Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans

The objective of this study was to evaluate the effects of nocturnal sleep, partial night sleep deprivation, and sleep stages on circulating concentrations of interleukin-6 (IL-6) in relation to the secretory profiles of GH, cortisol, and melatonin. In 31 healthy male volunteers, blood samples were obtained every 30 min during 2 nights: uninterrupted, baseline sleep and partial sleep deprivation-early night (awake until 0300 h). Sleep was measured by electroencephalogram polysomnography. Sleep onset was associated with an increase in serum levels of IL-6 (P < 0.05) during baseline sleep. During PSD-E, the nocturnal increase in IL-6 was delayed until sleep at 0300 h. Sleep stage analyses indicated that the nocturnal increase in IL-6 occurred in association with stage 1-2 sleep and rapid eye movement sleep, but levels during slow wave sleep were not different from those while awake. The profile of GH across the 2 nights was similar to that of IL-6, whereas the circadian-driven hormones cortisol and melatonin showed no concordance with sleep. Loss of sleep may serve to decrease nocturnal IL-6 levels, with effects on the integrity of immune system functioning. Alternatively, given the association between sleep stages and IL-6 levels, depressed or aged populations who show increased amounts of REM sleep and a relative loss of slow wave sleep may have elevated nocturnal concentrations of IL-6 with implications for inflammatory disease risk.     

On the gender differences in sleep-endocrine regulation in young normal humans.

Sleep-endocrine regulation in humans involves high activity of the somatotropic axis at the beginning of the night and an increase in the hypothalamic-pituitary-adrenocortical (HPA) system during the night. Gender differences were examined with regard to sleep-endocrine regulation in young healthy controls (10 men, 9 women). The sleep EEG was recorded (23:00-07:00 h) and plasma samples were collected and analyzed for GH, cortisol and ACTH at 20-min intervals. Cortisol secretion was significantly higher in females during the first half of the night (F = 9.9, p < 0.05), while ACTH was not different. In women, sleep-EEG analysis showed less slow wave sleep (SWS) during the second half of the night (F = 4.5, p < 0.05) and a significantly greater decrease in SWS and delta activity from the first to the second half of the night (F = 3.7 and 7.4, respectively, p < 0.05). Sigma activity increased during the night in women only (F = 3.7, p < 0.05). Our data are compatible with the hypothesis that in women compared to men activity of hypothalamic CRH neurons and central CRH release is greater, but is not reflected by greater HPA activity.     

Sleep-electroencephalography and the secretion of cortisol and growth hormone in normal controls

Sleep-electroencephalography, and the nocturnal secretion of cortisol and GH were investigated simultaneously in a sample of 25 male normal controls (27.1 +/- 1.3 years) in order further to examine interaction between sleep structure and concurrent endocrine activity. Slow wave sleep activity was increased during the first part of the night, whereas cortisol concentration was low and GH output reached maximal levels. The second half of the night was characterized by a relative preponderance of REM-sleep, low GH-concentration, and an increase in cortisol. However, no distinct reciprocal interaction between cortisol and GH concentration was noted. In all subjects, a pronounced GH surge between 22.00 and 02.00 h was recorded which occurred independently of the presence of slow wave sleep. Six out of the 25 subjects showed nocturnal GH increases even before sleep onset. These data indicate that somatotropic cell activity during night is less dependent upon the sleeping state or specific conventially defined sleep stages than originally reported.     

