Corticotropin-releasing Hormone Concentrations Research Articles

Preeclampsia Is Associated with Impaired Regulation of the Placental Nitric Oxide-Cyclic Guanosine Monophosphate Pathway by Corticotropin-Releasing Hormone (CRH) and CRH-Related Peptides

During pregnancy, CRH and CRH-related peptides appear to regulate the fetoplacental circulation via activation of the nitric oxide (NO)/cGMP pathway. Pregnancies with abnormal placental function such as preeclampsia (PE) are characterized by increased maternal plasma CRH concentrations and reduced placental CRH-receptor 1alpha (CRH-R1alpha) expression. In this study, we investigated the actions of CRH/CRH-related peptides on the NO/cGMP system in normal and PE placentas (n = 8 for each group). Fluorescent in situ hybridization, RT-PCR, and immunofluorescence experiments in human term placenta detected mRNAs expression for both R1 and R2 types of CRH-R, as well as urocortin (UCN) II and UCN III and showed CRH-R protein expression mainly in syncytiotrophoblast, whereas the endothelial NO synthase (eNOS) expression was confined within the cytoplasm of the chorionic villi. In placental explants, CRH and UCN induced mRNA and protein expression of eNOS, but not inducible NOS, and also caused an acute increase in cGMP levels (maximal stimulation, 80-90% above basal; P < 0.05). UCN II also induced a modest induction of cGMP (42% above basal; P < 0.05). These responses were attenuated by the NOS and soluble guanylyl cyclase inhibitors, l-N(G)-nitro-l-arginine methyl ester and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. In PE placental explants there was a significant reduction in CRH/CRH-related peptide-induced cGMP response; however, changes in the mRNA content of eNOS, inducible NOS, and soluble guanylyl cyclase (assessed by quantitative RT-PCR) between normal and PE placentas were not altered. In conclusion, we demonstrated that CRH and CRH-related peptides can positively regulate the placental NO/cGMP system. This pathway appears to be impaired in PE and may contribute toward dysregulation of the balance controlling vascular resistance.

A cohort study found that white blood cell count and endocrine markers predicted preterm birth in symptomatic women

ObjectiveThis cohort study investigated potential clinical and biochemical predictors of subsequent preterm birth in women presenting with threatened preterm labor. Study design and settingSubjects were 218 pregnant women admitted to hospital with a diagnosis of threatened preterm labor at 22–36 weeks gestation. Exclusion criteria were multiple pregnancy, fetal anomalies, diabetes mellitus, abruptio placenta, preeclampsia, intrauterine growth restriction, cervical dilatation>4 cm, and clinical signs of infection. Analyses used logistic regression. ResultsThe presence of ruptured membranes was the best predictor of birth within 48 hours. Other important predictors were maternal white blood cell count at 22–27 weeks gestation and maternal adrenocorticotropin and corticotropin-releasing hormone concentrations at 28–36 weeks gestation. ConclusionSubclinical infection may be an important etiologic factor in preterm births of gestational age < 28 weeks. For those at ≥28 weeks gestation, the findings support the etiologic role of activation of the fetal and/or maternal hypothalamic pituitary adrenal axis leading to preterm birth.

Central and peripheral effects of repeated noise stress on hypothalamic–pituitary–adrenocortical axis in pigs

The present study was performed to examine the effects of a repeated noise exposure (4 weeks) on basal and noise-induced plasma adrenocorticotrophin (ACTH), cortisol and corticosteroid binding globulin (CBG) levels, brain glucocorticoid receptors (GR) and corticotropin-releasing hormone (CRH) concentrations as well as on the morphology of adrenal glands in German Landrace pigs. Chronically cannulated pigs were exposed to either a daily stimulation with broad-band noise (2 h, 90 dB) (N1), or to the same stimulus three times a week (N2), or to an equal handling procedure without noise stimulation. Noise exposure caused an increase of basal CBG concentrations in N1 animals in the first week. During noise session, an increase of plasma ACTH and cortisol levels in N1 animals was measured in week 1 followed by a subsequent decrease until week 4. The ACTH and cortisol response of the N2 animals increased after week 1 and was significantly elevated in week 4. Furthermore, noise stress caused an increased hippocampal GR binding of N2 pigs, but had no effects on GR binding in the amygdala and on hypothalamic CRH levels. There were also significant structural modifications in the adrenal gland of N1 pigs resulting in differentiated effects on the adrenal cortex and medulla. The present results show that repeated noise exposure of pigs causes considerable alterations at different levels of the HPA system in association with the frequency of noise stimulation. This may have substantial impact on the general vulnerability of the animal with respect to productivity, health and welfare.

