Endocrine responses to growth hormone releasing hormone and corticotropin releasing hormone in early-onset Alzheimer's disease

In a study of the hypothalamic-pituitary-somatotropic (HPS) and the hypothalamic-pituitary-adrenal (HPA) systems in early-onset Alzheimer's disease (AD), 10 drug-naive patients and matched controls were given 50 micrograms growth hormone releasing hormone (GHRH) at 9 a.m. and 100 micrograms corticotropin releasing hormone (CRH) at 6 p.m. as an i.v. bolus dose. Compared with controls, patients with AD showed attenuated GHRH-induced growth hormone (GH) responses and decreased adrenocorticotropic hormone (ACTH) but normal cortisol secretion following CRH. GH responses to GHRH were negatively correlated with the plasma insulin-like growth factor (IGF-I) concentrations and the severity of dementia. A positive correlation was found between GHRH-evoked GH release and ACTH responses to CRH. The results suggest a pathological process at the level of the pituitary or the hypothalamus, possibly involving a cholinergic, monoaminergic, or peptidergic imbalance in AD, and support the view that altered HPS and HPA secretory dynamics in AD are related to the underlying brain dysfunction.     

Central alpha-adrenergic receptors and corticotropin releasing factor mediate hemodynamic responses to acute cold stress

Behavioral stress is likely to contribute to the development of hypertension in susceptible individuals. We reported that hemodynamic response patterns to acute startle vary and that those patterns predict the predisposition of rats to sustained stress-induced elevations in arterial pressure. Since considerable evidence suggests that central catecholamines and corticotropin releasing factor (CRF) contribute to the regulation of arterial pressure and the development of hypertension, we investigated the role of central alpha-adrenergic receptors and CRF in mediating different hemodynamic response patterns to acute cold water stress in conscious rats. Rats were instrumented for arterial pressure, heart rate and cardiac output determination and for intracerebroventricular (icv) administration of selective antagonists. After acclimation to a water tight cage, ice water (1 cm deep) was rapidly added then drained 1 min later. Although the early startle response to cold water stress elicited a pressor response in all rats, the hemodynamic response pattern varied between rats. Vascular responders (n=19) had an initial considerable increase in systemic vascular resistance and a decrease in cardiac output. In contrast, mixed responders (n=11) had a smaller increase in vascular resistance and an increase in cardiac output. Pretreatment with phentolamine (30 microgram/5 microliter, icv, n=8), prazosin (10 microgram/5 microliter, icv, n=12) or alpha-helical CRF(9-41) (10 microgram/5 microliter, icv, n=9) prevented the decrease in cardiac output elicited by acute cold water stress in vascular responders without affecting mixed responders. Yohimbine (3 microgram/5 microliter, icv, n=8) pretreatment did not alter hemodynamic responses. Therefore, we conclude that central alpha(1)-adrenoceptors and CRF mediate the specific hemodynamic response patterns to acute startle and may be responsible for the predisposition to develop hypertension in vascular responders.     

Pituitary and adrenocortical responses to the ovine corticotropin releasing hormone in depressed patients and healthy volunteers

It has been suggested that limbic system-hypothalamic "overdrive" may be the underlying mechanism causing an augmented secretion of corticotropin releasing hormone (CRH), heightened adrenocortical responsiveness to corticotropin (adrenocorticotropic hormone) (ACTH), and alteration in cortisol feedback regulatory mechanisms as demonstrated by the dexamethasone suppression test. We examined pituitary and adrenocortical responses after morning administration of ovine CRH (oCRH) in 26 depressed patients and 11 healthy volunteers. Basal plasma ACTH concentrations were similar in both groups, whereas patients had a significantly diminished cumulative ACTH response after administration of oCRH. In contrast, basal total cortisol concentrations and cumulative cortisol responses to oCRH were similar in depressed patients and controls. Patients with melancholic features demonstrated the most profound ACTH blunting after oCRH, whereas patients separated according to dexamethasone suppression test results had similar ACTH and cortisol responses to oCRH. The present results extend data from prior studies utilizing oCRH in the evening and demonstrate a dysregulation of the functional integrity of the hypothalamic-pituitary-adrenocortical axis in depressive illness after a morning oCRH test at both central and peripheral hypothalamic-pituitary-adrenocortical axis sites.     

CSF corticotropin releasing hormone, somatostatin, and thyrotropin releasing hormone in schizophrenia.

