Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in the hypothalamic-pituitary-adrenal (HPA) system are well documented in affective disorders. In depression these include increased secretion of cortisol, an insufficient suppressibility of cortisol by dexamethasone, a blunted corticotropin (ACTH) response to corticotropin-releasing hormone (CRH) and a dysfunction of the glucocorticoid receptor. Patients with atopic eczema, a common chronic skin disease, show seasonal variations in disease activity, symptoms of minor depression and immunological disturbances similar to those seen in patients with depression. To explore the integrity of the HPA system integrity in individuals with atopic eczema we studied the 24-h cortisol secretion and the cortisol, ACTH and beta-endorphin responses to CRH in such individuals and in healthy controls matched for sex and age. The 24-h secretion of cortisol did not differ between the patients with atopic eczema and the controls. The net response to CRH administered as a 100 micrograms i.v. bolus was significantly attenuated for both cortisol (24,235 +/- 12,443 vs. 47,019 +/- 34,515 nmol.min/dl; p < .03) and for ACTH (546 +/- 205 vs. 727 +/- 310 pmol.min/l; p < .05) in the patient group, whereas the beta-endorphin response did not differ between the groups (1072 +/- 448 vs. 1603 +/- 421 nmol.min/l). The blunted response of cortisol and ACTH cannot be explained by hypercortisolism as it is the case in major depression. Rather, it may be related to a prolonged underexposure to hypothalamic CRH or to an increased sensitivity of glucocorticoid feedback inhibition.
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PMID:Cortisol, corticotropin, and beta-endorphin responses to corticotropin-releasing hormone in patients with atopic eczema. 767 38

Previous research indicates that the offspring of dams exposed to stress during late gestation show altered hypothalamic-pituitary-adrenal (HPA) responses to stress. However, the results are inconsistent and a review of the literature suggests that the effects may differ depending upon the gender of the offspring. In the present study, we measured plasma adrenocorticotropin (ACTH) and corticosterone (B) levels prior to, and at 0, 20, 40 and 70 min following restraint stress in catheterized adult male and female offspring of dams stressed in the last week of gestation (i.e. days 15-19 of gestation). Prenatal stress significantly increased both plasma ACTH and B levels in response to restraint, but only in females; male offspring were largely unaffected. In addition, plasma corticosteroid-binding globulin (CBG) levels were significantly increased in prenatally-stressed females, but not in males. Despite these differences in plasma CBG, estimated free B levels following restraint were also significantly elevated in prenatally-stressed females. We then examined glucocorticoid receptor binding in a variety of forebrain structures. Prenatal stress had no effect on glucocorticoid receptor density in the hypothalamus or hippocampus in either males or females. Differences in glucocorticoid receptor density across groups were observed in the septum, frontal cortex, and amygdala. However, the pattern of observed differences across the groups was not consistent with the pattern of hormonal differences. In summary, the effect of prenatal stress on HPA function is substantially more marked in females than in males. Interestingly, a similar pattern of effects on HPA activity has been reported for prenatal alcohol exposure.
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PMID:Sex-specific effects of prenatal stress on hypothalamic-pituitary-adrenal responses to stress and brain glucocorticoid receptor density in adult rats. 772 Feb 17

The rapid activation of stress-responsive neuroendocrine systems is a basic reaction of animals to perturbations in their environment. One well-established response is that of the hypothalamo-pituitary-adrenal (HPA) axis. In rats, corticosterone is the major adrenal steroid secreted and is released in direct response to adrenocorticotropin (ACTH) secreted from the anterior pituitary gland. ACTH in turn is regulated by the hypothalamic factor, corticotropin-releasing hormone. A sex difference exists in the response of the HPA axis to stress, with females reacting more robustly than males. It has been demonstrated that in both sexes, products of the HPA axis inhibit reproductive function. Conversely, the sex differences in HPA function are in part due to differences in the circulating gonadal steroid hormone milieu. It appears that testosterone can act to inhibit HPA function, whereas estrogen can enhance HPA function. One mechanism by which androgens and estrogens modulate stress responses is through the binding to their cognate receptors in the central nervous system. The distribution and regulation of androgen and estrogen receptors within the CNS suggest possible sites and mechanisms by which gonadal steroid hormones can influence stress responses. In the case of androgens, data suggest that the control of the hypothalamic paraventricular nucleus is mediated trans-synaptically. For estrogen, modulation of the HPA axis may be due to changes in glucocorticoid receptor-mediated negative feedback mechanisms. The results of a variety of studies suggest that gonadal steroid hormones, particularly testosterone, modulate HPA activity in an attempt to prevent the deleterious effects of HPA activation on reproductive function.
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PMID:Gonadal steroid hormone receptors and sex differences in the hypothalamo-pituitary-adrenal axis. 772 15