Bacterial lipopolysaccharide (LPS) modulates corticotropin-releasing hormone (CRH) content and release in the brain of juvenile and adult tilapia (Oreochromis mossambicus; Teleostei)

Although immune endocrine interactions in teleost fish have been shown to involve adrenocorticotropin hormone (ACTH) and cortisol, the involvement of corticotropin-releasing hormone (CRH) has not been demonstrated. The present study investigates whether treatment with bacterial endotoxin (lipopolysaccharide, LPS) modulates brain CRH contents or in vitro CRH release in tilapia (Oreochromis mossambicus). 10 days LPS (Escherichia coli) exposure of juvenile tilapia (4.5 weeks post hatch) via the ambient water increased brain CRH and alpha-MSH content, whereas cortisol contents were not increased. This indicates that the elevation of brain CRH levels were not secondary to activation of HPI-axis. Adult tilapia were treated for 6 days with LPS (intraperitoneally) and were sampled before and after 24 h of confinement. Overall LPS pre-treatment modified the reaction of tilapia to the additional stressor of 24 h confinement, as interactions between LPS treatment and confinement were observed at the level of the hypothalamus (diencephalic CRH content), the pituitary (CRH and alpha-MSH content) and in plasma glucose levels. In vitro, LPS pre-treatment abolished CRH release from telencephalic tissues induced by norepinephrine, one of the CRH secretagogues released during stress in vivo. This effect might be a mechanism of action through which LPS in vivo abolished the up-regulation of telencephalic CRH induced by confinement stress. Our results provide evidence that the role of CRH in immune-endocrine interactions is a phylogenetically old mechanism, and we here demonstrate that LPS molecules are able to locally modulate CRH release in the central nervous system.

Placental corticotropin-releasing hormone (CRH), spontaneous preterm birth, and fetal growth restriction: A prospective investigation

Recent advances in the physiology of human pregnancy have implicated placental corticotropin-releasing hormone (CRH) as one of the primary endocrine mediators of parturition and possibly also of fetal development. The aim of this study was (1) to prospectively assess the relationship of maternal plasma concentrations of CRH in the early third trimester of gestation with two prematurity-related outcomes-spontaneous preterm birth (PTB), and small-for-gestational age birth (SGA), and (2) to determine whether the effects of CRH on each of these outcomes are independent from those of other established obstetric risk factors. In a sample of 232 women with a singleton, intrauterine pregnancy, maternal plasma was collected at 33 weeks' gestation and CRH concentrations were determined by radioimmunoassay. Each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, obstetric risk conditions for prematurity, mode of delivery, and birth outcomes were abstracted from the medical record. After adjusting for the effects of established obstetric risk factors, elevated CRH levels at 33 weeks' gestation were significantly associated with a 3.3-fold increase in the adjusted relative risk (RR) for spontaneous preterm birth and with a 3.6-fold increase in the adjusted relative risk for fetal growth restriction. Women who delivered postterm had significantly lower CRH levels in the early third trimester than those who delivered at term. When outcomes were stratified by gestational length and birth weight, the lowest CRH levels at 33 weeks' gestation were associated with the term non-SGA births, intermediate and approximately equal CRH levels were associated with the preterm non-SGA and term SGA births, and the highest CRH levels were associated with the preterm SGA births. For deliveries occurring after 33 weeks' gestation (the time of CRH sampling in this study), our findings support the notion that in humans placental CRH may play an impending, direct role in not only the physiology of parturition but also in processes related to fetal growth and maturation. Our results also support the notion that the timing of onset of parturition may be determined or influenced by events occurring earlier in gestation rather than those close to the time of actual onset of labor (ie, the notion of a "placental clock").

