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CONTEXT: The loss of progesterone during menopause is linked to sleep complaints of the affected women. Previously we demonstrated sleep promoting effects of oral progesterone replacement in postmenopausal women. The oral administration of progesterone, however, is compromised by individual differences in bioavailability and metabolism of the steroid. OBJECTIVE: We compared the sleep-endocrine effects after intranasal progesterone (MPP22), zolpidem and placebo in healthy postmenopausal women. DESIGN: This was a randomized double-blind cross-over study. SETTING: German monocentric study PARTICIPANTS: Participants were 12 healthy postmenopausal women. INTERVENTIONS: Subjects received in randomized order four treatments, 2 doses of intranasal progesterone (4.5 mg and 9 mg of MPP22), 10 mg of zolpidem and placebo. OUTCOME MEASURES: Main outcome were conventional and quantitative sleep-EEG variables. Secondary outcomes were the subjective sleep variables and the sleep related concentrations of cortisol, growth hormone (GH), melatonin and progesterone. RESULTS: Sleep promoting effects were found after the higher dosage of MPP22 and after zolpidem. Zolpidem prompted benzodiazepine-like effects on quantitative sleep EEG as expected, whereas no such changes were found after the two dosages of MP22. Nocturnal progesterone levels increased after 9.0 mg MPP22. No other changes of hormone secretion were found. CONCLUSIONS: Our study shows sleep promoting effects after intranasal progesterone. The spectral signature of intranasal progesterone did not resemble the sleep-EEG alterations induced by GABA active compounds. Progesterone levels were elevated after 9.0 mg MPP22. No other endocrine effects were observed.

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The trait-like nature of electroencephalogram (EEG) is well established. Furthermore, EEG of wake and non-rapid eye movement (non-REM) sleep has been shown to be highly heritable. However, the genetic effects on REM sleep EEG microstructure are as yet unknown. REM sleep is of special interest since animal and human data suggest a connection between REM sleep abnormalities and the pathophysiology of psychiatric and neurological diseases. Here we report the results of a study in monozygotic (MZ) and dizygotic (DZ) twins examining the heritability of REM sleep EEG. We studied the architecture, spectral composition and phasic parameters of REM sleep and identified genetic effects on whole investigated EEG frequency spectrum as well as phasic REM parameters (REM density, REM activity and organization of REMs in bursts). In addition, cluster analysis based on the morphology of the EEG frequency spectrum revealed that the similarity among MZ twins is close to intra-individual stability. The observed strong genetic effects on REM sleep characteristics establish REM sleep as an important source of endophenotypes for psychiatric and neurological diseases.

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OBJECTIVE: Recent theoretical approaches emphasize a disorder of face processing in the pathogenesis of the Capgras syndrome. We report a patient with the Capgras syndrome developing in the physical absence of the person who is believed to be replaced and thus a limited role for a disorder of face processing. METHOD: The clinical phenomenology of a case of the Capgras syndrome is explored. RESULTS: A disorder of face processing might not be a sufficient explanation of the course of the disorder in this patient. CONCLUSION: Face processing accounts, of the Capgras delusion, have to be supplemented by additional assumptions.

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OBJECTIVE: This study addressed the relationship between daytime sleepiness and spectral composition of the preceding NREM sleep. METHODS: Nineteen healthy volunteers (mean age: 36.5 years; SD: 10.1) underwent polysomnography during two consecutive nights and the multiple sleep latency test (MSLT) on the following day. Daytime sleepiness was also assessed by the Epworth sleepiness scale (ESS). The sleep recordings were visually scored according to standard criteria. The quantitative sleep EEG analysis was performed using a fast Fourier transform routine. The sleep parameters were compared between subjects with short and long MSLT sleep latencies (cut-off=10 min) and between subjects with low and high ESS scores (cut-off=6 points). RESULTS: Subjects with short MSLT sleep latencies showed a reduced theta EEG activity. There was no evidence of reduced synchronization of sleep EEG in subjects with high ESS scores. CONCLUSIONS: Moderately increased daytime sleepiness as indicated by MSLT sleep latency less than 10 min is accompanied by decreased power of theta activity during NREM sleep indicating a deficit of sleep EEG synchronization.

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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.

