General Characteristics: The sleep-wake cycle may be viewed as a 24-hour rhythm driven partially by the circadian pacemaker and partially by the homeostatic regulation of sleep pressure. Sleep itself is an ultradian rhythm in that it involves two states of distinct brain activity, each of which is generated in specific brain regions. The ultradian rhythm of normal sleep is an approximate 90-minute oscillation between non-REM (rapid eye movement) and REM stages. In healthy subjects, this pattern usually is repeated four to six times per night. REM sleep and non-REM sleep are characterized by distinct patterns of cerebral and peripheral activity.

In the normal sequence, sleep is intiated by the lighter stages of non-REM sleep (i.e., stages I and II), followed within 10 to 20 minutes by slow-wave sleep (SWS; stages III and IV). These deeper stages of sleep are maintained for nearly 60 minutes in normal young subjects but usually are much shorter (5 to 10 minutes), if present at all, in older adults. Then, lighter stages of non-REM sleep reappear, and the first REM period is initiated. As the night progresses, non-REM sleep becomes shallower, the duration of REM episodes becomes longer, and the number and duration of awakenings increase. In normal young subjects, approximately 50% of a normal night is spent in stages I and II sleep, 20% in SWS, 25% in REM, and 5% in wake. In adults over 60 years of age, SWS usually is reduced to only 5% to 10% and REM sleep to 10% to 15%, while the proportion of time awake may reach 30% of the night.

During deep non-REM sleep (SWS), the electroencephalogram (EEG) is synchronized with low-frequency, high-amplitude waveforms, referred to as slow waves or delta waves. During REM sleep, eye movements are present, muscle tone is inhibited, and the EEG resembles that of active waking. During REM sleep, cerebral glucose utilization is similar to that of waking, but it is decreased during SWS.

The all-night recording of EEG, muscle tone, and eye movements, called the polysomnogram, is scored visually over 20 or 30 second periods in stages I, II, III, IV, REM, and Wake with the use of standardized criteria.⁷⁴ This procedure allows determination of the duration of each sleep stage but does not quantify the intensity of non-REM sleep. In contrast, the quantification of EEG recordings by power spectral analysis provides useful information regarding sleep depth or sleep intensity, because spectral analysis is sensitive to the amplitude of the delta waves. Higher-amplitude delta waves reflect more intense, deeper sleep, with less sensitivity to arousal stimuli. Slow-wave activity (SWA), i.e., spectral EEG power in the low-frequency range (also called delta range; 0.5 to 4.0 Hz), is a marker of the intensity of non-REM sleep.

As detailed below, the timing, duration, and architecture of sleep are under the dual control of a homeostatic mechanism that relates sleep pressure to the duration of prior wakefulness and of central circadian rhythmicity.

Neuroanatomic Basis of Sleep Regulation: Normal waking is associated with neuronal activity in regions of the so-called ascending arousal system, which includes monoaminergic neurons in the brain stem and posterior hypothalamus, cholinergic neurons in the brain stem and basal forebrain, and orexin (hypocretin) neurons in the lateral hypothalamus.75,76 Initiation of sleep therefore requires the inhibition of these multiple arousal systems. In recent years, the ventrolateral preoptic area (VLPO) of the hypothalamus has been identified as involved in the inhibition of arousal. The VLPO contains sleep-active neurons that use the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) and have much higher firing rates during deep sleep than during wakefulness.^77–79 Lesions of the central cell cluster of the VLPO drastically reduce SW activity. Neurons of the VLPO provide GABAergic inhibitory innervation of the major monoamine arousal systems in the brain stem. Reciprocally, inhibitory pathways result from the monoamine arousal nuclei to the VLPO.⁸⁰ The orexin neurons in the lateral hypothalamus project to all components of the ascending arousal system and stimulate the cortex.⁸¹ REM sleep is regulated primarily by cholinergic nuclei in the pons.

Interactions Between Circadian Rhythmicity and Sleep-Wake Homeostasis: Several features of the interaction between sleep and circadian rhythmicity appear to be fairly unique to the human species. First, human sleep generally is consolidated in a single 6- to 9-hour period, whereas fragmentation of the sleep period in several bouts is the rule in most other mammals. Possibly as a result of this consolidation of the sleep period, the wake-sleep transition in man is associated with physiologic changes that usually are more marked than those observed in animals. For example, the secretion of growth hormone (GH) in normal adults is tightly associated with the beginning of the sleep period, whereas the relationship between GH secretory pulses and sleep stages is much less evident in rodents, primates, and dogs. Second, man is unique in his capacity to ignore circadian signals and to maintain wakefulness despite increased pressure to go to sleep. Finally, approximately 25% of human subjects maintained for prolonged periods in temporal isolation have shown behavioral modifications that have not been observed in laboratory animals under constant conditions. These modifications consist of a desynchronization between the sleep-wake cycle and other rhythms, such as those of body temperature and cortisol secretion, which continue to free-run with a circadian period. Under conditions of so-called internal desynchronization, the sleep-wake cycle may be lengthened suddenly to 30 hours or more, while the rhythm of body temperature continues to free-run with a circadian period.⁴ Wakefulness may last longer than 30 hours. Remarkably, the subjects are not aware of these drastic changes in their way of living. Instead, most of them believe that they are living on a more or less regular 24-hour schedule. This can be explained by the observation that time perception is altered profoundly: Subjective estimations of 1 hour intervals are positively correlated with the duration of wakefulness.⁸² Of particular interest is that subjects continue to have three meals per “day,” irrespective of the actual number of hours they are awake.⁸³ The intervals between meals as well as those between wake-up and breakfast, or between dinner and bedtime, are stretched or compressed in strong proportionality to the duration of wakefulness.⁸⁴ The mechanisms that cause spontaneous internal desynchronization are not completely understood.