Cerebrospinal fluid (CSF) corticotropin releasing hormone (CRH), somatostatin (SRIF), and thyrotropin releasing hormone (TRH) were measured by specific radioimmunoassay methods in 86 patients who met DSM-III-R criteria for schizophrenia or schizophreniform disorder and in 30 neurologic controls. The multivariate CSF peptide concentration was significantly different in patients compared with controls, but none of the individual variable differences reached statistical significance when analyzed separately. There were no significant CSF neuropeptide differences among patients with various schizophrenic subtypes. Neither global severity of illness nor individual symptoms were correlated with CSF neuropeptide concentrations. Although schizophrenic patients showed a pattern of mildly lower SRIF and TRH levels in their CSF, together with a weak tendency for higher CSF CRH values, these peptide changes did not appear to be specifically related to the core features of schizophrenia.     

Elevated corticotropin releasing hormone/corticotropin releasing hormone-R1 expression in postmortem brain obtained from children with generalized epilepsy

The corticotropin releasing hormone (CRH) system has been suggested to initiate seizure activity in the developing brain. However, human data to support this theory is lacking. In this study, we have demonstrated that the expression of CRH, CRH-binding protein, and CRH-R1 (a CRH membrane receptor) were significantly elevated in cortical tissue obtained from 6 children with generalized epilepsy (mean age 8.2+/-1.5 years) relative to age-matched controls (mean age 7.8+/-1.4 years). In contrast, no significant difference in the expression of CRH-R2 was observed. The advent of CRH-R1 receptor antagonists may prove useful as novel anticonvulsants.     

HPA axis dysregulation in mice overexpressing corticotropin releasing hormone.

BACKGROUND: Hypersecretion of corticotropin-releasing hormone (CRH) in the brain has been implicated in stress-related human pathologies. We developed a transgenic mouse line overexpressing CRH (CRH-OE) exclusively in neural tissues to assess the effect of long-term CRH overproduction on regulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Male transgenic CRH-OE(2122) mice on a C57BL/6J background were used. Littermate wildtype mice served as control animals. Basal plasma corticotropin and corticosterone concentrations were measured, and adrenal gland weight was determined. A dexamethasone suppression test measured the effects of long-term CRH hypersecretion on negative feedback control. Additionally, we measured plasma corticosterone concentrations in reaction to stress. RESULTS: CRH-OE(2122) mice showed elevated basal plasma corticosterone concentrations, hypertrophy of the adrenal gland, and dexamethasone nonsuppression. Basal plasma ACTH concentrations of wildtype and CRH-OE(2122) mice did not differ significantly. In reaction to stress, CRH-OE(2122) mice showed a normal corticosterone response. CONCLUSIONS: The HPA axis abnormalities observed in CRH-OE(2122) mice suggest that long-term hypersecretion of CRH in the brain can be a main cause of HPA axis dysregulation. The alterations in HPA axis regulation are reminiscent of changes reported in major depressive disorder. As such, these CRH -OE(2122) mice may model the neuroendocrine changes observed in major depressive disorder.     

Selective anorexigenic effects of corticotropin releasing hormone in the rhesus monkey

1. Rhesus monkeys were equipped with a novel intracerebroventricular (i.c.v.) cannula system and trained to respond under operant schedules of food presentation or termination of stimuli associated with the delivery of shock (escape). 2. CRH decreased food-maintained behavior in a dose-related manner over the range of (0.3-10 micrograms/kg) but did not affect escape responding, demonstrating a selective effect on food-maintained responding. 3. This selective effect was related to the tendency for responding to stop after delivery of a food pellet when higher doses of CRH were given, consistent with the notion that a conditioned aversion to food was established in the presence of CRH. 4. This may suggest that in hyperaroused clinical states such as depression and anorexia nervosa, focus is shifted away from appetitive tasks as a result of increased levels of CRH.     

A role for corticotropin releasing factor and urocortin in behavioral responses to stressors

