The effects of mutated skeletal ryanodine receptors on hypothalamic-pituitary-adrenal axis function in boars.
(49/1579)
The objectives of the current experiment were to determine whether boars heterozygous for the mutation in skeletal ryanodine receptors (sRyR), known to cause porcine stress syndrome, differed from wild-type boars in hypothalamic-pituitary-adrenal axis (HPA) function. We have examined basal plasma ACTH, cortisol, and corticosteroid-binding globulin (CBG) concentrations; plasma ACTH and cortisol responses to a nose-snare stressor and at slaughter; dexamethasone suppression of plasma ACTH and cortisol concentrations; and glucocorticoid receptor (GR) density in the pituitary gland, hippocampus, hypothalamus, and frontal cortex. We have also examined carcass yields, composition, and meat quality to determine whether differences in HPA activity were accompanied by an increased incidence of meat quality characteristics associated with pale, soft, exudative (PSE) meat. Thirty boars either heterozygous or wild-type (n = 15 per genotype) for mutated sRyR were tested for HPA function at 7 mo of age. Heterozygous boars had lower basal plasma ACTH (P < .05) and cortisol (P < .04) concentrations. Integrated basal plasma ACTH and cortisol levels were also lower (P < .05 and P < .005, respectively). Genotype had no significant effect on basal CBG, stressor-induced (nose snare or slaughter) or dexamethasone suppression of plasma ACTH or cortisol concentrations. No differences in immunoreactive GR levels were found in the pituitary gland or any brain region examined. We did find a significant, negative correlation (r = -.62, P < .02) between peak (0800) basal plasma ACTH concentrations and hippocampal GR levels. The alterations in basal HPA function in heterozygous boars were accompanied by lighter body weights (P < .03), decreased carcass fat depth (P < .04), and increased carcass lean yields (P < .02). There was a higher incidence of meat quality characteristics associated with PSE meat in heterozygous boars indicated by higher carcass temperatures (P < .04) and meat brightness (P < .0001) with lower carcass pH at slaughter (P < .03) and after chilling (P < .003). In conclusion, we have found differences in basal and not stressor-induced HPA function between boars heterozygous and wild-type for mutated sRyR. This altered basal HPA activity was accompanied by an increased incidence of meat quality aspects associated with PSE meat in heterozygous boars. (+info)
Effects of stress on reproduction in non-rodent mammals: the role of glucocorticoids and sex differences.
(50/1579)
The means by which stress influences reproduction is not clearly understood, but may involve a number of endocrine, paracrine and neural systems. Stress impacts on the reproductive axis at the hypothalamus (to affect GnRH secretion) and the pituitary gland (to affect gonadotrophin secretion), with direct effects on the gonads being of less importance. Different stressors have different effects and there are differences in response to short- and long-term stress. Many short-term stresses fail to affect reproduction and there are reports of stimulatory effects of some 'stressors'. There are species differences in the way that specific stressors affect reproduction. Sex differences in the effects of a particular stressor have been delineated and these may relate to effects of stress at different levels of the hypothalamo-pituitary axis. The significance of stress-induced secretion of cortisol varies with species. In some instances, there appears to be little impact of short-term increases in cortisol concentrations and protracted increases in plasma concentration seem to be required before any deleterious effect on reproduction is apparent. Issues of sex, sex steroid status, type of stressor and duration of stress need to be considered to improve understanding of this issue. (+info)
Comparable effects of inhaled fluticasone propionate and budesonide on the HPA-axis in adult asthmatic patients.