Detailed analyses of data obtained during temporal isolation and forced desynchrony protocols show that the timing, duration, and architecture of sleep are regulated in part by circadian rhythmicity.23,85 Thus, the duration of sleep episodes is correlated with the phase of the circadian rhythm of body temperature and not with the duration of prior wakefulness. Short (i.e., 7 to 8 hours) sleep episodes occur in free-running conditions when the subject goes to sleep around the minimum of body temperature, whereas long (i.e., 12 to 14 hours) sleep episodes occur when sleep starts at around the maximum of body temperature. Moreover, the distribution of REM sleep is markedly modulated by circadian timing. In contrast, the hourglass-like mechanism of sleep-wake homeostasis originally was thought to be largely independent of the circadian system and to involve one or several putative neural sleep factors, which rise during waking and decay exponentially during sleep.⁸⁶ This homeostatic mechanism regulates the timing, amount, and intensity of SWS and SWA. The VLPO has been proposed as a neuroanatomic locus for the interaction of the homeostatic process and central circadian rhythmicity, as it receives dense projections from the dorsomedial hypothalamic nucleus, which itself receives direct and indirect projections from the SCN.⁸⁷ Based on human studies described later, it is thought that the SCN generates a waking signal that promotes alertness during the active period. In support of this theory, studies have shown that rodents and monkeys with SCN lesions have increased sleep duration.^88,89 Furthermore, studies in rats have described an indirect neuronal circuit from the SCN to the locus coeruleus, an area of the midbrain involved in the control of arousal.⁹⁰ A role for the SCN in promoting sleep at other circadian times is suggested by the finding of decreased sleep in a mouse with a mutation of the Clock gene.⁹¹ The recent finding that the mutation or deletion of a number of circadian clock genes affects not only the timing of sleep but also many other sleep-wake traits, including traits linked to the homeostatic drive to sleep,^15,91–94 indicates that circadian and homeostatic processes underlying the regulation of the sleep-wake cycle may be linked at molecular and anatomic levels of organization.

The dual control of sleep by circadian and homeostatic mechanisms extends to the control of objective and subjective measures of sleep tendency, mood, and vigilance.95–98 When wakefulness is extended beyond the usual 16 to 18 hours, maximum subjective sleepiness coincides with the minimum of body temperature, mood, and performance. Remarkably, despite continued sleep deprivation, subjective fatigue then decreases, and mood and performance partially recover during the daytime hours, reflecting an interaction of circadian timing with the accumulation of waking time.^96–102 Currently, it is believed that the circadian clock generates a waking signal that increases from morning to evening and is expressed maximally in the early evening hours, 1 to 2 hours before the onset of nocturnal melatonin secretion.⁹⁷ This circadian waking signal counteracts the buildup of the putative factor “S” underlying the homeostatic process, allowing the individual to maintain a high level of alertness throughout the usual waking period. Current data from human studies are compatible with the hypothesis that the SCN generates a sleep signal in the early evening hours.¹⁰³

Circadian rhythmicity and sleep-wake homeostasis also interact to regulate hormonal secretion. These modulatory effects were long thought to be present only in hormones directly dependent on the hypothalamic-pituitary axis. However, it is now clear that modulation by circadian rhythmicity and sleep is also present in other endocrine systems, such as glucose regulation and the renin-angiotensin system.104,105 The multiple pathways by which circadian rhythmicity, sleep-wake homeostasis, and their interaction modulate hormonal release are incompletely understood. As is illustrated in Fig. 4-1, humoral and/or neural signals originating from the hypothalamic circadian pacemaker and from brain regions involved in sleep regulation affect the pulsatile release of hypothalamic neuroendocrine factors, which stimulate or inhibit intermittent secretion of pituitary hormones. The autonomic nervous system is another pathway linking the central control of sleep-wake homeostasis and circadian rhythmicity with peripheral endocrine organs. It appears that stimulatory or inhibitory effects of sleep on endocrine release are primarily associated with SW rather than REM sleep.^106–110 Pituitary hormones that influence endocrine systems not directly controlled by hypothalamic factors probably mediate, together with the autonomous nervous system, the modulatory effects of sleep and circadian rhythmicity on these systems (e.g., counterregulatory effects of GH and cortisol on glucose regulation¹⁰⁵).

