Ghrelin alone or co-administered with GHRH or CRH increases non-REM sleep and decreases REM sleep in young males.

Ghrelin activates the somatotropic and the hypothalamic-pituitary-adrenal axes, being crucially involved in sleep regulation. Simplified, growth hormone releasing hormone (GHRH) increases slow-wave sleep and REM sleep in males, whilst corticotropin-releasing hormone (CRH) increases wakefulness and decreases REM sleep. Ghrelin's role in sleep regulation and particularly its interactions with GHRH and CRH are not entirely clear. We aimed to elucidate the interactions between ghrelin, GHRH and CRH in sleep regulation and the secretion of cortisol and GH. Nocturnal GH and cortisol secretion and polysomnographies were determined in 10 healthy males (25.7+/-3.0 years) four times, receiving placebo (A), ghrelin (B), ghrelin and GHRH (C), or ghrelin and CRH (D) at 22:00, 23:00, 00:00, and 01:00h, in this single-blind, randomized, cross-over study. Non-REM sleep was significantly (p<0.05) increased in all verum conditions (mean+/-SEM: B: 355.3+/-7.4; C: 365.4+/-8.1; D: 371.4+/-3.9min) compared to placebo (336.3+/-6.8min). REM sleep was decreased (B: 84.3+/-4.2 [p<0.1]; C: 74.2+/-7.0 [p<0.05]; D: 80.4+/-2.7min [p<0.05]) compared to placebo (100.9+/-8.3). CRH+ghrelin decreased the time spent awake and enhanced the sleep efficiency; furthermore, the REM latency was decreased compared to the other treatment conditions. CRH enhanced the ghrelin-induced cortisol secretion but had no relevant effect on GH secretion. In turn, GHRH enhanced the ghrelin-induced GH secretion but had no effect on cortisol secretion. In conclusion, ghrelin exhibited distinct sleep effects, which tended to be enhanced by both GHRH and CRH. CRH had sleep-improving and REM permissive effects when co-administered with ghrelin, being in contrast to the effect of CRH alone in previous studies.

Systemic growth hormone-releasing hormone (GHRH) impairs sleep in healthy young women.

In young male subjects peripherally administered growth hormone-releasing hormone (GHRH) enhances GH and slow wave sleep (SWS) and blunts cortisol. In contrast, in a sample of females 19-76-year old, GHRH impairs sleep and enhances adrenocorticotropic hormone (ACTH) and cortisol. In the latter study, the days of investigation were not adapted to the menstrual cycle and premenopausal and postmenopausal women as well were included. Placebo and GHRH were given during consecutive nights. In order to confirm or reject the sexual dimorphism of the effects of GHRH on sleep we applied an improved study design. In the present study we examined the effect of pulsatile administration of two dosages of GHRH (4x25 or 4x50 microg intravenously, respectively) on sleep electroencephalogram (EEG) and nocturnal hormone secretion in healthy young women according to a randomized schedule. To rule out the influence of gonadal hormone activity, the study was adapted to the phase of the menstrual cycle and was performed at 4-6th day of menstrual cycle. A carry-over effect was excluded by the interval of at least 4 weeks between examinations. Compared to placebo rapid-eye-movement sleep decreased during the first half of the night after 4x25 microg GHRH and sleep stage 4 decreased after 4x50 microg GHRH. After both dosages GH increased whereas ACTH and cortisol remained unchanged. This study confirms that systemic GHRH impairs sleep in women.

Altered nocturnal growth hormone (GH) secretion in obsessive compulsive disorder.

Nocturnal patterns of growth hormone (GH) in obsessive compulsive disorder (OCD), which is physiologically released predominantly during the first half of night, have not been reported. However, altered GH responses to pharmacological challenges suggest a disturbed function of the somatotropic axis in OCD. In this study, nine inpatients with a DSM-IV diagnosis of OCD without comorbid major depression (Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score >15; HAMD-21 total score 16) and 9 healthy matched controls were included. Blood of patients (7 males, 31.8+/-9.3 years, Y-BOCS: 27.3+/-4.3, HAMD-21: 13.3+/-1.9) and controls (7 males, 31.6+/-9.1 years) was drawn every 20 min between 2300 and 0700 h during sleep using a long catheter for later GH analysis. Mean plasma GH levels peaked at 0040 h, however this peak was significantly blunted in patients (maximum 4.3+/-1.5 ng/ml) compared to controls (maximum 12.3+/-4.0 ng/ml; p<0.05). In patients but not controls two other, smaller peaks were observed (0220 and 0620 h). In patients but not in controls, GH values exceeding maximum GH values of the peak at 0040 h were observed already at 2300 h or during the second half of night. In conclusion, our results indicate that the nocturnal GH secretion in patients with OCD is altered compared to controls.

Changes of sleep architecture, spectral composition of sleep EEG, the nocturnal secretion of cortisol, ACTH, GH, prolactin, melatonin, ghrelin, and leptin, and the DEX-CRH test in depressed patients during treatment with mirtazapine.