Corticotropin-releasing factor (CRF) and CRF-related neuropeptides have an important role in the central nervous system to mediate behavioral responses to stressors. CRF receptor antagonists are very effective in reversing stress-induced suppression and activation in behavior. An additional CRF-like neuropeptide, urocortin, has been identified in the brain and has a high affinity for the CRF-2 receptor in addition to the CRF-1 receptor. Urocortin has many of the effects of CRF but also is significantly more potent than CRF in decreasing feeding in both meal-deprived and free-feeding rats. In mouse genetic models, mice over-expressing CRF show anxiogenic-like responses compared to wild-type mice, and mice lacking the CRF-1 receptor showed an anxiolytic-like behavioral profile compared to wild-type mice. Results to date have led to the hypothesis that CRF-1 receptors may mediate CRF-like neuropeptide effects on behavioral responses to stressors, but CRF-2 receptors may mediate the suppression of feeding produced by CRF-like neuropeptides. Brain sites for the behavioral effects of CRF include the locus coeruleus (LC), paraventricular nucleus (PVN) of the hypothalamus, the bed nucleus of the stria terminalis (BNST), and the central nucleus of the amygdala. CRF may also be activated during acute withdrawal from all major drugs of abuse, and recent data suggest that CRF may contribute to the dependence and vulnerability to relapse associated with chronic administration of drugs of abuse. These data suggest that CRF systems in the brain have a unique role in mediating behavioral responses to diverse stressors. These systems may be particularly important in situations were an organism must mobilize not only the pituitary adrenal system, but also the central nervous system in response to environmental challenge. Clearly, dysfunction in such a fundamental brain-activating system may be the key to a variety of pathophysiological conditions involving abnormal responses to stressors such as anxiety disorders, affective disorders, and anorexia nervosa.     

Corticotropin releasing hormone related behavioral and neuroendocrine responses to stress in Lewis and Fischer rats

We have recently shown that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is related to a lack of glucocorticoid restraint of inflammation while the relative SCW arthritis resistance in histocompatible Fischer (F344/N) rats is related to their greater hypothalamic-pituitary-adrenal (HPA) exis response. The difference in pituitary-adrenal responsiveness results from decreased inflammatory mediator-induced hypothalamic corticotropin-releasing hormone (CRH) biosynthesis and secretion in LEW/N rats. Because CRH not only activates the pituitary-adrenal axis, but also is associated with behavioral responses that are adaptive during stressful situations, we wished to determine if the differential LEW/N and F344/N CRH responsiveness to inflammatory mediators could also be associated with differences in neuroendocrine and behavioral responses to physical and emotional stressors. In this study, LEW/N rats exhibited significant differences compared to F344/N rats, in plasma adrenocorticotropin hormone (ACTH) and corticosterone responses during exposure to an open field, swim stress, restraint or ether. Furthermore, hypothalamic paraventricular CRH mRNA expression was also significantly lower in LEW/N compared to F344/N rats after restraint. These differences in neuroendocrine responses were associated with differences in behavioral responses in LEW/N compared to F344/N rats in the open field. Outbred HSD rats, which have intermediate and overlapping arthritis susceptibility compared to LEW/N and F344/N rats, exhibited intermediate and overlapping plasma corticosterone and behavioral responses to stressful stimuli compared to the two inbred strains. These data suggest that the differences in CRH responses in these strains may contribute to the behavioral and neuroendocrine differences we have observed. Therefore these strains may provide a useful animal model for studying the relationship between behavior, neuroendocrine and inflammatory responses.     

应激与早产孕妇胎盘促肾上腺皮质激素释放激素信使核糖核酸的表达

目的：探讨应激及其应对方式与早产和胎盘促肾上腺皮质激素释放激素（corticotropin releasing hormone,CRH）信使核糖核酸（mRNA）水平的相关性。方法：研究对象来自2003年6月至2005年3月在镇江第四人民医院产科分娩的单胎初产妇,早产组46例,正常产组42例;采用生活事件量表（LES）及防御方式问卷（DSQ）在第28周时进行自我评定,胎盘组织的CRH—mRNA的表达采用RT-PCR方法测定,以光密度值（OD值）作为观察数据。统计方法采用独立样本t检验和逐步回归分析。结果：早产组与正常产组在恶性生活事件频度和强度、DsQ的不成熟防御因子（DSQ1）分值的差异有显著性（P〈0．05～0．001）;早产因子、DSQ1分值与胎盘CRH—mRNA的相对含量（0D值）呈正相关,偏回归系数分别为0．552和0．345,t值分别为5.693和3．618,P值均〈0.001。结论：心理应激及其应对方式与早产的发生相关,胎盘CRH-mRNA的高度表达可能是心理应激与早产发生的病理生理中介机制。     

Growth hormone responses to growth hormone releasing factor in primary degenerative dementia

The growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin (PRL) responses to growth hormone releasing factor (GRF) were investigated in 18 patients suffering from primary degenerative dementia (PDD) and in 20 age- and sex-matched normal elderly controls. There was no significant difference in the growth hormone response to GRF stimulation between patients and controls, and in neither subject group was there a demonstrable TSH or prolactin response to GRF. These findings indicate that the pathophysiology underlying the blunted growth hormone response to pharmacological challenge in PDD must lie at a suprapituitary level.     