To delineate the relative roles of circadian and sleep effects in the temporal organization of hormonal secretion, strategies based on the fact that circadian rhythmicity needs several days to adapt to abrupt shifts in the sleep-wake cycle have been used. Thus, by shifting sleep times by 8 to 12 hours, masking effects of sleep on circadian inputs are removed, and the effects of sleep at an abnormal circadian time are revealed. Fig. 4-3 illustrates the mean profiles of plasma cortisol, GH, prolactin, and thyrotropin (TSH) as observed in normal subjects who were studied before and during an abrupt 12-hour shift in the sleep-wake and dark-light cycles. The study period extended over a 53-hour span and included an 8-hour period of nocturnal sleep, a 28-hour period of continuous wakefulness, and a daytime period of recovery sleep. To eliminate the effects of feeding, fasting, and postural changes, subjects remained recumbent throughout the study, and the normal meal schedule was replaced by intravenous glucose infusion at a constant rate. As shown in Figure 4-3, this drastic manipulation of sleep had only modest effects on the wave shape of the cortisol profile, in sharp contrast with the immediate shift of GH and prolactin rhythms, which followed the shift in the sleep-wake cycle. As will be reviewed in subsequent sections, numerous studies have indicated that control of diurnal rhythms of corticotropic activity is primarily dependent on circadian timing, whereas sleep-wake homeostasis appears to be an important factor in control of the 24-hour profiles of GH and prolactin.¹¹¹ Nevertheless, small modulatory effects of sleep-wake homeostasis on cortisol secretion and, conversely, influences of circadian timing on somatotropic function have been clearly demonstrated.¹¹² The diurnal variation in TSH levels includes an evening elevation that is thought to be under circadian control and nocturnal inhibition by sleep-dependent processes that is clearly demonstrated during sleep deprivation, when a large increase in nocturnal TSH levels is apparent, as is shown in the lower panel of Fig. 4-3.¹¹¹

Hormonal profiles thus are easily measurable reflections of central mechanisms of biologic time keeping. In clinical investigations of conditions of abnormal circadian rhythmicity such as jet lag, and in human studies of the effects of exposure to natural or artificial zeitgebers, hormonal profiles are commonly used as markers of the status of the circadian clock and of its interactions with sleep.

Normal Rhythms of Adrenocorticotropic Hormone and Adrenal Secretions: Outputs from the SCN activate rhythmic release of corticotropin-releasing hormone (CRH) that stimulates circadian ACTH release. The 24-hour rhythm of adrenal secretion is primarily dependent on the diurnal pattern of ACTH release. In addition, neuronal signals generated by the SCN are transmitted by a multisynaptic neural pathway to the adrenal cortex.¹⁶⁸ The presence in the adrenal cortex of an intrinsic circadian oscillator consisting of interacting positive and negative feedback loops in circadian gene expression has been demonstrated in various animals, including monkeys,^169–171 and it has been shown that this adrenal circadian pacemaker gates the physiologic adrenal response to ACTH (i.e., defines a time window during which the adrenal most effectively responds to ACTH).¹⁷²

The 24-hour profiles of ACTH and cortisol show an early morning maximum, declining levels throughout daytime, a quiescent period of minimal secretory activity centered around midnight, and an abrupt elevation during late sleep, resulting in an early morning maximum. Mathematical derivations of secretory rates from plasma concentrations have suggested that the 24-hour profile of plasma cortisol reflects a succession of secretory pulses of magnitude modulated by a circadian rhythm with no evidence of tonic secretion.120,173 In normal conditions, the acrophase of the pituitary-adrenal periodicity occurs between 06.00 and 10.00 hours. With a 15-minute sampling interval, 12 to 18 significant pulses of plasma ACTH and cortisol can be detected per 24-hour span.¹⁷⁴ Circadian and pulsatile variations parallel to those of cortisol have been demonstrated for the plasma levels of several other adrenal steroids, in particular dehydroepiandrosterone (DHEA).¹⁷⁵ The temporal concomitance of 24-hour profiles of ACTH, cortisol, and DHEA is illustrated in Fig. 4-6.

The profile shown in the upper panel of Fig. 4-3 illustrates the remarkable persistence of the cortisol and, by inference, ACTH secretory rhythm when sleep is manipulated. Indeed, the overall wave shape of the profile was not markedly affected by the absence of sleep or the presence of sleep at an abnormal time of day. Thus, this rhythm is controlled primarily by the circadian pacemaker.

However, modulatory effects of sleep-wake homeostasis have been clearly demonstrated. As illustrated in Fig. 4-7, sleep onset is consistently associated with short-term inhibition of cortisol secretion, which may not be detectable when sleep is initiated in the morning (i.e., at the peak of corticotropic activity).^176–179 This inhibitory effect of sleep appears to be related to SW sleep.^109,180 Conversely, final awakenings from sleep, as well as transient awakenings that interrupt the sleep period, consistently trigger pulses of cortisol secretion (see Fig. 4-7),^{120,178,180–183} and the number of nocturnal microarousals predicts morning plasma and saliva cortisol levels.¹⁸⁴ In an analysis of cortisol profiles during nocturnal sleep, it was observed that all transient awakenings that interrupt sleep and last at least 10 minutes were followed within the next 20 minutes by significant bursts of cortisol secretion.¹⁸³ In addition, a temporal coupling between pulses of cortisol secretion and ultradian variations in an EEG marker of alertness has been reported.¹¹⁴ Total nocturnal wake time is associated with increased 24-hour plasma cortisol concentrations,¹⁸⁵ and chronic insomnia with reduced total sleep time is associated with higher cortisol levels across the night.¹⁸⁶

Modulatory effects of dark-light transitions also have been noted. Cortisol secretory pulses associated with morning awakening are enhanced by increasing light intensity.¹⁸⁷ Moreover, the transition from darkness to dim light and from dim to bright light may stimulate cortisol secretion in subjects who are awake at bed rest.^183,188 The stimulatory effects of bright light exposure on nocturnal cortisol levels appear to be dependent on the timing of exposure.¹⁸⁹ When dark-light and sleep-wake transitions occur concomitantly, associated cortisol elevations are nearly two times as high as when the final awakening occurs in continuous darkness¹⁸³ (see Fig. 4-7). Thus, under usual bedtime schedules, both sleep-wake and dark-light transitions amplify the effects of circadian rhythmicity.