Time-dependent changes in CRH concentrations and release in discrete brain regions following global ischemia: effects of MK-801 pretreatment

The excitatory actions of corticotropin-releasing hormone (CRH) in the brain and the neuroprotective effects of CRH antagonists in models of ischemia suggest a role for this peptide in the cascade of events leading to cellular damage. The present study aimed to characterize endogenous activation of CRH in discrete brain regions following global ischemia. Time-dependent changes in CRH concentrations were assessed in 10 brain regions including hippocampal, parahippocampal, and hypothalamic regions as well as the amygdala and the frontal cortex at three post-ischemic intervals: 4, 24, and 72 h (Experiment 1). The impact of pretreatment with a neuroprotective dose of the NMDA antagonist (5R,10S)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801; hydrogen maleate) on 24-h ischemia-induced CRH concentrations in the 10 brain regions was also determined (Experiment 2). In vivo microdialysis was used to assess dynamic fluctuations in CRH release at the dorsal hippocampus (CA1 pyramidal layer) and central nucleus of the amygdala (CeA; Experiment 3). Our findings revealed a rapid elevation of CRH concentrations at the piriform cortex (Pir) and hypothalamic nuclei following global ischemia. This was followed by decreased CRH concentrations at the amygdala, the frontal cortex (FC), the CA3, and the hypothalamus 24-h post-ischemia. MK-801 reversed the decreases in the hypothalamic nuclei but not in the other brain regions. Seventy-two hours post-ischemia, CRH levels returned to control values in all regions except the dentate gyrus (DG) where elevated CRH levels were observed. In vivo, a significant increase in CRH release in response to global ischemia was found at the CeA with no alterations at the CA1. These findings support brain region-specific ischemia-induced CRH alterations and suggest that CRH actions to mediate neuronal damage at the hippocampal CA1 layer may be indirect.

Effects of acute and chronic ketoconazole administration on hypothalamo–pituitary–adrenal axis activity and brain corticotropin-releasing hormone

We have been investigating the effects of ketoconazole on cocaine reward in rats for several years now. However, we recently confirmed that ketoconazole-induced changes in cocaine self-administration and reinstatement do not always correspond with decreases in plasma corticosterone, which suggests that other mechanisms must be underlying the behavioral effects that we observe. This experiment was therefore designed to determine the effects of acute, repeated and chronic ketoconazole administration on corticotropin-releasing hormone (CRH) content in hypothalamic and extra-hypothalamic brain sites in rats following the same dosing regimen that we use in our behavioral studies. Although ketoconazole significantly increased the concentration of ACTH in trunk blood, there were no significant effects on plasma cortisol, corticosterone or testosterone. There was also a significant increase in CRH content in the median eminence after the acute administration of ketoconazole that just failed to reach statistical significance following repeated or chronic administration. However, acute, repeated and chronic treatment with ketoconazole each significantly increased CRH content in the medial prefrontal cortex (MPC), but did not consistently affect the peptide in any other brain region studied. Since the MPC and CRH have been implicated in the neurobiology of cocaine, CRH-induced alterations in dopaminergic neurotransmission may play an important role in this peptide’s effects on cocaine responsiveness. Taken together with the results from previous studies, these data suggest that ketoconazole may affect cocaine reward, at least in part, through interactions with dopamine and CRH within the MPC.

Corticotropin-releasing hormone in the teleost stress response: rapid appearance of the peptide in plasma of tilapia (Oreochromis mossambicus).

