Neuroendocrine Effects on Adrenal Hormone Secretion in Carp (Cyprinus carpio)

The responses of interrenal and chromaffin tissues of carp to acetylcholine (Ach) and its agonists/antagonists were studied in anin vitroperifusion system of head kidney. There was a dose-dependent release of epinephrine and norepinephrine to Ach between 0.01 and 100 mMadded for 15 min to the incubation medium. Cortisol secretion was also stimulated, but the response peaked at 1.0 mMAch and was attenuated with 10 or 100 mMAch. The maximal release occurred about 30 min after addition of the transmitter. Nicotine stimulated the catecholamines, but had no effect on cortisol, while carbamylcholine, a nicotinic agonist, increased both the catecholamines and cortisol. Muscarine increased cortisol secretion, but affected catecholamines only at higher doses. In contrast, pilocarpine, a muscarinic agonist, stimulated catecholamines more than cortisol. Atropine was not antagonistic, rather it increased the secretion of catecholamines in a dose-dependent manner, and inhibited the release of cortisol. It is concluded that both tissues are influenced by the autonomic nervous system, with the sympathetic system acting on chromaffin cells and the parasympathetic system acting on interrenal cells. However, the nerve supply cannot clearly be defined by agonists or antagonists as in mammals. There is evidence for paracrine effects, e.g., catecholamines inhibit cortisol release and cortisol influences catecholamine secretion.     

Dyslipidaemia in Adult Growth Hormone (GH) Deficiency and the Effect of GH Replacement Therapy: A Review.

Adult growth hormone (GH) deficiency is associated with a lipid profile known to be related to atherosclerosis. GH replacement therapy improves the lipid profile with the exception of lipoprotein (a) concentrations, which tend to increase after GH therapy. Plasma lipid concentrations depend on its plasma carriers, the lipoproteins. Possible mechanisms involved in the dyslipidaemia of GH-deficient patients and the effects of GH replacement therapy are discussed with a special focus on hepatic lipoprotein metabolism.     

Growth Hormone (GH) Secretion During Nocturnal Sleep and after Clonidine in Patients with Essential Hypertension

In order to estimate the neuroendocrine function of the central nervous system eventually leading to growth hormone (GH) secretion in essential hypertension, 17 patients with mild arterial hypertension (7 obese and 10 with normal body weight) were examined. The control group consisted of 16 normotensive volunteers (7 obese and 9 with normal body weight). The GH secretion was determined by radioimmunoassay during nocturnal sleep. In all the subjects, the serum GH was also measured after placebo and after the centrally acting alphas-adrenergic agonist-clonidine administered i.v. in a dose of 0.15 mg. The fasting serum insulin concentration was also measured in all the subjects. Clonidine decreased the mean arterial pressure in all the subjects investigated. However, in response to clonidine an increase in GH secretion in all hypertensive and normotensive cases with normal body weight was demonstrated, whereas in all obese hypertensive and normotensive patients no significant GH rise was found. It indicates that inhibition of GH secretion in patients with essential hypertension is related to coexistent obesity rather than with that of arterial hypertension. A strong (r=0.76) and ignificant (P<0.0005) correlation demoonstrated between the maximal GH concentration during the moctural sleep and after clonidine suggests that the mechanism of GH inhinition in response to both these stimuli is similar and it probably is related to the inhibition of neurohormonal secretion of the growth hornone releasing factor (GRF). However, the negative correlation between the fasting insulin concentration and GH response to closidine shown in obese subjects only,points to a more complex mechanism of GH inhibition in obesity.     

Circadian rhythms: a regulator of gastrointestinal health and dysfunction

Introduction: Circadian rhythms regulate much of gastrointestinal physiology including cell proliferation, motility, digestion, absorption, and electrolyte balance. Disruption of circadian rhythms can have adverse consequences including the promotion of and/or exacerbation of a wide variety of gastrointestinal disorders and diseases.