Studies of the 24-hour cortisol profile in the course of adaptation to shifts of the sleep-wake cycle have demonstrated that the end of the quiescent period, which coincides with the onset of the early morning rise, takes longer to adjust and appears to be a robust marker of circadian timing. Twin studies have demonstrated that the timing of the nadir is influenced by genetic factors,¹⁹⁰ providing evidence for genetic control of the human circadian phase. In contrast, the timing of the morning acrophase is more labile and may be influenced by the timing of sleep offset,¹⁸² the transition from dark to bright light,¹⁸⁷ and breakfast intake.¹⁹¹ Finally, anticipation of the expected time of waking has been reported to be associated with a rise in levels of ACTH, but not cortisol, during the end of the sleep period.¹⁹²

In addition to the immediate modulatory effects of sleep-wake transitions on ACTH and cortisol levels, acute total or partial (4 hours in bed) nocturnal sleep deprivation results in elevated cortisol concentrations in late afternoon and evening on the following day,¹⁹³ and the amplitude of the cortisol circadian variations is reduced by approximately 15%. Similarly, as illustrated in Fig. 4-8, recurrent partial sleep deprivation (4 hours in bed per night for 6 nights) also results in an elevation of cortisol levels in the late afternoon and evening.¹⁹⁴ These disturbances, which were observed in young healthy subjects, are strikingly similar to those noted in older healthy subjects with normal sleep schedules.^126,195,196 In any case, sleep loss appears to delay the return to quiescence of the hypothalamic-pituitary-adrenal axis (HPA) that normally occurs in the evening. This suggests that sleep loss, similar to aging, may slow down the rate of recovery of the HPA axis response following a challenge and therefore could facilitate the development of central and peripheral disturbances associated with glucocorticoid excess, in particular when cortisol concentrations are elevated at the time of the normal daily nadir, such as memory deficits, insulin resistance, and osteoporosis.^197–201 Conversely, decreased HPA resiliency results in HPA hyperactivity that inhibits SW sleep and promotes nocturnal awakenings, initiating a feed-forward cascade of negative events generated by both HPA and sleep disruptions.

The circadian rhythm of cortisol persists throughout adulthood and has been observed through the ninth decade.126,196 Among young adults, 24-hour cortisol levels are slightly lower in women than in men, primarily because of lower morning maxima. With aging, evening cortisol levels increase progressively in both men and women, so that the cortisol nadir is markedly higher in healthy subjects over 70 years of age than in young adults (see Fig. 4-4). It is interesting to note that this elevation of evening cortisol levels occurs with a chronology similar to that observed for a progressive decrease in the duration of REM sleep¹²⁹ (see Fig. 4-5). As a result, older subjects have elevated 24-hour mean cortisol levels and reduced amplitude of cortisol variations. In addition, the timing of the nadir is advanced by 1 to 2 hours, indicating that aging is associated with an advance in the circadian phase.^126,196

In pregnancy, placental CRH is secreted into the maternal circulation in a pulsatile but not in a circadian fashion, and no correlation has been noted between maternal levels of CRH and ACTH. However, ACTH and cortisol concentrations remain strongly correlated with each other over time, suggesting that diurnal variation in maternal ACTH probably is driven by another ACTH secretagogue.²⁰²

Alterations in Disease States: The 24-hour profile of pituitary-adrenal secretion remains largely unaltered in a wide variety of pathologic states. Disease states in which pronounced alterations of the cortisol rhythm have been observed include primarily (1) disorders involving abnormalities in binding and/or metabolism of cortisol; (2) the various forms of Cushing’s syndrome; and (3) depression and posttraumatic stress disorder (PTSD).

The relative amplitude of the circadian rhythm and of the episodic fluctuations in cortisol is blunted in patients with liver disease²⁰³ and in those with anorexia nervosa,²⁰⁴ primarily because of the decreased metabolic clearance of cortisol. Pulsatile secretion of ACTH, but not cortisol, was reportedly enhanced in obese premenopausal women.²⁰⁵ In hypothyroid patients, the mean level is markedly elevated and the relative amplitude of the rhythm is dampened.²⁰⁶ These alterations are thought to be due to both diminished clearance and decreased efficiency of feedback control. In contrast, in hyperthyroidism, where cortisol production and peripheral metabolism are increased, episodic pulses are enhanced.²⁰⁷

A low-amplitude circadian variation may persist in pituitary-dependent Cushing’s disease. Cortisol pulsatility is blunted in about 70% of patients with Cushing’s disease, suggesting autonomous tonic secretion of ACTH by a pituitary tumor. However, in about 30% of these patients, the magnitude of the pulses is enhanced instead.²⁰⁸ These hyperpulsatile patterns could be caused by enhanced hypothalamic release of CRH or persistent pituitary responsiveness to CRH. It also has been shown that patients with Cushing’s disease secrete ACTH and cortisol jointly more asynchronously than healthy subjects.²⁰⁹ The left and middle panels of Fig. 4-9 compare representative and mean 24-hour cortisol profiles in normal subjects and in patients with Cushing’s disease.