Altered growth hormone, cortisol, and leptin secretion in healthy elderly persons with sarcopenia and mixed body composition phenotypes

BACKGROUND: Obese phenotypes and aging are independently associated with hypothalamic-pituitary-adrenocortical (HPA) axis and leptin secretion alterations. However, leptin secretion and HPA axis function in elderly persons with other body composition phenotypes is largely unknown. METHODS: Forty-five healthy elderly participants were classified normal lean (NL), sarcopenic (SS), sarcopenic-obese (SO), or obese (OO) using dual-energy x-ray absorptiometry. Growth hormone (GH), cortisol, and leptin secretion were evaluated during a free-running night, and oral glucocorticoid suppression test (dexamethasone DEX). Diurnal cortisol secretion was assessed by hourly salivary samples with timed meals. Data were analyzed using cluster, deconvolution, and approximate entropy (ApEn) analyses. RESULTS: GH area, total secretion, and mean concentration during the free-running night was lower in the SO and OO groups verses the SS and NL groups (p <.02, Wilcoxon test). GH mean concentration and total secretion significantly increased in all groups during DEX (overall p <.05) except the SO group, in which ApEn increased (p =.03). Pre- and postbreakfast peak salivary cortisol (p =.004) and area under the curve (p =.03) was greatest in the SS group. Baseline leptin (11:00 pm) was significantly higher in the SO, OO, and SS groups verses the NL group (p =.01). Appendicular skeletal muscle mass was independently and negatively correlated with leptin in all groups, even after adjusting for percentage body fat (p =.001). CONCLUSIONS: In the presence of obesity, GH secretion was depressed with a blunted and disorderly response to oral glucocorticoid suppression in SO participants. Sarcopenic participants had concomitantly elevated leptin and cortisol relative to their low body fat mass. Complex or dysregulated neuroendocrine feedback systems appear to be operating in elderly persons with specific body composition phenotypes.     

Circadian interleukin-6 secretion and quantity and depth of sleep.

Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hypothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion. Eight healthy young male volunteers were sampled for 24 h twice, at the baseline state, after a normal night's sleep and after total overnight sleep deprivation. At the baseline state, IL-6 was secreted in a biphasic circadian pattern with two nadirs at 0800 and 2100 and two zeniths at 1900 and 0500 (P < 0.01). The baseline amount of sleep correlated negatively with the overall daytime secretion of the cytokine (P < 0.05). Also, depth of sleep at baseline correlated negatively with the postdeprivation increase of daytime secretion of IL-6 (P < 0.05). Sleep deprivation changed the temporal pattern of circadian IL-6 secretion but not the overall amount. Indeed, during the post-deprivation period, the mean daytime (0800-2200 h) levels of IL-6 were significantly higher (P < 0.05), whereas the nighttime (2200-0600 h) levels were lower than the predeprivation values. Thus, sleep-deprived subjects had daytime oversecretion and nighttime under-secretion of IL-6; the former might be responsible for their daylong somnolence and fatigue, the latter for the better quality (depth) of their sleep. These data suggest that a good night's sleep is associated with decreased daytime secretion of IL-6 and a good sense of well-being and that good sleep is associated with decreased exposure of tissues to the proinflammatory and potentially detrimental actions of IL-6. Sleep deprivation increases daytime IL-6 and causes somnolence and fatigue during the next day, whereas postdeprivation decreases nighttime IL-6 and is associated with deeper sleep.     

Impaired nighttime sleep in healthy old versus young adults is associated with elevated plasma interleukin-6 and cortisol levels: physiologic and therapeutic implications

IL-6 and TNF alpha secretion is increased by sleep loss or restriction. IL-6 secretion progressively increases with age, yet its association with decreased quality and quantity of sleep in old adults is unknown. This study examined the alteration of 24-h secretory pattern of IL-6, TNF alpha, and cortisol in 15 young and 13 old normal sleepers who were recorded in the sleep laboratory for four consecutive nights. Serial 24-h plasma measures of IL-6, TNF alpha, and cortisol were obtained during the fourth day, and daytime sleepiness was assessed with the multiple sleep latency test. Old adults, compared with young subjects, slept poorly at night (wake time and percentage stage 1 sleep were increased, whereas their percentage slow wave sleep and percentage sleep time were decreased, P < 0.05). Accordingly, their daytime sleep latency was longer than in young adults (P < 0.05). The mean 24-h IL-6 and cortisol levels were significantly higher in old than young adults (P < 0.05). In both groups, IL-6 and cortisol plasma concentrations were positively associated with total wake time, with a stronger association of IL-6 and cortisol with total wake time in the older individuals (P < 0.05); their combined effect was additive. IL-6 had a negative association with rapid eye movement (REM) sleep only in the young (P < 0.05), but cortisol was associated negatively with REM sleep both in the young and old, with a stronger effect in the young. We conclude that in healthy adults, age-related alterations in nocturnal wake time and daytime sleepiness are associated with elevations of both plasma IL-6 and cortisol concentrations, but REM sleep decline with age is primarily associated with cortisol increases.     