Areas covered: In this review, we evaluate some of the many gastrointestinal functions that are regulated by circadian rhythms and how dysregulation of these functions may contribute to disease. This review also discusses some common gastrointestinal disorders that are known to be influenced by circadian rhythms as well as speculation about the mechanisms by which circadian rhythm disruption promotes dysfunction and disease pathogenesis. We discuss how knowledge of circadian rhythms and the advent of chrono-nutrition, chrono-pharmacology, and chrono-therapeutics might influence clinical practice.

Expert opinion: As our knowledge of circadian biology increases, it may be possible to incorporate strategies that take advantage of circadian rhythms and chronotherapy to prevent and/or treat disease.     

Effects of Pinealectomy and Aging on the Serum Corticosterone Circadian Rhythm in Rats

Male Sprague-Dawley rats were housed in alternate light/dark conditions (light on, 7:00 AM, light off, 7:00 PM). Corticosterone was determined by radioimmunoassay from blood samples that were obtained by tail clip at 4-h intervals. Pinealectomized animals have shown significant increase of corticosterone levels at 7:00 AM, 11:00 AM and 7:00 PM in comparison with 2-month-old intact rats. There were no differences in serum corticosterone rhythm between 24-month-old and pinealectomized animals. Twelve-month-old rats have shown significant increase of corticosterone levels at 7:00 and 11:00 AM in comparison with 2-month-old animals. The age-associated increase of serum corticosterone and the similarity between serum corticosterone circadian rhythm in aged and pinealectomized animals suggest that an age-related decrease in melatonin production [Reiter et al., 1981] may contribute to age related changes of hypothalamic-pituitary adrenal axis regulation.     

针刺治疗对慢性疲劳综合征患者血促肾上腺皮质激素及皮质醇的影响

目的以针灸气街理论为指导,观察针刺对慢性疲劳综合征(CFS)患者血促肾上腺皮质激素(ACTH)及皮质醇(COR)水平的影响。方法将90例CFS患者随机分为观察组(45例)与对照组(45例)。观察组针刺人迎、风府、百会;对照组采用5%葡萄糖250mL加参麦注射液20mL静脉输注。比较两组治疗前后CFS患者ACTH及COR水平变化,并进行统计学分析。结果两组患者ACTH及COR水平均有上升,治疗后观察组血ATCH为(51.08±24.29)pg/mL、COR(336.86±242.72)pg/mL,明显高于对照组(P<0.05)。结论针刺治疗能提高气阴两虚型CFS患者血ATCH、COR水平,治疗效果明显优于参麦注射液。     

Withdrawal of long-term physiological growth hormone (GH) administration: differential effects on bone density and body composition in men with adult-onset GH deficiency

Adults with acquired GH deficiency (GHD) have been shown to have osteopenia associated with a 3-fold increase in fracture risk and exhibit increased body fat and decreased lean mass. Replacement of GH results in decreased fat mass, increased lean mass, and increased bone mineral density (BMD). The possible differential effect of withdrawal of GH replacement on body composition compartments and regional bone mass is not known. We performed a randomized, single blind, placebo-controlled 36-month cross-over study of GH vs. placebo (PL) in adults with GHD and now report the effect of withdrawal of GH on percent body fat, lean mass, and bone density, as measured by dual energy x-ray absorptiometry. Forty men (median age, 51 yr; range, 24-64 yr) with pituitary disease and peak serum GH levels under 5 microg/L in response to two pharmacological stimuli were randomized to GH therapy (starting dose, 10 microg/kg x day, final dose 4 microg/kg x day) vs. PL for 18 months. Replacement was provided in a physiological range by adjusting GH doses according to serum insulin-like growth factor I levels. After discontinuation of GH, body fat increased significantly (mean +/- SEM, 3.18 +/- 0.44%; P = 0.0001) and returned to baseline. Lean mass decreased significantly (mean loss, 2133 +/- 539 g; P = 0.0016), but remained slightly higher (1276 +/- 502 g above baseline; P = 0.0258) than at study initiation. In contrast to the effect on body composition, BMD did not reverse toward pretreatment baseline after discontinuation of GH. Bone density at the hip continued to rise during PL administration, showing a significant increase (0.0014 +/- 0.00042, g/cm2 x month; P = 0.005) between months 18-36. Every bone site except two (radial BMD and total bone mineral content), including those without a significant increase in BMD during the 18 months of GH administration, showed a net increase over the entire 36 months. Therefore, there is a critical differential response of the duration of GH action on different body composition compartments. Physiological GH administration has a persistent effect on bone mass 18 months after discontinuation of GH.     

