Influence of timing and intensity of musclar exercise on temporal patterns of plasma cortisol levels.

Plasma concentrations of cortisol were measured in 9 subjects form 0800 h to 1800 h at 10-min intervals during resting periods and 5 min intervals during exercise and recovery. This was done to assess to effect of exercise on the patterns of plasma cortisol levels. At 1000 h, 90 min exercise at a moderate work level (55% of Vo2 max) produced a transient rise in plasma cortisol which averaged 11.9 pg/100 ml (SE plus or minus 1.2) and introduced subsequent suppression of meal-related increase, At a lower work load (25% of Vo2 max) a similar transient rise occurred, avering 11.7 pg/100 ml (SE plus or minus 2.2); latency rate of concentration change and magnitude and not significatntly different from those at a moderate work load. A strenous work level was required to produce a more rapid response with an increased secretion rate. When 90 min exercise at a moderate work levels was preformed at 1300 h. (i.e. coinciding with postprandial cortisol concentration peak), the increase in plasma cortisol concentration (1.3 pg/100ml (SE plus or minus 0.3) was significantly lower than that induced by the same exercise performed in the morning. These results demonstrate that high plasma levels of cortisol diminish the subsequent stress response and that exercise-induced and meal-induced increases are not active.

Plasma free cortisol during secretory episodes.

Plasma free cortisol fractions were determined in normal men during spontaneous cortisol secretory episodes and ACTH- or exercise-provoked cortisol peaks in the physiological range. The percentage of free cortisol was measured using ultrafiltration by centrifugation at 37 C, and total cortisol concentrations were measured by RIA. The percent free cortisol varied with the time of day, as did total cortisol. It increased parallel to total cortisol increases, whether they were spontaneous, as occurring in the early morning or postprandially, or provoked by external stimulation. A highly significant positive correlation between relative increases in free and total cortisol was found throughout the experiment. As reported previously, total cortisol increases, according to their origin, did or did not reduce the effects of subsequent stimuli. The present results indicate that the variations in the percent free cortisol are not responsible for the differences in the cortisol responses to these stimuli.

Absence of the dawn phenomenon in normal subjects.

The existence of the dawn phenomenon, defined as an increase in plasma glucose levels and/or insulin requirements in the early morning hours, is well established in diabetic patients but remains controversial in normal subjects. To verify whether this phenomenon occurs in normal subjects, the nocturnal profiles in plasma glucose, insulin, and C-peptide levels; insulin to glucose ratio; and prehepatic insulin production were studied at short intervals (4 and 10 min) in 10 normal men. The first part of the night was characterized by a decrease in all values and the presence of 1 or 2 postprandial fluctuations, followed by a steady state until 0800 h. The individual profiles were frequently superimposable, with rapid 8- to 14-min oscillations. These results do not indicate the existence of a dawn phenomenon in normal subjects.

Ultradian oscillations of plasma glucose, insulin, and C-peptide in man during continuous enteral nutrition.

The profiles of plasma glucose, insulin, and C-peptide were studied in normal men receiving continuous enteral nutrition. Large oscillations occurred with periods of 53-113 min. Their mean amplitudes, expressed as a percentage of the 24-h mean, were as high as 20% for glucose, 54% for insulin, and 56% for C-peptide. The oscillations of plasma insulin levels throughout the 24 h were concomitant with those of C-peptide. Rapid 8- to 14-min plasma insulin and glucose oscillations were smaller in magnitude and could only be detected in some segments of the longer period oscillations. These results indicate that in addition to the previously described 8- to 14-min oscillations, plasma glucose, insulin, and C-peptide oscillate at a mean 80-min periodicity in man during continuous enteral nutrition. These oscillations may reflect a pancreatic oscillatory mechanism and/or cyclic variations in gastrointestinal motility or peripheral glucose uptake.

Feedback from meal-related peaks determines diurnal changes in cortisol response to exercise.