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We compared the sleep structure including a quantitative electroencephalographic (EEG) analysis and the frequency of periodic limb movements (PLM) in 17 patients with Parkinson's disease (PD; 10 men, seven women, mean age 65.9 years, mean Hoehn and Yahr stage 1.8) who had never been treated with dopaminergic agents (de novo), and 10 healthy controls (six men, four women, mean age 64.5 years). The REM sleep EEG of the PD patients was characterized by a sustained increase in the high-theta/alpha (7.8-10.5 Hz) frequency range during the first one-third (i.e., 11.00 p.m. to 01.40 a.m.) of the night. There was no significant difference in the sleep continuity and sleep architecture as well as in the PLM index between both groups. The analysis of the temporal dynamics of the observed changes suggests a dysregulation of the REM sleep homeostasis in the patients with PD.

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BACKGROUND: Parkinson disease (PD) is often difficult to distinguish from parkinsonian syndromes of other causes in early stages of the disease. In search of a suitable endocrinologic challenge test, we investigated dopaminergic sensitivity in patients with de novo parkinsonian syndromes. OBJECTIVE: We measured the growth hormone (GH) response to a subthreshold dose of the dopamine 1-dopamine 2 receptor agonist apomorphine hydrochloride to differentiate parkinsonian syndromes from PD. PATIENTS AND METHODS: Seventeen patients with a clinical diagnosis of PD, 16 patients with a clinical diagnosis of multiple system atrophy, and 11 healthy controls. The GH response to a subthreshold dosage of apomorphine and to somatorelin (GH-releasing factor) was tested in a randomized order; on the third day the protocol was repeated with a clinically effective dose of apomorphine. RESULTS: The GH response to the low dose of apomorphine was significantly increased in patients with PD when compared with patients with multiple system atrophy or the control subjects (multivariate analyses of covariance; univariate F test, all P<.05). In contrast, there were no significant group differences with use of the higher dose of apomorphine or in the somatorelin-induced GH release. CONCLUSIONS: The GH response to a subthreshold dose of apomorphine appears to be a useful tool to identify patients with PD vs multiple system atrophy. The enhanced GH response to a subthreshold dopaminergic stimulus may reflect a hypersensitivity of the extrastriatal dopamine receptors in PD.

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The process of the human non-rapid eye movement (non-REM) sleep period has not been clarified. Time-based analysis on sleep EEG may provide an explanation. We focused on chronological aspects of initiation and termination of non-REM episodes, using spectral analysis of sleep EEG. The subjects were healthy male volunteers (n14 Hz) and longer in lower frequency ranges (<14 Hz). There were significant differences in the rise and decay latencies between low and high sigma ranges, indicating that the whole frequency ranges were clearly separated at the middle of the sigma range (14 Hz). The rise and decay latencies were significantly different in lower frequency ranges. The clock time of the night significantly affected only the rise latencies of the delta (0.78-3.9 Hz), alpha (8.2-11.7 Hz) and low sigma (12.1-13.7 Hz) ranges. In conclusion, initiation and termination of non-REM sleep was represented by higher frequency ranges, whereas further evolution and devolution of non-REM sleep was represented by lower frequency ranges, and only the evolution process was affected by the clock time of the night.

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Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) have immunomodulatory effects in vitro and in vivo. Additionally, their plasma levels are altered during chronic infection and inflammation. However, it remains unknown whether these steroids are involved in early host responses to infection in humans. We examined DHEA and DHEA-S levels during experimental endotoxinemia, a well established pathophysiological model of bacterial infections in humans. Purified Salmonella abortus equi endotoxin (0.2, 0.4, or 0.8 ng/kg body weight) was injected in a single-blind, placebo-controlled experiment to 17 healthy male volunteers. During the following 12 h, rectal temperature and the plasma levels of ACTH, cortisol, DHEA, DHEA-S, interleukin 6, and tumor necrosis factor alpha were determined. Confirming earlier studies, temperature and cytokine levels showed monophasic, dose-dependent increases in response to endotoxin. In contrast, endocrinological effects of endotoxin showed a complex, biphasic pattern: cortisol levels were not affected by 0. 2 ng/kg but significantly increased during the first 6 h following 0. 4 and 0.8 ng/kg endotoxin, whereas ACTH and DHEA levels were significantly enhanced during the first 6 h following 0.8 ng/kg only. ACTH, DHEA, and cortisol secretion was blunted 6-12 h following 0.8 ng/kg. DHEA-S levels were unaffected during the first 6 h following all dosages, but between 6-12 h after injection they were significantly increased following 0.2 ng/kg, unaffected by 0.4 ng/kg, and significantly decreased following 0.8 ng/kg endotoxin. The present results suggest that similarly to glucocorticoids, the adrenal androgens DHEA and DHEA-S play an important role during early host responses to bacterial infections in humans.