Alloxan-Induced Diabetes and the Pineal Gland: Differential Effects on the Levels of Pineal N-Acetylserotonin, Pineal Melatonin, and Serum Melatonin

Effects of alloxan treatment on the levels of pineal melatonin, pineal N-acetylserotonin, and serum melatonin were investigated. Male rats were housed under a photoperiod of 12 h light: 12 h darkness and a temperature of 23 +/- 3 degrees C. Three weeks after alloxan (170 mg/kg) or carrier injection (s.c.), the animals were killed at mid-light (1200 h) and mid-dark (2400 h). Pineal and serum indoles were extracted and quantified by radioimmunoassays. It was found that pineal levels of N-acetylserotonin in the diabetic rats were significantly higher (P less than 0.05) than those of the controls. Conversely, pineal and serum levels of melatonin in the control rats were significantly higher (P less than 0.05) than those of the alloxan-induced diabetics. Our results suggest that alloxan-induced diabetes may decrease pineal melatonin synthesis in rats by reducing the activity of hydroxyindole-O-methyltransferase, resulting in a decrease in pineal melatonin secretion.     

Growth hormone (GH) secretion in the conscious rat: negative feedback of GH on its own release

The negative-feedback effects of GH on its own secretion were studied in conscious male and female rats bearing indwelling double-bore venous cannulae. Intravenous infusions of human GH (hGH; 20-60 micrograms/h) or somatostatin (SS; 10 micrograms/h) were given while frequent serial microsamples of blood were withdrawn using an automatic blood-sampling system. In both sexes, i.v. infusions of hGH for 6 h inhibited endogenous GH secretory pulses, with a slow onset of the inhibition. There was no rebound GH secretion immediately following the removal of the hGH infusion, but spontaneous GH secretion gradually returned to normal. Infusions of hGH did not inhibit the pituitary GH response to repeated GH-releasing factor (GRF) injections (1 microgram) given i.v. every 40 min to female rats. By contrast, infusions of SS, which also blocked spontaneous GH release, dramatically reduced the GH responses to serial GRF injections. When SS Infusions were stopped, the subsequent GRF-induced GH secretory responses were enhanced. These results show that GH can inhibit its own release when given by i.v. infusion to conscious male and female rats. Since GH responses to GRF are maintained during a GH infusion, the feedback effect of GH is unlikely to be exerted directly on the pituitary or by increasing SS release. Our results are consistent with the idea that GH feedback in the conscious rat involves an inhibition of GRF release.     

Dose-response study of biosynthetic human growth hormone (GH) in GH-deficient children: effects on auxological and biochemical parameters. Dutch Growth Hormone Working Group.

A multicenter dose-response study evaluated the effect of two different doses of biosynthetic GH on auxological and biochemical parameters in 38 prepubertal children with GH deficiency (GHD). Twenty-one were newly diagnosed, while 17 transfer patients had been on GH treatment for at least 1 yr before the study. New and transfer patients alike were treated with either 2 or 4 IU GH/m2.day sc. At evaluation all new patients had completed 1 yr of treatment, while transfers had completed 2 yr of treatment under study. In the new patients both doses resulted in a significant increase in height velocity (HV) and height SD score (SDS), with comparable bone maturation. After correction for the severity of GHD, the increase in HV SDS was significantly greater with 4 IU than with 2 IU (P less than 0.01). In the transfer patients HV, height SDS, and predicted adult height only increased significantly with 4 IU (P less than 0.05). Bone maturation was comparable for the two doses. There was a significant correlation between first year growth response and GH dose. In the new patients, the plasma insulin-like growth factor-I (IGF-I) concentration increased significantly without a significant difference between dosage groups. There was a positive correlation between growth response and increment of plasma IGF-I SDS. In new and transfer patients alike, above normal plasma IGF-I levels were observed, particularly with 4 IU. Hemoglobin-A1 remained constant with both GH doses in both groups, while cholesterol and LDL levels tended to decrease. In the new patients, the mean apolipoprotein-A1 level was lower than the control value after 1 yr on 4 IU GH. Treatment with 4 IU GH/m2.day led to a greater growth response than a dose of 2 IU in newly diagnosed as well as previously treated GHD patients. Bone maturation was comparable for both doses. No adverse effects were observed with the higher GH dose, but the long term effects on IGF-I and lipid metabolism need further attention.     

