Ghrelin, an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor, stimulates GH release, appetite, and weight gain in humans and rodents. Synthetic GHSs modulate sleep electroencephalogram (EEG) and nocturnal hormone secretion. We studied the effect of 4 x 50 microg of ghrelin administered hourly as intravenous boluses between 2200 and 0100 on sleep EEG and the secretion of plasma GH, ACTH, cortisol, prolactin, and leptin in humans (n = 7). After ghrelin administration, slow-wave sleep was increased during the total night and accumulated delta-wave activity was enhanced during the second half of the night. Rapid-eye-movement (REM) sleep was reduced during the second third of the night, whereas all other sleep EEG variables remained unchanged. Furthermore, GH and prolactin plasma levels were enhanced throughout the night, and cortisol levels increased during the first part of the night (2200-0300). The response of GH to ghrelin was most distinct after the first injection and lowest after the fourth injection. In contrast, cortisol showed an inverse pattern of response. Leptin levels did not differ between groups. Our data show a distinct action of exogenous ghrelin on sleep EEG and nocturnal hormone secretion. We suggest that ghrelin is an endogenous sleep-promoting factor. This role appears to be complementary to the already described effects of the peptide in the regulation of energy balance. Furthermore, ghrelin appears to be a common stimulus of the somatotropic and hypothalamo-pituitary-adrenocortical systems. It appears that ghrelin is a sleep-promoting factor in humans.

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 mg 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, mean7SEM 35716 ng/ml  min after placebo [P] to 28087533 ng/ml  min after ghrelin [G]; po0.001), cortisol (59087984 ng/ml  min [P] to 1017971293 ng/ml  min [G]; po0.001), and ACTH (9227103 pg/ml  min [P] to 30307763 pg/ml  min [G]; po0.02), 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.

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 39.974.2 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 À3 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 À3. The Hamilton Depression score decreased from 32.177.3 to 15.576.7 between days À1 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.

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SUMMAR Y 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.k e y w o r d s adrenocorticotrophic hormone, cortisol, gender, ghrelin, growth hormone, sleep endocrinology

. Growth hormone-releasing hormone and corticotropin-releasing hormone enhance non-rapid-eye-movement sleep after sleep deprivation. Am J Physiol Endocrinol Metab 291: E549 -E556, 2006; doi:10.1152/ajpendo.00641.2005.-The neuropeptides growth hormone (GH)-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) regulate sleep and nocturnal hormone secretion in a reciprocal fashion, at least in males. GHRH promotes sleep and GH and inhibits hypothalamo-pituitary-adrenocortical (HPA) hormones. CRH exerts opposite effects. In women, a sexual dimorphism was found because GHRH impairs sleep and stimulates HPA hormones. Sleep deprivation (SD) is the most powerful stimulus for inducing sleep. Studies in rodents show a key role of GHRH in sleep promotion after SD. The effects of GHRH and CRH on sleep-endocrine activity during the recovery night after SD are unknown. We compared sleep EEG, GH, and cortisol secretion between nights before and after 40 h of SD in 48 normal women and men aged 19 -67 yr. During the recovery night, GHRH, CRH, or placebo were injected repetitively. After placebo during the recovery night, non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS) increased and wakefulness decreased compared with the baseline night. After GHRH, the increase of NREMS and the decrease of wakefulness were more distinct than after placebo. Also, after CRH, NREMS increased higher than after placebo, and a positive correlation was found between age and the baseline-related increase of slow-wave sleep. REMS increased after placebo and after GHRH, but not after CRH. EEG spectral analysis showed increases in the lower frequencies and decreases in the higher frequencies during NREMS after each of the treatments. Cortisol and GH did not differ between baseline and recovery nights after placebo. After GHRH, GH increased and cortisol decreased. Cortisol increased after CRH. No sex differences were found in these changes. Our data suggest that GHRH and CRH augment NREMS promotion after SD. Marked differences appear to exist in peptidergic sleep regulation between spontaneous and recovery sleep. event history analysis; recovery sleep; cortisol; peptides SLEEP DEPRIVATION (SD) is the most powerful method to promote sleep. Recovery sleep following SD is characterized by increases of non-rapid-eye-movement sleep (NREMS), EEG slow-wave activity (SWA), and rapid-eye-movement sleep (REMS) and by decreases of sleep latency and the time spent awake compared with baseline conditions in humans (7) and in laboratory animals (8, 11). NREMS, particularly slow-wave sleep (SWS), and the nocturnal release of growth hormone (GH) are associated strictly, although not absolutely (37,41,44). After the selective 5-HT2 receptor antagonist ritanserin (14) and after ␥-hydroxybuyrate (42), both SWS and GH increase in normal male subjects. During the recovery night after SD, GH secretion was elevated in some (31), but not all (20), studies. These observations point to common regulators of sleep EEG and sleep-related GH secretio...

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