P. Schüssler

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.

Progesterone reduces wakefulness in sleep EEG and has no effect on cognition in healthy postmenopausal women.

Sleep is frequently impaired in postmenopausal women. Progesterone prompted benzodiazepine-like effects on sleep EEG in young normal male subjects. Aim of this study was to test if treatment with progesterone improves sleep after menopause. A randomised double blind crossover design study with 2 treatment intervals of 21 days duration separated by a 2 weeks washout was performed. An oral dose of 300 mg micronized progesterone was given each for 21 days. At the beginning and the end of the two intervals a sleep EEG was recorded and cognitive performance was assessed in 10 healthy postmenopausal women (age: 54-70 years). Progesterone treatment led to a decrease of intermittent time spent awake. During the first third of the night rapid eye movement (REM) sleep increased. The spectral analysis of the EEG resulted in no significant differences of the power spectra. Progesterone did not affect cognitive performance. In summary progesterone demonstrated a distinct sleep promoting effect by reduction of time of wake without impairing cognitive functions during daytime. As possible mechanisms of progesterone a GABA-agonistic effect and the regulation of gene expression via the progesterone receptor are discussed. Progesterone might be useful in the treatment of sleep disturbances of postmenopausal women.

Non-association of dopamine D4 and D2 receptor genes with personality in healthy individuals.

&NA; Recently, different research groups reported conflicting results with regard to an association of dopamine 4 receptor (DRD4) genotypes and the personality dimension of novelty seeking (NS). High scores for NS seemed to be associated with long alleles of a DRD4 polymorphism. Furthermore, an association between personality traits and the dopamine 2 (DRD2) receptor gene was reported. NS and persistence (PS) high scores seemed to be associated with alleles of DRD2. We examined 109 (78 female and 31 male) normal healthy individuals using Cloningers Temperament and Character Inventory (TCI) in order to replicate these findings. We genotyped a 48 base pair variable number of tandem repeats (from two to eight repeats) polymorphism in the third exon of DRD4 and a Cys311Ser polymorphism in exon 7 of DRD2. We tested alleles and genotypes of DRD4 (allele 7 absent or present; genotype 4,4 versus 4,7), and Ser/Cys and Cys/Cys genotypes of DRD2 for associations with TCI values. NS and the alleles and genotypes of DRD4 did not show any association. In associating the genotypes of DRD2 with TCI scales (NS, harm avoidance, reward dependence and PS), we also found no association. Recent findings associating NS with DRD4 could not be replicated. With regard to DRD2, we tested a different polymorphism as published recently and could not find an association of TCI scales with the gene. The present results therefore do not provide evidence that the DRD2 and DRD4 receptor genes contribute a common and relevant effect to personality traits.

Duloxetine increases stage 3 sleep and suppresses rapid eye movement (REM) sleep in patients with major depression

Sleep studies in patients with major depression receiving the new selective norepinephrine and serotonin reuptake inhibitor (SNRI) duloxetine are lacking. Therefore, polysomnography in 10 patients with major depression (7 males, 39.9+/-7.6 years, HAMD-21 score: 23.6+/-5.6) was recorded twice, before and after 7-14 days of treatment with duloxetine. Stage 3 sleep significantly (P<0.01) increased from 21.0+/-10.7 to 37.4+/-20.1 min. Rapid eye movement (REM) latency significantly (P<0.005) increased from 58.5+/-31.1 to 193.6+/-72.6 min. REM sleep significantly (P<0.005) decreased from 94.8+/-34.5 to 51.5+/-42.5 min. These results partly differ from those in healthy subjects receiving duloxetine.

Ghrelin Suppresses Secretion of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) in Women

CONTEXT Ghrelin has been shown to suppress secretion of LH and, less regularly, of FSH in male and female animals and human males. However, no such evidence exists for human females. OBJECTIVE The aim was to study the effect of ghrelin on secretion of LH and FSH in women. DESIGN/PARTICIPANTS/INTERVENTION: Nocturnal (2000-0700 h) secretion profiles of LH and FSH were determined in six healthy women (age, 25.5±2.9 yr) twice, receiving 50 μg ghrelin or placebo at 2200, 2300, 2400, and 0100 h in this single-blind, randomized, crossover study. RESULTS LH secretion after ghrelin injection as assessed by the area under the curve (4.01±1.37 mIU/min·ml) was significantly (P=0.031) lower than after placebo injection (5.46±1.33 mIU/min·ml). Also, FSH secretion after ghrelin injection (5.54±0.64 mIU/min·ml) was significantly (P=0.038) lower than after placebo injection (5.87±0.56 mIU/min·ml). LH pulses occurred significantly (P=0.007) less frequently after ghrelin injection (2.3±0.5) than after placebo injection (3.8±0.9). Accordingly, the interval between first and second LH pulse after treatment was significantly (P=0.002) longer after ghrelin injection (300±86 min) than after placebo injection (187±60 min). One of the six women exhibited clear FSH pulses, which overall paralleled LH pulses; two FSH and LH pulses occurred after ghrelin injection, but three occurred after placebo in this woman. CONCLUSIONS This is the first report that ghrelin suppresses the secretion of LH and FSH in women. These findings resemble those in male and female animals and in men.

