Simultaneous stimulation of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate in normal young Men.

The aim of this study was to investigate, in normal young men, whether gamma-hydroxybutyrate (GHB), a reliable stimulant of slow-wave (SW) sleep in normal subjects, would simultaneously enhance sleep related growth hormone (GH) secretion. Eight healthy young men participated each in four experiments involving bedtime oral administration of placebo, 2.5, 3.0, and 3.5 g of GHB. Polygraphic sleep recordings were performed every night, and blood samples were obtained at 15-min intervals from 2000 to 0800. GHB effects were mainly observed during the first 2 h after sleep onset. There was a doubling of GH secretion, resulting from an increase of the amplitude and the duration of the first GH pulse after sleep onset. This stimulation of GH secretion was significantly correlated to a simultaneous increase in the amount of sleep stage IV. Abrupt but transient elevations of prolactin and cortisol were also observed, but did not appear to be associated with the concomitant stimulation of SW sleep. Thyrotropin and melatonin profiles were not altered by GHB administration. These data suggest that pharmacological agents that reliably stimulate SW sleep, such as GHB, may represent a novel class of powerful GH secretagogues.

Effect of prolactin and estradiol on cell proliferation in the uterus and the MXT mouse mammary neoplasm.

With the use of an in vivo tritiated thymidine [( 3H]dThd) nuclear labeling followed by autoradiography, the effects at different times before sacrifice of prolactin (PRL) and/or 17 beta-estradiol (E2) were studied in C57BL X DBA/2f)F1 mice given transplants of the MXT hormone-sensitive mammary tumor whose growth was previously shown to be influenced by E2 and/or progesterone. Uteri were chosen as controls for the methodology. Experiments were conducted on ovariectomized mice submitted to endocrine manipulation to achieve plasma PRL modifications. In addition to E2, the proliferation of cancer cells, assessed by the measurement of thymidine labeling indices (TLIs), was demonstrated to be enhanced by ovine prolactin (oPRL) and Sulpiride and strongly slowed down by castration and 2-bromo-alpha-ergokryptin treatment, thus emphasizing the great importance of PRL in mammary cancer development. Moreover, a pulse of 1 mg oPRL/animal produced a marked TLI rise in tumors, lasting from the 6th to the 48th hour after its injection and reaching a maximum at 24 hours. PRL had no proliferative effect on the uterine luminal epithelium. When PRL and E2 were injected concomitantly, the profile of stimulation was quite similar to that obtained with E2 alone; i.e., a maximum stimulation was observed at the 24th and 36th hours after hormonal pulse. From these data it is concluded that, in spayed mice, not only E2 but also PRL is of major importance leading to enhanced proliferation of MXT mammary neoplastic cells. Further investigations are needed to throw light on the cellular events presiding over the action of PRL and E2 at the cancer cell level.

Stability of melatonin and temperature as circadian phase markers and their relation to sleep times in humans.

Circadian rhythms of core body temperature and melatonin are commonly used as phase markers of the circadian clock. Melatonin is a more stable marker of circadian phase when measured under constant routine conditions. However, little is known about the variability of these phase markers under less controlled conditions. Moreover, there is little consensus about the preferred method of analysis. The objective of this study was to assess various methods of calculating melatonin and temperature phase in subjects with regular sleep schedules living in their natural environment. Baseline data were analyzed from 42 healthy young subjects who were studied on at least two occasions. Each hospital admission was separated by at least 3 weeks. Subjects were instructed to maintain a regular sleep schedule, which was monitored for 1 week before admission by sleep logs and actigraphy. Subjects spent one habituation night under controlled conditions prior to collecting baseline temperature and melatonin measurements. The phase of the melatonin rhythm was assessed by 9 different methods. The temperature nadir (Tmin) was estimated using both Cleveland and Cosine curve fitting procedures, with and without demasking. Variability between admissions was assessed by correlation analysis and by the mean absolute difference in timing of the phase estimates. The relationship to sleep times was assessed by correlation of sleep onset or sleep offset with the various phase markers. Melatonin phase markers were more stable and more highly correlated with the timing of sleep than estimates of Tmin. Of the methods for estimating Tmin, simple cosine analysis was the least variable. In addition, sleep offset was more strongly correlated with the various phase markers than sleep onset. The relative measures of melatonin offset had the highest correlation coefficients, the lowest study-to-study variability, and were more strongly associated with sleep timing than melatonin onsets. Concordance of the methods of analysis suggests a tendency for the declining phase of the melatonin profile to be more stable and reliable than either markers of melatonin onset or measures of the termination of melatonin synthesis.