High concentrations (up to 600 pg/ml) of corticotropin-releasing hormone (CRH) were detected in plasma of the teleost fish Oreochromis mossambicus (tilapia) when screening peripheral tissues of tilapia exposed to stress. Notably, the plasma CRH response to stressors in tilapia is much more pronounced than that in higher vertebrates, such as rats. After characterisation by RIA, by spiking plasma with synthetic tilapia CRH and by methanol-acid extraction, it is concluded that the immunoreactive (ir) material in plasma represents tilapia CRH(1-41). Results indicate that a CRH-binding protein is absent in tilapia plasma. Unstressed fish had plasma CRH levels under the limit of detection (<2 pg/ml), but following capture stress plasma CRH levels (170-300 pg/ml) as well as plasma cortisol levels (120 ng/ml) increased rapidly to plateau levels, which were reached after approximately 5 min. Tilapia CRH(1-41) tested at concentrations between 10(-11) and 10(-7) M in vitro did not stimulate the cortisol release from interrenal tissue. Also pretreatment of interrenal tissue with 10(-9) M CRH did not sensitise the cortisol-producing cells to a subsequent ACTH challenge. Forty-eight hours of net confinement or 48 h of cortisol treatment abolished the plasma CRH response and cortisol response to capture stress. The rapidity of the plasma CRH response and its inhibition after 48 h of stress or cortisol treatment point to release by central nervous tissue. Therefore the distribution of glucocorticoid receptors (GRs) in the brain and pituitary of tilapia was investigated. Main GR-ir cell clusters were found in the medial part (Dm) and posterior part of the dorsal telencephalon, in the preoptic region, in the inferior lobe of the hypothalamus and in the cerebellum. We conclude from comparison of CRH brain contents of unstressed and stressed fish that plasma CRH was released by CRH-ir cells located in the lateral part of the ventral telencephalon (Vl), and suggest that the cortisol feedback on CRH release by Vl is mainly exerted via the forebrain Dm region. We propose that CRH is mobilised during stress to fulfil peripheral functions, such as the regulation of circulating leukocytes or of cardiac output, as CRH receptors have been reported in these organs for fish species.

Human fetal and maternal corticotrophin releasing hormone responses to acute stress

Objectives: To study the effect of acute stress, caused by intrauterine needling at the intrahepatic vein (IHV), on fetal plasma concentrations of corticotrophin releasing hormone (CRH), and to compare paired...

Covariates of corticotropin-releasing hormone (CRH) concentrations in cerebrospinal fluid (CSF) from healthy humans

BackgroundDefine covariates of cerebrospinal corticotropin-releasing hormone (CRH) levels in normal humans. CRHCSF was measured in 9 normal subjects as part of an intensive study of physiological responses stressors in chronic pain and fatigue states. CRHCSF was first correlated with demographic, vital sign, HPA axis, validated questionnaire domains, baseline and maximal responses to pain, exercise and other stressors. Significant factors were used for linear regression modeling.ResultsHighly significant correlations were found despite the small number of subjects. Three models were defined: (a) CRHCSF with blood glucose and sodium (explained variance = 0.979, adjusted R2 = 0.958, p = 0.02 by 2-tailed testing); (b) CRHCSF with resting respiratory and heart rates (R2 = 0.963, adjusted R2 = 0.939, p = 0.007); and (c) CRHCSF with SF-36 Vitality and Multidimensional Fatigue Inventory Physical Fatigue domains (R2 = 0.859, adjusted R2 = 0.789, p = 0.02).ConclusionsLow CRHCSF was predicted by lower glucose, respiratory and heart rates, and higher sodium and psychometric constructs of well being. Responses at peak exercise and to other acute stressors were not correlated. CRHCSF may have reflected an overall, or chronic, set-point for physiological responses, but did not predict the reserves available to respond to immediate stressors.

Distribution of corticotropin releasing hormone in the fetus, newborn, juvenile, and adult baboon.

Corticotropin releasing hormone (CRH) has previously been identified in extrahypothalamic tissues and may act in a paracrine fashion within these tissues. To date, CRH production and its role in the fetus and newborn have not been investigated. The aim of this study was to explore the distribution and ontogeny of CRH in extrahypothalamic tissues of the fetus, newborn, juvenile, and adult baboon. Pituitary, adrenal, kidney, liver, and lung tissues from baboons at 125 d gestation, 140 d gestation, 185 d gestation (term), juveniles, and adults were obtained at necropsy. The tissues were quantified for protein and immunoreactive CRH was determined by a RIA. CRH levels were normalized to the protein content of each tissue. CRH was present in all tissues and varied over a 100-fold range according to tissue type. The highest concentration of CRH was found in the pituitary, which did not differ with the gestation and/or age of the animal. In the lung tissues of 125- and 140-d gestation animals, CRH was greater than the term, juvenile, and adult lung (p < 0.02). CRH in the adrenal gland of the 125-d samples was greater than the other four ages tested (p < 0.02). Liver CRH levels were higher in the term animals compared with the juvenile baboons. Our study documents the existence of CRH in extrahypothalamic tissues of the baboon from 125 d of gestation to adulthood. Given its presence and distribution, we speculate that CRH may exert ongoing paracrine and/or autocrine actions in these tissues from the time of intrauterine life throughout adulthood.

