Simulation of long-haul flights in humans: prolonged mild hypoxia does not alter the circadian time structure of plasma testosterone and gonadotrophins.

Mild hypobaric hypoxia caused by pressurisation may contribute to alter rhythmicity after long-haul flights, independently of the number of time zones crossed. In this controlled crossover study, we assessed the effects of two levels of hypoxia, equivalent to 8000 ft and 12,000 ft above sea level, on the rhythm of plasma concentrations of three hormones: testosterone, LH, and FSH. A hypoxia-induced decrease in LH and FSH has often been reported during mountaineering while testosterone is considered a marker of fatigue. Sixteen healthy male volunteers, aged 23-39 years, spent 8 h in a hypobaric chamber (08:00-16:30), simulating conditions at 8000 ft. This was followed by an additional 8 h four weeks later, simulating conditions at 12,000 ft. Plasma hormones were assayed every 2 h over two 24-h cycles (control and hypoxic-exposure cycles). We found no significant effects of hypoxia on the circadian profile of the gonadal axis hormones and, therefore, conclude that these hormones do not serve as valuable markers of post-flight alterations of the circadian system in human.

Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder.

BACKGROUND: Many studies in autistic disorder report sleep problems and altered circadian rhythms, suggesting abnormalities in melatonin physiology. Additionally, melatonin, a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. METHODS: Nocturnal urinary excretion of 6-sulphatoxymelatonin was measured by radioimmunoassay in groups of children and adolescents with autistic disorder (n = 49) and normal control individuals (n = 88) matched on age, sex, and Tanner stage of puberty. RESULTS: Nocturnal 6-sulphatoxymelatonin excretion rate was significantly and substantially lower in patients with autism than in normal controls (mean +/- SEM, .75 +/- .11 vs. 1.80 +/- .17 microg/hr, p =.0001), and was significantly negatively correlated with severity of autistic impairments in verbal communication and play (p < .05). CONCLUSIONS: These findings indicate clearly that nocturnal production of melatonin is reduced in autism. Further research is warranted in order to understand the mechanisms underlying the lower melatonin production, to assess the impact of altered melatonin on the pathophysiology and behavioral expression of autistic disorder, and to determine the utility of melatonin administration in individuals with autism.

Old rats are more sensitive to photoperiodic changes. A study on pineal melatonin.

After having previously demonstrated that beta-adrenergic stimulation of melatonin under a standard light:dark (LD) cycle regimen of 12:12 is more effective in young than in old pineal glands, we have now studied how the daylength change LD 18:6 affects pineal melatonin secretion and its regulation by the beta-adrenergic system. Young (10 weeks) and old (22 months) male Wistar rats were synchronized with either a standard LD 12:12 for 4 weeks, or acclimatized under the same LD conditions for 4 weeks, then subjected to a long LD 18:6 photoperiod for 1 week. The rats were sacrificed at three time samplings: 0, 4, and 7h after dark onset (HADO) for LD 12:12 or 0, 2, and 3.5 HADO for LD 18:6. Pineal glands were collected and perifused for 480 min. Isoproterenol (10(-4)M) was infused for 20 min, 4h 10 min after the beginning of the perifusion. Basal levels of melatonin production in the young rats displayed a 1.5-2.5-fold increase compared to those in the old rats. Interestingly, mean basal melatonin levels in old rats under standard LD 12:12 conditions were significantly higher (P<0.05) than mean levels at the same relative dark phase intervals under LD 18:6 conditions. Isoproterenol stimulated melatonin production in both young and old rat pineal glands, regardless of time sampling or photoperiodic conditions. The magnitude of the response to 10(-4)M isoproterenol infusion in old pineals was approximately half that found in young glands (P<0.001), and tended to be higher under LD 12:12, in both young and old rat pineal glands, although no significant difference was found in melatonin response between the two photoperiods (P>0.05). This study shows that basal pineal melatonin levels in old rats are more sensitive to photoperiod changes than in young rats. These results also demonstrate that isoproterenol can stimulate both young and old rat pineal glands irrespective of time or photoperiod and confirm previous findings, showing that the melatonin response to isoproterenol is age-dependent and that pineal gland response to isoproterenol is not photoperiod-dependent, at least under our experimental conditions.

Hypoxic alterations of cortisol circadian rhythm in man after simulation of a long duration flight.