Growth hormone (GH) replacement therapy in GH deficient adults: predictors of one-year metabolic and clinical response.

OBJECTIVE: This study investigated whether baseline status could predict the responsiveness to one-year growth hormone (GH) replacement therapy in adult GH deficient (GHD) patients. DESIGN: A total of 380 European patients with adult onset GHD due to non-functioning pituitary adenoma that had been enrolled in Pfizer International Metabolic Database (KIMS), and that had completed one year of GH replacement therapy within KIMS, were studied. RESULTS: The mean initial dose of GH was 0.22 (SEM 0.01) mg/day and after one year, the mean dose was 0.36 (0.01) mg/day. The mean insulin-like growth factor-I (IGF-I) SD score increased from -1.75 (0.08) at baseline to 0.47 (0.05) after one year. Quality of life (QoL)-Assessment of GHD in Adults (QoL-AGHDA), waist circumference, waist:hip ratio, and serum lipid pattern improved. Women received a higher dose of GH than men after one year, and demonstrated similar treatment response. In multiple stepwise forward regression analyses, the one-year changes in QoL-AGHDA score, waist:hip ratio, and serum low density lipoprotein-cholesterol (LDL-C) level correlated inversely with the baseline values of the same variable. In addition, the change after one year in QoL-AGHDA score correlated inversely with duration of hypopituitarism and baseline serum high density lipoprotein-cholesterol (HDL-C) level, and the change in waist:hip ratio correlated inversely, although more weakly, with baseline serum HDL-C level and UK citizenship and positively with baseline waist circumference and the initial GH dose. The change in serum LDL-C level additionally correlated inversely with the mean GH dose and duration of hypopituitarism and positively with UK citizenship. CONCLUSIONS: Baseline status could, with moderate strength, predict the responsiveness in the same variable whereas it could not, or only weakly, predict the response in other variables. Therefore, when the decision to start GH replacement is undertaken, as many outcome variables as possible should be evaluated in order to adequately evaluate the likelihood of clinical benefit. Finally, women have a similar response to GH replacement as men when individualised GH dosing schedules are employed and should therefore be selected for GH therapy to a similar extent.     

Growth Hormone (GH) Peaks versus Areas Under the Curve in the Diagnosis of Adult GH Deficiency: Analysis of the Variables Provided by the GHRH + GHRP-6 Test

BACKGROUND: The diagnosis of growth hormone deficiency (GHD) relies on provocative tests of GH reserve. The aim in these tests is to obtain an objective, biochemical-based, measure of gland function, but clinicians and researchers rely on the GH peak, as a surrogate of the 24-hour pituitary secretion. However, on a mathematical basis the area under the secretory curve (AUC) should be more valid for this evaluation. OBJECTIVES: To validate which variable provided by a provocative test of GH secretion is mathematically more robust for supporting the clinical diagnosis. Adult normal subjects and GHD patients were challenged with the combined stimulus GHRH + GHRP-6. The diagnostic efficacy of the GH peak, and the AUC were compared by the receiver operating characteristic (ROC) curve methodology. PATIENTS AND METHODS: 146 patients with GH deficiency due to organic pituitary disease and 184 healthy subjects were administered GHRH 1 microg/Kg iv, plus GHRP-6 1 microg/Kg iv, and GH was determined. Four variables were studied: (a) the GH peak; (b) the "standard" AUC, (c) the "stimulated" AUC and (d) the basal value, used as internal control. RESULTS: Under ROC curve analysis, the basal variable was devoid of diagnostic capability, while the other variables performed strikingly well, the ROC curve area for the GH peak was 0.9997; and for the AUC 0.9993, with no statistical differences. CONCLUSIONS: The variables provided by measuring the GH peak and the area under the curve were similarly effective for diagnosis, although on clinical grounds, the peak was more convenient as needed no calculation. If results for other test were similar the time-honored method of measuring the GH peak could be considered mathematically validated.     