Impaired off-line memory consolidation in depression

Sleep is critically involved in the consolidation of procedural memory. In major depression (MD) and during antidepressant pharmacotherapy, changes in sleep EEG are well documented. Here, we test if off-line motor memory consolidation is impaired in MD. 50 medicated patients with an acute episode of MD, 50 normal controls and 12 patients with a remitted episode of MD were assessed using a sequential finger tapping task before and after a night of sleep. Although depressed patients and control subjects did not differ in practice-dependent learning, healthy subjects showed markedly overnight improvements in tapping performance of 18% while patients failed to show any improvement. This pattern became even more striking when the subjects were divided by an age threshold of 30years: In the 30+yrs group the healthy subjects showed 16% overnight increase in motor performance, whereas the patients showed -10% overnight decrease. In contrast, patients and controls in the </=30yrs group showed virtually the same motor performance, as well as remitted patients and controls in the 30+yrs group. In addition, the younger controls showed stronger overnight improvements than the older controls. This pattern might be interpreted as a synergistic interaction between age and depression: Off-line motor memory consolidation is not affected in young patients, but severely impaired in older patients with an acute episode of MD. This impairment seems to recover after remission from depression.

Ghrelin in mental health, sleep, memory

Ghrelin acts as a neuropeptide. It participates in sleep-wake regulation. After systemic ghrelin treatment nonREM sleep is promoted in male humans and mice. This effect is influenced by gender, time of administration and depression. Ghrelin does not modulate sleep in healthy women and during the early morning in male subjects. In depressed women REM sleep is diminished after ghrelin. In elderly men and depressed men sleep promotion by ghrelin was preserved. In rats after central ghrelin feeding and wakefulness increased. The nocturnal secretion pattern of cortisol, GH, LH, FSH and hypothalamo-pituitary-thyroid hormones are influenced by ghrelin. Furthermore ghrelin appears to be related to memory and to be involved in the pathophysiology of CNS disorders, particularly depression.

Ghrelin plasma levels are not altered in major depression.

Background: In patients with major depression, the function of most endocrine axes is altered compared to healthy subjects. The orexigenic hormone ghrelin, which shows higher plasma levels in females than males, interacts with several of these endocrine axes. In addition, ghrelin levels in depressed patients decrease with psychopathological improvement. Therefore, we hypothesized that ghrelin levels in patients with major depression would be higher than in healthy subjects. Methods: Nocturnal (20:00–07:00 h) secretion patterns of ghrelin in 20 patients with major depression [11 females, age 39.4 ± 10.2 years (mean ± standard deviation); 9 males, age 38.3 ± 10.4 years] with a total score on the Hamilton Depression Rating Scale, 21-item version, of 24.8 ± 5.2 and 20 healthy subjects [11 females, age 38.7 ± 10.8 years; 9 males, age 39.1 ± 11.2 years] were determined following an adaptation night. Results: Ghrelin plasma levels of depressed patients and matched healthy subjects did not differ at any point in time when stratified for sex. Accordingly, the area under the curve was comparable: depressed females, 423.3 ± 103.4; healthy females, 398.0 ± 94.6; depressed males, 266.3 ± 56.9, and healthy males, 228.4 ± 41.3. Conclusion: This is the first comparison of ghrelin secretion patterns in patients with major depression and healthy controls. Surprisingly, no relevant differences were ascertained between the two groups.

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. Ghrelins 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 increases slow wave sleep and stage 2 sleep and decreases stage 1 sleep and REM sleep in elderly men but does not affect sleep in elderly women

Ghrelin increases non-REM sleep and decreases REM sleep in young men but does not affect sleep in young women. In both sexes, ghrelin stimulates the activity of the somatotropic and the hypothalamic-pituitary-adrenal (HPA) axis, as indicated by increased growth hormone (GH) and cortisol plasma levels. These two endocrine axes are crucially involved in sleep regulation. As various endocrine effects are age-dependent, aim was to study ghrelins effect on sleep and secretion of GH and cortisol in elderly humans. Sleep-EEGs (2300-0700 h) and secretion profiles of GH and cortisol (2000-0700 h) were determined in 10 elderly men (64.0+/-2.2 years) and 10 elderly, postmenopausal women (63.0+/-2.9 years) twice, receiving 50 microg ghrelin or placebo at 2200, 2300, 0000, and 0100 h, in this single-blind, randomized, cross-over study. In men, ghrelin compared to placebo was associated with significantly more stage 2 sleep (placebo: 183.3+/-6.1; ghrelin: 221.0+/-12.2 min), slow wave sleep (placebo: 33.4+/-5.1; ghrelin: 44.3+/-7.7 min) and non-REM sleep (placebo: 272.6+/-12.8; ghrelin: 318.2+/-11.0 min). Stage 1 sleep (placebo: 56.9+/-8.7; ghrelin: 50.9+/-7.6 min) and REM sleep (placebo: 71.9+/-9.1; ghrelin: 52.5+/-5.9 min) were significantly reduced. Furthermore, delta power in men was significantly higher and alpha power and beta power were significantly lower after ghrelin than after placebo injection during the first half of night. In women, no effects on sleep were observed. In both sexes, ghrelin caused comparable increases and secretion patterns of GH and cortisol. In conclusion, ghrelin affects sleep in elderly men but not women resembling findings in young subjects.