The noradrenergic and specific serotoninergic antidepressant mirtazapine improves sleep, modulates hormone secretion including blunting of hypothalamic-pituitary-adrenocortical (HPA) activity, and may prompt increased appetite and weight gain. The simultaneous investigation of sleep electroencephalogram (EEG) and hormone secretion during antidepressive treatment helps to further elucidate these effects. We examined sleep EEG (for later conventional and quantitative analyses) and the nocturnal concentrations of cortisol, adrenocorticotropin (ACTH), growth hormone (GH), prolactin, melatonin and the key factors of energy balance, ghrelin, and leptin before and after 28 days of treatment of depressed patients (seven women, three men, mean age 39.9+/-4.2 years) with mirtazapine. In addition, a sleep EEG was recorded at day 2 and the dexamethasone-corticotropin-releasing hormone (DEX-CRH) test was performed to assess HPA activity at days -3 and 26. Psychometry and mirtazapine plasma concentrations were measured weekly. Already at day 2, sleep continuity was improved. This effect persisted at day 28, when slow-wave sleep, low-delta, theta and alpha activity, leptin and (0300-0700) melatonin increased, and cortisol and ghrelin decreased. ACTH and prolactin remained unchanged. The first two specimens of GH collected after the start of quantitative EEG analysis were reduced at day 28. The DEX-CRH test showed, at day 26, a blunting of the overshoot of ACTH and cortisol found at day -3. The Hamilton Depression score decreased from 32.1+/-7.3 to 15.5+/-6.7 between days -1 and 28. A weight gain of approximately 3 kg was observed. This unique profile of changes is compatible with the action of mirtazapine at 5-HT-2 receptors, at presynaptic adrenergic alpha 2 receptors, at the HPA system, and on ghrelin and leptin.

Nocturnal ghrelin levels--relationship to sleep EEG, the levels of growth hormone, ACTH and cortisol--and gender differences.

Ghrelin, an endogenous ligand of the growth hormone (GH) secretagogue receptor, stimulates sleep, appetite and weight gain as well as the secretion of GH, adrenocorticotropic hormone (ACTH), cortisol in humans and rodents. The interaction between nocturnal ghrelin levels, sleep EEG and the secretion of these hormones was not investigated systematically so far. Furthermore conflicting data exist on gender differences in nocturnal ghrelin secretion. We examined simultaneously sleep EEG and the nocturnal levels of ghrelin, GH, ACTH and cortisol in young and middle-aged normal human subjects (eight males, eight females). A significant interaction between gender and the course of ghrelin concentration was observed to the interval between 20:00 and 23:00 hours. In males a continuous increase of ghrelin levels before sleep onset was found. In females, however, a rise of ghrelin during the night was missed. We found a trend suggesting a lower time spent in stage I sleep in subjects with high nocturnal ghrelin levels. Other systematic interactions between plasma ghrelin, sleep EEG and other hormones were not found. No peak in plasma ghrelin levels resembling the GH surge was observed. We suggest that under naturalistic conditions plasma ghrelin levels show no distinct interaction with sleep.

Ghrelin stimulates appetite, imagination of food, GH, ACTH, and cortisol, but does not affect leptin in normal controls.

Ghrelin, a growth hormone (GH) secretagogue receptor ligand was isolated from the stomach and hypothalamus of rats and humans. In rodents, ghrelin exerts distinct orexigenic action, probably as counterpart of the anorexigenic leptin. In humans, ghrelin infusion enhances appetite. It is unknown whether single intravenous (i.v.) injections of ghrelin affect human eating behavior. Therefore, we investigated the influence of a single i.v. bolus injection of 100 microg ghrelin on appetite, ideas about food, hormone levels, and glucose concentration in young control subjects. In order to test gender differences, we included five women and four men. After ghrelin administration, appetite was enhanced in eight of nine subjects. Seven probands reported a vivid, plastic image of their preferred meal. Furthermore, ghrelin stimulated an immediate increase in plasma levels of GH (area under the curve, mean+/-SEM 35+/-16 ng/ml x min after placebo [P] to 2808+/-533 ng/ml x min after ghrelin [G]; p<0.001), cortisol (5908+/-984 ng/ml x min [P] to 10179+/-1293 ng/ml x min [G]; p<0.001), and ACTH (922+/-103 pg/ml x min [P] to 3030+/-763 pg/ml x min [G]; p<0.02), whereas leptin levels remained unchanged. Contrary to placebo, glucose concentration did not decrease markedly after administration of ghrelin. Our data suggest that i.v. ghrelin stimulates appetite and images of food in young women and men. Obviously, leptin is not involved in these effects.

N(omega)-nitro-L-arginine methyl ester effects on neutrophil function and bacterial clearance.

Nitric oxide synthase (NOS) inhibitors are considered promising as a therapeutic option in severe septic shock. The aim of this study was to investigate the effects of N-nitro-L-arginine methyl ester (L-NAME) application on neutrophil (PMN) respiratory burst, phagocytosis, and elimination of Escherichia coli from blood and tissue in rabbits. Twenty-eight female chinchilla rabbits were randomized to a treatment and control group. To quantify the bacterial clearance process, 10 colony forming units (CFU) of E. coli were injected intravenously into anesthetized rabbits. Animals in the L-NAME group had a significantly higher mortality compared with controls. NOS inhibition resulted in a significant delay of bacterial clearance (P < 0.001). These findings correlated with a significant augmentation of all organ E. coli findings (P = 0.002-0.035). PMN phagocytosis activity was notably reduced by L-NAME treatment during the experimental observation. Neutrophil burst, on the other hand, was amplified by NOS inhibition (P = 0.008). Our findings point to an interference with the PMN-dependent immune mechanisms after L-NAME treatment. The augmented PMN burst reaction could be a compensatory mechanism, potentially leading to tissue damage. Therefore, in this model, we find sufficient evidence pointing to a possible cause for the deleterious effect of early nonselective NOS inhibition in critically ill patients.