In patients with primary adrenal Cushing’s syndrome, increased cortisol secretion appears to result from both increased basal secretion and increased pulse frequency.²¹⁰ Although the persistence of a low-amplitude circadian cortisol variation has been claimed,²¹⁰ examination of the individual profiles does not support this notion. Nevertheless, the partial persistence of cortisol rhythmicity in the absence of ACTH could reflect the newly described neural pathway between the SCN and the adrenal cortex.¹⁶⁸

The absence or even the dampening of cortisol circadian variations in Cushing’s syndrome has obvious implications for clinical diagnosis, as time of day when plasma samples are obtained has to be taken into account during evaluation of the result. Differentiation between normal and pathologic levels may be greatly improved by adequate selection of the sampling time, because the overlap between normal individual values and values in patients with Cushing’s syndrome is minimal during a 4-hour interval centered around midnight.

Hypercortisolism with persistent circadian rhythmicity and increased pulsatility is found in a majority of severely depressed patients.211–213 This is illustrated in the right panels of Fig. 4-9. In these patients, who do not develop the clinical signs of Cushing’s syndrome despite high circulating cortisol levels, the quiescent period of cortisol secretion is shorter and more fragmented, and it often starts later and ends earlier than in normal subjects of comparable age. These alterations could reflect the impact of sleep disturbances, as well as an advance in circadian phase. When clinical remission of the depressed state is obtained, hypercortisolism and alterations in the quiescent period disappear, indicating that these disturbances are “state” rather than “trait” dependent.²¹⁴

In PTSD, some authors have reported that plasma cortisol levels are decreased in the afternoon and/or in the evening, and that the amplitude of circadian variations is enhanced.215–217 In fibromyalgia and in the chronic fatigue syndrome, cortisol levels have been reported to be low, normal, or elevated, depending on the study, but ACTH and cortisol pulsatility were found to be normal.²¹⁸ In a well-documented study performed in constant routine conditions, normal circadian variations of plasma cortisol levels were evidenced in women with fibromyalgia.²¹⁹

The 24 Hour Profile of Growth Hormone in Normal Subjects: Pituitary secretion of GH is stimulated by hypothalamic GH-releasing hormone (GHRH) and is inhibited by somatostatin. In addition, the acylated form of ghrelin (acyl-ghrelin), a peptide produced predominantly by the stomach, binds to the GH-secretagogue receptor and therefore is another potent endogenous stimulus of GH secretion.220,221 In normal adult subjects, the 24-hour profile of plasma GH levels consists of stable low levels abruptly interrupted by bursts of secretion. The most reproducible pulse occurs shortly after sleep onset, in association with the first phase of SW sleep.²²² Other secretory pulses may occur in later sleep and during wakefulness, in the absence of any identifiable stimulus. Studies in young male twins have evidenced a major genetic effect on GH secretion during waking, but not during sleep.²²³ In adult men, the sleep-onset GH pulse generally is the largest pulse observed over the 24-hour span. In normally cycling women, 24-hour GH levels are higher than in age-matched men, daytime pulses are more frequent, and the sleep-associated pulse, although still present in most cases, does not generally account for most of the 24-hour GH release.²²⁴ Typical profiles of young men and women are shown in Fig. 4-10. Well-documented studies have demonstrated that in women, the amplitude of GH secretory pulses is correlated with the circulating level of estradiol.^224,225 In normally cycling young women, it also was observed that daytime GH secretion was increased during the luteal phase as compared with the follicular phase, and that this elevation correlated positively with plasma levels of progesterone but not estradiol.²²⁶

Sleep onset will elicit a GH secretory pulse, whether sleep is advanced, delayed, interrupted, or fragmented.²²² Thus, as illustrated in Fig. 4-3, shifts in the sleep-wake cycle are followed immediately by parallel shifts in GH rhythm.²²² In night workers, the main GH secretory episode occurs during the first half of the shifted sleep period.²²⁷ The release of GH in early sleep is temporally and quantitatively associated with the amount of SW sleep.^228,229 Both SW sleep and GH levels are increased during the recovery night following nocturnal total sleep deprivation as compared with the baseline predeprivation night, especially during the first 4 hours of sleep.²³⁰ Good evidence suggests that the mechanisms underlying the relationship between SW sleep and GH release involve synchronous activity of at least two different populations of hypothalamic GHRH neurons.²³¹ Indeed, inhibition of endogenous GHRH by administration of a specific antagonist or by immunoneutralization inhibits both sleep and GH secretion.²³² Additional evidence for the existence of a robust relationship between SW activity and GH release has been provided by studies using pharmacologic stimulation of SW sleep. Indeed, enhancement of SW sleep by oral administration of low doses of gamma-hydroxybutyrate (GHB), a natural metabolite of GABA used in treatment for narcolepsy, or of ritanserin, a selective serotonin (5-HT)₂ antagonist, results in simultaneous and highly correlated increases in nocturnal GH secretion.^108,233 Conversely, transient awakenings during sleep inhibit GH secretion.²³⁴ Thus, sleep fragmentation generally will decrease nocturnal GH release.