Diurnal variations in cortisol response to exercise and their relation to the events of the day were assessed by comparing daily cortisol patterns on the control day and on days when exercise was performed at different times. A remarkable midday cortisol peak coincided with the noon meal, but cortisol levels were irregularly affected by an identical meal in the evening. However, the exercise produced equal increases when performed during quiescent periods (i.e. without any secretory peaks at 1000, 1430, 1700, and 2130 h), but peak levels for exercise at 2130 h were significantly lower because of the lower basal levels in the evening. When the same exercise was performed at 1300 h (i.e. coinciding with the postprandial peak), only a brief leveling-off interrupted the decline in cortisol levels. The meal-related evening peak, if any, provoked a similar decrease in response to exercise performed at 2000 h. Similarly, the midday peak itself was reduced by a prior exercise-induced cortisol rise. These results show that the daily cortisol pattern results from the interactions between the meal-related peaks, especially the major midday cortisol peak, and the exercise-induced increases, both of which inhibit the response to subsequent stimulation. The identical responses to exercise at the different quiescent periods tested, despite a general downward trend in basal cortisol levels, establish the primacy of such feedback mechanisms over those responsible for the circadian rhythm.

Diurnal cortisol peaks and their relationships to meals.

Relationships between diurnal plasma cortisol peaks and meals were evaluated for 30 male subjects divided into 5 groups. At 1300 h, at the time of a slow increase of plasma cortisol in fasting subjects, a reproducible rapidly increasing meal-related peak appeared in all subjects studied. An identical meal at 2000 h led to a lower mean response, with larger interindividual variations. This attenuated evening response does not seem attributable to any daily rhythm in responsiveness nor to changing basal levels, since only slight nonsignificant rises in cortisol appeared after an identical meal at 1000 h. The usual mean cortisol pattern with a midday peak was observed in subjects accustomed to different activity and meal-time schedules, which excludes the role of dietary habits. Satiety did not seen to play a determining role in the response to the 1000 h meal, as was shown by comparing subjects who did or did not have breakfast after overnight fasting. Meal intake was not necessary to provoke peaking in cortisol levels, and it has been established that neural and behavioral factors associated with meal presentation play a predominant role in some subjects. The results given clear evidence of the influence of meal timing on the daily plasma cortisol pattern, but no clue was found as to why eating affects the pituitary-adrenal axis differently according to the time of day. The noon meal may at least have a synchronizing role on normally existing plasma cortisol fluctuations.

Interactions between spontaneous and provoked cortisol secretory episodes in man.

This study describes the interactions between cortisol peaks due to spontaneous episodic release and peaks provoked by external stimuli. Successive and equidistant transitory rises of similar amplitude and duration were produced either by muscular exercise (30 min, 75% VO2max) or by injecting ACTH1-24 (Synacthen: 250 ng) before and after the midday meal-related peak. ACTH1-24 was also injected during sleep before the nocturnal sequence of the major secretory episodes. In all instances, cortisol levels had reverted to basal levels when the second stimulus was applied. ACTH-induced cortisol peaks depressed the subsequent meal-related peaks, the exercise-induced peaks, and the spontaneous secretory episodes at the end of the night, and thus had a strong depressor capacity. When exercise was the prior stimulus, the subsequent meal-related peaks were depressed, but the response to later exercise was not affected. Meal-related peaks and the spontaneous diurnal or nocturnal peaks did not depress the subsequent secretory episodes. These quantitatively comparable cortisol episodes were preceded by ACTH rises whose amplitude and duration were not identical: spontaneous and meal-related ACTH peaks were smaller than the provoked one; exercise-induced ACTH peaks were of longer duration than those after ACTH1-24 injection. The different depressor capacities of similar sized cortisol episodes and the lack of proportionality between spontaneous and provoked ACTH and cortisol peaks suggest that there are separate adrenocortical activation channels, which depend on the origin of the stimulation.

Ultradian oscillations in plasma renin activity: their relationships to meals and sleep stages.

The 24-h pattern of PRA was studied in 6 supine normal subjects, and the relationship between sleep stages and PRA oscillations was analyzed using 18 nighttime profiles and the concomitant polygraphic recordings of sleep. Blood was collected at 10-min intervals. The slow trends obtained by adjusting a third degree polynomial to the 24-h data were not reproducible among individuals, and no circadian pattern was detected. Sustained oscillations in PRA occurred throughout the day. Spectral analysis revealed that PRA oscillated at a regular periodicity of about 100 min during the night. This periodicity was modified during the daytime by meal intake, which induced PRA peaks with large interindividual variations in size. A close relationship was found between the nocturnal PRA oscillations and the alternance of rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep invariably coincided with increasing or peaking PRA levels. REM sleep occurred as PRA was declining or at nadirs. More precisely, increases in PRA marked the transition from REM sleep to stage II, whereas stages III and IV usually occurred when PRA was highest. This relationship between the periodic nocturnal oscillations in PRA and the alternance of the REM-non-REM cycles may translate a similar oscillatory process in the central nervous system or may be linked to hemodynamic changes during sleep that might be partly controlled by the renin-angiotensin system.