Stress represents a complex stimulus to neuroendocrine systems regulating homeostasis. By and large, stress effects are mediated by stress-integrative corticotropin-releasing hormone (CRH) neurons present in the medial parvocellular division of the hypothalamic paraventricular nucleus (PVN). These neurons summate a large variety of neuronal and hormonal signals to eventually yield a physiologically meaningful level of circulating glucocorticoids. In the present experiments, we examined the effects of a chronic variable-stressor paradigm on indices of adrenocorticotropic hormone (ACTH) secretagogue biosynthesis in the PVN and adrenocorticosteroid receptor mRNA expression in the hippocampal formation, PVN and cortex. The variable-stressor paradigm produces a syndrome consistent with chronic stress, including baseline hypersecretion of corticosterone, ACTH and prolactin, and adrenal hypertrophy. CRH mRNA levels in the PVN are increased some 61%, consistent with the observed hypothalamo-pituitary-adrenal (HPA) up-regulation. There was a small but significant increase in arginine vasopressin (AVP) mRNA expression in individual parvocellular PVN neurons (16%), and no demonstrable increase in the number of AVP mRNA-containing neurons. No change in AVP expression was seen in the magnocellular PVN, supraoptic or suprachiasmatic nuclei. In all, these data highlight the importance of CRH in maintaining HPA up-regulation in the face of prolonged challenge. To investigate effects of chronic stress on the regulation of glucocorticoid receptivity, mineralocorticoid receptor (MR) and glucocorticoid receptor mRNA expression was assessed in the hippocampus, frontoparietal cortex and PVN. Chronic stress significantly down-regulated MR mRNA expression in subfields CA1, CA3 and the dentate gyrus (DG), and GR mRNA expression in subfields CA1, the DG and frontoparietal cortex. The reduction in receptor biosynthesis suggests the capacity for stress to modulate the impact of glucocorticoid on hippocampal cell physiology at the genomic level, potentially influencing processes ranging from cognition to feedback regulation of the HPA axis. At the level of the parvocellular PVN, GR mRNA expression was decreased to 60% of control values. GR mRNA expression was negatively correlated with PVN CRH mRNA expression, suggesting a relationship between elevated CRH gene expression and down-regulation of GR at the level of the PVN.
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PMID:Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm. 775 37

The long-term consequences of neonatal endotoxin exposure on hypothalamic-pituitary-adrenal axis (HPA) function were assessed in adult female and male Long-Evans rats. At 3 and 5 d of age, pups were administered endotoxin (Salmonella enteritidis, 0.05 mg/kg, i.p.) at a dose that provokes a rapid and sustained physiological response, but with no mortality. As adults, neonatally endotoxin-treated animals exhibited significantly greater adrenocorticotrophic hormone (ACTH) and corticosterone responses to restraint stress than controls. In addition, dexamethasone pretreatment was less effective in suppressing ACTH responses to restraint stress in endotoxin-treated animals than in controls, suggesting decreased negative-feedback sensitivity to glucocorticoids. Neonatal endotoxin treatment elevated resting-state median eminence levels of corticotropin-releasing hormone (CRH) and arginine vasopressin in adult male animals, and arginine vasopressin in both adult males and females. Neonatal exposure to endotoxin also increased CRH mRNA expression in the paraventricular nucleus of the hypothalamus of adult males, with no difference in females. Finally, glucocorticoid receptor density was reduced across a wide range of brain regions in the neonatal endotoxin-treated, adult animals. These data illustrate the interactive nature of immune and endocrine systems during development. It appears that endotoxin exposure during critical stages of development decreases glucocorticoid negative-feedback inhibition of ACTH secretagogue synthesis, thus increasing HPA responsiveness to stress. The implication of these findings is that exposure to gram-negative LPS in early life can alter the development of neural systems which govern endocrine responses to stress and may thereby predispose individuals to stress-related pathology.
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PMID:Neonatal endotoxin exposure alters the development of the hypothalamic-pituitary-adrenal axis: early illness and later responsivity to stress. 782 42

