Promoting adjustment of the sleep-wake cycle by chronobiotics.

Chronobiotics are substances that adjust the timing of internal biological rhythms. Many classes of drugs have been claimed to possess such properties and arouse growing interest as the circumstances for their use in sleep disturbances caused by circadian rhythms alterations (delayed or advanced sleep-phase syndromes, non-24-h sleep-wake disorders, jet lag, shift work sleep disorders and so on) have become progressively more frequent. Amongst the substances potentially presenting chronobiotic properties, a consensus seems to be reached on the possible use of melatonin or its agonists to shift the phase of the human circadian clock, but optimizing the dose, formulation and especially the time of administration require further studies.

Human immune circadian system in prolonged mild hypoxia during simulated flights.

An impairment of immunity is reported after long-haul flights, and the mild hypobaric hypoxia caused by pressurization in the passenger airline cabin may contribute to it. In this controlled crossover study, the effects of two levels of hypoxia, equivalent to 8000 and 12,000 feet above sea level, on the rhythm of CD3, CD4, and CD8 lymphocytes and plasma concentrations of the immunoglobulins A, G, and M were assessed. Fourteen healthy male volunteers, aged 23 to 39 years, spent 8.5 h in a hypobaric chamber (08:00 to 16:30 h), simulating an altitude condition at 8,000 feet. This was followed by an additional 8.5 h study four weeks later simulating altitude conditions at 12,000 feet. The variables were assayed every 2 h over two 24 h cycles (control and hypoxic-exposure cycles). No significant effect of hypoxia on the studied circadian immune profiles were found. Therefore, the authors conclude that mild hypobaric hypoxia does not seem to be responsible for any quantitative changes during long-haul flights in the immune assays commonly used in routine clinical medicine practice.

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.

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.

Circadian rhythm characteristics of serum cortisol and dehydroepiandrosterone sulfate in healthy Chinese men aged 30 to 60 years. A cross-sectional study.

The relation of adrenal function and aging has been the subject of intense interest in recent years. The circadian variations of plasma cortisol have been described in Caucasians, but little information is available on such hormone variations among the Chinese population, especially its changes with age. This study was, therefore, designed to examine the effects of age on the circadian variations of serum cortisol, dehydroepiandrosterone sulfate (DHEAS) and the molar ratio of cortisol/DHEAS in Chinese men, stratified by 10-year age-groups (i.e. men in their 30-60s, aged from 31 to 63 years old). Circadian variations of serum cortisol and DHEAS were documented at 2-h intervals from 8:00 to 22:00 and hourly from 22:00 to 8:00 in 26 healthy Chinese men. We found that the serum levels of both hormones showed a statistically significant circadian rhythmicity in all age-groups. The circadian pattern of serum cortisol was characterized by peaks (04:00-06:00) and troughs (18:00-24:00) occurring approximately 2h earlier than those usually reported in Caucasians. Aging did not significantly influence serum cortisol concentrations, but serum DHEAS levels declined significantly with age: subjects in their 60s had significantly lower levels, and their cortisol/DHEAS molar ratios were significantly higher than those in the younger age-groups.

Cortisol secretion in the elderly. Influence of age, sex and cardiovascular disease in a Chinese population.

Adrenal function and aging have been the object of intense interest in recent years. In this study we analyzed morning (08:00 h) serum cortisol concentrations from a sample of Chinese subjects aged from 31 to 110 years. These levels differed according to age, health status and sex, although the sex difference was confirmed only among the healthy elderly. These results suggest that age (older than 60 years), disease and male sex are associated with increased morning serum cortisol levels in a Chinese population.

Cortisol diurnal variation in blood and saliva of patients with metastatic colorectal cancer: relevance for clinical outcome.

BACKGROUND: In healthy humans, cortisol displays marked 24-hour rhythms in serum and saliva, with a strong correlation between both fluids; the circadian variation of salivary cortisol is prognostic of longer survival in patients with metastatic breast cancer. In order to confirm these results in a non-hormone-dependent cancer, cortisol concentrations in serum and saliva were compared at different circadian stages, in patients with metastatic colorectal cancer. PATIENTS AND METHODS: A first study consisted of round-the-clock sampling for two 24-hour periods, in 18 patients. A second study consisted of blood and salivary sampling at 8:00h and 16:00h, on 2 consecutive days, in 192 patients. RESULTS: Group circadian variations were validated in both body fluids. Cortisol concentrations in the serum and in saliva were significantly correlated in only 62% of the 18 patients in the first study. In the second study, the average cortisol concentrations were higher at 8:00h than at 16:00h, in serum as well as in saliva. Measures from both body fluids were correlated in patients with a marked 24-hour rhythm, but plasma and salivary cortisol did not correlate in patients with a damped diurnal variation. The patient's performance status and extent of liver involvement, as well as the patient's rest activity cycle were influential on cortisol average concentration, but not on its circadian variation. The circadian variation in cortisol was prognostic of neither response, nor survival. CONCLUSION: These results indicate that the assessment of salivary cortisol cannot substitute for that of serum cortisol in metastatic colorectal cancer. This study suggests that the clinical relevance of cortisol circadian rhythm for patient outcome may differ according to the hormonal dependency of the tumor.