(51/1579)
This randomized, double-blind, double-dummy, multicentre cross-over study compared the effects on the hypothalamic-pituitary-adrenal (HPA) axis of fluticasone propionate (750 microg twice daily given via the Diskus) and budesonide (800 microg twice daily given via the Turbuhaler). Two treatment periods of 2 weeks each were preceded by a 2-week run-in period and separated by a 2-week washout period. During run-in and washout, patients received beclomethasone dipropionate (BDP) or budesonide at a constant dose of 1500-1600 microg day(-1). Sixty patients aged 18-75 years with moderate to severe asthma not fully controlled by treatment with 1500-1600 microg day(-1) budesonide or BDP entered run-in and 45 completed the study. HPA axis suppression was assessed by morning serum cortisol (area under the curve from 08.00 to 10.30 hours) and 12-h nocturnal urinary cortisol excretion, measured at the end of run-in (baseline 1), at the end of washout (baseline 2), and at the end of each treatment period. Neither budesonide nor fluticasone produced significant suppression of either parameter compared to baselines. Only a few patients had serum-cortisol and urinary cortisol values below the normal range, before and after treatment. This shows that the patients did not have adrenal suppression before entering the study. The ratio between the AUC serum cortisol measured after fluticasone treatment and after budesonide treatment was 0.99 (95% CI 0.92-1.06), indicating equivalent effects on the HPA axis. This result was achieved after having omitted two patients' results, due to their very sensitive reaction to budesonide, but not to fluticasone. Two exacerbations of acute asthma occurred during budesonide treatment and none during fluticasone treatment. Both treatments were well tolerated. In conclusion, budesonide 1600 microg day(-1) via Turbuhaler and fluticasone propionate 1500 microg day(-1) via Diskus had no clinical effects on the HPA axis in patients with moderate to severe asthma. (+info)
The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia.
(52/1579)
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. (+info)
A cholecystokinin-mediated pathway to the paraventricular thalamus is recruited in chronically stressed rats and regulates hypothalamic-pituitary-adrenal function.
(53/1579)
Chronic stress alters hypothalamic-pituitary-adrenal (HPA) responses to acute, novel stress. After acute restraint, the posterior division of the paraventricular thalamic nucleus (pPVTh) exhibits increased numbers of Fos-expressing neurons in chronically cold-stressed rats compared with stress-naive controls. Furthermore, lesions of the PVTh augment HPA activity in response to novel restraint only in previously stressed rats, suggesting that the PVTh is inhibitory to HPA activity but that inhibition occurs only in chronically stressed rats. In this study, we further examined pPVTh functions in chronically stressed rats. We identified afferent projections to the pPVTh using injection of the retrograde tracer fluorogold. Of the sites containing fluorogold-labeled cells, neurons in the lateral parabrachial, periaqueductal gray, and dorsal raphe containing fluorogold also expressed cholecystokinin (CCK) mRNA. We then examined whether these CCKergic inputs to the pPVTh were involved in HPA responses to acute, novel restraint after chronic stress. We injected the CCK-B receptor antagonist PD 135,158 into the PVTh before restraint in control and chronically cold-stressed rats. ACTH responses to restraint stress were augmented by PD 135,158 only in chronically stressed rats but not in controls. In addition, CCK-B receptor mRNA expression in the pPVTh was not altered by chronic cold stress. We conclude that previous chronic stress specifically facilitates the release of CCK into the pPVTh in response to acute, novel stress. The CCK is probably secreted from neurons in the lateral parabrachial, the periaqueductal gray, and/or the dorsal raphe nuclei. Acting via CCK-B receptors in pPVTh, CCK then constrains facilitated ACTH responses to novel stress in chronically stressed but not naive rats. These results demonstrate clearly that chronic stress recruits a new set of pathways that modulate HPA responsiveness to a novel stress. (+info)
The adrenal steroid status in relation to inflammatory cytokines (interleukin-6 and tumour necrosis factor) in polymyalgia rheumatica.