Fatigue is often reported after long duration flights. Mild hypobaric hypoxia caused by pressurisation may be involved in this effect through disruption of circadian rhythms, independently of the number of time zones crossed. In this controlled crossover study, we assessed the effects of two levels of hypoxia equivalent to 8000 and 12,000 ft on the circadian rhythm of plasma cortisol, a marker of the circadian time structure. Sixteen healthy young male volunteers (23-39 years) were exposed in a hypobaric chamber for 8 h (08:00-16:00 h) to 8000 ft, followed 4 weeks later to 12,000 ft. Plasma cortisol was assayed during two 24-h cycles (control and hypoxic exposure) every 2h in all subjects. We found a significant change in the pattern of cortisol secretion during both hypoxic exposures, with an initial fall in cortisol followed by a transient rebound, whereas the phase and the 24-h mean level remained unchanged. The change in cortisol pattern followed the alterations in autonomic balance assessed by heart rate variability (HRV) spectral analysis. The normalised high frequencies and the low-to-high frequencies ratio showed a significant shift toward sympathetic dominance with some differences in time course for both altitudes studied. HRV analysis improved the interpretation of cortisol 24-h profiles. Our data, which strongly suggest that prolonged mild hypoxia alters the expression of cortisol circadian rhythm, should be taken into account to interpret secretory rhythm changes after transmeridian flights.

Isoproterenol-stimulated melatonin production by perifused rat pineal glands: age- and time-related effects.

OBJECTIVES: The purpose of this study was to investigate and compare the effects of the beta-adrenergic agonist, isoproterenol, on induced increase in melatonin production in the pineal gland of young and old rats, at different circadian stages. MATERIALS AND METHODS: We report here the effects of 10(-6) M isoproterenol-stimulated melatonin production by perifused pineal glands obtained from young (55 day old) and old (21 month old) male Wistar rats acclimatised to light:dark cycles regimen of 12:12 for 3 weeks. Pineal glands were collected at different circadian stages: 3, 7, 11, 15, 19 and 23 hours after light onset (HALO), and perifused for 510 min. RESULTS: The basal levels of melatonin production in the young rats were approximately twice greater than those of the old rats. Isoproterenol stimulated melatonin production in both young and old rat pineal glands, whatever the circadian stage. The intensity of the response to 10(-6) M isoproterenol infusion was greater in young than in old rat pineal glands (P<0.001), with a trend towards an increase during the light phase, at 7 HALO, in both young and old rat pineal glands, although this trend towards increased melatonin response did not reach statistical significance (P>0.05). CONCLUSIONS: These results show that isoproterenol is able to stimulate both young and old rat pineal glands whatever the circadian stage. The magnitude of isoproterenol stimulation is greater in young than in old glands. Our results also suggest that the pineal gland response to isoproterenol is not dependent on circadian stage, at least, under our experimental conditions.

Altered circadian patterns of salivary cortisol in low-functioning children and adolescents with autism.

BACKGROUND: Reports of higher stress responsivity, altered sleep-wake cycle and a melatonin deficit in autism have stimulated interest in the cortisol circadian rhythm in individuals with autism. METHODS: The study was conducted on 55 low-functioning children and adolescents with autism (11.3 ± 4.1 years-old) and 32 typically developing controls (11.7 ± 4.9 years-old) matched for age, sex and puberty. Behavioral assessment was performed using the Autism Diagnostic Observation Schedule (ADOS). Salivary samples for measurement of cortisol were collected during a 24-h period (at least 0800 h-Day 1, 1600 h, 0800 h-Day 2 for 46 individuals with autism and 27 controls, and 0800 h-Day 1, 1100 h, 1600 h, 2400 h, 0800 h-Day 2 for 13 individuals with autism and 20 controls). Overnight (2000 h-0800 h) urinary cortisol excretion was also measured. RESULTS: The autism group displayed significantly higher levels of salivary cortisol at all time-points, flatter daytime and nighttime slopes, higher 0800 h cortisol levels on Day 2 compared to Day 1, and greater variances of salivary and urinary cortisol. There was a significant relationship between salivary cortisol levels and impairments in social interaction and verbal language. Overnight urinary cortisol excretion was similar in the autism and control groups. CONCLUSION: Anticipation of the stressful collection procedure appears to contribute to the higher 0800 h-Day 2 versus 0800 h-Day 1 salivary cortisol levels in autism. This sensitization to stressors might be as, or even more, important clinically than exposure to novelty in autism. The similar group means for overnight urinary cortisol excretion indicate that basal HPA axis functioning is unaltered in low-functioning autism. The elevated salivary cortisol levels observed in autism over the 24-h period in a repeated stressful condition, flattened diurnal cortisol patterns and the apparent effect of anticipation are consistent with prior findings in high trait anxiety.

Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder.