Identification of stimulatory and inhibitory inputs to the hypothalamic-pituitary-adrenal axis during hypoglycaemia or transport in ewes.

This study used the novel approach of statistical modelling to investigate the control of hypothalamic-pituitary-adrenal (HPA) axis and quantify temporal relationships between hormones. Two experimental paradigms were chosen, insulin-induced hypoglycaemia and 2 h transport, to assess differences in control between noncognitive and cognitive stimuli. Vasopressin and corticotropin-releasing hormone (CRH) were measured in hypophysial portal plasma, and adrenocorticotropin hormone (ACTH) and cortisol in jugular plasma of conscious sheep, and deconvolution analysis was used to calculate secretory rates, before modelling. During hypoglycaemia, the relationship between plasma glucose and vasopressin or CRH was best described by log10 transforming variables (i.e. a positive power-curve relationship). A negative-feedback relationship with log10 cortisol concentration 2 h previously was detected. Analysis of the "transport" stimulus suggested that the strength of the perceived stimulus decreased over time after accounting for cortisol facilitation and negative-feedback. The time course of vasopressin and CRH responses to each stimulus were different However, at the pituitary level, the data suggested that log10 ACTH secretion rate was related to log10 vasopressin and CRH concentrations with very similar regression coefficients and an identical ratio of actions (2.3 : 1) for both stimuli. Similar magnitude negative-feedback effects of log10 cortisol at -110 min (hypoglycaemia) or -40 min (transport) were detected, and both models contained a stimulatory relationship with cortisol at 0 min (facilitation). At adrenal gland level, cortisol secretory rates were related to simultaneously measured untransformed ACTH concentration but the regression coefficient for the hypoglycaemia model was 2.5-fold greater than for transport. No individual sustained maximum cortisol secretion for longer than 20 min during hypoglycaemia and 40 min during transport. These unique models demonstrate that corticosteroid negative-feedback is a significant control mechanism at both the pituitary and hypothalamus. The amplitude of HPA response may be related to stimulus intensity and corticosteroid negative-feedback, while duration depended on feedback alone.

Maternal serum corticotropin-releasing hormone at midgestation in hispanic and white women

Objective Maternal circulating corticotropin-releasing hormone analysis at midgestation has been proposed as a parameter for the prediction of preterm birth. However, one recent study has reported that corticotropin-releasing hormone concentrations at midgestation differ in the black and white populations. These findings led us to investigate whether other populations have differing concentrations of maternal circulating corticotropin-releasing hormone that may require reference to specific population-based medians for optimal midgestational screening. Methods In this study we have defined the mean and median concentrations of maternal circulating corticotropin-releasing hormone in Hispanic and white populations at each gestational week from 14 to 18 weeks of pregnancy, using a sensitive and specific radioimmunoassay. Results Corticotropin-releasing hormone concentrations were found to be significantly lower in the Hispanic population as compared with whites at 16, 17, and 18 weeks’ gestation. The distribution of corticotropin-releasing hormone, expressed as multiples of the median (MoM) using the appropriate ethnicity-related median, was estimated for each gestational week and for each population. No differences were observed in the distribution of the ethnicity-adjusted MoM for Hispanics and whites. Conclusion These data demonstrate that ethnicity is a significant factor affecting corticotropin-releasing hormone concentrations at midgestation in the Hispanic and white populations. The use of ethnicity-specific medians to estimate the ethnicity-specific MoM for the corticotropin-releasing hormone concentrations may enhance the predictive value of midgestational maternal corticotropin-releasing hormone as a screening parameter for the prediction of preterm birth.

