Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:040593 (CRH)
 2,662 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Corticosteroid type I and II receptors mediate the negative feedback effects of these hormones at various central nervous system sites involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. To examine the effects of chronic treatment with dexamethasone (DEX), a type 2 receptor agonist, on the regulation of this axis, male Sprague-Dawley rats weighing 200-250 g were given daily injections of DEX for 1,2,3, and 4 weeks or were treated with a subcutaneously implanted DEX-releasing minipump for one week. At the end of treatment, the animals were weighed and brains and truncal blood were collected. Daily intermittent DEX treatment reduced the body weight of the rats in a time-dependent fashion, but had little or no effect on their wet brain weight. Plasma ACTH and corticosterone, measured by RIA, were fully suppressed after one week of intermittent treatment and did not show any further reduction in rats treated for longer periods. In these animals, the content of immunoreactive corticotropin-releasing hormone (iCRH), arginine vasopressin (AVP), ACTH and beta-endorphin (beta-EP) in the hypothalamus, hippocampus, cerebral cortex and cerebellum and pituitary ACTH content did not show any difference compared to vehicle-treated rats. In contrast, continuous DEX treatment increased iCRH content in the cortex, reduced AVP content in the cerebellum, increased ACTH content in the hippocampus, decreased ACTH and beta-EP content in the hypothalamus, and reduced pituitary ACTH content. Hypothalami explanted from rats treated with DEX for one week released lower basal amounts of iCRH in vitro and did not respond to a maximally stimulatory concentration of serotonin (5-HT), a known CRH secretagogue. Continuous DEX administration suppressed also potassium chloride-induced iCRH release. Interestingly, hypothalami explanted from rats receiving daily injection of vehicle, but not from unhandled, untreated controls, did not respond to 5-HT with an increase of iCRH release in vitro. In conclusion, prolonged and continuous, but not intermittent, administration of DEX had a strong effect on brain neuropeptide content. Both regimens of DEX reduced the hypothalamic iCRH responsiveness to stimuli in vitro. Chronic handling also decreased the responsiveness of the hypothalamus to a stimulatory neurotransmitter and may confound the interpretation of data pertinent to inhibitory mechanisms.
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PMID:Hypothalamic and suprahypothalamic effects of prolonged treatment with dexamethasone in the rat. 165 Aug 4

We have used a sensitive radioimmunoassay to quantify and characterize PBMC-associated immunoreactive ACTH (ACTH-IR). Mean ACTH content of freshly isolated human PBMCs was 3.8 +/- 0.72 pg (SEM) per 10(6) cells. During 3 days of incubation ACTH-IR in conditioned media of control PBMCs increased significantly, p less than 0.02. Gel filtration chromatography revealed a minor peak of ACTH-IR coeluting with ACTH (1-39) and a major peak coeluting with ACTH (11-24). Treatment with 15 nM CRH did not alter the amount of ACTH-IR secreted or its gel pattern. Synthetic ACTH (11-24), was radioiodinated and was used for binding experiments that demonstrated specific high- and low-affinity binding sites for ACTH (11-24) on a human T cell line. These results add support for a role of ACTH and related peptides in immune regulatory systems and suggest that cell-specific post-translational processing of POMC may generate an expanding number of biologically active moieties.
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PMID:Quantification and characterization of ACTH-related peptides produced by human peripheral blood mononuclear cells. 165 66