BACKGROUND: Several reports indicate that nocturnal production of melatonin is reduced in autism. Our objective was to examine whether melatonin production is decreased during the whole 24-h cycle, whether the melatonin circadian rhythm is inverted, and whether the reduction in melatonin production is related to the severity of autistic behavioral impairments. METHOD: Day and nighttime urinary excretion of 6-sulphatoxymelatonin (6-SM) was examined during a 24-h period in post-pubertal individuals with autism (N=43) and typically developing controls (N=26) matched for age, sex and pubertal stage. RESULTS: Low 6-SM excretion (mean ± SEM) was observed in autism, both at daytime (0.16 ± 0.03 vs. 0.36 ± 0.05 µg/h, p<0.01), nighttime (0.52 ± 0.07 vs. 1.14 ± 0.23 µg/h, p<0.05), and during 24h (8.26 ± 1.27 vs. 18.00 ± 3.43 µg/24-h collection, p<0.001). Intra-individual nighttime-daytime differences (delta values) in 6-SM excretion were smaller in individuals with autism than in controls (0.36 ± 0.07 vs. 0.79 ± 0.23 µg/h, p<0.05). Nocturnal excretion of 6-SM was negatively correlated with autism severity in the overall level of verbal language (Spearman ρ=-0.30, p<0.05), imitative social play (Spearman ρ=-0.42, p<0.05), and repetitive use of objects (Spearman ρ=-0.36, p<0.05). CONCLUSION: A deficit in melatonin production is present both at daytime and at nighttime in individuals with autism, particularly in the most severely affected individuals. These results highlight interest in potential therapeutic uses of melatonin in autistic disorder, especially in individuals with severe autistic impairment and/or low urinary 6-SM excretion.

Magnetic fields and the melatonin hypothesis: a study of workers chronically exposed to 50-Hz magnetic fields.

Because epidemiological studies report clinical disorders (mainly neurobehavioral alterations and/or cancer) that may be related to diminished melatonin secretion or to changes in its circadian rhythm in subjects living or working in environments exposed to magnetic fields, research on the effects of these fields in humans is particularly important. In this study, we examine the circadian rhythm of melatonin in 15 men exposed chronically and daily for a period of 1-20 yr, in the workplace and at home, to a 50-Hz magnetic field in search of any cumulative effect from those chronic conditions of exposure. The weekly geometric mean of individual exposures ranged from 0.1 to 2.6 microT. The results are compared with those for 15 unexposed men who served as controls (individual exposures ranged from 0.004 to 0.092 microT). Blood samples were taken hourly from 2000 to 0800. Nighttime urine was also collected and analyzed. This work shows that subjects exposed over a long period (up to 20 yr) and on a daily basis to magnetic fields experienced no changes in their plasma melatonin level, their urinary 6-sulfatoxymelatonin level, or the circadian rhythm of melatonin. Our data strongly suggest that magnetic fields do not have cumulative effects on melatonin secretion in humans and thus clearly rebut the "melatonin hypothesis" that a decrease in plasma melatonin concentration (or a disruption in its secretion) explains the occurrence of clinical disorders or cancers possibly related to magnetic fields.

Hypoxic depression of melatonin secretion after simulated long duration flights in man.

Fatigue is often reported after long duration flights. Mild hypobaric hypoxia caused by pressurization may be involved in this effect through disruption of circadian rhythms, independent of the number of time zones crossed. In this controlled crossover study we assessed the effects of two levels of hypoxia equivalent to 8000 and 12,000 ft on the rhythm of plasma melatonin concentrations, a marker of circadian rhythmicity. Sixteen healthy young male volunteers (23-39 years) were exposed in a hypobaric chamber for 8 hr (08:00-16:00 hours) to 8000 ft, followed 4 wk later by 12,000 ft. Plasma melatonin was assayed over two 24-hr cycles (control and hypoxic exposure) every 2 hr in all subjects. We found a significant decrease in the nocturnal melatonin peak after hypoxic exposure at both altitudes, and we found that this effect was age dependent for the 12,000-ft exposure: the decrease was only seen in the younger subjects (23-28 years). Analysis of heart rate variability allowed us to demonstrate that the older and less trained subjects (29-39 yr) in our study exhibited a far greater increase in sympathetic tone than the younger subjects during the 12,000-ft exposure. These results show that hypoxic depression of melatonin secretion may be influenced by individual factors such as age, physical fitness and sympathetic reactivity to hypoxia. Our findings suggest that hypoxia may by itself contribute at least in part to postflight fatigue after long duration flights, and to the clinical disorders of jet lag in transmeridian flights through its effects on the circadian system.