Modulation of episodic renin release during sleep in humans.

We previously described a strong concordance between nocturnal oscillations in plasma renin activity and sleep cycles. To examine whether modifying renal renin content or release influences the response to central stimuli linked to sleep stage alternation, plasma renin activity was measured every 10 minutes from 11:00 PM to 8:00 AM in three groups of six subjects. The first group received one 40 mg dose of the diuretic furosemide; the second group underwent the night experiment after 3 days on a low sodium diet; the third group received one 100 mg dose of the beta-blocker atenolol. Each subject underwent a control night when a placebo was given. The nocturnal curves were analyzed with a pulse detection program. For the control nights, 74 of the 83 sleep cycles were associated with significant plasma renin activity oscillations; non-rapid eye movement sleep occurred in the ascending portions and rapid eye movement sleep in the declining portions of the oscillations. These oscillations persisted in the three groups of subjects during the experimental nights and the relation with the sleep stages was not disturbed. Acute stimulation by furosemide amplified the oscillations and led to a general upward trend of the nocturnal profiles. Similarly, a low sodium diet, which led to a slow increase in renal renin content, provoked large oscillations with high initial levels. However, in both cases the mean relative amplitude of the oscillations, expressed as a percentage of the nocturnal means, was similar to that of the control nights and approximated 60%.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty-four-hour profiles of plasma renin activity in relation to the sleep-wake cycle.

OBJECTIVE: To evaluate the relative contribution of sleep and the endogenous circadian rhythmicity in producing the 24-h variations in the plasma renin activity. METHODS: Ten normal young men were studied, under basal conditions with normal nocturnal sleep from 2300-0700 h and once after a night of total sleep deprivation followed by 8 h daytime sleep from 0700 to 1500 h. Plasma renin activity was measured every 10 min for 24 h and the profiles were analysed using the pulse detection program ULTRA. RESULTS: During the 8 h night-time sleep a significant increase in the mean plasma renin activity levels occurred compared with the subsequent 8-h waking periods. After the shift in the sleep period, a sleep-associated increase was clearly apparent during the daytime hours. The number of the amplitude of the oscillations, linked to the non-rapid eye movement-rapid eye movement sleep cycles, increased during sleep (at whatever time it occurred), and were dependent on the regularity and the length of the sleep cycles. In awake subjects the plasma renin activity generally fluctuated in a more damped and irregular manner, but occasionally the plasma renin activity oscillated at a regular periodicity with two dominant peaks centred around 100 and 50 min. CONCLUSION: These results demonstrate that the 24-h plasma renin activity variations are not circadian in nature but are related to sleep processes, which create the nycthemeral rhythm by increasing both the frequency and the amplitude of the oscillations.

REM sleep in humans begins during decreased secretory activity of the anterior pituitary.

The purpose of this study was to define the temporal relationship between anterior pituitary hormone profiles and rapid-eye-movement (REM) sleep occurrence. Plasma levels of prolactin (PRL), adrenocorticotropic hormone (ACTH), luteotropin (LH), thyroid-stimulating hormone (TSH) and growth hormone (GH) were measured in 10 min blood samples. Analysis of the nocturnal profiles for these hormones and the concomitant patterns of sleep stage distribution indicate that the onset of REM sleep very seldom occurred during the increasing phase of secretory episodes. In 93-98% of cases, depending on the hormone studied, it occurred either during the declining phase, at peak level, or at nadir, each of these phases reflecting a decrease in glandular activity. This relationship differed from the very close association previously found between the sleep stage alternation and plasma renin activity. These findings seem to fit in with the concept of reduced sympathetic activity and disruption of the vegetative functions during REM sleep.

Nocturnal oscillations in plasma renin activity and REM-NREM sleep cycles in humans: a common regulatory mechanism?