The present study was designed to determine whether the baboon fetal pituitary at midgestation was responsive in utero to a bolus injection of CRH. On day 100 of gestation (term = day 184), baboons were anesthetized with halothane/nitrous oxide, the fetus was exteriorized, and a cannula was inserted into a fetal carotid artery. Five minutes later (experimental time zero), a fetal carotid blood sample was obtained, and saline (0.5 ml) with (n = 6) or without (n = 3) ovine CRH (100 ng estimated to equal 500 ng/kg BW) was then infused via the fetal carotid over a 3-min period. Fetal blood samples were taken 5, 15, 30, 45, and 60 min post-CRH/saline treatment and assayed for ACTH. Mean (+/- SE) pretreatment fetal plasma ACTH concentrations were similar in animals that subsequently received saline (26 +/- 3 pg/ml) or CRH (29 +/- 6 pg/ml). Fetal plasma ACTH remained constant after the infusion of saline. In contrast, CRH increased (P less than 0.05) fetal plasma ACTH within 5 min in six of six baboons to a value (58 +/- 12 pg/ml) that exceeded (P less than 0.05) the zero time value and the respective mean value (27 +/- 5 pg/ml) in saline-treated fetuses. Fetal plasma ACTH concentrations continued to rise in four of six baboons 15 min after CRH injection to a level (68 +/- 15 pg/ml) which exceeded that in saline controls (27 +/- 2 pg/ml). In fetuses treated with CRH, overall mean fetal plasma ACTH concentrations from 0-60 min increased at a rate (1.47 pg/min) greater (P less than 0.05) than that in fetuses injected with saline (0.07 pg/min). In contrast to the effects of intracarotid CRH injection, fetal plasma ACTH was not increased after the infusion of 100 ng CRH into a fetal antecubital vein of three additional animals. Collectively, these findings indicate that intracarotid injection of a bolus of CRH into the baboon fetus rapidly increased fetal plasma ACTH concentrations. Moreover, the site of action of CRH was presumably the fetal pituitary. Therefore, we suggest that the baboon fetal hypothalamic-pituitary axis at midgestation has the capacity to secrete ACTH in response to a challenge of CRH.
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PMID:Responsivity of the baboon fetal pituitary to corticotropin-releasing hormone in utero at midgestation. 165 49

Central release of CRH has recently been implicated in modulating natural killer cell (NK) activity independent of its role in activation of the hypothalamic-pituitary-adrenal axis. In the present study, NK- and interleukin-2 (IL-2)-activated NK cytotoxicity against K-562 target cells was examined in porcine lymphocytes cultured in vitro with ACTH or pig lymphocytes after iv or im ACTH administration. Physiological concentrations of porcine ACTH (10(-8)-10(-11) M) added to the culture medium had no direct influence on NK- or IL-2-stimulated NK cytotoxicity. In a second experiment four unrestrained pigs with indwelling catheters given an iv bolus of vehicle or ACTH (1 IU/kg BW) at 0800 h showed significantly elevated cortisol levels for 3 h after ACTH. Although serum cortisol had returned to baseline by 4 h after ACTH treatment, NK- and IL-2-stimulated NK cytotoxicity was dramatically elevated (P less than 0.01) compared to that in saline-injected controls. NK cytotoxicity in control pigs followed a diurnal pattern, with low morning and high evening cytotoxicity. Exogenous ACTH, given by bolus in the morning, prevented the normal morning decline in NK cytotoxicity. Because of this unexpected dramatic increase in NK- and IL-2-stimulated NK cytotoxicity in animals given ACTH, the experiment was replicated in two subsequent studies using 16 pigs (8 controls and 8 experimental) in each. Pigs were injected im with either ACTH (1 IU/kg BW) or an equivalent volume of saline at 0600 h. Two hours later, blood was collected by venipuncture to determine NK cytotoxicity and measure the cortisol response. As was observed in the previous study, NK- and IL-2-stimulated NK cytotoxicity was significantly greater (P less than 0.01) than that in saline-injected controls. In the final experiment pigs were given either ACTH (1 IU/kg BW) or an equivalent volume of saline at 1800 h. Two hours later, blood was collected by venipuncture to determine NK cytotoxicity and cortisol response. ACTH administered in the evening increased NK cytotoxicity, but the effect was only marginally significant and far less dramatic than in previous studies. Because ACTH had little effect on NK- and IL-2-stimulated NK activity in vitro, we hypothesize that the stimulatory effect of exogenous ACTH is mediated through an indirect mechanism, possibly through the suppression of central CRH as a result of elevated cortisol. This effect is more pronounced when the stimulatory dose of ACTH is given at a time in the circadian cycle when NK cytotoxicity is normally low.
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PMID:Adrenocorticotropin stimulates natural killer cell activity. 165 55

