A benzodiazepine hypnotic facilitates adaptation of circadian rhythms and sleep-wake homeostasis to an eight hour delay shift simulating westward jet lag.

STUDY OBJECTIVES: To determine whether appropriately timed administration of a short-acting benzodiazepine hypnotic, which has proven effective in an animal model of jet lag, also facilitates adaptation of circadian rhythmicity and sleep-wake homeostasis in a human model of jet lag. DESIGN: Subjects participated in two double-blind, placebo-controlled studies of adaptation to an 8-hr delay shift of sleep-wake and dark-light cycles simulating westward travel. Each 9-day laboratory study began with a 3-day habituation period followed by a 24-hr study to obtain basal hormonal and sleep profiles (23:00-07:00). Subjects were then kept awake until 07:00 the next day and slept in darkness 07:00-15:00 for the next five 24-hr spans post-shift. SETTING: N/A. PARTICIPANTS: 6 normal, healthy men 24-31 years of age. INTERVENTIONS: Oral Triazolam (0.5 mg) or placebo given at 04:00 before the first shifted sleep/dark period (3 hours before bedtime) and at 07:00 (at bedtime) on days 2-5 post-shift. MEASUREMENTS AND RESULTS: Sleep recordings and 24-hr cortisol and growth hormone profiles were obtained at baseline and on the first, third, and fifth days post-shift. Global measures of treatment efficacy were calculated for multiple endpoints representing circadian rhythmicity and sleep-wake homeostasis. With placebo, the shift induced disturbances of sleep and hormonal secretion, and a gradual re-entrainment of circadian rhythmicity. Triazolam significantly facilitated adaptation by accelerating re-entrainment of circadian rhythms (chronobiotic effect) and normalizing markers of sleep/wake homeostasis (hypnotic effect). CONCLUSIONS: Appropriately timed administration of a benzodiazepine hypnotic appears to facilitate the adaptation of both circadian rhythmicity and sleep-wake homeostasis to a shifted dark/sleep cycle. Compounds with combined chronobiotic/hypnotic properties may be useful in conditions of jet lag or night work.

Interrelationships between growth hormone and sleep.

In healthy young adults, the 24-hour profile of plasma growth hormone (GH) levels consists of stable low levels abruptly interrupted by bursts of secretion. In normal women, daytime GH secretory pulses are frequent. However, in normal men, a sleep-onset-associated pulse is generally the major or even the only daily episode of active secretion. Extensive evidence indicates the existence of a consistent relationship between slow-wave (SW) sleep and increased GH secretion. There is a linear relationship between the amount of SW sleep (measured by either visual scoring or spectral analysis of the EEG) and the amount of concomitant GH secretion. During ageing, SW sleep and GH secretion decrease exponentially and with the same chronology. Pharmacological stimulation of SW sleep results in increased GH release, and compounds that increase SW sleep may therefore represent a novel class of GH secretagogues.

Adaptation of the 24-h growth hormone profile to a state of sleep debt.

In normal men, the majority of GH secretion occurs in a single large postsleep onset pulse that is suppressed during total sleep deprivation. We examined the impact of semichronic partial sleep loss, a highly prevalent condition, on the 24-h growth hormone profile. Eleven young men were studied after six nights of restricted bedtimes (0100-0500) and after 7 nights of extended bedtimes (2100-0900). Slow-wave sleep (SWS) was estimated as the duration of stages III and IV. Slow-wave activity (SWA) was calculated as electroencephalogram power density in the 0.5- to 3-Hz frequency range. During the state of sleep debt, the GH secretory pattern was biphasic, with both a presleep onset "circadian" pulse and a postsleep onset pulse. Postsleep onset GH secretion was negatively related to presleep onset secretion and tended to be positively correlated with the amount of concomitant SWA. When sleep was restricted, both SWS and SWA were increased during early sleep. Unexpectedly, the increase in SWA affected the second, rather than the first, SWA cycle, suggesting that presleep onset GH secretion may have limited SWA in the first cycle, possibly via an inhibition of central GH-releasing hormone activity. Thus neither the GH profile nor the distribution of SWA conformed with predictions from acute sleep deprivation studies, indicating that adaptation mechanisms are operative during chronic partial sleep loss.