On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders

The hypothalamic-pituitary-adrenal (HPA) axis plays important roles in maintaining alertness and modulating sleep. Dysfunction of this axis at any level (CRH receptor, glucocorticoid receptor, or mineralocorticoid receptor) can disrupt sleep. Herein, we review normal sleep, normal HPA axis physiology and circadian rhythm, the effects of the HPA axis on sleep, as well as the effects of sleep on the HPA axis. We also discuss the potential role of CRH in circadian-dependent alerting, aside from its role in the stress response. Two clinically relevant sleep disorders with likely HPA axis dysfunction, insomnia and obstructive sleep apnea, are discussed. In insomnia, we discuss how HPA axis hyperactivity may be partially causal to the clinical syndrome. In obstructive sleep apnea, we discuss how HPA axis hyperactivity may be a consequence of the disorder and contribute to secondary pathology such as insulin resistance, hypertension, depression, and insomnia. Mechanisms by which cortisol can affect slow wave sleep are discussed, as is the role the HPA axis plays in secondary effects of primary sleep disorders.     

Middle-aged men show higher sensitivity of sleep to the arousing effects of corticotropin-releasing hormone than young men: clinical implications

The prevalence of insomnia associated with emotional stress increases markedly in middle-age. Both the top and end hormones of the hypothalamic-pituitary-adrenal axis, i.e. CRH and glucocorticoids, stimulate arousal/wakefulness and inhibit slow wave (deep) sleep in experimental animals and man. The objective of this study was to test the hypothesis that middle-age is characterized by increased sensitivity to the sleep-disturbing effects of the hypothalamic-pituitary-adrenal axis. We studied 12 healthy middle-aged (45.1 +/- 4.9) and 12 healthy young (22.7 +/- 2.8) men by monitoring their sleep by polysomnography for 4 consecutive nights, including in tandem 1 adaptation and 2 baseline nights and a night during which we administered equipotent doses of ovine CRH (1 microg/kg, iv bolus) 10 min after sleep onset. Analyses included comparisons within and between groups using multiple ANOVA and regression analysis. Although both middle-aged and young men responded to CRH with similar elevations of ACTH and cortisol, the former had significantly more wakefulness and suppression of slow wave sleep compared with baseline sleep; in contrast, the latter showed no change. Also, comparison of the change in sleep patterns from baseline to the CRH night in the young men to the respective change observed in middle-aged men showed that middle-age was associated with significantly higher wakefulness and significantly greater decrease in slow wave sleep than in young age. We conclude that middle-aged men show increased vulnerability of sleep to stress hormones, possibly resulting in impairments in the quality of sleep during periods of stress. We suggest that changes in sleep physiology associated with middle-age play a significant role in the marked increase of prevalence of insomnia in middle-age.     