To explore the effects of repeated episodes of hypercortisolemia on hypothalamic-pituitary-adrenal axis regulation, we studied plasma ACTH and cortisol (CORT) responses to 100 micrograms human CRH (hCRH) in 10 dexamethasone (1.5 mg)-pretreated elderly endurance athletes who had abstained from physical activity for at least 48 h before testing and 13 sedentary age-matched controls. Basal CORT and ACTH levels were indistinguishable between runners and sedentary controls, whereas CORT responses to hCRH were significantly increased in endurance athletes, and ACTH responses tended to be higher in this group. Comparing the dexamethasone/hCRH test results of the runners with those of an age-matched sample of previously studied depressed patients (n = 9), similar hormone responses to CRH challenge were noted. The mechanisms underlying these alterations may either be a stepwise decrease in corticotropic sensitivity to the negative feedback signal leading to a switch to positive glucocorticoid feedback, an enhanced cosecretion of ACTH secretagogues such as vasopressin, or a combination of both. In conclusion, hypothalamic-pituitary-adrenal axis physiology seems to be determined by previous stressful events associated with hypercortisolemia, regardless of its etiology.
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PMID:Hypothalamic-pituitary-adrenal axis function in elderly endurance athletes. 165 55

We investigated the effects of age on pituitary-adrenocortical function in healthy young (21-38 yr, n = 11) vs. old (66-78 yr, n = 11) men by drawing frequent serial basal blood samples from 2000-0800 h for measurement of ACTH and cortisol, followed by an iv ovine CRH (oCRH) stimulation test. Subjects were readmitted at intervals and given increasing doses of oral dexamethasone (0.15, 0.3, 0.6, 1 mg) at midnight, followed by repeat blood sampling from 0400-0800 h and oCRH testing. We compared mean hormone levels for the entire 12-h and three component 4-h periods of the basal visit, and for each 4-h dexamethasone visit using the Mann-Whitney U test and repeated measures analysis of variance. Pulsatile secretion was characterized using the Pulsar computer program. Basal mean 12-h and 4-h ACTH and cortisol values did not differ with age (P greater than 0.1). Pulse analysis revealed no age change in the corresponding values for peak frequency, amplitude, or duration for either hormone examined. Increasing doses of dexamethasone produced progressive inhibition of mean ACTH and cortisol levels (P less than 0.001) as well as decreased (P less than 0.01) pulse frequency, amplitude, and duration with no age differences (P greater than 0.1). ACTH and cortisol responses to oCRH were progressively suppressed by increasing doses of dexamethasone (P less than 0.02) and did not differ between age groups (P greater than 0.3) except for a slightly higher peak cortisol response (P = 0.05) in the older men at the 0.3 mg dexamethasone dose. We conclude that basal and oCRH-stimulated ACTH and cortisol secretion, as well as sensitivity of the ACTH-cortisol axis to glucocorticoid feedback suppression, are essentially unaltered with age in healthy men.
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PMID:Spontaneous and glucocorticoid-inhibited adrenocorticotropic hormone and cortisol secretion are similar in healthy young and old men. 165 56

The availability of CRH for clinical use and the data so far generated by clinical investigators interested in its application to the problem of Cushing's syndrome have resulted in a new approach to the differential diagnosis of Cushing's syndrome (Fig. 2). Once the diagnosis of Cushing's syndrome is made with certainty, an initial separation into ACTH-dependent versus ACTH-independent categories is made on the basis of the plasma ACTH response to CRH. Plasma ACTH levels in excess of 10 pg/mL imply an ACTH-dependent process. Patients with an ACTH-dependent process are then divided into eutopic versus ectopic sources on the basis of the central to peripheral gradient of ACTH measured in the inferior petrosal sinuses simultaneously 3 to 5 minutes after the administration of CRH, 1 microgram/kg. The average post-CRH gradient in patients with eutopic ACTH-dependent Cushing's syndrome is 50. The lower bound is 3.3. Ectopic sources have a gradient of less than 2. Patients with ACTH-independent Cushing's syndrome can be confidently evaluated with imaging techniques, such as CT or MRI, looking for adrenal neoplasm or the "normal to small" glands characteristic of micronodular adrenal dysplasia.
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PMID:Corticotropin-releasing hormone testing in pituitary disease. 165 35

