Metabolic and endocrine effects of sleep deprivation

Sleep deprivation has multiple effects on endocrine and metabolic function. In particular, sleep restriction is accompanied by increased cortisol levels in the afternoon and early evening and a shorter quiescent period compared with extended sleep periods. Those alterations could facilitate central and peripheral disturbances that are associated with glucocorticoid excess, such as memory deficits, and are similar to those observed in aging. Thus, chronic sleep loss could contribute to acceleration of the aging process. Sleep restriction is also associated with an impairment of carbohydrate tolerance, similar to that observed in individuals with clinically significant impaired glucose tolerance. Thus, chronic sleep deprivation may increase the risk for diabetes. Finally, sleep plays an important role in energy balance. Partial sleep deprivation was found to be associated with a decrease in plasma levels of leptin and a concomitant increase in plasma levels of ghrelin; subjective ratings of hunger and appetite also increased (the appetite for protein-rich foods was not significantly affected). Moreover, a remarkable correlation was found between the increase in hunger and the increase in the ghrelin:leptin ratio. Thus, the neuroendocrine regulation of appetite and food intake appears to be influenced by sleep duration, and sleep restriction may favor the development of obesity.     

The metabolic consequences of sleep deprivation

The prevalence of diabetes and obesity is increasing at an alarming rate worldwide, and the causes of this pandemic are not fully understood. Chronic sleep curtailment is a behavior that has developed over the past 2-3 decades. Laboratory and epidemiological studies suggest that sleep loss may play a role in the increased prevalence of diabetes and/or obesity. Current data suggest the relationship between sleep restriction, weight gain and diabetes risk may involve at least three pathways: (1) alterations in glucose metabolism; (2) upregulation of appetite; and (3) decreased energy expenditure. The present article reviews the current evidence in support of these three mechanisms that might link short sleep and increased obesity and diabetes risk.     

Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans

Ghrelin is an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor. It is hypothesised to play a key role in energy balance stimulating food intake and body weight. Besides GH-releasing hormone (GHRH) and somatostatin, it is thought to be a regulating factor of GH release. Ghrelin also appears to be involved in sleep regulation. We showed recently that ghrelin promotes slow-wave sleep and the nocturnal release of GH, cortisol and prolactin in humans. Similarly, promotion of non-rapid-eye-movement (NREM) sleep was reported in mice after systemic ghrelin. If ghrelin is a factor that induces and/or maintains sleep, it should be enhanced after a period of sleep deprivation (SD). To clarify this issue, nocturnal ghrelin, GH, ACTH and cortisol plasma concentrations were determined and simultaneously sleep electroencephalogram (EEG) was recorded (2300-0700 h) during sleep before and after 1 night of total SD in 8 healthy subjects. Compared to baseline, ghrelin levels increased earlier by a non-significant trend, already before the beginning of recovery sleep. Further a non-significant trend occurred, suggesting higher ghrelin secretion in the first half of the night. The ghrelin maximum was found significantly earlier after SD than at baseline. GH secretion during the first half of the night and total night after SD were elevated. ACTH and cortisol were also elevated, which was most pronounced during the second half of the night. No effects of SD on the time of the maximum were found for GH, ACTH and cortisol. The increase in ACTH after SD is a novel finding. Whereas the effects of SD on ghrelin levels were relatively weak, our findings are in line with the hypothesis that ghrelin is a sleep-promoting factor in humans. Ghrelin may be involved in sleep promotion after SD.     

Association between actigraphy-based sleep duration variability and cardiovascular risk factors – Results of a population-based study

