Assessment of hypothalamic-pituitary-adrenal axis and sympathetic nervous system activity in pregnant sows through the measurement of glucocorticoids and catecholamines in urine.
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We validated the use of urine to monitor changes in the activity of both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) in swine. Ten pregnant sows were fitted with venous catheters 3 wk after mating. In the early (wk 6), middle (wk 9), and late (wk 14) stages of gestation, blood and urine were collected over 24 h to monitor diurnal changes in plasma cortisol, urinary cortisol, and urinary catecholamines (norepinephrine [NE] and epinephrine [EPI]). Dexamethasone suppression tests (DST) and ovine corticotropin-releasing hormone (CRH) challenge tests were also performed at each stage of gestation. All plasma and urinary values changed markedly around the clock. Diurnal variations of urinary cortisol were comparable to those in plasma, with a late nocturnal peak and a trough occurring in the evening. During the dark period, urinary catecholamines were lower than during the light period. Norepinephrine increased sharply after lights came on and peaked after meal time. Epinephrine began to rise at the end of the dark period and peaked just before meal time. Average plasma cortisol increased with the stage of gestation, due to higher levels during daylight hours. Dexamethasone at 2000 (20 microg/kg i.v.) decreased plasma cortisol at 0830 and nocturnal cortisol excretion. The magnitude of the decrease in plasma ACTH and urinary cortisol after DST was lower in late than in early and midgestation, indicating increased feedback resistance at that stage. The CRH (1 microg/kg i.v.) increased plasma and urinary cortisol. Peak levels occurred 30 min and 2 to 3 h after the injection, respectively. Catecholamines and cortisol in urine produced during the night (2000 to 0800) and the early morning (0400 to 0800 and 0800 to 0900) were highly correlated with their 24-h excretion rate. These results indicate that it is possible to monitor changes in the HPA axis and SNS activity through urinary measurements in pigs. (+info)
Effects of repeated maternal betamethasone administration on growth and hypothalamic-pituitary-adrenal function of the ovine fetus at term.
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Synthetic glucocorticoids have become an important clinical tool with which to advance fetal lung maturation in women at risk of early preterm birth, and this has succeeded in reducing neonatal mortality and morbidity from respiratory distress syndrome. Although previous studies have shown that glucocorticoids have deleterious consequences on fetal development, there is little information regarding the effects of clinically relevant repeated maternal doses of glucocorticoids on fetal growth and hypothalamic-pituitary-adrenal (HPA) function. We hypothesised that repeated prenatal exposure to increased concentrations of glucocorticoids would alter fetal growth and HPA axis development. Pregnant ewes were injected with betamethasone (0.5 mg/kg) or vehicle at 104, 111 and 118 days of gestation (term 150 days). Animals were sacrificed at 125 and 146 days of gestation, at which time fetal weights were recorded. Maternal and fetal blood samples were gathered and fetal tissue collected. Maternal oestradiol concentrations were significantly greater than those in controls at 125 days of gestation, but were not different at 146 days. Maternal plasma progesterone concentrations were similar between groups at both 125 and 146 days of gestation. Weight at birth was significantly reduced by 23% at 125 days and 19% at 146 days of gestation (P<0.05) after exposure to glucocorticoid. Cord plasma ACTH concentrations were not significantly different between groups at day 125, but were significantly increased in day 146 fetuses of ewes that had received betamethasone (P<0.05). Cord plasma cortisol concentrations followed the same trend, although differences were not statistically significant. Cord plasma corticosteroid binding capacity (CBC) was significantly increased at 125 days of gestation in fetuses of betamethasone-treated animals (P<0.05), but not at 146 days of gestation. To examine the mechanisms regulating the increase in cord plasma ACTH of 146-day fetuses, we used in situ hybridisation to determine the distribution and levels of mRNA encoding key pituitary and hypothalamic neuropeptides of the HPA axis. In pituitaries of 146-day fetuses, there were no significant differences in the regional pattern of distribution or amounts of pro-opiomelanocortin (POMC) mRNA between betamethasone-treated animals and controls, in either the pars intermedia or the inferior and superior regions of the pars distalis. Neither prohormone convertase (PC)-1 nor PC-2 mRNA levels in pituitaries of 146-day fetuses were significantly different between treatment groups. After maternal betamethasone, immunoreactive ACTH peptide content in the fetal pars distalis was not different but glucocorticoid receptor (GR) mRNA levels in the pars distalis were increased significantly (P<0.05). No significant difference in distribution pattern or concentrations of corticotrophin-releasing hormone (CRH) mRNA, GR mRNA, oxytocin mRNA and pre-proenkephalin mRNA were found in hypothalami from fetuses at 146 days of gestation after betamethasone treatment. We conclude that antenatal betamethasone given to pregnant sheep in a manner similar to that used in human obstetric practice results in reduced weight at birth at 125 and 146 days, and altered basal cord levels of plasma ACTH and corticosteroid binding capacity, but these changes are not reflective of changes in steady state concentrations of POMC and CRH mRNA in the fetal pituitary or hypothalamus. (+info)
Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: a pilot study in fibromyalgia.