Pathophysiology of human circadian rhythms.

The 24 h profiles of hormonal secretions represent a good model for the study of the human circadian system. Diurnal hormonal variations generally reflect the modulation of ultradian or pulsatile release at 1-2 h intervals by signals occurring at nearly 24 h periods and result from the interaction of an internal timekeeping system--or circadian clock--with the sleep-wake homeostasis and various environmental factors, including the light-dark cycle, periodic changes in activity levels and the meal schedule. This temporal organization is altered in many pathophysiological conditions, including ageing, sleep loss, night or shift work, jet lag, affective disorders and endocrine diseases. Both photic and non-photic stimuli may affect the regulation of the circadian pacemaker and, therefore, the diurnal pattern of hormonal secretions. Appropriately timed stimuli may induce either a phase-advance or a phase-delay of the circadian clock, according to the timing of administration. Phase-shifting effects have been shown in humans for light and for dark pulses, physical exercise, melatonin and melatonin agonists, and benzodiazepine hypnotics. These results open new perspectives for the treatment of a variety of disorders involving dysregulation of the circadian rhythmicity.

[Biologic rhythms. Effect of aging on the desynchronization of endogenous rhythmicity and environmental conditions]. / Les rythmes biologiques. Effets du veillissement et de la désynchronisation entre la rythmicité endogène et les conditions d'environnement.

CIRCADIAN AND PULSATILE RHYTHMICITY IN THE AGING PROCESS: The aging process produces morphological and neurochemical alterations in the suprachiasmatic nuclei as well as major alterations in the quality of sleep. In addition, aging is frequently accompanied by changes in life style due to different, often less demanding, social and occupational activities, leading to an attenuation of the synchronizing effects of the light-dark and activity-rest cycles. Together, these different elements contribute to a decline in temporal organization in the elderly, a phenomenon which starts in the third decade for some variables. There is a characteristic phase shift with age: in an 80-year-old individual, the circadian cortisol peak occurs about 3 hours earlier than in a 20 year-old-individual. JET LAG AND NIGHT SHIFT WORK: The circadian rhythm and environmental conditions can become desynchronized after transmeridian flights, a phenomenon commonly called jet lag. In night shift workers, such desynchronization creates an important public health problem. The impact may be underestimated since 15 to 20% of the work force in industrialized countries work permanently or occasionally on night shifts. The resulting dissociation between environmental signals and the wake-sleep cycle leads to various health problems. No truly effective therapeutic strategy has been developed although ongoing research, particularly on the use of light and/or melatonin, provides some promising perspectives.

[Biologic rhythms. Circadian, ultradian and seasonal rhythms]. / Les rythmes biologiques. Rythmes circadiens, ultradiens et saisonniers.

CIRCADIAN RHYTHMS: Our knowledge of the genetic and molecular mechanisms regulating the principal circadian clock located in the suprachiasmatic nuclei is progressing. The clock's intrinsic period varies from one species to another and to a lesser degree from one individual to another. In humans, the intrinsic period is slightly over 24 hours. The clock is capable of synchronizing itself to the surrounding environment by reacting to outside factors or zeitgebers (time-givers). Light-dark cycles are the main zeitgebers; meals, the social environment, and locomotor activity also affect the circadian clock. In addition, the circadian clock acts as an internal timer, providing the organism with a means of synchronizing the function of multiple biochemical and physiological systems. ULTRADIAN RHYTHMS: The frequency of ultradian rhythms varies considerably form one species to another and from one parameter to another. In humans, several functions oscillate at 60-120 minute intervals, rhythms which are sometimes superimposed on other functions oscillating at 3 to 5 minute intervals. SEASONAL RHYTHMS: Several mechanisms allow living organisms to adapt to seasonal variations in the environment. In certain species, reproduction functions are stimulated at appropriate moments in the yearly cycle, optimizing the newborn's chances of survival. Such seasonal variations are much less marked in humans.