Cortisol secretary pattern and glucocorticoid feedback sensitivity in women from a Mediterranean area: relationship with anthropometric characteristics, dietary intake and plasma fatty acid profile

BACKGROUND: Chronic stress is associated with a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis consisting on disturbances on the cortisol response and lipid metabolism. OBJECTIVE: To evaluate the HPA axis activity in women from a Mediterranean area, comparing three different measurements: daily cortisol secretory variability, postprandial cortisol secretion and glucocorticoid feedback sensitivity. In addition, HPA axis disturbance is correlated with dietary habits and plasma fatty acid profiles. DESIGN: The participants were 41 women born during the first 6 months of 1960 and living in a Mediterranean area (Murcia, Spain). They were of normal weight, with a waist circumference of 80.5 +/- 9.3 cm. Their salivary cortisol levels, 7-day dietary record and plasma fatty acid profile were evaluated. Daily cortisol variability and postlunch cortisol secretion were recorded and a dexamethasone suppression test is performed in order to detect possible HPA disturbance. RESULTS: Both the methods used for HPA axis evaluation were positively correlated (r = 0.448, P = 0.004). Subjects with normal diurnal curves (high cortisol variability) showed significantly higher cortisol values in the morning and postprandial cortisol secretion than women with pathological curves (medium and low variability). Cortisol variability was inversely correlated with waist circumference (r = -0.312, P = 0.047), suggesting that a disturbed HPA axis response may lead to an android pattern of body fat distribution. Dietary fat and saturated fatty acid intake were lower in the high cortisol variability group, while monounsaturated fatty acid intake was higher (P < 0.05). No major differences were reported in plasma fatty acid profile. CONCLUSIONS: A disturbed HPA axis is associated with abdominal fat distribution and a higher content of fat and saturated fatty acids in the diet. Women who chose a dietary pattern closer to the Mediterranean diet, with high monounsaturated fatty acid intake, showed lower levels on HPA axis disturbance.     

Obesity and the hypothalamic-pituitary-adrenal axis in adolescent girls

Stress and stress-related concomitants, including hypothalamic-pituitary-adrenal (HPA) axis activation, are implicated in obesity and its attendant comorbidities. Little is known about this relationship in adolescents. To begin to address this important knowledge gap, we studied HPA axis activity in 262 healthy adolescent girls aged 11, 13, 15, and 17 years. We hypothesized that obesity would be correlated with increased HPA axis activity and reactivity. Measures of HPA axis activity included 3 blood samples obtained midday (between 1:00 and 2:00 pm) over the course of 40 minutes; overnight urine free cortisol; and cortisol levels 0, 20, and 40 minutes after venipuncture (cortisol reactivity). Measures of adiposity included body mass index (BMI), BMI z score (BMI-Z), percentage body fat, and fat distribution (central adiposity) assessed by dual-energy x-ray absorptiometry. Daytime levels of serum cortisol were inversely associated with BMI-Z and central adiposity (P < .05). The urine free cortisol excretion rate was positively correlated with BMI, BMI-Z, and central adiposity. There was blunting of cortisol response to venipuncture with increasing adiposity. Our results suggest that there may be reduced cortisol levels during the day and increased levels at night with increasing degree of adiposity. This study provides preliminary findings indicating an alteration of the circadian rhythm of cortisol with obesity. We conclude that obesity is associated with altered HPA activity in adolescent girls. The clinical implications of our findings require further investigation.     

Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications

Although insomnia is, by far, the most commonly encountered sleep disorder in medical practice, our knowledge in regard to its neurobiology and medical significance is limited. Activation of the hypothalamic-pituitary-adrenal axis leads to arousal and sleeplessness in animals and humans; however, there is a paucity of data regarding the activity of the hypothalamic-pituitary-adrenal axis in insomniacs. We hypothesized that chronic insomnia is associated with increased plasma levels of ACTH and cortisol. Eleven young insomniacs (6 men and 5 women) and 13 healthy controls (9 men and 4 women) without sleep disturbances, matched for age and body mass index, were monitored in the sleep laboratory for 4 consecutive nights, whereas serial 24-h plasma measures of ACTH and cortisol were obtained during the fourth day. Insomniacs, compared with controls, slept poorly (significantly higher sleep latency and wake during baseline nights). The 24-h ACTH and cortisol secretions were significantly higher in insomniacs, compared with normal controls (4.2 +/- 0.3 vs. 3.3 +/- 0.3 pM, P = 0.04; and 218.0 +/- 11.0 vs. 190.4 +/- 8.3 nM, P = 0.07). Within the 24-h period, the greatest elevations were observed in the evening and first half of the night. Also, insomniacs with a high degree of objective sleep disturbance (% sleep time < 70), compared with those with a low degree of sleep disturbance, secreted a higher amount of cortisol. Pulsatile analysis revealed a significantly higher number of peaks per 24 h in insomniacs than in controls (P < 0.05), whereas cosinor analysis showed no differences in the temporal pattern of ACTH or cortisol secretion between insomniacs and controls. We conclude that insomnia is associated with an overall increase of ACTH and cortisol secretion, which, however, retains a normal circadian pattern. These findings are consistent with a disorder of central nervous system hyperarousal rather than one of sleep loss, which is usually associated with no change or decrease in cortisol secretion or a circadian disturbance. Chronic activation of the hypothalamic-pituitary-adrenal axis in insomnia suggests that insomniacs are at risk not only for mental disorders, i.e. chronic anxiety and depression, but also for significant medical morbidity associated with such activation. The therapeutic goal in insomnia should be to decrease the overall level of physiologic and emotional arousal, and not just to improve the nighttime sleep.     

Hypothalamo-pituitary-adrenal axis activity is related to the level of central arousal: effect of sleep deprivation on the association of high-frequency waking electroencephalogram with cortisol release

The temporal and quantitative interrelationships between the hypothalamo-pituitary-adrenal (HPA) axis activity and the level of central arousal were studied in 10 healthy young men during daytime wakefulness. Two experimental sessions were conducted randomly between 09.00 and 18.00 h, once after nocturnal sleep and once after a night of total sleep deprivation. Spectral analysis of serial waking electroencephalography (EEG) from a short target fixation task repeated every 10 min was undertaken, along with an estimation of cortisol secretory profiles by deconvolution of plasma radioimmunoassay measures obtained from continuous blood withdrawal with regular sampling at a 10-min interval. Following nocturnal sleep, a temporal association between the HPA axis activity and the waking EEG activity was found, cortisol secretory rate following changes in frontal gamma (20-45 Hz) band power by 10 min (average R = 0.458, p < 0.001). Although it remained significant (average R = 0.276, p < 0.05), the association strength decreased significantly following total sleep deprivation (p < 0.05, Wilcoxon test). Cortisol plasma level, secretory rate and pulse amplitude were increased as well as waking EEG power in the delta (0.5-5.5 Hz), theta (5.5-8.5 Hz) and gamma frequency bands (all p values <0.05, Student t tests). The sleep deprivation-related increases in cortisol secretory rate and waking EEG gamma activity were quantitatively associated (R = 0.504, p < 0.05). These results support the existence of a common ultradian regulatory mechanism, co-ordinating HPA axis activity to the level of central arousal in man, which seems involved in the sleep deprivation-induced hyper-arousal.     