To establish the strength of the relationship between the nocturnal oscillations in plasma renin activity (PRA) and the sleep stage patterns, 42 PRA profiles from blood collected at 10-min intervals and the concomitant polygraphic sleep recordings were analyzed. In all cases, PRA curves exactly reflected the pattern of sleep stage distribution. When sleep cycles were complete, PRA levels oscillated at a regular 100-min period, with a strong spectral density. Declining PRA levels always coincided with REM sleep phases and increasing levels with NREM sleep phases. More precisely, peak levels corresponded to the transition from deep sleep stages toward lighter ones. The start of the rises in PRA generally marked the transition from REM sleep to stage 2. For incomplete sleep cycles, PRA curves reflected all disturbances and irregularities in the sleep structure. Spontaneous and provoked awakenings blunted the rise in PRA normally associated with NREM sleep, which indicates that disturbing sleep modifies the renin release from the kidneys. These results suggest that a common mechanism within the central nervous system controls both PRA oscillations and the REM-NREM sleep alternation.

Slow oscillations of plasma glucose and insulin secretion rate are amplified during sleep in humans under continuous enteral nutrition.

Concomitant oscillations of plasma glucose and insulin secretion rate with a periodicity of about 80 minutes have been identified in normal humans. To determine whether these slow oscillations are influenced by sleep, peripheral levels of glucose and C-peptide were measured at 10-minute intervals over 24 hours in seven subjects, once with a normal nocturnal sleep from 2300 to 0700 hours, and once with a shifted daytime sleep from 0700 to 1500 hours. The subjects received continuous enteral nutrition and remained supine for the 8 hours preceding blood sampling and throughout the whole experiment. Insulin secretion rate was estimated by deconvoluting peripheral C-peptide levels using an open two-compartment model. The amplitude of glucose and insulin secretion rate oscillations increased by 160% during the 8-hour sleep periods, at whatever time they occurred, whereas the influence of the time of day was not significant. Glucose and insulin secretion rate mean levels were also significantly increased during normal nocturnal sleep compared to the remaining 8-hour waking periods, but this effect did not persist when sleep was shifted to the daytime. The number of oscillations was similar in both experimental series and was not affected by sleep. No systematic concordance was found between glucose and insulin secretion rate oscillations and the rapid eye movement-nonrapid eye movement sleep cycles, despite them having similar periodicities. This study demonstrates that increased amplitude of glucose and insulin secretion rate oscillations is related to sleep rather than to the time of day, without any associated frequency variations.(ABSTRACT TRUNCATED AT 250 WORDS)

Obstructive sleep apnea treatment: peripheral and central effects on plasma renin activity and aldosterone.

To assess the effect of obstructive sleep apnea treatment on plasma renin activity (PRA) and plasma aldosterone seven male patients were studied under two conditions: untreated and treated with nasal continuous positive airways pressure (CPAP). PRA and plasma aldosterone were measured at 10-min intervals for both nights. CPAP treatment diminished the urinary and Na+ excretion, whereas plasma volume increased. The mean levels of PRA and aldosterone were significantly enhanced by the treatment, increasing respectively from 1.5 +/- 0.3 to 3.0 +/- 0.7 ngAI ml-1.hr-1 (p less than 0.05) and from 8.0 +/- 1.0 to 12.0 +/- 1.7 ng.100 ml-1 (p less than 0.05). PRA curves reflected the overall sleep structure as similarly described in normal subjects. The apnea-induced sleep disturbance led to flat PRA profiles and the restoration of a normal sleep pattern by treatment restored the PRA oscillations related to the sleep cycles and consequently restored aldosterone oscillations. The mean amplitude of these oscillations increased respectively from 1.0 +/- 0.1 to 1.8 +/- 0.4 ngAI ml-1.hr-1 and from 5.4 +/- 1.2 to 10.9 +/- 1.9 ng.100 ml-1. These results suggest that CPAP treatment modifies the nocturnal patterns of PRA and aldosterone by increasing their mean levels and their oscillation amplitude. This indicates increased secretion, which contributes to the normalization of urine and Na output.

Comparative effect of night and daytime sleep on the 24-hour cortisol secretory profile.