[Biologic rhythms. Nyctemeral variation in man]. / Les rythmes biologiques. Les variations au cours du nycthémère chez l'homme.

CORTICOTROPIC AXIS: The nycthemeral pattern of cortisol is a good marker of the circadian clock. Cortisol levels fluctuate between a peak level, observed in the early hours of the morning, and a minimal level around midnight. This variability is considerably reduced or even abolished in Cushing s syndrome. THYREOTROPIC AXIS: The nycthemeral pattern of TSH secretion is dependent on both the circadian clock and sleep (which inhibits hormone secretion). The moment of the evening rise is a reliable marker of the circadian rhythmicity. SOMATOTROPIC AXIS: Growth hormone is essentially pulsatile. GH levels are often undetectable between pulses. The circadian rhythmicity plays only a minor role in the regulation of growth hormone secretion. LACTOTROPIC AXIS: Nycthemeral variations in prolactin secretion are mainly regulated by wake-sleep cycles; peak levels occur in the middle of the night. Prolactin secretion is also modulated by the circadian rhythmicity. GONADOTROPIC AXIS: Gonadotropins are secreted in pulses, following the pulses of GnRH secretion. In adult women, nycthemeral variations in LH are strongly modulated by the menstrual cycle. MELATONIN: The nychtemeral pattern of melatonin is an excellent marker of the circadian clock. Diurnal concentrations are low and vary little whereas peak levels are observed in the middle of the night. Melatonin rhythmicity is not influenced by sleep, but is dependent on exposure to light and darkness.

Genetic control of 24-hour growth hormone secretion in man: a twin study.

The aim of this study was to delineate the contributions of genetic and environmental factors in the regulation of the 24-h GH secretion. The 24-h profile of plasma GH was obtained at 15-min intervals in 10 pairs of monozygotic and 9 pairs of dizygotic normal male twins, aged 16-34 yr. Sleep was polygraphically monitored. Significant pulses of GH secretion were identified using a modification of the computer algorithm ULTRA. For each significant pulse, the amount of GH secreted was calculated by deconvolution. A procedure specially developed for twin studies was used to partition the variance of investigated parameters into genetic and environmental contributions. A major genetic effect was evidenced on GH secretion during wakefulness (with a heritability estimate of 0.74) and, to a lesser extent, on the 24-h GH secretion. Significant genetic influences were also identified for slow wave sleep and height. These data demonstrate that human GH secretion in young adulthood is markedly dependent on genetic factors.

Interrelations between sleep and the somatotropic axis.

In the human as in other mammals, growth hormone (GH) is secreted as a series of pulses. In normal young adults, a major secretory episode occurs shortly after sleep onset, in temporal association with the first period of slow-wave (SW) sleep. In men, approximately 70% of the daily GH output occurs during early sleep throughout adulthood. In women, the contribution of sleep-dependent GH release to the daily output is lower and more variable. Studies involving shifts of the sleep-wake cycle have consistently shown that sleep-wake homeostasis is the primary determinant of the temporal organization of human GH release. Effects of circadian rhythmicity may occasionally be detected. During nocturnal sleep, the sleep-onset GH pulse is caused by a surge of hypothalamic GHRH release which coincides with a circadian-dependent period of relative somatostatin disinhibition. Extensive evidence indicates the existence of a consistent relationship between SW sleep and increased GH secretion and, conversely, between awakenings and decreased GH release. There is a linear relationship between amounts of SW sleep--whether measured by visual scoring or by delta activity--and amounts of concomitant GH secretion, although dissociations may occur, most likely because of variable levels of somatostatin inhibition. Pharmacological stimulation of SW sleep results in increased GH release, and compounds which increase SW sleep may therefore represent a novel class of GH secretagogues. During aging, SW sleep and GH secretion decrease with the same chronology, raising the possibility that the peripheral effects of the hyposomatotropism of the elderly may partially reflect age-related alterations in sleep-wake homeostasis. While the association between sleep and GH release has been well documented, there is also evidence indicating that components of the somatotropic axis are involved in regulating sleep. The studies are most consistent in indicating a role for GHRH in promoting NREM and/or SW sleep via central, rather than peripheral, mechanisms. A role for GH in sleep regulation is less well-documented but seems to involve REM, rather than NREM, sleep. It has been proposed that the stimulation of GH release and the promotion of NREM sleep by GHRH are two separate processes which involve GHRH neurons located in two distinct areas of the hypothalamus. Somatostatinergic control of GH release appears to be weaker during sleep than during wake, suggesting that somatostatinergic tone is lower in the hypothalamic area(s) involved in sleep regulation and sleep-related GH release than in the area controlling daytime GH secretion. While the concept of a dual control of daytime and sleep-related GH secretion remains to be directly demonstrated, it allows for the reconciliation of a number of experimental observations.