Aging and the circadian rhythm of melatonin: a cross-sectional study of Chinese subjects 30-110 yr of age.

Although previous reports indicate that nocturnal plasma melatonin secretion declines with age, some recent findings do not support this point. In the present cross-sectional study, we documented serum melatonin concentrations at two time points, 02:00 and 08:00 h, in 144 persons aged 30-110 yr and found a significant age-related decline. It began around the age of 60 and reached a very significantly lower level in subjects in their 70s and over 80 yr of age (P < 0.01, when compared with age <60 yr). Nocturnal melatonin levels were higher among (post-menopausal only) women than men overall (P < 0.05). In the older age-groups, nocturnal melatonin levels did not differ between healthy controls and subjects with high blood pressure or ischemic heart disease. To further check these results, we also assessed the circadian pattern of serum melatonin in four subgroups of healthy men, aged 30-39, 40-49, 50-59, and 60-69 yr: blood samples were taken at 2 h intervals from 08:00 to 22:00 h and hourly from 22:00 to 08:00 h. Our results showed generally similar circadian melatonin patterns that peaked at night with very low levels during the daytime. No significant difference was found among the three younger groups, but nocturnal melatonin levels were significantly lower in the men in their 60s.

Marker rhythms of circadian system function: a study of patients with metastatic colorectal cancer and good performance status.

Cancer patients may exhibit normal or altered circadian rhythms in tumor and healthy tissues. Four rhythms known to reflect circadian clock function were studied in 18 patients with metastatic colorectal cancer and good performance status. Rest-activity was monitored by wrist actigraphy for 72 h before treatment, and its circadian rhythm was estimated by an autocorrelation coefficient at 24h and a dichotomy index that compared the activity level when in and out of bed. Blood samples (9-11 time points, 3-6 h apart) were drawn on day 1 and day 4 of the first course of chronochemotherapy (5-fluorouracil: 800 mg/m2/day; folinic acid: 300 mg/m2/day; oxaliplatin: 25 mg/m2/day). Group 24h rhythms were validated statistically for plasma concentrations of melatonin, 6-alpha-sulfatoxymelatonin, and cortisol and for lymphocyte counts. Significant individual 24h rhythms were displayed in melatonin by 15 patients, cortisol by seven patients, lymphocytes by five patients, and prominent circadian rhythms in activity were displayed by 10 patients; only one patient exhibited significant rhythms in all the variables. The results suggest the rhythms of melatonin, cortisol, lymphocytes, and rest/activity reflect different components of the circadian system, which may be altered differently during cancer processes. Such 24h rhythm alterations appeared to be independent of conventional clinical factors.

Response of circulating leptin to Ramadan daytime fasting: a circadian study.

Although the effects of short-term fasting on serum leptin concentrations are known, those resulting from long-lasting modifications of food intake schedule, as during the month of Ramadan, have not yet been extensively studied. Therefore, serum concentrations of leptin were measured around the clock at 4-hourly intervals before the beginning of Ramadan and on the twenty-third day of Ramadan daytime fasting in ten male subjects keeping the same usual activity pattern and general synchronisation in both situations. Time series were analysed with repeated measures ANOVA and Cosinor. No significant changes in amplitude or 24 h mean concentration were seen, but significant shifts of 5 h 30 min in peak and trough serum leptin levels were found on the twenty-third day of Ramadan.

Age-related modifications of circadian rhythm of serum leptin in healthy men.

BACKGROUND: Leptin, the product of the ob gene, is secreted by the adipocyte and is involved in the regulation of body weight, energy homeostasis and a wide spectrum of biological activities. OBJECTIVE: We studied how variations in circadian serum leptin levels change as people age. METHODS: Serum leptin levels were studied on a circadian basis in 26 men, 6 overweight (BMI >27.8) and 20 with normal weight. The normal-weight men were divided into four age groups: (A) in their 30s, (B) in their 40s, (C) in their 50s, and (D) in their 60s. Serum samples were drawn at 2-hour intervals from 8:00 to 22:00 and hourly from 22:00 to 8:00 for a total of 24 h. RESULTS: A significant circadian variation of leptin levels was found whatever the age with a peak at night and a trough around noon. The circadian leptin levels were higher in the older normal-weight groups (50s and 60s) and in the groups with a BMI >27.8. CONCLUSION: Our study demonstrates that changes in the characteristics of the circadian rhythm of serum leptin in healthy men are associated with both advancing age and increased BMI.