Maternal Serum Corticotropin-Releasing Hormone at Midgestation in Hispanic and White Women

In Brief OBJECTIVE Maternal circulating corticotropin-releasing hormone analysis at midgestation has been proposed as a parameter for the prediction of preterm birth. However, one recent study has reported that corticotropin-releasing hormone concentrations at midgestation differ in the black and white populations. These findings led us to investigate whether other populations have differing concentrations of maternal circulating corticotropin-releasing hormone that may require reference to specific population-based medians for optimal midgestational screening. METHODS In this study we have defined the mean and median concentrations of maternal circulating corticotropin-releasing hormone in Hispanic and white populations at each gestational week from 14 to 18 weeks of pregnancy, using a sensitive and specific radioimmunoassay. RESULTS Corticotropin-releasing hormone concentrations were found to be significantly lower in the Hispanic population as compared with whites at 16, 17, and 18 weeks' gestation. The distribution of corticotropin-releasing hormone, expressed as multiples of the median (MoM) using the appropriate ethnicity-related median, was estimated for each gestational week and for each population. No differences were observed in the distribution of the ethnicity-adjusted MoM for Hispanics and whites. CONCLUSION These data demonstrate that ethnicity is a significant factor affecting corticotropin-releasing hormone concentrations at midgestation in the Hispanic and white populations. The use of ethnicity-specific medians to estimate the ethnicity-specific MoM for the corticotropin-releasing hormone concentrations may enhance the predictive value of midgestational maternal corticotropin-releasing hormone as a screening parameter for the prediction of preterm birth. Maternal circulating corticotropin-releasing hormone at midgestation differs in Hispanic and white populations, and the ethnicity-specific medians are defined for weeks 14–18 of pregnancy.

Acute Stress Results in Skin Corticotropin-Releasing Hormone Secretion, Mast Cell Activation and Vascular Permeability, an Effect Mimicked by Intradermal Corticotropin-Releasing Hormone and Inhibited by Histamine-1 Receptor Antagonists

Background: Mast cells play an important role in allergic inflammation by releasing vasoactive molecules, proteases and cytokines. Corticotropin-releasing hormone (CRH) and its structural analogue urocortin (Ucn) were shown to trigger skin mast cell activation and vascular permeability. We investigated the effect of acute stress on rat skin vascular permeability and CRH secretion, as well as the effect of intradermal CRH, and that of two histamine-1 receptor antagonists, azelastine and olopatadine, on vascular permeability. Methods: Rats were stressed by restraint and vascular permeability was assessed by extravasation of ⁹⁹Tc-gluceptate, while mast cell activation was determined by skin rat mast cell protease-1 (RMCP-1) content. Skin CRH content was evaluated by ELISA. The effect of intradermal injection of CRH and Ucn, as well as that of two histamine-1 receptor antagonists, azelastine and olopatadine, was assessed by Evan’s blue extravasation. Purified rat peritoneal mast cells (RPMCs) were also pretreated with azelastine (24 µM) or olopatadine (133 µM) for 5 min before challenge with compound 48/80 (0.5 µg/ml) for 30 min. Histamine secretion was measured fluorometrically. Intracellular Ca²⁺ ions were evaluated in RPMCs loaded with calcium crimson and stimulated with compound 48/80. Results: Acute stress increased skin vascular permeability and CRH content, while it decreased RMCP-1. Intradermal injection of CRH or Ucn induced substantial Evan’s blue extravasation that was inhibited by pretreatment with azelastine (24 µM) and olopatadine (133 µM). Both antihistamines also inhibited histamine release and intracellular increase of Ca²⁺ ions from RPMCs stimulated by compound 48/80. Conclusions: These results indicate that acute stress increases skin CRH that can trigger mast cell-dependent vascular permeability, effects inhibited by certain histamine-1 receptor antagonists, possibly acting to reduce intracellular Ca²⁺ ion levels.