However, although sleep is clearly the major determinant of GH secretion in man, evidence for the existence of a circadian modulation of the occurrence and amplitude of GH pulses also has been found. This may reflect decreased somatostatin inhibitory activity in the evening and during the night,²³⁵ or it could result from the nocturnal rise in ghrelin, which occurs even in the absence of sleep.²³⁶ Thus, the major sleep-onset associated GH pulse is caused by a surge of hypothalamic GHRH coincident with a circadian period of relative somatostatin disinhibition.^222,232 In normal-weight subjects, fasting, even for only 1 day, enhances GH secretion via an increase in pulse amplitude.²³⁷ Presleep GH pulses, reported by some investigators in normal men,²³⁸ may reflect the presence of a sleep debt, thus unmasking the circadian component of GH secretion.²³⁹ A recent study provides evidence for modulation of GH secretion by endogenous acyl-ghrelin, leading to higher GH peaks before times of food intake in subjects given regular meals.²³⁷

After a night of total sleep deprivation, a compensatory increase in GH release is observed during the daytime, so that the overall 24-hour secretion is not altered significantly.²⁴⁰ The mechanisms underlying this compensatory increase might involve decreased somatostatinergic tone and/or elevated ghrelin levels. Recurrent partial sleep restriction is associated consistently with the appearance of a presleep GH pulse.²³⁹

Aging is associated with dramatic decreases in circulating levels of GH (see Figs. 4-4 and 4-5).^126,224 This reduction is achieved by a decrease in amplitude, rather than in frequency, of GH pulses.^126,241,242 It also has been reported that the orderliness of GH secretion is decreased in the elderly.²⁴³ As illustrated in Fig. 4-5, this age-related GH decrease occurs in an exponential fashion between young adulthood and midlife and follows the same chronology as the decrease in SW sleep. Despite the persistence of high levels of sex steroids, plasma concentrations and pulsatile secretion rates of GH fall in midlife to less than half the values achieved in young adulthood. Thereafter, smaller and more progressive decrements occur from midlife to old age.¹²⁹ Among the elderly, GH secretory profiles are similar in men and in women.²²⁴ The age-related reduction of GH secretion appears to result from increased somatostatin secretion and diminished GHRH responsiveness.²⁴⁴

It is interesting to note that during pregnancy, a placental GH variant, which substitutes for pituitary GH to regulate maternal insulin-like growth factor-1 (IGF-1) levels,²⁴⁵ is released in a tonic rather than a pulsatile fashion.²⁴⁶

Alterations in Disease States: Abnormalities in the 24-hour profile of plasma GH have been reported in a variety of metabolic, endocrine, neurologic, and psychiatric conditions.

An inverse relationship between adiposity and GH release has been noted, which results in marked suppression of GH levels throughout the 24-hour span in obese subjects. A normal pattern can be restored after prolonged fasting.²⁴⁷ In anorexia nervosa, GH pulse amplitude and frequency are increased, and the orderliness of GH release is disrupted.²⁴⁸ Nonobese juvenile or maturity-onset diabetic patients hypersecrete GH during wakefulness as well as during sleep, primarily because of an increase in the amplitude of pulses.²⁴⁹ This abnormality may disappear when glycemia is strictly controlled.

In functional hypothalamic amenorrhea, 24-hour mean GH levels are normal, but the pattern of pulsatile GH release is distinctly altered, with a decrease in pulse amplitude, a 40% increase in pulse frequency, and a twofold increase in interpulse GH concentrations.²⁵⁰ In lean women with the polycystic ovary syndrome (PCOS), the amplitude, but not the frequency, of GH pulses is increased as compared with body mass index (BMI)-matched normal cycling controls. In contrast, pulse amplitude is similarly reduced in obese patients with PCOS and obese controls.²⁵¹

Diurnal and nocturnal episodes of GH secretion are more frequent and of higher amplitude in adult subjects with hyperthyroidism, who have an overall daily GH production rate fourfold greater than normal.²⁵² Patients with major endogenous depression often have the major nocturnal GH pulse before, rather than after, sleep onset.²⁵³

In Cushing’s disease, an inverse relationship has been noted between the degree of cortisol hypersecretion and total GH secretion, and the frequency and the disorderliness of GH pulses are increased.²⁵⁴ In acromegaly, GH is hypersecreted throughout the 24-hour span, with a highly irregular pulsatile pattern superimposed on elevated basal levels, indicating the presence of tonic secretion.^255,256 After pituitary surgery, a normal 24-hour pattern of GH release can be restored in most, but not all, patients.^255,257

The 24-Hour Profile of Prolactin in Normal Subjects: Under normal conditions, the 24-hour profile of prolactin levels exhibits minimal levels around noon, a modest increase in the afternoon, and a major nocturnal elevation starting shortly after sleep onset and culminating around midsleep at levels corresponding to an average increase of more than 200% above minimum levels (see Fig. 4-3).^258,259 Episodic pulses occur throughout the 24-hour span, but their amplitude and their frequency are higher during the night than during the day. Decreased dopaminergic inhibition of prolactin secretion during sleep is likely to be the primary mechanism underlying this nocturnal elevation. Mean prolactin levels, pulse amplitude, and pulse frequency are higher in normally cycling women than in postmenopausal women or in normal young men.²⁶⁰ In normally cycling young women, it has also been observed that daytime prolactin pulsatility was enhanced during the luteal phase as compared with the follicular phase, leading to increased late afternoon and evening levels.²²⁶ In the luteal phase, the magnitude of the evening prolactin rise correlated positively with both estradiol and progesterone levels.²²⁶ These data indicate that endogenous estrogens and progesterone play a critical role in the differential regulation of prolactin secretion associated with sex and age. Deconvolution analysis has shown that the prolactin profile reflects both tonic and intermittent release.¹¹⁹ Twin studies have revealed that genetic factors determine partially the temporal organization of prolactin secretion.²⁶¹