Gonadotropin releasing hormone elicits abnormal hormone responses in schizophrenia

We studied the non-specific responses of GH and PRL to gonadotropin releasing hormone (GnRH) in eleven male patients aged 18–30 in whom a diagnosis of acute schizophrenia was made according to Crow's criteria. GnRH administration was followed by a significant increase in plasma GH in five patients; plasma PRL increased in two patients. The two prolactin responders were also GH responders. Non-specific GH response was confirmed on repeated testing in two patients in whom GnRH stimulation was performed twice. During saline control, non-specific hormone responses were not observed. The abnormal hormone responses observed in acute schizophrenia are probably due to the disordered monoamine regulation characteristic of this condition.     

Hyperkinesia, plasma corticotropin releasing hormone and ACTH in senile dementia.

Senile dementia of the Alzheimer type (SDAT), in contrast to multi-infarct dementia (MID) was associated with delirium and marked increases in the number of walking steps taken during both the day and night. In SDAT patients, plasma ACTH levels in the afternoon and evening were higher but plasma corticotropin releasing hormone (CRH) levels in the evening were lower than in the MID patients. A positive correlation between ACTH levels and walking steps and a negative correlation between plasma levels of CRH and ACTH were found. These results suggest relevance of hyper-kinetic delirium to disruption of diurnal rhythm of the pituitary-adrenal axis, and a possible mechanism of the short feedback suppression of CRH release by increased circulating ACTH.     

Crossroads of corticotropin releasing hormone,corticosteroids and monoamines. About a biological interface between stress and depression

Mental disorders are frequently preceded by stressful events or situations. Depression is a typical case in point. This raises the question, is depression - or possibly better: are certain forms of depression - caused by stress? Can stress be a true pathogenic factor? Phrased differently: can stress destabilize neuronal systems in the central nervous system to such an extent that depressive symptoms are generated? This question is discussed with the corticotrophin releasing hormone (CRH) and MA systems and hypothalamic-pituitary-adrenal (HPA) axis as major foci. The following issues are explored: the effect of antidepressants on corticosteroid receptor gene expression; the behavioral sequellae of CRH administration; CRH disturbances in depression; the impact of early life adversity on the development of the CRH system and on stress reactivity; the interrelationships of stress hormones and monoaminergic (MA ergic) transmission and finally the therapeutic potential of CRH and cortisol antagonists. The available data suggest that CRH overdrive and cortisol overproduction may play a pathogenic role in the occurrence of certain types of depression, directly and/or indirectly, i.e. by induction or exacerbation of disturbances in MA ergic transmission. Stress should, thus, become a major focus of biological depression research.     

Developmental profile of corticotropin releasing hormone messenger RNA in the rat inferior olive

Corticotropin releasing hormone is a neurotransmitter in the inferior olive complex of marsupials and mammals. The ontogeny of corticotropin releasing hormone gene expression in the rat inferior olive has not been described. Using in-situ hybridization histochemistry in 25 animals, we established the developmental profile of the peptide's messenger ribonucleic acid in the postnatal rat. CRH-messenger RNA was first detectable in two of four animals on the fifth postnatal day. Subsequently, gene expression increased linearly with age: by day 14, CRH was expressed in all olivary complex nuclei, and the distribution and relative abundance on day 18 were comparable to those in the adult. The developmental profile of CRH-mRNA in the rat inferior olive differs from those in the mouse and opossum, and from the pattern in the rat hypothalamus, suggesting species- and site-specificity of the peptide's function.     

Ganglionic blockade alters behavioral and cerebral metabolic responses to corticotropin releasing factor in the rat

Corticotropin releasing factor (CRF) has potent stimulating effects on behavior and cerebral metabolism. To investigate the role of altered peripheral autonomic function in central actions of CRF, we measured the effects of intracerebroventricular CRF (2 μg) on locomotor activity and regional cerebral metabolic rates for glucose (rCMRglc) in control, saline pretreated rats and in rats pretreated with the ganglionic receptor blocker hexamethonium bromide (HEX) (5 mg/kg). Locomotor activity was assessed in a familial environment with an activity meter. rCMRglc were measured in 74 brain regions with the quantitative autoradiographic [¹⁴C]2-deoxy-d-glucose technique. In control rats, CRF increased the spontaneous locomotor activity and rCMRglc in 14 sensorimotor, limbic, hypothalamic and brainstem regions. HEX pretreatment blunted locomotor activations induced by CRF. While HEX did not affect cerebral metabolic activation by CRF in sensorimotor areas, it reduced metabolic activations in hippocampal and hypothalamic regions and increased metabolic activations in the brainstem reticular formation. These data indicate that CRF increases rCMRglc in the sensorimotor areas by direct CNS activity and in the limbic areas by indirect, autonomically mediated, activity. Autonomic activation also accounts, at least in part, for the motor activating properties of CRF.     