Rapid phase advance of the 24-h melatonin profile in response to afternoon dark exposure.

To investigate the adaptation of melatonin secretion to an abrupt time shift and the effects of sleep facilitation with a hypnotic, eight subjects were submitted to an 8-h advance shift achieved by advancing bedtimes from 2300-0700 to 1500-2300. Each subject participated in two studies (i.e., placebo and zolpidem). Each study included a baseline period with dim light during waking hours and 2300-0700 bedtimes in total darkness. Blood samples for determination of plasma melatonin were obtained at 20-min intervals for 68 h. Advanced exposure to sleep and darkness resulted in a nearly 2-h advance of melatonin onset, which appeared within 6 h after lights-out during the first shifted night, and an almost 1-h advance of the melatonin offset. No further adaptation occurred during the second shifted sleep period. Zolpidem had no beneficial effects on the adaptation of the melatonin profile. There was no relationship between sleep parameters and the magnitude of the melatonin shifts. Thus the overall advance of melatonin profiles was primarily achieved during the initial exposure to an 8-h period of darkness. The present data suggest that exposure to dark affects human circadian phase.

Evidence against a role for the growth hormone-releasing peptide axis in human slow-wave sleep regulation.

A complex interrelationship exists between sleep and somatotropic activity. In humans, intravenous injections of growth hormone-releasing hormone (GHRH) given during sleep consistently stimulate slow-wave (SW) sleep, particularly when given in the latter part of the night. In the present study, the possible somnogenic effects induced under similar conditions by GH-releasing peptide (GHRP) were investigated in seven young healthy men. Bolus intravenous injections of GHRP-2 (1 microgram/kg body wt) or saline, in randomized order, were given after 60 s of the third rapid-eye-movement period. All GHRP injections were immediately followed by transient prolactin elevations and by GH pulses of a magnitude within or around the upper limit of the physiological range. Except for a nonsignificant tendency to increased amounts of wakefulness during the 1st h after the injection, no effects of GHRP-2 administration on sleep were detected. There was in particular no enhancement of SW sleep. Thus, in contrast to GHRH, late-night single injections of GHRP-2 at a dosage resulting in similar GH elevations have no stimulatory effects on SW sleep. The present data provide evidence against the involvement of the GHRP axis in human SW sleep regulation.

Alterations of circadian rhythmicity and sleep in aging: endocrine consequences.

All 24-hour endocrine rhythms partially reflect the interaction of circadian rhythmicity with sleep-wake homeostasis but their relative contributions vary from one system to another. In older adults, many 24-hour rhythms are dampened and/or advanced, including those of cortisol and GH. Amplitude reduction and phase advance of 24-hour rhythms may represent age-related changes in the central nervous systems underlying circadian rhythmicity and sleep-wake homeostasis. Age-related alterations in circadian function could also reflect decreased exposure and/or responsivity to the synchronizing effects of both photic (e.g. light exposure) and nonphotic (e.g. social cues) inputs. There are pronounced age-related alterations in sleep quality in aging which consist primarily of a marked reduction of slow-wave sleep, a reduction in REM stages and a marked increase in the number and duration of awakenings interrupting sleep. Alterations in slow-wave sleep occur abruptly in young adulthood (30-40 years of age) whereas disturbances in amounts of REM and wake appear more gradually. This article reviews evidence indicating that deficits in characteristics of sleep-wake homeostasis and circadian function may mediate age-related alterations in somatotropic and corticotropic function. Because sleep loss in young subjects results in endocrine disturbances which mimic those observed in aging, it is conceivable that the decrease in sleep quality which characterizes aging may contribute to age-related alterations in hormonal function and their metabolic consequences.