Circadian and sleep-related endocrine rhythms in schizophrenia.

Plasma levels of prolactin, growth hormone, corticotropin, and cortisol were measured at 15-minute intervals for 24 hours in nine unmedicated male schizophrenic patients and in nine age-matched normal male subjects. Each study was preceded by 3 days of habituation to the laboratory environment. Sleep was polygraphically recorded. The circadian and pulsatile variations present in each hormonal profile were quantitatively characterized with the use of computer algorithms specifically designed for analyses of hormonal fluctuations. The major abnormality of neuroendocrine release that was observed in the schizophrenic patients was an almost threefold enhancement of the sleep-related increase in the prolactin level, associated with an intensified frequency of nocturnal prolactin pulses. This increased stimulatory effect of sleep on prolactin secretion was evident immediately after sleep onset. The normal inhibition of cortisol secretion during early sleep was absent in schizophrenic patients. The major sleep abnormalities were a prolonged sleep latency and a reduction in total rapid eye movement stage sleep. During wakefulness, prolactin and cortisol levels were normal. The 24-hour profile of growth hormone was unaltered in schizophrenic patients, and a sleep-onset growth hormone pulse was observed in all patients. No abnormalities were noted in the levels or temporal organization of corticotropin secretion. Both the amplitude and the timing of the cortisol rhythm were normal. We conclude that, in schizophrenic men, pituitary-adrenal function and circadian time-keeping are normal but prolactin secretion is hyperresponsive to the physiologic stimulus of sleep onset. Schizophrenia thus appears to be characterized by a subset of neuroendocrine disturbances distinct from that observed in major endogenous depression.

The 24-hour profiles of cortisol, prolactin, and growth hormone secretion in mania.

OBJECTIVE: To characterize sleep and the 24-hour profiles of cortisol, prolactin (PRL), and growth hormone (GH) secretion in mania. METHODS: Blood was sampled at 15-minute intervals, and sleep was polygraphically recorded in eight unmedicated male patients with pure mania and the results compared with those from a group of 14 healthy age-matched controls. The circadian, sleep-related, and pulsatile hormonal variations were quantitatively characterized using specifically designed computer algorithms. RESULTS: The manic state was associated with alterations of corticotropic activity and circadian rhythmicity partially overlapping those previously observed in acute endogenous depression, consisting of an elevation of nocturnal cortisol levels and an early timing of the nadir of the circadian variation. Sleep onset was delayed and the sleep period was reduced. A trend for short rapid eye movement latencies was apparent in the adult patients. Both the amount and the temporal organization of PRL and GH secretion were normal. CONCLUSION: The manic state seems to be characterized by similar but less severe neuroendocrine and circadian abnormalities, compared with major depression.

The 24-hour profile of plasma prolactin in men with major endogenous depressive illness.

Plasma prolactin (PRL) levels were measured at 15-minute intervals for 24 hours in 18 men suffering from major endogenous depressive illness and in 7 age-matched healthy men. Eleven of the 18 depressed patients were restudied during clinical remission following either electroconvulsive therapy or treatment with amitriptyline hydrochloride. During the acute phase of the illness, the unipolar depressed patients had fragmented patterns of PRL secretion with an early timing of the nocturnal secretory phase of PRL, which started, on the average, 2 hours earlier than in healthy subjects. Moreover, the amplitude of the circadian variation of PRL was reduced in these patients, with subnormal PRL levels occurring during the midsleep period. This latter abnormality was also observed in bipolar patients, who had otherwise normal PRL profiles. These lower midsleep PRL concentrations were associated with a significant increase in the amount of time spent awake during the same period. Antidepressant treatment did not consistently correct the abnormalities in the patterns of PRL release observed during the acute phase of the illness. These results indicate that early timing of nocturnal PRL secretion and damping of the nighttime PRL elevation may be found in men with endogenous depressive disorders. In contrast to disturbances of the corticotropic and somatotropic axes, these abnormalities of PRL secretion may still be present during clinical remission following antidepressant treatment.