BackgroundAlthough a few studies suggest an adverse effect of sleep duration variability on cardiovascular risk factor, others did not and this association remains controversial. Moreover, most studies were non-representative of the general population, used different sleep duration variability measures, and relied on self-reported sleep duration. We aimed to assess the association between different, actigraphy-based sleep duration variability measures and cardiovascular risk factors in a population-based sample.MethodsIn a middle-aged population-based cohort, 2598 subjects had data on sleep duration variability measured by actigraph over 14 days. Multivariable logistic regressions were performed to assess the relationship between different sleep duration variability measures [ie, night-to-night variability (NNV), range between shortest and longest sleep duration (RSL), range between average weekday and weekend sleep duration (RWW)] and cardiovascular risk factors including obesity, diabetes and hypertension.ResultsSubjects with highest sleep duration variability - measured as NNV, RSL and RWW, were more likely to be obese. These associations robust in most but not all sensitivity analyses, and no associations between sleep duration variability measures and diabetes or hypertension were found.ConclusionThere is a possible association between high sleep duration variability and obesity, although results were not robust in all sensitivity analyses. Further, no associations between sleep duration variability and other cardiovascular risk factor such as diabetes or hypertension were found.     

Effect of hippocampectomy on sleep patterns in cats.

The study was planned to see if the hippocampus has an influence on fast wave sleep (FWS) as well as on slow wave sleep (SWS). From 8 male cats EEG, EMG and EOG were recorded for 24 h, first under normal conditions, secondly after cortical damage to the dorsal marginal portion of posterior ectosylvian gyrus, and thirdly following hippocampectomy done through the cortical damage. From the records, SWS, FWS and the sleep state (defined as a sequence of SWS or SWS-FWS phases between two successive waking states) were measured in terms of their occurrence, the mean duration and the total time they occupied in the day, night and 24 h. In addition, sleep sequences were classified according to the number of constituent sleep phases. Cortical damage did not affect SWS, FWS, or sleep state with regard to their occurrence, the mean duration, and the total time they occupied in 24 h. Nor did it affect the proportion of short and long sequences. The circadian variation of sleep was clearly retained. Hippocampectomy significantly reduced the total time occupied by sleep state, SWS and FWS, increased the occurrence of sleep state and SWS phase against decreased incidence of FWS phase, and reduced the mean duration of sleep state and SWS phase. Hippocampectomy also significantly increased the occurrence of sleep sequences with only one SWS phase at the cost of sequences with alternating SWS and FWS phases. Following hippocampectomy, the circadian variation of sleep was not only retained, but actually exagerated. The hippocampus in inferred to facilitate the FWS as well as the SWS phase of sleep.     

Association between sleep deficiency and cardiometabolic disease: implications for health disparities

BackgroundCardiometabolic diseases, which include obesity, diabetes, hypertension, and cardiovascular disease, are associated with reduced quality of life and reduced life expectancy. Unfortunately, there are racial/ethnic and socioeconomic disparities associated with these diseases such that minority populations, such as African Americans and Hispanics, and those of lower socioeconomic status, experience a greater burden. Several reports have indicated that there are differences in sleep duration and quality that mirror the disparities in cardiometabolic disease. The goal of this paper is to review the association between sleep and cardiometabolic disease risk because of the possibility that suboptimal sleep may partially mediate the cardiometabolic disease disparities.MethodsWe review both experimental studies that have restricted sleep duration or impaired sleep quality and examined biomarkers of cardiometabolic disease risk, including glucose metabolism and insulin sensitivity, appetite regulation and food intake, and immune function. We also review observational studies that have examined the association between habitual sleep duration and quality, and the prevalence or risk of obesity, diabetes, hypertension, and cardiovascular disease.ConclusionMany experimental and observational studies do support an association between suboptimal sleep and increased cardiometabolic disease risk.     

L-tryptophan and sleep in healthy man.

The effect of L-tryptophan on night-time and day-time sleep (from 14.00 h) sleep was studied in six healthy males aged between 20 and 30 years. The doses used in the night-time studies were 2, 4 and 6 g, and in the day-time studies 1, 2 and 4 g. It was not possible to establish an effect of L-tryptophan compared with placebo on night-time sleep, but analysis of the sleep measures with 4 g compared with placebo and the other doses of L-tryptophan considered together suggested reduced awakenings, increased stage 3 and an increased percentage of REM sleep. With 4 g L-tryptophan there was an increase in the duration of stage 3 of day-time sleep compared with placebo. The studies provide marginal evidence that REM sleep may be modified by L-tryptophan in man, though the evidence is somewhat stronger that SWS may be increased. The effect on REM sleep may involve circadian mechanisms. The hypnotic activity of L-tryptophan per se is limited and uncertain.     