Two years of replacement therapy in adults with growth hormone deficiency.

OBJECTIVES: Although several studies have shown beneficial short-term effects of recombinant human growth hormone (rhGH) therapy in adult GH deficient (GHD) patients, few data are available on large groups of patients treated for more than one year. In addition, the optimal dose of rhGH for each patient and the baseline parameters that predict which patients will benefit most from therapy or will have adverse events are not entirely elucidated. DESIGN: 148 adult GHD patients were enrolled in a multicentre 2-year rhGH replacement study which was placebo controlled for the first six months. rhGH (Genotropin/Genotonorm Pharmacia & Upjohn) was given in a dose of 0.25 IU/kg/week sc (1.5 IU/m2/day). MEASUREMENTS: Every 3-6 months body composition was measured using body impedance analysis and general well being was assessed using the Nottingham Health Profile (NHP) and social self-reporting questionnaire. At the same time patients had a full clinical examination and blood was sampled for glucose, HbA1c, IGF-1, creatinine, full blood count, thyroid hormones and liver function tests. RESULTS: With rhGH therapy IGF-1 levels increased from -2.00 +/- 2.60 SDS to 1.47 +/- 2.6 SDS after six months (P < 0.001), continued to rise despite no change in dose to 1.84 +/- 2.8 SDS after one year and remained constant thereafter (1.98 +/- 2.4 after 2 years). 56% of patients ultimately attained supranormal IGF-1 levels (+2 SD), 22% had levels below the mean, of which 9% were below -2 SD. Within 3 months lean body mass (LBM) increased by +5.09% (P < 0.001), total body water (TBW) by +5.40% (P < 0.001), while body fat (BF) dropped by -10.89% (P < 0.001) and waist circumference by -1.42% (P < 0.004). These effects were maintained during the first year of therapy, but the effect was attenuated after 24 months: LBM, +3.91% (P < 0.001); TBW, +3.28%, P < 0.001, BF, -6.42% (P < 0.001) and waist -2.22% (P < 0.009). Individual differences in response were large and could not be predicted by any of the baseline parameters, except for a better response in males. Treatment resulted in a large and progressive improvement on the NHP scale, especially energy, emotions and sleep, but a similar change was also found in patients during placebo treatment. With rhGH the number of full days of sick leave/6 months decreased from 12.17 +/- 3.90 days (SEM) to 7.15 +/- 3.50 days after six months (P = 0.009), 2.93 +/- 1.55 days after 12 months (P = 0.01), 0.39 +/- 0.17 days after 18 months (P < 0.001) and 3.3 +/- 2.51 days after 24 months (P = 0.026). Similarly, the hospitalization rate went down from 14.9 to 7% after 6 months and remained at this level thereafter (P = 0.12). About one third of patients on rhGH experienced fluid-related adverse events, most often within the first 3 months. They usually disappeared spontaneously or responded well to dose reduction. Cumulative dropout rates were 29% after 1 year and 38% after two years. Two thirds of these patients stopped treatment because of insufficient subjective improvement. Neither drop-outs nor fluid retention could not be predicted by any of the baseline parameters. CONCLUSIONS: We confirmed in a large group of patients the beneficial effects of rhGH therapy on body composition, metabolic parameters and general well-being and found a consistent drop in number of sick days and hospitalization rate. These effects were maintained during two years of therapy, except for an attenuation in body composition changes after 24 months. The high incidence of fluid-related adverse events suggests that it may be better to start with lower doses of rhGH and to increase the dose more slowly over a number of weeks. The finding of suboptimal high or low IGF-1 levels in many patients reinforces guidelines not to give rhGH in a weight-dependent dose but to titrate it individually for each patient.