Familial glucocorticoid resistance (FGR) is a rare hereditary disorder characterized by hypercortisolism and the absence of stigmata of Cushing's syndrome. The inability of glucocorticoids to exert their effects on target tissues is compensated for by increases in circulating corticotropin (ACTH) and cortisol, the former causing excess secretion of both adrenal androgens and adrenal steroid-biosynthesis intermediates with salt-retaining activity. There is considerable variability in the clinical presentations of FGR ranging from asymptomatic, to isolated chronic fatigue and to hypertension with or without hypokalemic alkalosis or to hyperandrogenism, or both. In women, hyperandrogenism can result in acne, hirsutism, menstrual irregularities, oligoanovulation, and infertility; in men it may lead to infertility and in children to precocious puberty. The reported molecular defects in FGR, such as point mutations and a microdeletion of the glucocorticoid receptor (GR) gene, cause partial resistance by, respectively, compromising the function of the GR or decreasing its intracellular concentration in glucocorticoid target tissues. Complete glucocorticoid resistance is believed to be incompatible with life in humans. Hence, the glucocorticoid resistance cases reported have been partial and of variable degree. The extreme variability in the clinical manifestations of the disorder can, additionally, be explained by differing sensitivity of target tissues to mineralocorticoids or androgens or both, and perhaps by different biochemical defects of the glucocorticoid receptor, causing selective resistance of certain glucocorticoid responses in specific tissues. Isolated tissue-resistance from a somatic mutation of the GR in a corticotropinoma from a patient with Nelson's syndrome was also found, suggesting that this may be a mechanism of tumorigenesis. There is additional evidence that defects of GR function can appear surreptitiously in a variety of clinical conditions, suggesting that glucocorticoid resistance in humans may be involved in the pathogenesis and/or clinical picture of a plethora of disease states, of which FGR is the archetype.
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PMID:Glucocorticosteroid resistance in humans. Elucidation of the molecular mechanisms and implications for pathophysiology. 782 90

The biological effects of pituitary adenylate cyclase-activating peptide (PACAP) 27 and 38 on peptide secretion and gene regulation were studied in the mouse corticotrope-derived cell line AtT20. Treatment of these cells with PACAP 27/38 led to a dose-dependent increase in cAMP content and ACTH accumulation in the medium with an apparent ED50 value close to 10(-9) M. The genomic effects of PACAP were first investigated by using a reporter gene containing a cAMP responsive element (CRE: TGACGTCA) PACAP 27/38 stimulate transcription from this construction and the effect is further increased when cells are cotreated with the phosphodiesterase inhibitor rolipram. Furthermore, we show by measuring nuclear heterologous proopiomelanocortin (POMC) RNA levels or by using a reporter gene containing the POMC promoter region, that PACAP stimulates POMC transcription. This transcriptional stimulation is mediated by the cAMP-dependent protein kinase (PKA) since genetic inactivation of PKA by a dominant inhibitory mutant of this enzyme completely abolished the effect of PACAP on POMC transcription. Finally, we show that the transcriptional stimulation of POMC by PACAP is repressed by the glucocorticoid receptor agonist dexamethasone. Taken together, these data suggest that PACAP is a hypophysiotropic hormone that exert similar if not identical functions as corticotropin-releasing hormone (CRH) on corticotrope cells.
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PMID:Pituitary adenyl cyclase-activating peptide: a hypophysiotropic factor that stimulates proopiomelanocortin gene transcription, and proopiomelanocortin-derived peptide secretion in corticotropic cells. 784 39