阻塞性睡眠呼吸暂停低通气综合征患者下丘脑-垂体-肾上腺轴和生长激素轴激素水平的变化分析

目的探讨阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者下丘脑-垂体-肾上腺轴和生长激素轴激素水平的变化及相互调节。方法对 OSAHS 患者(OSAHS 组)和单纯肥胖者(对照组)进行多导睡眠监测,应用酶联免疫吸附测定(ELISA)和放射免疫法测定睡前和睡后血浆促肾上腺皮质素释放激素(CRH)、促肾上腺皮质素(ACTH)、皮质醇、促生长素释放激素(GHRH)和生长激素(GH),分析其间的变化关系。结果与对照组比较,OSAHS 组患者 CRH、皮质醇明显升高[对照组睡前、睡后 CRH 分别为(0.67±0.42)、(2.27±1.10)mmol/L,OSAHS 组分别为(1.66±0.34)、(4.96±0.98)mmol/L;对照组睡前、睡后皮质醇分别为(68.94±20.13)、(146.05±30.48)μg/L,OSAHS 组分别为(152.93±136.15)、(445.53±123.09)μg/L;P 均<0.01];GHRH 降低[对照组睡前、睡后 GHRH 分别为(1.99±0.34)、(1.58±0.15)mmol/L,OSAHS 组分别为(1.42±0.07)、(1.01±0.05)mmol/L;P 均<0.05],而 GH 未表现明显差异(P>0.05);睡眠前后 CRH、GHRH 变化值之比(ΔCRH/ΔGHRH,285.02±143.32)也显著高于对照组(71.15±15.37,P<0.01);ΔCRH/ΔGHRH 与平均觉醒时间呈正相关(r=0.882),与平均血氧饱和度呈负相关(r=-0.696),平均血氧饱和度与平均觉醒时间呈负相关(r=-0.729)。结论 OSAHS 患者下丘脑-垂体-肾上腺轴和生长激素轴水平异常,反馈调节紊乱,并与睡眠觉醒和夜间低氧有关。     

Differential effects of hydrocortisone, fluocortolone, and aldosterone on nocturnal sleep in humans

Previous experiments have suggested that sleep processes are sensitive to influences of corticosteroids. The present experiment was designed to compare effects of three different corticosteroids on human sleep: fluocortolone (a synthetic pure glucocorticoid), cortisol which possesses glucocorticoid and mineralocorticoid activity, and aldosterone (the major mineralocorticoid). Ten male adult subjects were tested in four experimental nights according to a double-blind latin-square design under conditions of either 1.0 mg of aldosterone, 20 mg of fluocortolone, 80 mg of hydrocortisone, or placebo. Substances were administered orally (fluocortolone, 23.00 h) or infused iv throughout the night (hydrocortisone, aldosterone) starting at 23.00 h. Hydrocortisone and fluocortolone induced a substantial reduction of rapid eye movement sleep. Hydrocortisone increased slow wave sleep activity. No such effect was observed after fluocortolone. Effects on sleep processes of aldosterone, in general, seemed to be neglegible. The results demonstrate differential effects of synthetic glucocorticoid, cortisol, and aldosterone on sleep in humans, which may be attributed to the heterogeneity of corticosteroid receptors in the brain.     

Effects of sleep and sleep deprivation on catecholamine and interleukin-2 levels in humans: clinical implications.

The objective of this study was to evaluate the effects of nocturnal sleep, partial night sleep deprivation, and sleep stages on catecholamine and interleukin-2 (IL-2) levels in humans. Circulating levels of catecholamines and IL-2 were sampled every 30 min during 2 nights: undisturbed, baseline sleep and partial sleep deprivation-late night (PSD-L; awake from 0300-0600 h) in 17 healthy male volunteers. Sleep was monitored somnopolygraphically. Sleep onset was associated with a significant (P < 0.05) decline of circulating concentrations of norepinephrine and epinephrine, with a nocturnal nadir that occurred 1 h after nocturnal sleep. On the PSD-L night, levels of norepinephrine and epinephrine significantly (P < 0.05) increased in association with nocturnal awakening. During stage 3-4 sleep, levels of norepinephrine, but not epinephrine, were significantly lower (P < 0.05) compared to average levels during the awake period, stages 1-2 sleep, and rapid eye movement sleep. Nocturnal levels of circulating IL-2 did not change with sleep onset or in relation to PSD-L or the various sleep stages. We conclude that sleep onset is associated with changes in levels of circulating catecholamines. Loss of sleep and disordered sleep with decreases in slow wave sleep may serve to elevate nocturnal catecholamine levels and contribute to cardiovascular disease.     

Effects of thyrotropin-releasing hormone on sleep and sleep-related growth hormone release in normal subjects.