A mechanism underlying the sexually dimorphic ACTH response to lipopolysaccharide in rats: sex steroid modulation of cytokine binding sites in the hypothalamus

It is well established that the hypothalamic-pituitary-adrenal responses to immune stressors are sexually dimorphic in rodents (females > males), but the underlying mechanism is still unclear. To investigate the mechanism, in this study we examined whether the sex steroid environment affects the following variables in male and female rats: (1) plasma levels of ACTH, interleukin (IL)-1β, IL-6 and tumour necrosis factor-α (TNF-α) after systemic lipopolysaccharide (LPS) administration; (2) static concentrations of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in the mediobasal hypothalamus (MBH) and those of ACTH in the anterior pituitary (AP); and (3) the binding characteristics of IL-1β, IL-6 and TNF-α in the MBH and AP. LPS-induced ACTH release was significantly higher in female than in male rats, and this sexual difference was abolished by performing gonadectomy in both sexes. Administration of physiological doses of testosterone and oestradiol to gonadectomized males and females, respectively, restored the altered ACTH responses to normal. Changes in the sex steroid milieu did not affect plasma cytokine responses to LPS, tissue contents of CRH, AVP and ACTH, or the IL-6 binding characteristics in the MBH and AP. However, the number of IL-1β and TNF-α binding sites, but not their binding affinities, in the MBH showed significant changes according to altered sex hormone milieu, in the same direction as the LPS-induced ACTH response. These results suggest that the hypothalamic sensitivity to peripheral IL-1β and TNF-α may be an important mechanism underlying the sexually dimorphic ACTH response to LPS in rats.

Corticotropin-releasing hormone induces proliferation and TNF-alpha release in cultured rat microglia via MAP kinase signalling pathways.

We have previously demonstrated that corticotropin-releasing hormone (CRH) receptor 1 (CRH-R1) is functionally expressed in rat microglia. In the present study, we show that CRH, acting on CRH-R1, promoted cell proliferation and tumour necrosis factor-alpha (TNF-alpha) release in cultured rat microglia. Exogenous CRH resulted in an increase in BrdU incorporation compared with control cells, which was observed in a range of concentrations of CRH between 10 and 500 nm, with a maximal response at 50 nm. The effect of CRH on BrdU incorporation was inhibited by a CRH antagonist astressin but not by a cAMP-dependent protein kinase inhibitor H89. Exposure of microglial cells to CRH resulted in a transient and rapid increase in TNF-alpha release in a dose-dependent manner. In the presence of astressin, the effects of CRH on TNF-alpha release were attenuated. CRH effects on TNF-alpha release were also inhibited by specific inhibitors of MEK, the upstream kinase of the extracellular signal-regulated protein kinase (ERK) (PD98059) or p38 mitogen-activated protein kinase (SB203580), but not by H89. Furthermore, CRH induced rapid phosphorylation of ERK and p38 kinases. Astressin, PD98059, and SB230580 were able to inhibit CRH-induced kinase phosphorylation. These results suggest that CRH induces cell proliferation and TNF-alpha release in cultured microglia via MAP kinase signalling pathways, thereby providing insight into the interactions between CRH and inflammatory mediators.

Distribution and quantification of corticotropin-releasing hormone (CRH) in the brain of the teleost fish Oreochromis mossambicus (tilapia).