Diurnal prolactin variations are regulated primarily by sleep-wake homeostasis. Sleep onset is invariably associated with an increase in prolactin secretion, irrespective of the time of the day. Thus, as illustrated in Fig. 4-3, shifts in the sleep-wake cycle are followed immediately by parallel shifts in the prolactin rhythm,²²² but the amplitude of the prolactin rise may be dampened when associated with daytime sleep as compared with nocturnal sleep.²⁶² Conversely, modest elevations in prolactin levels may occur during waking around the time of the usual sleep onset, particularly in women.²⁵⁹ Thus, prolactin secretion appears to be modulated in part by circadian rhythmicity, and maximal secretion occurs when sleep and circadian effects are superimposed (i.e., at the usual bedtime).^258,259,263 Benzodiazepine (e.g., triazolam) and imidazopyridine (e.g., zolpidem) hypnotics taken at bedtime generally enhance the nocturnal prolactin elevation.^264,265

A close temporal relationship has been evidenced between increased prolactin secretion and SW activity when sleep structure was characterized by power spectral analysis of the EEG.¹¹⁰ Conversely, prolonged awakenings that interrupt sleep are consistently associated with decreasing prolactin concentrations.¹¹⁰ Thus, SW sleep is associated with elevated prolactin secretion, and shallow and fragmented sleep generally is associated with dampening of the nocturnal prolactin rise. This is indeed observed in elderly subjects, who have a nearly 50% dampening of the nocturnal prolactin elevation (see Fig. 4-4).^126,266

During pregnancy, serum prolactin levels rise but the 24-hour pattern of secretion is maintained, albeit at a higher level. During the postpartum period, prolactin secretory pulses follow suckling episodes, and the nocturnal rise, independent of suckling, is evident only after breastfeeding has ceased.²⁶⁷

Alterations in Disease States: Absence or blunting of the nocturnal increase in plasma prolactin has been reported in a variety of pathologic states, including uremia and breast cancer in postmenopausal women. In Cushing’s disease, prolactin levels are elevated throughout the 24-hour cycle, and the relative amplitude of the nighttime rise is reduced.²⁶⁸ In subjects with insulin-dependent diabetes, the circadian and sleep modulation of prolactin secretion is preserved, but overall levels are markedly diminished.²⁶⁹ Obesity is associated with an increase in overall prolactin secretion, in proportion to excess visceral fat, without alteration of the diurnal variation. This enhancement is achieved by an increase in the amplitude and duration of secretory pulses.²⁷⁰

In hyperprolactinemia associated with prolactinomas, or secondary to functional pituitary stalk disconnection, the number of prolactin pulses is increased, and the regularity of the pulsatile pattern is decreased.271,272 The nocturnal elevation in prolactin may be preserved.^271,273 Selective removal of prolactin-secreting adenomas generally results in normalization of the prolactin pattern.

Abnormal prolactin profiles have been reported in a variety of neurologic and psychiatric disorders, including narcolepsy, depression, and schizophrenia.

Normal Diurnal Profiles of Gonadotropins and Sex Steroids: Rhythms in the gonadotropic axis cover a wide range of frequencies, from episodic release in the ultradian range, to diurnal rhythmicity and menstrual cycles. These various rhythms interact to provide a coordinated temporal program that governs the development of the reproductive axis and its operation at every stage of maturation. The following description of the current state of knowledge in this area will be limited to 24-hour rhythms and their interaction with pulsatile release during adulthood.

Patterns of LH release in adult men exhibit episodic pulses with large interindividual variability.²⁷⁴ LH secretory episodes mainly reflect GnRH pulsatility. A recent study indicates that LH pulsatility is inhibited by acyl-ghrelin, suggesting that the ghrelin system may play a centrally mediated inhibitory role in the gonadal axis.²⁷⁵ The diurnal variation is of low amplitude or is even undetectable. During the sleep period, LH pulses appear to be temporally related to the REM–non-REM cycle.²⁷⁶ FSH profiles may show some occasional pulses, with no diurnal variation.

In contrast, a marked diurnal rhythm in circulating testosterone levels is present in young normal men, with minimal levels in the late evening and maximal levels in the early morning.175,277 In young adult men, the amplitude of the testosterone rhythm averages 25%.¹⁷⁵ With a 15-minute sampling interval, 17 to 18 testosterone pulses per 24-hour span can be detected.¹⁷⁵ Growing evidence suggests that diurnal testosterone variations are controlled primarily by the sleep-wake cycle. Experimental sleep fragmentation (schedule allowing 7 minutes of sleep every 20 minutes) results in dampening of the nocturnal testosterone rise, particularly in subjects who do not achieve REM sleep.²⁷⁸ Daytime sleep, as well as nocturnal sleep, is associated with a robust rise in testosterone levels.²⁷⁹ However, a progressive elevation in testosterone levels persists during nocturnal wakefulness, albeit blunted as compared with nocturnal sleep,²⁷⁹ indicating the existence of a circadian component that could reflect adrenal androgen secretion. Diurnal profiles of testosterone are paralleled by inhibin B variations, with peak values in the early morning and nadirs in the late afternoon, and significant cross-correlations between inhibin B and testosterone or estradiol have been detected.²⁸⁰