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OBJECTIVE: To determine whether deficient activity of the hypothalamic corticotropin-releasing hormone (CRH) neuron, which stimulates the hypothalamic-pituitary-adrenal (HPA) axis and the central control nuclei of the sympathetic nervous system and inhibits ascending pain pathways, may be pathogenic in patients with fibromyalgia (FM). METHODS: We administered interleukin-6 (IL-6; 3 microg/kg of body weight subcutaneously), a cytokine capable of stimulating hypothalamic CRH release, and measured plasma levels of adrenocorticotropic hormone (ACTH), cortisol, and catecholamines and their metabolites and precursors. Thirteen female FM patients and 8 age- and body mass index-matched female controls were studied. The diagnosis of FM was made according to American College of Rheumatology criteria. Tender points were quantitated by pressure algometry. All subjects had HPA axis studies. Seven FM patients and 7 controls also had catecholamine measurements. RESULTS: After IL-6 injection, delayed ACTH release was evident in the FM patients, with peak levels at 96.9 +/- 6.0 minutes (mean +/- SEM; control peak 68.6 +/- 10.3 minutes; P = 0.02). Plasma cortisol responses to IL-6 did not differ significantly between patients and controls. Basal norepinephrine (NE) levels were higher in the FM patients than in the controls. While a small, although not significant, rise in NE levels occurred after IL-6 injection in the controls, NE levels dramatically increased over basal levels in the FM patients between 60 and 180 minutes after IL-6 injection. Both peak NE levels (mean +/- SEM 537.6 +/- 82.3 versus 254.3 +/- 41.6 pg/ml; P = 0.0001) and time-integrated NE responses (93.2 +/- 16.6 pg/ml x minutes(-3) versus 52.2 +/- 5.7 pg/ml x minutes(-3); P = 0.038) were greater in FM patients than in controls. Heart rate was increased by IL-6 injection in FM patients and controls, but rose to significantly higher levels in the FM patients from 30 minutes to 180 minutes after IL-6 injection (P < 0.03). CONCLUSION: Exaggerated NE responses and heart rate increases, as well as delayed ACTH release, were observed among female FM patients compared with age-matched female controls. Delayed ACTH release after IL-6 administration in FM is consistent with a defect in hypothalamic CRH neuronal function. Exaggerated NE release may reflect abnormal regulation of the sympathetic nervous system, perhaps secondary to chronically deficient hypothalamic CRH. The excessive heart rate response after IL-6 injection in FM patients may be unrelated to the increase in NE, or it may reflect an alteration in the sensitivity of cardiac beta-adrenoceptors to NE. These responses to a physiologic stressor support the notion that FM may represent a primary disorder of the stress system. (+info)
Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation.
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We have investigated whether exposure to Gram-negative bacterial endotoxin in early neonatal life can alter neuroendocrine and immune regulation in adult animals. Exposure of neonatal rats to a low dose of endotoxin resulted in long-term changes in hypothalamic-pituitary-adrenal (HPA) axis activity, with elevated mean plasma corticosterone concentrations that resulted from increased corticosterone pulse frequency and pulse amplitude. In addition to this marked effect on the development of the HPA axis, neonatal endotoxin exposure had long-lasting effects on immune regulation, including increased sensitivity of lymphocytes to stress-induced suppression of proliferation and a remarkable protection from adjuvant-induced arthritis. These findings demonstrate a potent and long-term effect of neonatal exposure to inflammatory stimuli that can program major changes in the development of both neuroendocrine and immunological regulatory mechanisms. (+info)
The metabolic effect of antenatal corticosteroid therapy.