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.

Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man.

Previous studies have indicated the existence of common mechanisms regulating sleep and somatotropic activity. In the present study, we investigated the effects of prolonged treatment with a novel, orally active, growth hormone secretagogue (MK-677) on sleep quality in healthy young and older adults. Eight young subjects (18-30 years) followed a double-blind, placebo-controlled, three-period crossover design. Each subject participated in three 7-day treatment periods (with bedtime drug administration), presented in random (Latin square) order, and separated by at least 14 days. Doses were 5 and 25 mg MK-677 and matching placebo. Six older subjects, ages 65-71 years, each participated in two 14-day treatment periods (with bedtime drug administration) separated by a 14-day washout. Doses were 2 and 25 mg MK-677 during the first and second periods, respectively. Baseline sleep and hormonal data were obtained on the 2 days preceding the beginning of the first 14-day treatment period. In young subjects, high-dose MK-677 treatment resulted in an approximately 50% increase in the duration of stage IV and in a more than 20% increase in REM sleep as compared to placebo (p < 0.05). The frequency of deviations from normal sleep decreased from 42% under placebo to 8% under high-dose MK-677 (p < 0.03). In older adults, treatment with MK-677 was associated with a nearly 50% increase in REM sleep (p < 0.05) and a decrease in REM latency (p < 0.02). The frequency of deviations from normal sleep also decreased (p < 0.02). The present findings suggest that MK-677 may simultaneously improve sleep quality and correct the relative hyposomatotropism of senescence.

Sleep loss results in an elevation of cortisol levels the next evening.

Sleep curtailment constitutes an increasingly common condition in industrialized societies and is thought to affect mood and performance rather than physiological functions. There is no evidence for prolonged or delayed effects of sleep loss on the hypothalamo-pituitary-adrenal (HPA) axis. We evaluated the effects of acute partial or total sleep deprivation on the nighttime and daytime profile of cortisol levels. Plasma cortisol profiles were determined during a 32-hour period (from 1800 hours on day 1 until 0200 hours on day 3) in normal young men submitted to three different protocols: normal sleep schedule (2300-0700 hours), partial sleep deprivation (0400-0800 hours), and total sleep deprivation. Alterations in cortisol levels could only be demonstrated in the evening following the night of sleep deprivation. After normal sleep, plasma cortisol levels over the 1800-2300-hour period were similar on days 1 and 2. After partial and total sleep deprivation, plasma cortisol levels over the 1800-2300-hour period were higher on day 2 than on day 1 (37 and 45% increases, p = 0.03 and 0.003, respectively), and the onset of the quiescent period of cortisol secretion was delayed by at least 1 hour. We conclude that even partial acute sleep loss delays the recovery of the HPA from early morning circadian stimulation and is thus likely to involve an alteration in negative glucocorticoid feedback regulation. Sleep loss could thus affect the resiliency of the stress response and may accelerate the development of metabolic and cognitive consequences of glucocorticoid excess.

Growth hormone assays: early to latest test generations compared.

We compared the data from four growth hormone (GH) immunoassays for analyzing 24-h GH profiles in four apparently normal subjects and four obese subjects (508 serum samples). The detection limit was 0.02 microgram/L for one immunochemiluminometric assay (ICMA), 0.1 microgram/L for two IRMAs, and 0.4 microgram/L for one RIA. All GH pulses with a peak ICMA value > 1 microgram/L were detected by each of the other methods. Overall, the correlation coefficient between the values obtained with all four assays exceeded 0.90. However, for GH concentrations < or = 0.25 microgram/L, acceptable concordance (r2 > or = 0.80) was reached only between the ICMA and one IRMA; between the ICMA and the RIA, concordance was acceptable only for GH concentrations > or = 10 micrograms/L. In the normal subjects, the percentage of undetectable values was 0% with the ICMA but 29% with one of the IRMAs; in obese subjects, the corresponding values were 12% and 38%.

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.