Slow-wave sleep and delta power in rapid eye movement sleep behavior disorder

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by the loss of normal muscle atonia during REM sleep, leading to an increase of phasic muscle activity and complex motor behaviors during the night. There is some evidence that RBD patients have more of slow-wave sleep (SWS) than healthy elderly subjects. No study has looked at quantitative electroencephalogram analysis during non-REM sleep in either primary or secondary RBD. The aim of this study was to assess the increase of SWS and to analyze different electroencephalographic frequency ranges during non-REM sleep in 28 idiopathic RBD patients compared with 28 age- and sex-matched healthy volunteers. Idiopathic RBD patients spent more time in SWS (men: 1.4%; women: 5.9%) than control subjects (men: 0.4%; women: 0.6%; p = 0.004). Spectral analyses demonstrated that idiopathic RBD patients had increased all-night delta power in comparison with control subjects (p = 002). This study shows an increase of SWS and power in the delta band during non-REM sleep in idiopathic RBD patients compared with control subjects. Results are discussed about the possible nigrostriatal dopaminergic impairment in RBD patients and the association between RBD and neurodegenerative disorders.     

Predator-induced plasticity in sleep architecture in wild-caught Norway rats (Rattus norvegicus)

Sleep is a prominent behaviour in the lives of animals, but the unresponsiveness that characterizes sleep makes it dangerous. Mammalian sleep is composed of two neurophysiological states: slow wave sleep (SWS) and rapid-eye-movement (REM) sleep. Given that the intensity of stimuli required to induce an arousal to wakefulness is highest during deep SWS or REM sleep, mammals may be most vulnerable during these states. If true, then animals should selectively reduce deep SWS and REM sleep following an increase in the risk of predation. To test this prediction, we simulated a predatory encounter with 10 wild-caught Norway rats (Rattus norvegicus), which are perhaps more likely to exhibit natural anti-predator responses than laboratory strains. Immediately following the encounter, rats spent more time awake and less time in SWS and REM sleep. The reduction of SWS was due to the shorter duration of SWS episodes, whereas the reduction of REM sleep was due to a lower number of REM sleep episodes. The onset of SWS and REM sleep was delayed post-encounter by about 20 and 100 min, respectively. The reduction of REM sleep was disproportionately large during the first quarter of the sleep phase, and slow wave activity (SWA) (0.5-4.5 Hz power density) was lower during the first 10 min of SWS post-encounter. An increase in SWA and REM sleep was observed later in the sleep phase, which may reflect sleep homeostasis. These results suggest that aspects of sleep architecture can be adjusted to the prevailing risk of predation.     

Bacterial peptidoglycans as modulators of sleep. II. Effects of muramyl peptides on the structure of rabbit sleep

Sleep-promoting substances derived from human urine and rabbit brain were identified as muramyl peptides (MPs). We report in the accompanying paper that in the molecular structure of MPs, the 1,6-anhydro muramic acid moiety of MPs is important for enhancement of slow-wave sleep (SWS) in rabbits. Here, we document more extensively the effects of one MP: 1,6-anhydro-muramyl-alanyl-glutamyl-diaminopimelyl-alanine (AMTP for anhydro-muramyl tetrapeptide) on sleep structure of rabbits. AMTP significantly increased percent of time spent in SWS but its effects on rapid eye movement (REM) sleep were dose-dependent. Brain temperatures were significantly elevated but continued to fluctuate with sleep and wake state transitions indistinguishably from control. Sleep was episodic and animals could be easily aroused. AMTP increased number of SWS episodes and decreased number of REM episodes. There was a shift in the distribution of sleep-wake episode durations: longer waking and REM episodes were decreased, thus increased the proportion of shorter episodes. Increased duration of SWS resulted from a larger number of SWS episodes longer than 8 min. We conclude that AMTP amplifies the SWS compenent of physiological sleep.     