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The use of antenatal dexamethasone to mature the fetal lung in pregnancies likely to deliver before 34 weeks is almost universal. It reduces the incidence of respiratory distress syndrome in the newborn and results in an overall improvement in neonatal morbidity and mortality. Although considered to be generally safe, there are concerns about adverse maternal and fetal effects. In a series of studies, we have found that antenatal dexamethasone administration is associated with reduced placental hormone production and maternal bone formation, impaired glucose tolerance and altered function of the hypothalamic-pituitary-adrenal axis. In this article, we have compared our data with other reports in the human and reviewed the relevant animal data. We conclude that further studies on the long-term effects of antenatal dexamethasone therapy in the human are warranted with particular emphasis on the long-term effects on the fetus. (+info)
Endogenous opioid activity is associated with obsessive-compulsive symptomology in individuals with a family history of alcoholism.
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Endogenous opioid activity has been associated with the regulation of mood and inhibition of the hypothalamic-pituitary-adrenal (HPA) axis. We assessed differences in psychological symptomology and naloxone sensitivity in non-alcoholic males and females with a family history of alcoholism (FHP) and without a family history of alcoholism (FHN). This was followed by assessment of the association between naloxone sensitivity and psychological symptomology. Psychological symptomology was measured using the Revised Symptom Checklist (SCL-90-R) during enrollment. Adrenocorticotropin was measured following intravenous administration of naloxone/placebo. FHP males reported more obsessive-compulsive symptomology as well as increased sensitivity to naloxone relative to other groups. A positive association was observed between degree of obsessive-compulsive symptomology and naloxone sensitivity, and the association was strongest among FHP males. These findings suggest that the increased risk of alcoholism in FHP subjects (especially males) may be associated with altered opioid activity, which is expressed through an elevated level of obsessive compulsive symptomology. (+info)
Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency.
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Corticotropin-releasing hormone (CRH)-deficient (KO) mice provide a unique system to define the role of CRH in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite several manifestations of chronic glucocorticoid insufficiency, basal pituitary proopiomelanocortin (POMC) mRNA, adrenocorticotrophic hormone (ACTH) peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. The normal POMC mRNA content in KO mice is dependent upon residual glucocorticoid secretion, as it increases in both KO and WT mice after adrenalectomy; this increase is reversed by glucocorticoid, but not aldosterone, replacement. However, the normal plasma levels of ACTH in CRH KO mice are not dependent upon residual glucocorticoid secretion, because, after adrenalectomy, these levels do not undergo the normal increase seen in KO mice despite the increase in POMC mRNA content. Administration of CRH restores ACTH secretion to its expected high level in adrenalectomized CRH KO mice. Thus, in adrenal insufficiency, loss of glucocorticoid feedback by itself can increase POMC gene expression in the pituitary; but CRH action is essential for this to result in increased secretion of ACTH. This may explain why, after withdrawal of chronic glucocorticoid treatment, reactivation of CRH secretion is a necessary prerequisite for recovery from suppression of the HPA axis. (+info)
Effects of an organophosphate pesticide, quinalphos, on the hypothalamo-pituitary-gonadal axis in adult male rats.
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The effects of chronic sub-lethal doses (7-14 mg kg-1 a day for 15 days) of quinalphos were evaluated in adult male rats for changes in testicular morphology, circulatory concentrations of hormones (LH, FSH, prolactin and testosterone), activities of acetylcholinesterase (AChE) and angiotensin converting enzyme (ACE) as well as metabolism of biogenic amines (dopamine, noradrenaline and 5-hydroxytryptamine (5-HT)) in the hypothalamus and pituitary. Hormones were assayed by radioimmunoassay or chemiluminescent immunoassay (testosterone). The enzymes were estimated after spectrophotometry and the biogenic amines by HPLC-electrochemistry. Sub-lethal chronic administration of quinalphos resulted in: decreased testicular mass and AChE activity in central as well as peripheral organs; increased serum LH, FSH, prolactin and testosterone concentrations; decreased pituitary or increased testicular ACE activity; severe disruption of spermatogenesis with increasing doses of pesticide; and no significant effects on dopamine, noradrenaline or 5-HT concentrations in the hypothalamus or pituitary. Administration of oestradiol (50 micrograms per rat a day) during pesticide treatment resulted in: a significant decrease in the mass of the testis and accessory sex organs; decreases in serum LH, FSH, testosterone concentrations; an increase in prolactin concentration; and a decrease in dopamine or an increase in noradrenaline and 5-HT in the hypothalamus or pituitary. Oestradiol had a marked effect: in pesticide-treated animals, the pesticide effects were significantly reversed. This indicates that in pesticide toxicity, the hypothalamo-pituitary-gonadal axis is operational. Since many of the observed pesticide effects could be inhibited by oestradiol, it is suggested that the pesticide acts directly on the gonadotrophins. In conclusion, quinalphos decreases fertility in adult male rats by affecting the pituitary gonadotrophins. (+info)