To determine whether cortisol secretion interacts with daytime sleep in a similar manner to that reported for night sleep, 14 healthy young men were studied during two 24-hour cycles. During one cycle they slept during the night, during the other the sleep period was delayed by 8 hours. Secretory rates were calculated by a deconvolution procedure from plasma cortisol, measured at 10-minute intervals. The amount of cortisol secreted during night sleep was lower than during the corresponding period of sleep deprivation (12.7 +/- 1.1 vs. 16.3 +/- 1.6 mg; p < 0.05), but daytime sleep beginning at the habitual time of morning awakening failed to inhibit cortisol secretion significantly. There was no difference between the amount of cortisol secreted from 0700 to 1500 hours in sleeping subjects and in subjects who were awake during the same period of time (24.2 +/- 1.5 vs. 22.5 +/- 1.4 mg). Even if the comparison between sleeping and waking subjects was restricted to the period 0700-1100 hours or 0700-0900 hours, no significant difference was found. Neither secretory pulse amplitude nor frequency differed significantly in either period. However, detailed analysis of the secretory rates in day sleepers demonstrated a transient decrease in cortisol secretion at about the time of sleep onset, which began 10 minutes before and lasted 20 minutes after falling asleep. Spontaneous or provoked awakenings had a determining influence on the secretory profiles. Ten to 20 minutes after awakening from either night or day sleep cortisol secretion increased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma renin activity and sleep-wake structure of narcoleptic patients and control subjects under continuous bedrest.

In order to determine if renin release would be affected by a dysfunction of the circadian and ultradian organization of sleep, 24-hour profiles of plasma renin activity (PRA) concomitant with sleep stages were established in 10 normal subjects and nine narcoleptic patients, with 10-minute blood sampling intervals. Mean PRA levels were similar in control subjects and narcoleptic patients. Individual 24-hour profiles revealed that the previously described association between renin oscillations and sleep stage alternations was preserved. Increased PRA release was observed during the transition from rapid eye movement (REM) sleep or waking periods to nonrapid eye movement (NREM) sleep, and REM sleep occurred as PRA levels were decreasing. Thus, PRA curves exactly reflected the irregularities and disturbances in the sleep structure of the narcoleptic patients. The 24-hour PRA profiles of the patients did not show the general upward trend during nighttime sleep, which is probably induced in the control subjects by the repetitive recurrence of longer episodes of undisturbed NREM sleep. Because of marked sleep fragmentation in the patients, the duration of NREM sleep was often insufficient to allow for the occurrence of a significant PRA increase. Because sleep onset REM (SOREM) episodes, characteristic of narcolepsy, are not preceded by NREM sleep and its associated increase in PRA, no relative PRA decline occurred during this type of REM sleep. In conclusion, the 24-hour PRA profiles of the narcoleptic patients reflected exactly their sleep stage distribution, confirming previous findings that PRA oscillations appear to be inseparable from the NREM-REM sleep cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolactin secretion and sleep.

To clarify the relationship between prolactin (PRL) secretion and sleep, three experimental procedures were employed and secretory rates were estimated from plasma levels using a deconvolution procedure. Eight healthy young men participated in two 24-hour studies, one using normal night sleep and one using delayed sleep, to determine the influence of sleep as a whole on the PRL rhythm. Another group of 24 subjects underwent a 1-night study to investigate the relationship between PRL secretion and the internal sleep structure. The influence of sleep quality was studied in two more groups of eight subjects. Secretory rates were calculated by deconvolution from plasma PRL measured at 10-minute intervals. Sleep was recorded polygraphically in all experiments. PRL secretory pulses occurred throughout the 24-hour cycle without significant variation in frequency, but with enhanced pulse amplitude for both night and day sleep periods. Sleep onset was rapidly followed by an increase in secretion, and awakenings coincided with an immediate offset of active secretion. Analyzing the association between secretory pulses and sleep stages demonstrated that PRL secretory rate is low at the time of rapid eye movement sleep onset. Sleep quality appeared not to affect the PRL secretory profile. These results confirmed that PRL secretion is enhanced during the whole sleep period, as inferred from plasma levels. Considering secretory pulses provides a precise determination of the temporal relations between PRL and sleep structure and demonstrates that occasionally poor sleep does not influence PRL secretion in normal humans.