Ontogeny of corticotropin releasing hormone gene expression in rat hypothalamus--comparison with somatostatin.

Using in situ hybridization histochemistry, corticotropin-releasing hormone gene expression is first detectable in the parvocellular portion of the rat paraventricular nucleus on the 17th fetal day. The prevalence of messenger RNA for corticotropin releasing hormone decreases perinatally, specifically between the 19th and 21st fetal days. By the 4th postnatal day, CRH gene expression is similar to that of the adult rat. Somatostatin messenger-RNA is detectable on the 14th fetal day in the periventricular nucleus. No perinatal hiatus in somatostatin gene expression is evident.     

Involvement of central, but not placental corticotropin releasing hormone (CRH) in heat stress induced immunosuppression during pregnancy

To clarify whether corticotropin releasing hormone (CRH) and beta-endorphin (betaEP) system mediate maternal immunosuppression in pregnant rats exposed to heat through central or placental pathway, we examined the effects of intravenous (iv) (100 or 500 microg) or intracerebroventricular (icv) (5 microg) administration of CRH receptor antagonist alpha-helical CRH (9-41) on splenic natural killer cell activity (NKCA) as well as betaEP in blood, pituitary lobes, and placenta in pregnant rats at 15 to 16 days gestation. Two-way ANOVA revealed that heat reduced NKCA and elevated blood and pituitary betaEP but did not change placental betaEP. Iv administered 500 microg and icv administered alpha-helical CRH reversed the reduced NKCA and the elevated pituitary betaEP, while iv administration of 100 microg alpha-helical CRH did not. The increased blood betaEP was reversed by iv 100 and 500 microg alpha-helical CRH and icv administration. Both iv and icv administrations reduced placental betaEP independent of heat exposure. Thus, the response of placental betaEP to iv administration of alpha-helical CRH seemed to be stronger than that of pituitary betaEP. These results indicate that alpha-helical CRH which acts on pituitary betaEP antagonizes heat-induced immunosuppression during pregnancy, suggesting that immunosuppression produced by heat stress during pregnancy is mediated by the central CRH system. The placental CRH-betaEP system seems unlikely to be involved in the immunosuppression. Physiologic roles of placental CRH and opioid system should be clarified by future in vitro experiments using placenta specimen including placental immunocyte.     

Interaction of vasoactive intestinal peptide (VIP) and growth hormone releasing factor (GRF) with corticotropin releasing factor (CRF) on corticotropin secretion in vitro

The possible interaction of VIP and GRF with CRF on ACTH release was examined by using superfused rat anterior pituitary fragments. ACTH was measured in effluent medium samples by RIA. Increasing concentrations of VIP and GRF (10(-8) to 10(-6)M) had no effect on spontaneous ACTH secretion but potentiated CRF (10(-10)M) induced ACTH release in a dose dependent manner. The high concentrations of VIP or GRF required to produce the effect suggest that both the peptides could interfere with a common unidentified binding site on corticotrophs or stimulate a second messenger by a paracrine action.     

Abnormal ACTH and cortisol responses to ovine corticotropin releasing factor in patients with primary affective disorder

To further explore hypothalamic pituitary adrenal regulation in patients with affective illness, we administered 1 microgram/kg of synthetic ovine corticotropin releasing factor at 2000h to 26 drug-free patients with this disorder and to 15 healthy controls. Compared to controls, depressed patients (N = 12) showed a significant elevation in baseline cortisol and significant reductions in the net ACTH and cortisol responses to corticotropin releasing factor. These findings were normal in manic (N = 6) and improved (N = 8) subjects. An additional finding was that baseline cortisol and net ACTH and cortisol responses to CRF were negatively correlated in the entire group of patients and controls as well as in the patients alone. These data indicate that the reduced ACTH and cortisol responses to CRF in depression reflect normal functioning of the pituitary corticotroph cell (i.e., that the negative feedback effect of cortisol on ACTH secretion in depression is physiologically intact, effectively serving as a brake on the ACTH response to exogenous CRF. Thus, the hypercortisolism of depression may be due to a hypothalamic defect, possibly involving hypersecretion of endogenous CRF. This possibility may be of particular interest in light of clinical observations that depression can often be precipitated by stress and by data in experimental animals that CRF may influence several processes known to be altered in the overall symptom complex of depression.