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Dehydroepiandrosteone (DHEA) and its sulfate ester (DHEAS) are the major secretory products of the human adrenal glands and serve as precursors for both androgenic and estrogenic steroids. DHEA/S concentrations are particularly high in the brain, and DHEA/S and related steroids can be synthesized de novo in brain glial cells. Therefore, the term 'neurosteroids' has been coined for these compounds. This review summarizes findings in neurosteroid physiology on a cellular and molecular level, and outlines current concepts of how these compounds modulate physiological functions of the brain. Today, despite promising preclinical and human data the present clinical studies provide only weak evidence, if any, in favour of a DHEA replacement therapy.

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Basic and clinical research suggest that disturbed neuroendocrine function may be involved in the pathogenesis and course of autoimmune diseases including multiple sclerosis (MS). Dehydroepiandrosterone (DHEA) in this connection is of particular interest as it appears to have effects on the immune system. Moreover, DHEA levels are decreased in chronic inflammatory diseases. To further investigate the role of DHEA in MS, we administered the adrenocorticotropin (ACTH) stimulation test and the combined dexamethasone and corticotropin-releasing hormone (DEX-CRH) test to 24 patients with active MS (13 women, 11 men; age 39 +/- 2 years, mean +/- SEM; Expanded Disability Status Scale, EDSS score 4.4 +/- 0. 4, mean +/- SEM; 12 with acute relapse, 12 with chronic progression) and to 18 healthy controls matched for age and sex (8 women, 10 men; age 37 +/- 3 years). There were no statistically significant differences in the plasma cortisol response to ACTH between any groups. In the DEX-CRH test, plasma cortisol concentrations showed higher values before (DEX-pretreated) and after CRH stimulation in the MS patients than in the controls (AUC(cortisol) 738.3 +/- 154.5 vs. 295.7 +/- 55.8; p < 0.05), this finding was more pronounced in chronic progressive patients. DHEA concentrations were decreased in MS patients (AUC (DHEA) 14.4 +/- 1.6 vs. 23 +/- 2.4; p < 0.05) and cortisol/DHEA ratios were increased in the patients compared to the controls (p < 0.05). There was a positive correlation between the EDSS score and maximum cortisol/DHEA ratio (r = 0.45; p = 0.031). As with the hypothalamic-pituitary-adrenal axis system, our results suggest a dysfunction in the DHEA secretion in patients with MS.

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Administration of hormones to humans and animals results in specific effects on the sleep electroencephalogram (EEG) and nocturnal hormone secretion. Studies with pulsatile administration of various neuropeptides in young and old normal controls and in patients with depression suggest they play a key role in sleep-endocrine regulation. Growth hormone (GH)-releasing hormone (GHRH) stimulates GH and slow wave sleep (SWS) and inhibits cortisol, whereas corticotropin-releasing hormone (CRH) exerts opposite effects. Changes in the GHRH:CRH ratio contribute to sleep-endocrine aberrations during normal ageing and acute depression. In addition, galanin and neuropeptide Y promote sleep, whereas, in the elderly, somatostatin impairs sleep. The rapid eye movement (REM)-nonREM cycle is modulated by vasoactive intestinal polypeptide. Cortisol stimulates SWS and GH, probably by feedback inhibition of CRH. Neuroactive steroids exert specific effects on the sleep EEG, which can be explained by gamma-aminobutyric acid(A) receptor modulation.

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In aging, a decline in sleep continuity, a decreased slow wave sleep, an earlier nocturnal cortisol rise, and a blunted growth hormone (GH) secretion occur. Pulsatile administration of GH-releasing hormone (GHRH) in young controls enhanced slow wave sleep and suppressed cortisol release. We administered GHRH 4 x 50 microg or placebo i.v. to 13 healthy seniors (5 women, 8 men, mean age 69.3 y +/- 8.3 SD). We observed significantly reduced nocturnal awakenings and an increased first non-rapid-eye-movement sleep period. In a subgroup (n = 9), we found a significant activation of GH secretion but unchanged cortisol secretion. Our data underscore that GHRH is capable of promoting sleep in the elderly, but much less than in young subjects. Contrasting to young subjects, the hypothalamic-pituitary-adrenocortical system remains unaffected by GHRH in the elderly. These results provide further evidence that a decrease in the efficacy of GHRH is involved in the biological mechanisms underlying aging.