Effects of selective neuronal nitric oxide synthase inhibition on sleep and wakefulness in the rat

The role played by the unconventional messenger Nitric Oxide (NO) upon the sleep-wake cycle remains controversial. Evidence suggests a positive role of NO on Slow Wave Sleep (SWS) and Paradoxical Sleep (PS) regulation, favoring sleep. However, other studies have found a role of NO upon wakefulness and alertness, inhibiting sleep. Divergences have been explained in part because of the use of different inhibitors of nitric oxide synthases (NOS). The aim of this study is to analyse the effects of a highly selective neuronal NOS inhibitor (3-Bromo7-Nitroindazole) on sleep-wake states in rats. Male Wistar rats were stereotaxically prepared for polysomnography. 3-Bromo-7-Nitroindazole (10, 20, 40 mg/kg, i.p.) dissolved in DMSO 10% filled with saline, or vehicle (DMSO 10% in saline) was administered at the beginning of the light period. Three hours of polygraphic recordings were evaluated for stages of vigilance. Results show dose-dependent effects of 3-Bromo7-Nitroindazole upon sleep: 10 mg/kg decreases duration and number of episodes of deep SWS, increasing duration of light SWS. 20 mg/kg decreased duration of light and deep SWS, while active and quiet wake increased. Deep SWS and PS latency increased. Number of episodes of PS decreased, as well as number of cycles of sleep and time spent asleep. 40 mg/kg reduced duration of deep SWS and increased mean episode duration of light SWS. Therefore, sleep states are affected by selective inhibition of nNOS, reducing in all cases deep SWS. These results support the hypothesis that nitric oxide, produced by nNOS, is involved in sleep processes, favoring sleep.     

Acute sleep deprivation reduces amygdala-kindled seizure thresholds in cats

It is well known that sleep loss activates human and experimental epilepsy. Because sleep deficits are also common among epileptics, it is possible that sleep loss enhances seizures by worsening these spontaneous sleep abnormalities. We examined this hypothesis by documenting the effects of acute (72 h) sleep deprivation on seizures in fully kindled cats. We have reported elsewhere sustained decrements in both slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep with the development of amygdala kindling in this species. In the present experiment, eight cats underwent an A₁ B₁ A₂ paradigm in which sleep state physiology (12-h polygraphic recordings) and seizure thresholds were examined in both an experimental (sleep deprivation) and control (nonsleep deprived) sequence of conditions, with order of presentation counterbalanced. Sleep deprivation was produced by a modification of the “flower pot” procedure and involved placing the cat on a small platform over water so as to prevent REM sleep. In the control sequence, cats underwent the same procedure except the platform was large enough to allow normal SWS and REM sleep. A significant reduction in both REM and SWS sleep occurred exclusively during the experimental B₁ condition and was accompanied by a significant reduction in seizure threshold for partial or generalized tonic-clonic convulsions. These findings indicated that this procedure, thought to influence only REM sleep, also disrupts SWS; further, this generalized disruption of sleep reduced kindled seizure thresholds, perhaps by compounding existing sleep deficits. Collectively, these observations again suggest that the integrity of both SWS and REM sleep may be an important consideration in the etiology of amygdala-kindled seizures.     

NREM sleep instability in children with sleep terrors: the role of slow wave activity interruptions.

OBJECTIVE: To evaluate NREM sleep instability, as measured by the cyclic alternating pattern (CAP), in children with sleep terrors (ST) vs. normal controls. METHODS: Ten boys (mean age: 8.5 years, range 5-13) meeting the following inclusion criteria: (a) complaint of ST several times a month, (b) a history of ST confirmed by a third person, and (c) a diagnosis of ST according to the ICSD-2 criteria. Eleven age-matched control children with parental report of at least 8.5h of nightly sleep, absence of known daytime consequences of sleep disorders were recruited by advertisement from the community. Sleep was visually scored for sleep macrostructure and CAP using standard criteria. RESULTS: Sleep macrostructure showed only a significantly increased number of awakenings per hour and reduced sleep efficiency in ST subjects. CAP parameters analysis revealed several significant differences in ST vs. controls: an increase of total CAP rate in SWS, of A1 index in SWS and of the mean duration of A phases while B phases had a decreased duration, exclusively in SWS. The normalized CAP interval-distribution graphs showed significant differences in SWS with interval classes 10< or = i < 35s higher in children with ST and intervals classes above 50s higher in normal controls. CONCLUSIONS: Children with ST showed faster alternations of the amplitude of slow EEG bursts during SWS. This abnormally fast alternation of the EEG amplitude in SWS is linked to the frequent intrusion of CAP B phases interrupting the continuity of slow delta activity and could be considered as a neurophysiological marker of ST. SIGNIFICANCE: This abnormal alternation of the EEG amplitude in SWS is associated with the occurrence of parasomnias and might be considered as a neurophysiological marker of disorders of arousal.     

