Sleep after intranasal progesterone vs. zolpidem and placebo in postmenopausal women - A randomized, double-blind cross over study.

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.

Genetics of rapid eye movement sleep in humans.

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.

Changes in dehydroepiandrosterone (DHEA) and DHEA-sulfate plasma levels during experimental endotoxinemia in healthy volunteers.

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.

Reduced efficacy of growth hormone-releasing hormone in modulating sleep endocrine activity in the elderly.

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.

Increased growth hormone response to apomorphine in Parkinson disease compared with multiple system atrophy.

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.

Steroid effects on central neurons and implications for psychiatric and neurological disorders.

Acute and chronic stress as well as a number of psychiatric and neurological disorders are accompanied by profound disturbances of the HPA system. These neuroendocrine alterations act back on the central nervous tissue mainly via corticosteroids-affecting glucocorticoid and mineralocorticoid receptors. The major conclusions drawn from studies probing these receptors in clinical investigations are: (1) In many such conditions central corticosteroid receptors are weakened in their capacity to curtail spontaneous and stress-elevated corticosteroid levels; (2) the combined DEX-CRH test is the best neuroendocrine tool currently available for identifying HPA abnormalities in psychiatric patients; (3) in depression the decreased corticosteroid receptor capacity in transient, and antidepressants act through reinstatement of GR and MR function probably resulting in reduced hypothalamic CRH and AVP production; (4) several neurological disorders such as MS and HIV infection are often accompanied by altered HPA function, which has therapeutic implications; and (5) various corticosteroids, their biosynthetic precursors and their metabolites have differentiable effects on the sleep EEG, which can be attributed to their mode of action; specifically, steroids such as pregnenolone and DHEA most likely are produced in glia cells and act in a paracrine fashion at neurons, thus modifying the sleep EEG in humans in a manner that suggests their potential as memory enhancers.

Cholecystokinin, gastrin and stress hormone responses in marathon runners.

The purpose of this investigation was to determine the influence of long-distance running on the secretion of the gastrointestinal peptide hormones cholecystokinin (CCK) and gastrin. Several known stress hormones, ACTH, cortisol and norepinephrine, were also measured. The hormones were estimated before and after a competitive marathon run of 46.5 km and under control conditions a few weeks later. Except gastrin, all hormones were significantly higher under prerun conditions than under control conditions and were highest after the run. The most marked prerun elevation was in CCK. Therefore, CCK seems to be an important regulation factor in response to anticipatory stress.

Growth hormone-releasing hormone (GHRH)-induced effects on sleep EEG and nocturnal secretion of growth hormone, cortisol and ACTH in patients with major depression.

Studies in normal human subjects and animals suggest that the neuropeptide growth hormone-releasing hormone (GHRH) is a common regulator of the sleep EEG and nocturnal hormone secretion. In healthy volunteers GHRH prompts an increase in the amount of slow wave sleep (SWS) and in growth hormone (GH) secretion and blunting of cortisol release. Inhibition of GHRH may contribute to sleep-endocrine aberrances during depression. We tested the effects of pulsatile application of 4 x 50 micrograms GHRH on the sleep EEG and simultaneously investigated nocturnal hormone secretion in 10 inpatients (four females, six males) with the acute episode of major depression. In contrast to the effects of placebo, GH secretion increased distinctly and rapid-eye-movement (REM) density decreased during the second half of night. No other significant changes in sleep-endocrine activity, including SWS, cortisol and ACTH secretion, could be observed. We assume that hypothalamic-pituitary-adrenocortical system activity and slow wave sleep are inert to the influence of GHRH during acute depression. Cortisol and ACTH remained unchanged even in a subsample of five younger (aged 19-28 years) patients. This observation is in contrast to our recent finding that cortisol secretion is blunted in young normal volunteers after GHRH. But on the other hand, GHRH is capable of stimulating GH and inducing a decrease in REM density in these subjects.

Temporal EEG dynamics of non-REM sleep episodes in humans.

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.

Effects of pulsatile cortisol infusion on sleep-EEG and nocturnal growth hormone release in healthy men.

This study investigates the short-term effects of pulsatile cortisol administrations upon sleep electroencephalogram (EEG) and spontaneous release of growth hormone (GH) in humans. Ten young healthy male volunteers received intravenous injections of either placebo or cortisol every 60 min between 17.00 hours and 06.00 hours (1 mg kg-1 BW with a loading dose of 20% starting at 17.00 hours, followed by a dose of 6% every hour until 06.00 hours). The amount of rapid eye-movement (REM) sleep was significantly reduced (placebo: 19.9 +/- 1.8; cortisol: 12.2 +/- 1.5%; P < 0.05), whereas the time spent in slow-wave sleep (SWS) was significantly increased (placebo: 9.4 +/- 1.6; cortisol: 13.9 +/- 1.9%; P < 0.05). The SWS-promoting effect was most prominent during the first hours of sleep, but tended to persist also during the second half of the night. The pulsatile cortisol administration augmented the total amount of plasma GH concentrations (mean area under the time course curve, AUC, placebo: 3.2 +/- 0.5; cortisol: 4.4 +/- 0.6 [ng x 1000 x ml min-1]; P < 0.05) due to an increase of GH release before sleep onset, and during the second half of the night, while the GH surge at sleep onset remained unchanged. Our data are in accordance with the hypotheses that cortisol-induced changes of both sleep-EEG and GH secretion involve a common mechanism that includes activation of the hypothalamic-somatotrophic (growth hormone releasing hormone-growth hormone) system.

Spectral composition of NREM sleep in healthy subjects with moderately increased daytime sleepiness.

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.

Dieting and pain sensitivity: a validation of clinical findings.

To validate findings of a reduced pain sensitivity in anorexia and bulimia nervosa, the effects of dieting on somatosensation (especially pain sensitivity) were investigated in healthy young women. One group of subjects (n = 11) received a calorically reduced balanced diet for 21 days, while the other group (n = 14) continued to eat normally. The fasting state induced in the dieting subjects was comparable to that of eating disorder patients, since the dieters showed a reduction of the body mass index, a decrease in triiodothyronine and an increase in beta-hydroxybutyric acid plasma levels. However, neither the thresholds of pain, warmth, cold and vibration sensitivity nor the peripheral skin temperature changed systematically under the diet. Therefore, the reduced pain sensitivity in eating disorder patients is apparently not a mere effect of fasting, but a true pathological feature.

On the immunological detection of X-ray induced DNA damage.

Denatured calf-thymus DNA was X-irradiated, coupled to methylated bovine serum albumin and injected into rabbits to study the possible formation of specific antibodies. The serological activity was tested by a modified Farr-test, a micro complement binding reaction and by caesium chloride isopycnic ultracentrifugation. It was found with all assays that the immunological reaction was mainly due to unspecific DNA-binding and only a very small amount to radiation products. It seems, therefore, that this approach is not suitable for the analytical investigation of DNA damage produced by ionizing radiation.

Dehydroepiandrosterone--a neurosteroid.

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.

Capgras syndrome--out of sight, out of mind?

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.

Assessment of cognitive performance after progesterone administration in healthy male volunteers.

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.

The hypothalamic-pituitary-adrenocortical system and sleep in man.

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.