Acute and delayed effects of exercise on human melatonin secretion.

Accumulating evidence suggests that exercise may have both rapid and delayed effects on human melatonin secretion. Indeed, exercise may acutely (i.e., within minutes) alter melatonin levels and result in a shift of the onset of nocturnal melatonin 12 to 24 h later. The presence and nature of both acute and delayed effects appear to be dependent on the timing of exercise. The presence of a detectable acute effect also depends on the duration, intensity, and type of exercise. Late evening exercise during the rising phase of melatonin secretion may blunt melatonin levels. High-intensity exercise during the nighttime period, when melatonin levels already are elevated, consistently results in a further (nearly 50%) elevation of melatonin levels. No effect of low-intensity exercise performed at the same circadian phase could be detected. Irrespective of intensity, exercise near the offset of melatonin secretion or during the daytime has no consistent acute effect on melatonin secretion. Nighttime exercise, whether of moderate or high intensity, results in phase delays of the melatonin onset on the next evening. In support of the concept that a shift of the melatonin onset on the day after nighttime exercise represents a shift of intrinsic circadian timing is the observation that similar phase shifts (in both direction and magnitude) may be observed simultaneously for the onset of the circadian elevation of thyrotropin secretion. The observation of exercise-induced phase shifts of the onset of melatonin secretion is, therefore, interpreted as evidence that, in humans as in rodents, increased physical activity during the habitual rest period is capable of altering circadian clock function.

Exercise-induced prolactin release is related to anaerobiosis.

The response of plasma PRL to exercise, as performed on a bicycle ergometer under conditions below and above the anaerobic threshold, was studied in 10 normal young men. One hour of submaximal work against a workload at which blood lactic acid remained below 4 mmol/liter (anaerobic threshold) was accompanied by a slight decrease in plasma PRL levels, similar to the changes occurring under control conditions in the same subjects. However, during graded maximal ergometric exercise until exhaustion, plasma PRL rose promptly and significantly (P less than 0.05) when the anaerobic threshold was reached. These data suggest that PRL levels increase provided that the intensity of exercise is such that the anaerobic threshold is reached.

Transition from dim to bright light in the morning induces an immediate elevation of cortisol levels.

The only well documented effect of light exposure on endocrine function is the suppression of nocturnal melatonin. Bright light exposure has behavioral effects, including the alleviation of sleepiness during nocturnal sleep deprivation. The present study examines the effects of bright light on the profiles of hormones known to be affected by sleep deprivation (TSH) or involved in behavioral activation (cortisol). Eight healthy men participated each in three studies involving 36 h of continuous wakefulness. In one study, the subjects were exposed to constant dim light (baseline). In the two other studies, dim light exposure was interrupted by a 3-h period of bright light exposure either from 0500-0800 h (early morning study) or from 1300-1600 h (afternoon study). Blood samples were obtained every 15 min for 24 h to determine melatonin, cortisol, and TSH concentrations. Alertness was estimated by the number of lapses on two computerized vigilance-sensitive performance tasks. The early morning transition from dim to bright light suppressed melatonin secretion, induced an immediate, greater than 50% elevation of cortisol levels, and limited the deterioration of alertness normally associated with overnight sleep deprivation. No effect was detected on TSH profiles. Afternoon exposure to bright light did not have any effect on either hormonal or behavioral parameters. The data unambiguously demonstrate an effect of light on the corticotropic axis that is dependent on time of day.

Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning.

To determine whether elevations of cortisol levels have more pronounced effects on glucose levels and insulin secretion in the evening (at the trough of the daily rhythm) or in the morning (at the peak of the rhythm), nine normal men each participated in four studies performed in random order. In all studies, endogenous cortisol levels were suppressed by metyrapone administration, and caloric intake was exclusively under the form of a constant glucose infusion. The daily cortisol elevation was restored by administration of hydrocortisone (or placebo) either at 0500 h or at 1700 h. In each study, plasma levels of glucose, insulin, C-peptide, and cortisol were measured at 20-min intervals for 32 h. The initial effect of the hydrocortisone-induced cortisol pulse was a short-term inhibition of insulin secretion without concomitant glucose changes and was similar in the evening and in the morning. At both times of day, starting 4-6 h after hydrocortisone ingestion, glucose levels increased and remained higher than under placebo for at least 12 h. This delayed hyperglycemic effect was minimal in the morning but much more pronounced in the evening, when it was associated with robust increases in serum insulin and insulin secretion and with a 30% decrease in insulin clearance. Thus, elevations of evening cortisol levels could contribute to alterations in glucose tolerance, insulin sensitivity, and insulin secretion.

Progressive elevation of plasma thyrotropin during adaptation to simulated jet lag: effects of treatment with bright light or zolpidem.

It is well known that TSH secretion is modulated by sleep and circadian rhythmicity, but effects of abrupt shifts of the sleep-wake and dark-light cycles such as occur in jet lag and shift work have not been investigated. The present study examines alterations in the 24-h profiles of plasma TSH and thyroid hormones following an 8-h advance shift achieved without enforcing prolonged sleep deprivation. The effects of bright light exposure or sleep facilitation with zolpidem were investigated in separate studies performed in the same subjects. Each study involved blood sampling at 20-min intervals for 68 h and included a baseline period with dim light during waking hours and 2300-0700 h bedtimes in total darkness. The 8-h shift was achieved by advancing bedtimes to 1500-2300 h. In the course of adaptation to the shift, TSH levels increased progressively in all three studies because daytime sleep failed to inhibit TSH and nighttime wakefulness was associated with large TSH elevations. The overall elevation of TSH tended to be paralleled by a small increase in T3, but not free T4, levels. In the absence of treatment, mean TSH levels following awakening from the second shifted sleep were more than 2-fold higher than during the same time interval following normal nocturnal sleep (2.10 +/- 0.22 mU/L vs. 1.04 +/- 0.14 mU/L; n = 8, P < 0.001). Bright light exposure limited the overall increase of TSH, and mean TSH levels at the end of the study were lower than in the absence of treatment (P < 0.03). Treatment with zolpidem during the first shifted night limited the overall increase in TSH levels during the following waking period (P < 0.05), but the beneficial effect was no longer significant following the second shifted night. Thus, the jet lag syndrome may be associated with a prolonged elevation of peripheral TSH levels that may be limited by treatment with bright light exposure or hypnotic facilitation of sleep.

Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men.

To assess the effects of prolonged administration of a novel analog of GH-releasing peptide (MK-677), nine healthy young men participated in a randomized, double blind, three-period cross-over comparison of orally administered placebo and 5- and 25-mg doses of MK-677. Each period involved bedtime administration of the drug for 7 consecutive days. At the end of each period, plasma levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were measured at 0745 h, and 24-h profiles of plasma GH and cortisol were obtained at 15-min intervals together with the 24-h urinary excretion of free cortisol. Profiles of plasma free cortisol were calculated at hourly intervals. The amounts of GH secreted were similar in all three conditions, but GH pulse frequency was increased with both dosages of the drug, primarily because of an increase in the number of low amplitude pulses. Plasma IGF-I levels were increased in a dose-dependent manner, whereas IGFBP-3 levels were increased only with the highest dosage. There was a positive relationship between GH pulse frequency and IGF-I increase. Except for an advance in the nocturnal nadir and in the morning elevation, MK-677 had no effect on cortisol profiles. In particular, 24-h mean levels of plasma total and free cortisol and urinary excretion of free cortisol were similar under all conditions. The present data suggest that the use of MK-677 for the treatment of relative somatotropic deficiency, particularly in older adults compromised by such deficiency, deserves further investigation.