The effects of ghrelin on sleep,appetite, and memory,and its possible role in depression: A review of the literature

Objectives

Ghrelin is an orexigenic digestive hormone that plays a role in sleep and memory. Our work aims is to synthesize the effects of ghrelin on appetite, sleep and memory, and also to evidence its role in depressive disorders.

Is sleep duration related to obesity? A critical review of the epidemiological evidence

1. Observational studies have implicated habitual sleep duration as a risk factor for mortality and morbidity. Part of this association might be mediated by obesity, which has also been associated with habitual sleep duration. These studies generate wide media attention because of the public's health concerns surrounding increasing obesity and the temporal association with the other modern "epidemic" of sleep loss. Some commentators have recommended public health interventions to control obesity via habitual sleep duration modification. We conducted a critical review of the available literature describing the relationship between habitual sleep duration and obesity in community-based studies in both adults and children, with particular emphasis on longitudinal studies and on studies with objective measures of habitual sleep duration. 2. Existing data have variable consistency. Only one study objectively measured sleep duration for more than one 24-h period. Cross-sectional and longitudinal studies in adults often demonstrated an association of short sleep duration with BMI. However, some of these studies also showed that long sleep duration was also associated with obesity. In contrast, other studies showed that neither long nor short sleep was associated with obesity. In paediatric populations there appeared to be a clear pattern where shorter sleep durations were associated with obesity. We did not locate any interventional studies where sleep duration had been manipulated in order to prevent or treat obesity. 3. We contend that the evidence base is not yet strong enough to give public health advice to the general population or specific groups about sleep duration being a modifiable risk factor for obesity. We need to experimentally clarify whether sleep duration variability is a risk factor for obesity, in what manner, and in which populations. If a reliable aetiological model could be found, we would ideally then need community-based randomised controlled trials that show that sleep duration can be changed and that sleep duration manipulation produces actual weight loss and/or prevents the development of obesity without undue side-effects.     

Recovery within day-time sleep after slow wave sleep suppression.

Six subjects had their SWS activity suppressed by acoustic stimulation during a day-time (11.00 h) recovery sleep after a 4 h night sleep (03.00-07.00 h). Sleep was disturbed for a period corresponding to 90% of the duration of a preceding undisturbed baseline sleep (also at 11.00 h and preceded by a 4 h night sleep) and thereafter allowed to continue undisturbed until spontaneous awakening. The results showed that SWS and EEG power density were significantly reduced during suppression and that full recovery occurred before spontaneous awakening. The disturbed sleep was significantly longer than the baseline sleep. The increase in duration consisted mainly of SWS, stage 2 and REM. The results suggest that the suppression of SWS activity caused a need for an extension of sleep in order to allow recovery.     

Selective slow-wave sleep suppression affects glucose tolerance and melatonin secretion. The role of sleep architecture