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Progesterone administration induces a reduction of the vigilance state in humans during wakefulness. It has been been suggested that this effect is mediated via neuroactive metabolites that interact with the gamma-aminobutyric, acidA (GABAA) receptor complex. To investigate the effects of progesterone administration on the sleep electroencephalogram (EEG) in humans we made polysomnographic recordings, including sleep stage-specific spectral analysis, and concomitantly measured plasma concentrations of progesterone and its GABA-active metabolites 3 alpha-hydroxy-5 alpha-dihydroprogesterone (allopregnanolone) and 3 alpha-hydroxy-5 beta-dihydroprogesterone (pregnanolone) in nine healthy male subjects in a double-blind placebo-controlled crossover study. Progesterone administration at 9:30 PM induced a significant increase in the amount of non-rapid eye movement (REM) sleep. The EEG spectral power during non-REM sleep showed a significant decrease in the slow wave frequency range (0.4-4.3 Hz), whereas the spectral power in the higher frequency range (> 15 Hz) tended to be elevated. Some of the observed changes in sleep architecture and sleep-EEG power spectra are similar to those induced by agonistic modulators of the GABAA receptor complex and appear to be mediated in part via the conversion of progesterone into its GABA-active metabolites.

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Administration of progesterone produces sleep EEG patterns that resemble those of agonistic modulators at the GABAA receptor. Previous studies evaluating the effects of an oral progesterone administration on attention performance in females pointed to putative sedative effects of progesterone at high dosages. However, no data are available whether progesterone dosages that influence sleep produce sedative hangover effects on the following morning. Therefore, we assessed the effects of a single oral dose of 300 mg micronized progesterone administered in the evening on cognitive performance parameters in male healthy volunteers on the following morning using a placebo-controlled double-blind crossover design. There was a great variability in bioavailability following progesterone intake. The administration of progesterone produced no consistent effects on attention performance. Thus, dosages of progesterone that are sufficient to modulate sleep are not likely to exert sedative hangover effects.

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This review article summarizes the major findings about the interactions of human sleep structure and the hypothalamo-pituitary-adrenocortical (HPA) system under physiological and pathophysiological conditions, including studies that probe the sleep effects of systemically administered HPA hormones. Human sleep is regulated by a concerted action of various signal compounds acting at sleep-generating neurons whose central organization is not yet fully understood. During nocturnal sleep the endocrine system is remarkably active, the longest established finding being that growth hormone (GH) release is associated with the initiation of sleep and that there is a steep morning rise of cortisol (Weitzman et al., 1966; Takahashi et al., 1968). Moreover, the effects of exogenously administered corticosteroids and of their excessive endogenous release (e.g. Cushing's disease) were recognized more than 20 years ago.

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Dehydroepi-androsterone (DHEA) exhibits various behavioral effects in mammals, at least one of which is enhancement of memory that appears to be mediated by an interaction with the gamma-aminobutyric acidA (GABAA) receptor complex. We investigated the effects of a single oral dose of DHEA (500 mg) on sleep stages, sleep stage-specific electroencephalogram (EEG) power spectra, and concurrent hormone secretion in 10 healthy young men. DHEA administration induced a significant (P < 0.05) increase in rapid eye movement (REM) sleep, whereas all other sleep variables remained unchanged compared with the placebo condition. Spectral analysis of five selected EEG bands revealed significantly (P < 0.05) enhanced EEG activity in the sigma frequency range during REM sleep in the first 2-h sleep period after DHEA administration. In contrast, the EEG power spectra of non-REM sleep were not affected, nor were the nocturnal time course curves of plasma cortisol, growth hormone, or testosterone concentration. The results suggest that DHEA administration has a mixed GABAA-agonistic/antagonistic effect, exerted either directly or through DHEA-induced changes in steroid metabolism. Because REM sleep has been implicated in memory storage, its augmentation in the present study suggests the potential clinical usefulness of DHEA in age-related dementia.

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