Effects of bedtime administration of zolpidem on circadian and sleep-related hormonal profiles in normal women.

Short-acting benzodiazepine hypnotics may phase-shift circadian rhythms and improve adaptation of sleep patterns to abrupt time shifts, depending on the timing of administration. The aim of the present study was to determine whether bedtime administration of zolpidem, a non-benzodiazepine hypnotic, causes alterations in circadian rhythmicity or in the normal interactions between sleep and hormones. Eight normal women (aged 21-33 years) each participated in a baseline study and a study with zolpidem administration. On each occasion, blood samples were obtained at 20-minute intervals for 25 hours, starting at 1000 hours. Zolpidem (10 mg) was given orally at 2245 hours. Zolpidem administration was associated with an increase in stages III + IV sleep. Cortisol, melatonin, thyrotropin and growth hormone profiles were similar in both experimental conditions. In contrast, though remaining in the normal range, the nocturnal elevation of prolactin was enhanced two-fold in all subjects after zolpidem during early sleep, and prolactin levels were still 50% higher than baseline in late sleep. Morning levels were similar in both studies. In conclusion, bedtime administration of 10 mg zolpidem, a standard clinical dosage, systematically induces a transient moderate hyperprolactinemia, but does not alter other sleep-related hormonal secretions or endocrine markers of circadian rhythmicity.

Effects of the short-acting benzodiazepine triazolam, taken at bedtime, on circadian and sleep-related hormonal profiles in normal men.

Studies in rodents have shown that triazolam, a commonly used hypnotic, may shift circadian rhythms, with the direction and magnitude of the phase-shifts being dependent on the time of drug administration. To determine whether benzodiazepine, taken at standard bedtime, modifies the amount and/or temporal organization of hormonal secretion, six normal men were studied during basal conditions and on the first and third days of treatment with 0.5 mg triazolam. In each study, sleep was polygraphically monitored and plasma cortisol, growth hormone (GH), melatonin, and prolactin (PRL) (i.e., hormones influenced by circadian rhythmicity and/or sleep) were measured at 20-min intervals for 24 h. The sleep latency and the number and duration of awakenings were reduced during triazolam treatment as compared to baseline conditions. The only alteration of sleep architecture was a partial suppression of stages III + IV (SW) in late sleep. Triazolam did not affect the mean cortisol and melatonin levels or the total amount of GH secreted over the 24-h span. The circadian timings of the onsets of cortisol and melatonin secretions were essentially unaltered. The nocturnal rise of melatonin was prolonged by 45 to 60 minutes. Sleep-associated GH release was not modified by triazolam. Sleep-associated PRL secretion persisted, but in half of the nights studied was enhanced almost threefold. This effect of the drug on nocturnal PRL secretion was not specific to either the first or the third night of treatment, nor was it specific to certain subjects. Irrespective of the magnitude of the nocturnal elevation, morning PRL levels were slightly but consistently higher after triazolam treatment than under basal conditions. Normal PRL levels resumed around noon. In conclusion, administration of 0.5 mg triazolam at normal bedtime (2230) for three consecutive days may induce a transient hyperprolactinemia, but does not abolish sleep-related hormone secretion and does not affect the timing of endocrine events controlled by the circadian clock. These findings are consistent with studies in hamsters where treatment with triazolam in the early subjective night was also without effect on the rodent circadian clock.

Serum melatonin and urinary 6-sulfatoxymelatonin in major depression.