Growth hormone (GH)-dependent hepatic GH receptors in the Japanese eel, Anguilla japonica: effects of hypophysectomy and GH injection.

Control mechanisms of growth hormone (GH) receptors in the eel liver were examined by following the time course of changes in total (MgCl2-treated membranes) and free (untreated membranes) GH-binding sites after hypophysectomy and replacement therapy with homologous GH. Both total and free binding sites decreased significantly 1 week after hypophysectomy. Scatchard analysis indicated that the reduction in GH receptors was primarily due to a decrease in the number of binding sites, rather than to a change in binding affinity. When recombinant eel GH was injected intramuscularly into hypophysectomized eels (2 micrograms/g body wt), plasma GH concentration increased to a maximal value after 10 hr and decreased to the initial level by 72 hr. Free binding sites decreased to a minimal value 24 hr after the injection and returned to the initial level after 72 hr. The reduction in free binding sites seems to be due to occupation of GH receptors. Total binding sites increased gradually to almost twofold over those of the controls 5 days after the injection, the increase being due to an increase in the binding capacity. GH appears to be importantly involved in inducing and maintaining its own receptors in the eel liver.     

Effects of Chronic Alcohol on Immunoreactive β-Endorphin Secretion from Hypothalamic Neurons in Primary Cultures: Evidence for Alcohol Tolerance, Withdrawal, and Sensitization Responses

Endogenous opioid peptides are known to be involved in the alcohol tolerance and dependence following alcohol abuse. However, the cellular mechanisms involved in the ethanol tolerance and dependence are not well established. We have previously shown that low concentrations of ethanol stimulate immunoreactive β-endorphin (IR-β-EP) release from the cultured hypothalamic neurons and that chronic ethanol exposure desensitizes these neurons to ethanol challenges. In this study, we determined the IR-β-EP response to increasing doses of ethanol during the desensitizing phase of moderate ethanol doses to test whether the cultured IR-β-EP-secreting neurons develop tolerance to ethanol following constant exposure. We also determined IR-β-EP responses following withdrawal from chronic ethanol challenge and compared the IR-β-EP secretory response to various doses of ethanol in ethanol-naive and ethanol-preexposed cultures. The IR-β-EP responses to increasing doses of ethanol (50-150 mM) were markedly reduced in the cultures preexposed to a 50 mM dose of ethanol when compared with those that were naive to ethanol. The ethanol-exposed cultures showed hypersecretion of IR-β-EP after removal from 48 hr of constant ethanol, as compared with ethanol-naive cultures. When ethanol-preexposed cultures were challenged with various doses of ethanol 4 days after ethanol withdrawal, the cultures showed higher IR-β-EP secretory responses than did the ethanol-naive cultures. These data suggest that IR-β-EP secretory neurons in primary cultures develop tolerance to chronic ethanol, show withdrawal response after removal of chronic ethanol exposure, and develop sensitization following repeated ethanol challenges.     

Growth hormone (GH) deficiency treatment in children: comparison between uses of pen versus bottles/syringes on GH administration

The aim of this study was to compare two preparations of recombinant human GH (rGH) in the treatment of GH deficient patients. Ten prepubertal GH-deficient children were followed during 6 months. They received injections with syringe for 3 months, followed by pen administration for the subsequent 3 months. Acceptability was evaluated through a questionnaire. Waste of medication was calculated by the difference between the number of used bottles or refills and the calculated amount for the period. Treatment response was evaluated by SDS gain of height measured each 3 months. After 6 months, 90% of patients/family members declared they preferred the pen regarding technical facility and local pain, and all patients considered the pen easier to transport and store. The waste of medication was lower with pen administration, as was the final cost. We concluded that pen-administered rGH treatment is more convenient, better accepted by the patients, and leads to less waste of medication when compared to the syringe administration.