A quantitative evaluation of the relationships between growth hormone secretion and delta wave electroencephalographic activity during normal sleep and after enrichment in delta waves.

The existence of a relationship between growth hormone (GH) release and slow-wave sleep (SWS), often studied in the past using conventional scoring of sleep stages, remains controversial. In the present study, this relationship was reevaluated by spectral analysis of the sleep electroencephalogram (EEG) and deconvolution analysis of the plasma GH concentrations during normal nocturnal sleep and after enrichment in SWS by means of ritanserin, a selective 5-HT2 receptor antagonist. Eight healthy male subjects each participated in two randomized night studies after having received either a placebo or a 5-mg dose of ritanserin. They were subjected to 8 hours of polysomnography, including spectral analysis of the sleep EEG. Plasma GH levels were measured at 10-minute intervals. The mean delta absolute power and the mean GH secretory rates were significantly higher under ritanserin than under placebo for the first 3 hours after sleep onset (+24% and +29%, respectively). Their nocturnal profiles were significantly and positively correlated in all subjects (average r = 0.710 under placebo, 0.567 under ritanserin; p < 0.0001 in both cases). GH secretory pulses were found to be coincident with delta activity peaks in both directions. The amount of GH secreted during significant GH pulses was correlated with the amount of concomitant delta wave activity (r = 0.803 under placebo, r = 0.764 under ritanserin, p < 0.0001). Similarly, the amount of delta wave activity found during delta wave peaks was correlated with the amount of GH secreted concomitantly (r = 0.715 under placebo, r = 0.723 under ritanserin: p < 0.0001). These results demonstrate a close temporal and quantitative relationship between GH secretion and delta wave activity, which may be evidence of common stimulatory mechanisms.

Nocturnal cortisol release in relation to sleep structure.

The relationship between the temporal organization of cortisol secretion and sleep structure is controversial. To determine whether the cortisol profile is modified by 4 hours of sleep deprivation, which shifts slow-wave sleep (SWS) episodes, 12 normal men were studied during a reference night, a sleep deprivation night and a recovery night. Plasma cortisol was measured in 10-minute blood samples. Analysis of the nocturnal cortisol profiles and the concomitant patterns of sleep stage distribution indicates that the cortisol profile is not influenced by sleep deprivation. Neither the starting time of the cortisol increase nor the mean number and amplitude of pulses was significantly different between the three nights. SWS episodes were significantly associated with declining plasma cortisol levels (p less than 0.01). This was especially revealed after sleep deprivation, as SWS episodes were particularly present during the second half of the night, a period of enhanced cortisol secretion. In 73% of cases, rapid eye movement sleep phases started when cortisol was reflecting diminished adrenocortical activity. Cortisol increases were not concomitant with a specific sleep stage but generally accompanied prolonged waking periods. These findings tend to imply that cortisol-releasing mechanisms may be involved in the regulation of sleep.

Temporal relationship between prolactin secretion and slow-wave electroencephalic activity during sleep.

It is well established that plasma prolactin (PRL) concentrations exhibit a sleep-dependent pattern, with the highest levels occurring during sleep and the lowest during waking. Still, controversy exists concerning an association between rapid eye movement (REM) and non-REM sleep cycles and plasma PRL pulses. These studies were all based on conventional scoring of sleep stages. In the present study, plasma PRL concentrations were analyzed at 10-minute intervals in 10 subjects during the night when sleeping. PRL secretory rates were calculated by a deconvolution procedure. Spectral parameters of sleep electroencephalographic (EEG) recordings were analyzed together with PRL secretion using cross-correlation. Slow-wave activity of the EEG and PRL secretion ran parallel in all individuals. Conversely, alpha and beta bands and the EEG mean frequency were inversely proportional to PRL secretion. In 9 of the 10 subjects studied, PRL secretion was concomitant with delta waves or lagged behind by 10-20 minutes, depending on subjects, with maximum cross-correlation coefficients ranging between 0.40 and 0.67. This temporal relationship between PRL secretion and delta waves was further assessed by a pulse-by-pulse analysis based on the calculation of probability levels after computer simulations. Nine of the 10 subjects displayed significant concomitance between delta wave activity and PRL secretory oscillations. These results demonstrate that PRL secretion during sleep is coupled to delta waves in young healthy men.