in depressed patients than in healthy controls or in schizophrenic patients. Plasma cortisol levels were significantly increased both in schizophrenic and in depressed patients compared with values in healthy controls. Values of plasma PRL were similar across groups. A significant correlation was found between platelet 5-HT and plasma cortisol, and platelet 5-HT and plasma PRL concentrations in healthy controls, but not in schizophrenic or depressed patients. There was no significant relationship between plasma PRL and cortisol levels in any of the groups. Our data, although obtained on peripheral biochemical markers, indicate that depression and schizophrenia are characterized by disturbed 5-HT transmission and dysregulated HPA axis activity.

Vasopressin and the regulation of hypothalamic-pituitary-adrenal axis function: Implications for the pathophysiology of depression

The role of arginine vasopressin (AVP/VP) in the control of adrenocorticotropic hormone (ACTH) secretion is explored, and in particular, its involvement in various stress response paradigms which may be of relevance in our understanding of the pathophysiology of depression. VP is released from two sites in the hypothalamus; the parvicellular division of the paraventricular nucleus (PVN), where corticotropin releasing hormone (CRH) is also formed, and from the magnocellular neurons of the supraoptic nucleus (SON) and the PVN. The intricate interaction with CRH, the other main ACTH secretagogue, and with glucocorticoids, the inhibitory feedback component of hypothalamic-pituitary-adrenal -axis (HPA) activity, is outlined. That VP plays an important role in the stress response is now beyond doubt. Examination of the impact of psychological stressors on the differential expression of VP and CRH at a hypothalamic and pituitary level has been facilitated by advances in molecular biological techniques. Of importance has been the cloning of the V 1b receptor gene, the receptor at which AVP is active in the anterior pituitary. Chronic stress paradigms, associated with HPA hyperresponsiveness, and ACTH release following a novel superimposed stress, have been found with relative consistency to show a shift in the CRH:AVP ratio. This may relate to differing feedback sensitivity of AVP to glucocorticoid feedback restraint and the greater responsivity of AVP over CRH to chronic stimulatory stress input. Evidence for functionally distinct pools of ACTH releasing corticotropes, and the finding that AVP levels more closely correlate with ACTH levels than do CRH levels, suggest a more dynamic role for AVP in activity of the stress axis, and a primarily permissive function for CRH. The renewed interest in the role of VP in HPA axis activity may have important implications for furthering our understanding of psychiatric conditions such as depression, where significant dysregulation of this axis is seen. Elevated baseline cortisol, dexamethasone non-suppression and blunted CRH/ACTH release have been consistently documented. The possible contribution of VP to this hyperactivity, despite its known synergy with CRH, has been largely neglected. In animal models there is clear evidence that chronic psychological Stressors increase the ratio of AVP to CRH production. Psychosocial Stressors are intrinsically linked with depressive illness. The finding of elevated levels of AVP in postmortem studies of depressives and the lowering of CSF AVP levels by antidepressants, raises the question of the precise role of AVP in the overactivity of the HPA in depression, a finding that is currently attributed to overdrive of its HPA regulatory companion, CRH.