ObjectivesOur study aimed to assess the impact of one night of slow-wave sleep (SWS) suppression on glucose tolerance, and explore whether melatonin plays a role in glucose tolerance impairment after SWS suppression.MethodsIn sum, 20 volunteers participated in two experimental sessions: a session with SWS suppression during one night's sleep and a session with a regular night's sleep (control). Each session included collecting seven salivary samples. The following morning, an oral glucose tolerance test (OGTT) was performed.ResultsSWS suppression effects depended on the individual blood glucose response to the OGTT. During the control session, ‘responders’ (N = 11), already presented with low glucose tolerance, which further declined after SWS suppression. ‘Non-responders’ (N = 9) experienced high glucose tolerance in both conditions. Among the responders, SWS suppression led to an increase in melatonin at the moment of awakening, while in non-responders melatonin increased during the first half of the night. In both conditions, responders were characterized by a shorter total sleep time (TST) and less rapid eye movement (REM) sleep. During SWS suppression, they had more non-rapid eye movement (NREM) stage 1 and longer nocturnal wakefulness. Responders and non-responders showed a comparable amount of SWS.ConclusionsThis study highlights three key findings: first, SWS suppression leads to an increase in salivary melatonin; second, melatonin's effect on glucose tolerance depends on its secretion timing; and third, durations of REM sleep and nocturnal awakenings, appear to play an important role in melatonin secretion and glucose tolerance, indicating the potential clinical relevance of these findings for type 2 diabetes risk assessment.     

Ghrelin administered in the early morning increases secretion of cortisol and growth hormone without affecting sleep

Ghrelin and growth hormone (GH) releasing hormone (GHRH) both stimulate GH secretion and slow wave sleep (SWS), whereas ghrelin increases, and GHRH decreases cortisol in males. However, GHRH's effect on sleep and cortisol was abolished, on GH mitigated, when administered in the early morning, possibly due to counteracting corticotropin releasing hormone (CRH). Aim of this study was to investigate ghrelin's influence on sleep, GH and cortisol when administered in the early morning. Nocturnal (2000-1000 h) GH and cortisol patterns and polysomnography (2300-1000 h) were determined in 12 healthy males (25.3+/-3.2 yr) twice, receiving 50 microg ghrelin or placebo at 0400, 0500, 0600, and 0700 h, in this single-blind, randomized, cross-over study. The first ghrelin bolus caused the strongest (38.7+/-6.5 ng/ml, placebo: 0.4+/-1.1 ng/ml), second and third smaller, the fourth no GH peak. GH levels remained significantly (p<0.05) higher from 0420-0740 h in the ghrelin condition. Comparably, the first ghrelin bolus caused the strongest cortisol response (156.0+/-12.6 ng/ml; placebo: 78.0+/-10.5 ng/ml). Cortisol was significantly higher from 0440 to 0540 and at 0720 h and decreased thereafter to significantly lower levels (0820-0840 h). Sleep variables did not differ in both conditions. In contrast to GHRH, ghrelin's stimulatory effects were apparently not counteracted (GH), and enhanced (cortisol), respectively, by high CRH in the second half of night.     

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.     

Ghrelin enhances the nocturnal secretion of cortisol and growth hormone in young females without influencing sleep

Ghrelin was shown to increase slow wave sleep (SWS) and the secretion of growth hormone (GH) and cortisol in young males. In terms of sleep, such information for females, however, is lacking. Therefore, polysomnographies were recorded (23:00-07:00 h) and nocturnal (20:00-07:00 h) secretion profiles of GH and cortisol were determined in 10 healthy females (24.9+/-2.4 years, body mass index: 21.2+/-1.1) twice, receiving four boluses of 50 microg ghrelin or placebo at 22:00, 23:00, 00:00, and 01:00 h, in this single-blind, randomized, cross-over study. No significant differences of conventionally or quantitatively analyzed sleep were observed between ghrelin and placebo condition. First administration of ghrelin caused a marked mean increase of GH by 53.3 to 64.4+/-14.2 ng/ml (placebo: 5.9+/-1.5 ng/ml) and cortisol by 54.2 to 96.4+/-15.3 ng/ml (placebo: 27.5+/-4.7 ng/ml). The following ghrelin injections were associated with smaller increases of GH and cortisol. In the ghrelin condition, GH plasma levels remained significantly (P<0.05) higher from 22:20 to 02:00 h and cortisol plasma levels from 22:20 to 02:20 h. In contrast to findings in young men, ghrelin did not affect sleep in young women, indicating a sexual dimorphism. In accordance with the findings in young men, ghrelin stimulated secretion of GH and cortisol.