(54/1579)
OBJECTIVES: To determine the correlation between inflammatory cytokines and adrenal hormones in patients with polymyalgia rheumatica (PMR) and to compare the ratio of serum cortisol and androstenedione (ASD) or dehydroepiandrosterone sulphate (DHEAS) in normal subjects with PMR patients. METHODS: In 102 patients with PMR (32 beginning and 70 chronic disease) and 31 age-matched and sex-matched healthy subjects, ASD, cortisol, DHEAS, interleukin-6 (IL-6), and tumour necrosis factor (TNF) were measured by immunometric assays. RESULTS: Serum levels of IL-6 were elevated in patients with PMR as compared with normal subjects (10.0 +/- 1.6 vs 2.1 +/- 0.1 pg/ml, P = 0.01), which was not found for TNF. In PMR patients, serum levels of IL-6 were positively correlated with serum levels of ASD (P < 0.001), cortisol (P < 0.001), and DHEAS (P = 0. 038) irrespective of corticosteroid treatment. Serum levels of cortisol in relation to IL-6 were significantly lower in patients with chronic disease and long-standing corticosteroid administration as compared with patients with recent onset of the disease and without corticosteroid therapy (P < 0.01). CONCLUSIONS: In PMR, as expected, there was an increase in IL-6 serum levels that was associated with elevated serum levels of ASD, DHEAS, and cortisol which was more marked in patients with recent-onset disease and without corticosteroids. However, serum levels of cortisol in patients with and without corticosteroids were lower than expected by considering the inflammatory status (increased IL-6). This may indicate a change in the hypothalamic-pituitary-adrenal (HPA) axis responsiveness to inflammatory stimuli such as IL-6 during chronic disease. Furthermore, there seems to be a shift of biosynthesis to cortisol in relation to DHEAS or ASD in chronic disease. (+info)
Onset and severity of inflammation in rats exposed to the learned helplessness paradigm.
(55/1579)
OBJECTIVE: To test the hypothesis that there is an association between susceptibility to inflammation and a hyporesponsive hypothalamo-pituitary-adrenal (HPA) axis. METHODS: Animals were separated on the basis of behaviour in the learned helplessness (LH) paradigm into groups of LH(+) (i.e. animals which did not escape footshock) and LH(-) animals. Adjuvant-induced arthritis (AA) was subsequently induced in the LH(+) and LH(-) animals. RESULTS: Plasma corticosterone was significantly increased in response to the LH test in the LH(-) compared with the LH(+) rats. We observed an earlier onset and increased inflammation in the LH(-) rats in spite of the greater corticosterone response to the acute stress. We noted lower levels of plasma testosterone in the LH(-) animals suggesting a possible influence for this protective factor in AA. CONCLUSION: These data suggest that increased onset and severity of inflammation in AA is not a simple consequence of an attenuated HPA axis response to stress as proposed in the Lewis rat. Indeed we have observed the converse. Together these data suggest that the balance of pro- and anti-inflammatory factors released in response to stress may influence the progress of AA. (+info)
Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning.
(56/1579)
The primary neuroendocrine interface, hypothalamus and pituitary, together with adrenals, constitute the major axis responsible for the maintenance of homeostasis and the response to the perturbations in the environment. The gene expression profiling in the human hypothalamus-pituitary-adrenal axis was catalogued by generating a large amount of expressed sequence tags (ESTs), followed by bioinformatics analysis (http://www.chgc.sh.cn/ database). Totally, 25,973 sequences of good quality were obtained from 31,130 clones (83.4%) from cDNA libraries of the hypothalamus, pituitary, and adrenal glands. After eliminating 5,347 sequences corresponding to repetitive elements and mtDNA, 20,626 ESTs could be assembled into 9, 175 clusters (3,979, 3,074, and 4,116 clusters in hypothalamus, pituitary, and adrenal glands, respectively) when overlapping ESTs were integrated. Of these clusters, 2,777 (30.3%) corresponded to known genes, 4,165 (44.8%) to dbESTs, and 2,233 (24.3%) to novel ESTs. The gene expression profiles reflected well the functional characteristics of the three levels in the hypothalamus-pituitary-adrenal axis, because most of the 20 genes with highest expression showed statistical difference in terms of tissue distribution, including a group of tissue-specific functional markers. Meanwhile, some findings were made with regard to the physiology of the axis, and 200 full-length cDNAs of novel genes were cloned and sequenced. All of these data may contribute to the understanding of the neuroendocrine regulation of human life. (+info)