In this study, serum melatonin and urinary 6-sulfatoxymelatonin (aMT6s) were measured in 14 major depressive inpatients, compared to 14 matched controls according to age, gender, season and hormonal treatment in women. Moreover, the relationship between serum melatonin and urinary aMT6s levels was analysed in the two groups. Results indicated that the two groups of subjects showed a clear melatonin rhythm without significant difference in the mean level of melatonin or aMT6s, in the area under the curve of melatonin or in the melatonin peak. However, the time of the nocturnal melatonin peak secretion was significantly delayed in depressive subjects as compared to healthy controls. Moreover, the depressed patients showed urinary aMT6s concentrations enhanced in the morning compared to night time levels, while these concentrations were lowered from the night to the morning in the control group. These results suggest that the melatonin production is phase-shifted in major depression.

Pergolide mesylate inhibits exercise-induced prolactin release in man.

The effects of Pergolide, a potent dopamine agonist, on exercise-induced plasma prolactin (PRL) changes were studied in normal men. Exercises consisted of a graded bicycle ergometer test and of a 20-km endurance run. In both circumstances, treatment with Pergolide, when compared with placebo or control values, resulted in a significant suppression of basal PRL (P less than 0.001) as well as of exercise-induced PRL increase (P less than 0.01). From these experiments it was concluded that augmented levels of PRL in plasma, as seen during or after muscular exercise, are caused by increased pituitary secretion, rather than decreased elimination.

Estrogens delay the postpartum recovery of the LH-RH-induced gonadotropin release.

In 27 healthy postpartum women, who were neither lactating nor receiving any therapy, LH-RH stimulation tests (50 micrograms i.v.) were performed on days 7, 14, 21 and 28 of the puerperium. In a second group of 9 postpartum women an i.m. injection of 10 mg estradiol valerianate was administered within the 3rd postpartum day, and an LH-RH stimulation test was performed on days 14 and 21 of the puerperium. Blood was withdrawn at standard intervals and LH and FSH measured by radioimmunoassay. No significant FSH and LH response was found on day 7. On day 14 there was a significant release of FSH but no LH was released. On days 21 and 28 there was a significant release of FSH and LH but the magnitude of the FSH response was greater than that of the LH release. The administration of estrogens did inhibit the recovery of the pituitary from its refractoriness: on day 14 no release of LH and FSH was observed; on day 21, only a significant release of FSH could be detected in the second group of postpartum women. This emphasizes the major role played by steroids in the regulation of the hypothalamo-pituitary-gonadal function.

Adverse effects of two nights of sleep restriction on the hypothalamic-pituitary-adrenal axis in healthy men.

CONTEXT: Insufficient sleep is associated with increased cardiometabolic risk. Alterations in hypothalamic-pituitary-adrenal axis may underlie this link. OBJECTIVE: Our objective was to examine the impact of restricted sleep on daytime profiles of ACTH and cortisol concentrations. METHODS: Thirteen subjects participated in 2 laboratory sessions (2 nights of 10 hours in bed versus 2 nights of 4 hours in bed) in a randomized crossover design. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 9:00 am to midnight to measure ACTH and total cortisol. Saliva was collected every 20 minutes from 2:00 pm to midnight to measure free cortisol. Perceived stress, hunger, and appetite were assessed at hourly intervals by validated scales. RESULTS: Sleep restriction was associated with a 19% increase in overall ACTH levels (P < .03) that was correlated with the individual amount of sleep loss (rSp = 0.63, P < .02). Overall total cortisol levels were also elevated (+21%; P = .10). Pulse frequency was unchanged for both ACTH and cortisol. Morning levels of ACTH were higher after sleep restriction (P < .04) without concomitant elevation of cortisol. In contrast, evening ACTH levels were unchanged while total and free cortisol increased by, respectively, 30% (P < .03) and 200% (P < .04). Thus, the amplitude of the circadian cortisol decline was dampened by sleep restriction (-21%; P < .05). Sleep restriction was not associated with higher perceived stress but resulted in an increase in appetite that was correlated with the increase in total cortisol. CONCLUSION: The impact of sleep loss on hypothalamic-pituitary-adrenal activity is dependent on time of day. Insufficient sleep dampens the circadian rhythm of cortisol, a major internal synchronizer of central and peripheral clocks.