The recent characterization of the corticotropin-releasing hormone (CRH) prehormone of the fish tilapia (Oreochromis mossambicus) showed that more variation exists between vertebrate CRH amino acid sequences than recognized before. The present study investigates whether the deviating composition of tilapia CRH coincides with an atypical distribution of CRH in the brain. For this purpose we applied immunohistochemistry, as well as radioimmunoassay (RIA) quantification in brain slices. The results are plotted in a new atlas and reconstruction of the tilapia brain. The largest population of CRH-immunoreactive (ir) neurons is present in the lateral part of the ventral telencephalon (Vl). Approximately tenfold less CRH-ir neurons are observed in the preoptic and tuberal region. The CRH-ir neurons observed in the preoptic region are parvocellular and do not, or hardly, display arginine-vasotocin (AVT) immunoreactivity. CRH-ir neurons are also present in the glomerular layer of the olfactory bulb, in the periventricular layer of the optic tectum, and caudal to the glomerular nucleus. A very dense plexus of CRH-ir terminals is located in the most rostral part of the dorsal telencephalon. This region has not been described in other teleosts and is in the present study subdivided into the anterior part of the dorsal telencephalon (Da) and the anterior part of the laterodorsal telencephalon (Dla). High densities of CRH-ir terminals were observed in and around Vl, in the tuberal region, around the rostral part of the lateral recess, and in the caudal part of the vagal lobe. In the pituitary, CRH-ir terminals are concentrated in the neuro-intermediate lobe. Overall, the immunohistochemical and quantitative data correlated well, as the RIA CRH profile in serial 160-microm slices revealed four peaks, which corresponded with major ir-cell groups and terminal fields. Our results strongly suggest that the CRH-ir cells of Vl project to the rostro-dorsal telencephalon. Consequently, they may not be primarily involved in regulation of pituitary cell types but may subserve other functions. The presence of a CRH-containing Vl-Da/Dla projection seems to be restricted to the most modern group of teleosts, i.e., the Acanthopterygians. Further anatomic indications for non-pituitary-related functions of CRH are found in the vagal lobe and the optic tectum of tilapia. Although the low CRH content of the preoptic region reported here for tilapia may be typical for unstressed fish, the fact remains that remarkably few CRH-ir neurons are involved in regulating the pituitary. Overall, the CRH distribution in the brain of tilapia is more widespread than previously reported for other teleosts.

Atrial natriuretic hormone, vessel dilator, long acting natriuretic hormone, and kaliuretic hormone decrease circulating prolactin concentrations.

The present investigation was designed to test whether four cardiac hormones--long acting natriuretic hormone, vessel dilator, kaliuretic hormone and atrial natriuretic hormone--decrease the circulating concentration of prolactin in humans (n = 30). Vessel dilator, kaliuretic hormone, long acting natriuretic hormone and atrial natriuretic hormone decreased the circulating concentration of prolactin to 3 %, 31 %, 27 %, and 23 % of control values, respectively, at the end of their infusions when infused at concentrations of 100 ng/kg body weight per minute for 60 minutes (p < 0.001 for each). Vessel dilator, kaliuretic hormone, long acting natriuretic hormone and atrial natriuretic hormone had sustained effects on modulating prolactin's concentrations, with circulating concentrations of 1 %, 64 %, 28 %, and 2 % of control values (p < 0.001) 3 hours after stopping their respective infusions. These results suggest that there are four circulating prolactin-inhibitory hormones in addition to the hypothalamic mediators, dopamine and corticotropin-releasing hormone, which modulate prolactin release. These peptide hormones' ability to decrease circulating prolactin concentrations may be mediated in part by dopamine and in part by their demonstrated ability to decrease corticotropin-releasing hormone concentrations, which stimulate prolactin release.

Reduced startle reactivity and plasticity in transgenic mice overexpressing corticotropin-releasing hormone

Background: Corticotropin-releasing hormone (CRH) hyperactivity in transgenic mice overexpressing CRH in the brain (CRH-OE 2122) appears to be associated with chronic stress-like alterations, including increased CRH content in the hypothalamus, changes in hypothalamus-pituitary-adrenal axis regulation, and increased heart rate and body temperature. In the present study, we investigated if sensory information processing of startling auditory stimuli was affected in CRH-OE 2122 mice. Methods: CRH-OE 2122 mice (on C57BL/6J background) were subjected to a number of procedures probing sensory information processing mechanisms, including the acoustic startle response, habituation, and prepulse inhibition of startle. Results: CRH-OE 2122 mice displayed reduced acoustic startle reactivity and increased motor activity during startle testing compared to wild-type mice. Furthermore, transgenic mice did not show habituation of the startle response after repeated exposure to the auditory stimulus, or habituation across procedures. CRH-OE 2122 mice exhibited robust impairments of prepulse inhibition in two different paradigms. Conclusions: The results in CRH-OE 2122 mice indicate that chronic CRH hyperactivity is associated with reductions in startle reactivity, habituation, and prepulse inhibition. The latter two abnormalities are also observed in schizophrenia patients. We conclude that chronic CRH excess may reduce behavioral reactivity to environmental stimuli and impair information processing mechanisms.