We studied four patients with adrenocorticotropic hormone (ACTH)-independent hypercortisolism due to bilateral massive enlargement of the adrenal glands. The combined weight of the adrenal glands ranged from 69 to 149 g and the adrenal cortex was replaced in three of four patients by multiple nodules ranging from microscopic to 4 cm in diameter. One patient had massive diffuse enlargement. All patients had low or undetectable levels of serum ACTH, absence of petrosal sinus to peripheral gradients of ACTH in bilateral samples from the inferior petrosal sinuses before and after stimulation by corticotropin releasing hormone, and absence of an adenoma on MR imaging of the pituitary gland. The marked degree of adrenocortical enlargement and absence of ACTH dependency separates this massive macronodular disease from the more common ACTH-dependent macronodular hyperplasia encountered in older patients with pituitary-dependent Cushing disease. All patients required bilateral adrenalectomy to control hypercortisolism. We present the spectrum of nodular adrenal disease associated with hypercortisolism and a differential diagnosis based on morphologic criteria.
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PMID:CT and MR imaging of massive macronodular adrenocortical disease: a rare cause of autonomous primary adrenal hypercortisolism. 165 80

Subnormal free T4 index (FT4I) values (less than 80) with inappropriately normal serum TSH concentrations that could not be attributed to illness or drugs were found in 2.5% of ambulating elderly clinic patients. Six such individuals (three men and three women, aged 68.8 +/- 4.8 yr) were selected for their persistent thyroid test abnormalities and were sex and age matched to six subjects (67.7 +/- 4.9 yr) with normal FT4I (greater than 90) and TSH levels. The former also had low serum total T4 (TT4) and rT3 (TrT3) concentrations, but total T3 (TT3) and basal TSH values were normal and did not differ between the groups. Responses of ACTH, LH, FSH, TSH, and PRL to stimulation with CRH, GnRH, and TRH showed no differences between the two groups, indicating that the normal TSH concentration, inappropriate for the low FT4I level, is not due to generalized hypothalamic or pituitary dysfunction. Administration of 3 g iopanoic acid (IOP) daily for 3 days produced significant increases in the TT4 and TrT3 concentrations to the same degree in both groups. Also, in both groups the IOP-induced suppression of T4 to T3 conversion in the pituitary gland provoked similar increases in basal TSH (280 +/- 47% and 288 +/- 33%) and TSH secretion in response to TRH (173 +/- 7% and 156 +/- 13%). These results indicate that the low FT4I is not the consequence of reduced pituitary TSH reserve. In addition, evidence for normal thyroid gland reserve and the secretion of TSH of normal biological activity was obtained by comparing the acute iodothyronine responses to TRH-induced TSH release in both groups. It is concluded that the normal serum TSH concentration, inappropriate for the low FT4I value in some elderly subjects, is due to an apparent resetting of the thyroid hormone feedback regulation threshold of TSH secretion. It may, in turn, be the result of enhanced pituitary conversion of T4 to T3 or increased T4 uptake by the thyrotrophs.
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PMID:Low serum free thyroxine index in ambulating elderly is due to a resetting of the threshold of thyrotropin feedback suppression. 165 84

The role of alpha-1 adrenergic mechanism in the shaking stress-induced adrenocorticotropic hormone (ACTH), and plasma noradrenaline secretion and pressor response were investigated using conscious rats. We also studied whether or not central corticotropin releasing hormone (CRH) is involved in the shaking stress-induced ACTH secretion. The shaking stress caused significant elevations of plasma ACTH, noradrenaline, and systolic blood pressure. Intra-third ventricular administration of alpha-1 adrenergic blocker, bunazosin, inhibited the shaking stress-induced ACTH secretion, but did not alter stress-induced noradrenaline secretion and pressor response. Furthermore, intra-third ventricular administration of CRH antagonist, alpha-helical CRH, significantly attenuated stress-induced ACTH secretion. These results indicate that alpha-1 adrenergic pathway and CRH at least partly mediate the shaking stress-induced ACTH secretion.
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PMID:A role of central alpha-1 adrenergic mechanism in shaking stress-induced ACTH and noradrenaline secretion. 165 19


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