Effects of TRH on sleep and sleep-related growth hormone (GH) release were examined in four normal volunteers. A bolus of 500 microgram of synthetic TRH was injected iv at the onset of sleep, followed by continuous iv infusion of 1000 microgram of TRH dissolved in saline for 3 h on two nights. Saline alone was infused on two control nights in each of these subjects. Polygraphic sleep records showed that TRH transiently interrupted sleep on both nights in all of the four subjects. The arousal phenomenon was observed from 80 to 151 min after the start of TRH administration until 20 to 212 min after the end of TRH infusion. The mean (+/-SE) percentage of awakening on the nights of TRH administration was significantly larger than on the control nights (36.4 +/- 1.9% vs. 1.3 +/- 0.8%, P less than 0.001). Plasma GH increased in close relationship to the initial appearance of slow wave sleep (SWS) within 40 min after sleep onset on both control nights in all four subjects. On nights of TRH administration, however, plasma GH levels during the initial 80 min of sleep were significantly lower (P less than 0.005) than on control nights, whereas SWS was demonstrated before the interruption of sleep. On nights when sleep was interrupted by forced wakefulness 1 h after sleep onset, plasma GH rose to levels comparable to those on control nights during early sleep periods in all subjects examined. These results suggest that TRH inhibits sleep and sleep-related GH release in normal subjects.     

Reliability of stimulated and spontaneous growth hormone (GH) levels for identifying the child with low GH secretion.

The reliability of stimulated and spontaneous GH levels for identifying the child with low GH secretion has been the subject of debate. We compared the ability of GH concentrations after pharmacological stimulation with levodopa and clonidine and of spontaneous peak and 12-h pooled GH concentrations during sleep on a single night to estimate the maximum spontaneous GH secretion from 2 nights in 55 children, aged 5-16 yr, with heights below the 3rd percentile and/or height velocities below the 25th percentile for age, who had two consecutive overnight GH secretory profiles. Maximum stimulated GH concentrations correctly categorized 80% of children who had maximum spontaneous GH concentrations above and below 4 micrograms/L using a double monoclonal immunoradiometric assay for GH (Tandem-R HGH, Hybritech). The remaining 20% of children had stimulated GH concentrations below but spontaneous GH concentrations above 4 micrograms/L. Using this cut-off, the maximum GH concentrations from the first and second nights correctly categorized 98% and 95% of the children, respectively. Night to night variation in GH secretion was low in children who had low spontaneous GH secretion (maximum spontaneous peak and pool GH concentrations, less than 4 and less than or equal to 0.7 micrograms/L, respectively), and pooled GH concentrations from the 2 nights were concordant in 98% of the cases. We conclude that it is not uncommon for stimulated GH concentrations to underestimate spontaneous GH secretion. Even without acclimatization to the hospital setting, measurement of spontaneous GH secretion on a single night was more reliable for identifying the child with low endogenous GH secretion than was GH stimulation testing alone.     

Brief wake episodes modulate sleep-inhibited luteinizing hormone secretion in the early follicular phase

To determine the influence of sleep, sleep stage, and time of day on the dynamics of pulsatile LH secretion in the early follicular phase (EFP) of the menstrual cycle, 11 normal women underwent simultaneous polysomnographic monitoring of sleep and measurement of LH in frequent sampling studies during a 40-h protocol that consisted of one night of normal sleep and one night of sleep deprivation followed by an afternoon nap. The interpulse interval of LH was longer during sleep than wake whether it occurred at night or during the day (P < 0.002), implying a decrease in GnRH pulse frequency associated with sleep in the EFP. LH pulse amplitude was greater during sleep than wake (P < 0.001) and greater pulse amplitudes were associated with longer interpulse intervals during sleep (P < 0.005), but not wake. An interaction between sleep and time of day was observed for mean LH, with lower mean LH levels during sleep than wake at night (P < 0.02), but not during the day. Wakefulness was more likely to be associated with an LH pulse than were stages I/II, III/IV (slow wave), or rapid eye movement sleep (P < 0.005). In addition, the probability of wakefulness within the sleep episode increased 5-15 min before the onset of LH pulses (relative to randomly selected nonpulse LH; P < 0.05), suggesting that wakefulness was the primary event. In the absence of sleep, there was an effect of time of day on mean LH (P < 0.02) and LH pulse amplitude (P < 0.03), with greatest values seen during the evening. In conclusion, in the EFP, inhibition of LH pulse frequency is related to sleep rather than time of day. During periods of sleep, LH pulses occur most commonly in association with brief awakenings, suggesting that interruptions from sleep allow escape from the inhibitory effect of sleep on pulsatile GnRH secretion. A separate effect of time of day on LH pulse dynamics in the absence of sleep was also observed with evening augmentation of LH pulse amplitude and mean level; however, additional studies will be required to determine whether this represents a true circadian effect.     