By means of in situ hybridization and immunocytochemical techniques it has been possible to follow the prenatal development of glucocorticoid receptor (GR) messenger RNA (mRNA) expression and GR immunoreactivity (IR) in the rat brain from embryonic day (E) 15 to 22. A 700-base-pair GR cDNA fragment was used for RNA probe generation. In the immunocytochemical analysis a mouse monoclonal antibody (IgG2a) against the rat liver GR was used in combination with the indirect fluorescence technique or the avidin-biotin immunoperoxidase method. At E15 till E22 a moderate to strong GR mRNA signal was observed within the neuro-epithelium from the medulla oblongata to the telencephalon. A moderate to strong labelling was also present within the paraventricular hypothalamic nucleus, the arcuate nucleus, the nucleus raphe magnus, the nucleus raphe obscurus and the locus coeruleus. In these areas a weak to moderate nuclear GR IR developed in nerve cells 1 or 2 days after the appearance of the GR mRNA signal. From E15 the adenohypophysis showed the strongest expression of GR mRNA. At E17 a strong GR IR was especially demonstrated in the nuclei of many pituitary cells, some exhibiting adrenocorticotropin IR. The results open up the possibility that there exist active GR in embryonic life capable of regulating proliferation events within the adenohypophysis and the neuro-epithelia of the brain. This embryonic GR may modulate the development of inter alia neuro-endocrine areas such as the paraventricular and arcuate nuclei and arousal-related areas such as the central 5-hydroxytryptamine and noradrenaline neuronal systems. Provided that this embryonic GR is capable of becoming activated by glucocorticoids in fetal life, it may mediate several neurochemical and behavioural impairments caused by prenatal stress.
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PMID:Prenatal development of glucocorticoid receptor gene expression and immunoreactivity in the rat brain and pituitary gland: a combined in situ hybridization and immunocytochemical analysis. 823 69

Glucocorticoid resistance results from the partial, albeit apparently generalized, inability of glucocorticoids to exert their effects on target tissues. The condition is associated with compensatory increases in circulating pituitary corticotropin and cortisol, with the former causing excess secretion of both adrenal androgens and adrenal steroid biosynthesis intermediates with salt-retaining activity. The manifestations of glucocorticoid resistance vary from chronic fatigue (perhaps a result of glucocorticoid deficiency in the central nervous system) to various degrees of hypertension with or without hypokalemic alkalosis or hyperandrogenism, or both, caused by increased cortisol and other salt-retaining steroids and adrenal androgens, respectively. In women, hyperandrogenism can result in acne, hirsutism, menstrual irregularities, oligoanovulation, and infertility; in men, it may lead to infertility and in children, to precocious puberty. Different molecular defects, such as point mutations or a microdeletion of the highly conserved glucocorticoid receptor gene, alter the functional characteristics or concentrations of the intracellular receptor and appear to cause glucocorticoid resistance. The extreme variability in the clinical manifestations of glucocorticoid resistance and its mimicry of many common diseases can be explained by the overall degree of glucocorticoid resistance, differing sensitivity of target tissues to mineralocorticoids or androgens or both, and perhaps different biochemical defects of the glucocorticoid receptor, with selective resistance of certain glucocorticoid responses in specific tissues. The various different symptoms of classic glucocorticoid resistance and the theoretical potential of this condition to appear surreptitiously emphasize the importance of the glucocorticoid receptor in the pathogenesis of human disease.
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PMID:Syndromes of glucocorticoid resistance. 818 39

To differentiate between ectopic ACTH syndrome and Cushing's disease, gene expression of corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), and glucocorticoid receptor was examined in 10 pituitary adenomas (Cushing's disease) and in 10 ectopic ACTH-producing tumors. CRH increased plasma ACTH levels in all patients with Cushing's disease and in five patients with ectopic ACTH syndrome whose tumors contained CRH and CRH mRNA. In five CRH nonresponders, CRH was not detected in tumors that contained no CRH mRNA or that contained only long-size CRH mRNA. Dexamethasone (Dex) decreased plasma ACTH levels in all patients with Cushing's disease and in three patients with ectopic ACTH-producing bronchial carcinoid. These tumors contained glucocorticoid receptor mRNA. CRH increased and Dex decreased ACTH release and POMC mRNA levels in pituitary adenoma and bronchial carcinoid cells. PMA increased POMC mRNA levels only in carcinoid cells. These results reveal characteristics of ectopic ACTH-producing tumors: long-size CRH mRNA and PMA-induced POMC gene expression. In addition, there are two ectopic ACTH syndrome subtypes: tumors containing ACTH with CRH (CRH responder) and tumors without CRH. Dex decreases ACTH release and POMC mRNA levels in some bronchial carcinoids. Therefore, CRH and Dex tests have limited usefulness in differentiating between Cushing's disease and ectopic ACTH syndrome.
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PMID:Corticotropin-releasing hormone, proopiomelanocortin, and glucocorticoid receptor gene expression in adrenocorticotropin-producing tumors in vitro. 825 33


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