Rhythms of pituitary-adrenal activity during sleep in patients with Cushing's disease.

Previous studies have indicated a dependence of nocturnal pituitary-adrenal secretory activity on central nervous sleep processes in healthy humans: Under normal physiological conditions the release of ACTH/cortisol is inhibited during early sleep and becomes entrained to periods of NonREM sleep during late sleep. Here, we compared nocturnal dynamics in plasma concentrations of ACTH/cortisol in 7 patients with Cushing's disease with those of 7 healthy controls matched in age and sex with the patients. The patients in part were repeatedly tested. The total of 13 nights is composed of 7 nights of hyperpulsatile secretion pattern (5 patients) and 6 nights from hypopulsatile secretion pattern (4 patients). After an adaptation night polysomnographic sleep recordings were obtained and blood was sampled every 15 min between 23.00 and 7.00 h. Controls displayed the typical minimum in ACTH/cortisol concentrations during the early part of the night and maximum concentrations during the late part of the night, whereas ACTH/cortisol levels of Cushing patients indicated a relatively constant elevated pituitary-adrenal activity throughout the night, lacking any circadian variation. Autocorrelation functions revealed the presence of cortisol secretory rhythms with a similar period length in healthy controls (155.6+/-17.4 min) and patients with a hyperpulsatile pattern (142.4+/-6.6 min). In patients displaying hypopulsatility, no significant rhythmicity was observed. However, regardless of the type of secretory pulsatility, adrenal secretory activity started predominantly during periods of NonREM sleep (p<0.01) in healthy controls as well as in patients with Cushing's disease. This data indicates that the normal nocturnal circadian oscillation of pituitary-adrenal activity is absent in Cushing patients, whereas a link between pituitary-adrenal activity and ultradian rhythms of sleep appears to be preserved.     

Diurnal changes in the content of indoleamines, catecholamines, and methoxyindoles in the pineal gland of the Djungarian hamster (Phodopus sungorus): Effect of photoperiod

Abstract: Early investigations of the effect of sleep deprivation on plasma melatonin reported no major changes. Recently, 36 hrs of sleep deprivation was reported to elevate melatonin levels on the post-sleep deprivation night. Given these contradictions melatonin, Cortisol, prolactin, and thyroid stimulating hormone before, during, and, after sleep deprivation were examined in nine healthy young males following one night of sleep deprivation. Hormone levels at hourly intervals, for each night, were statistically analyzed by a repeated measures, two-way factorial ANOVA. ANOVA was also performed for measures of area under the curve (AUC). No significant differences were observed for melatonin levels. Cortisol was significantly higher on the sleep deprivation night presumably reflecting the aroused state accompanying being awake; however, there were several time points on the control night when it was elevated also. Prolactin was higher on the post-sleep deprivation and control nights but did not rise on the deprivation night, indicating a useful nonpolysomnographic index for discriminating overnight sleep and awake states. TSH levels showed a similar rise during the control and sleep deprivation nights, but remained flat on the post-sleep deprivation night. It appears that the pineal is insulated against feedback from changes to the level of arousal accompanying sleep and wakefulness. In comparison, Cortisol, prolactin, and TSH levels vary with these states and are, therefore, useful indices of arousal and sleep-wake.