A progressive decline in testosterone levels, together with an increase in sex hormone–binding globulin (SHBG) levels, is observed in normal men from 30 years of age onward, so that the decrease in bioavailable testosterone is more important than the decline in total testosterone.²⁸¹ In elderly men, the diurnal variation in testosterone is still present but may be markedly dampened.^277,282 A strong positive correlation has been evidenced between total sleep time and morning testosterone levels.²⁸³ Pulsatile testosterone secretion is attenuated, suggesting possible partial desensitization of Leydig cells to LH.²⁸⁴ Mean LH levels are increased, but the amplitude of LH pulses is decreased,^285,286 their frequency is increased,²⁸⁴ and no significant diurnal pattern can be detected.²⁸² In contrast, pulsatile FSH secretion is increased in older men.²⁸⁷ In addition, older males secrete LH and testosterone more irregularly, and jointly more asynchronously, than do younger men.²⁸⁸

In adult women, diurnal profiles of LH, FSH, estradiol, and progesterone exhibit episodic pulses throughout the 24-hour span.²⁸⁹ The 24-hour variations in plasma LH are markedly modulated by the menstrual cycle.²⁹⁰ Nocturnal slowing of pulsatile LH secretion is observed during the early follicular phase.²⁹⁰ This nocturnal slowing is related specifically to sleep rather than to time of day, since it is also observed during daytime sleep but not during nighttime wake.²⁹¹ During periods of sleep, LH pulses were found to occur preferentially in association with brief awakenings, suggesting an inhibitory effect of sleep on pulsatile LH secretion.²⁹¹ Since night and shift work is consistently associated with shorter and more fragmented sleep, these results indicate that altered menstrual function, which frequently is observed in night and shift workers, could result directly from altered sleep patterns. Evening elevation of LH levels and LH pulse amplitude is observed in the absence of sleep, suggesting the existence of a circadian modulation of LH secretion.²⁹¹ Circulating levels of LH and FSH and LH pulse frequency increase with aging and are higher in normal women older than 40 years of age with regular menstrual cycles than in women younger than age 40.²⁹² Gonadotropin levels remain elevated after menopause.

Alterations in Disease States: Early studies on the 24-hour profile of plasma LH in anorexia nervosa have established the importance of an adequate temporal secretory program in the maintenance of normal reproductive function. In women with amenorrhea secondary to anorexia nervosa, the secretory pattern of LH regresses to the pubertal or prepubertal pattern, with low daytime pulsatility and increased secretion at night.²⁹³ Secretory profiles of LH usually return to normal following weight gain and clinical remission. Short-term fasting was shown to suppress pulsatile LH secretion while enhancing its regularity in young, but not older, men.²⁹⁴

Abnormalities in the 24-hour profile of gonadotropin secretion are present in hypothalamic amenorrhea, hyperprolactinemia, and PCOS.

In most men with idiopathic hypogonadotropic hypogonadism, LH pulses are undetectable.²⁹⁵ In a small number of patients, an early pubertal pattern, with enhanced pulse amplitude during the nighttime, may be observed.²⁹⁵ Attenuation of pulsatile LH secretion has been reported in men, but not in women, during both hypocortisolism and hypercortisolism. The authors have speculated that this sex difference could be due to a higher level of hypothalamic opioid activity in men.²⁹⁶ Poorly controlled type 1 diabetes mellitus has been found to be associated with decreased amplitude of pulsatile LH secretion.²⁹⁷

The 24-Hour Profile of Thyrotropin in Normal Subjects: In normal adult men and women, TSH levels are low and relatively stable throughout the daytime and begin to increase in the late afternoon or early evening. Maximal levels occur around the beginning of the sleep period.²⁹⁸ TSH levels progressively decline during the latter part of sleep, and daytime values resume shortly after morning awakening. Onset of the nocturnal rise in TSH well before sleep onset is believed to reflect a circadian effect. This 24-hour pattern of TSH levels appears to be generated by frequency, as well as amplitude modulation, of thyrotropin-releasing hormone (TRH)-driven secretory pulses.¹¹⁸ Studies involving sleep deprivation and shifts in the sleep-wake cycle have consistently indicated that sleep exerts an inhibitory influence on TSH secretion; sleep deprivation relieves this inhibition.^298,299 It is interesting to note that when sleep occurs during the daytime, TSH secretion is not suppressed significantly below normal daytime levels.³⁰⁰ Profiles of plasma TSH during normal nocturnal sleep, nocturnal sleep deprivation, and daytime sleep are illustrated in the lower panel of Fig. 4-3. When depth of sleep at the habitual time is enhanced by previous sleep deprivation, inhibition of the nocturnal TSH rise is more pronounced than in basal conditions. Descending slopes of TSH concentrations during sleep are consistently associated with SW stages, and negative cross-correlations have been found between TSH fluctuations and SW activity,^107,301 suggesting that SW sleep probably is the primary determinant of the sleep-associated TSH decrease. Conversely, awakenings are frequently associated with TSH increments.³⁰⁰ The timing of the TSH evening rise seems to be controlled by circadian rhythmicity and shifts in concordance with the melatonin rhythm following exposure to light or nocturnal exercise.⁵⁸ Free triiodothyronine shows a diurnal rhythm that parallels TSH variations.³⁰²

Under conditions of sleep deprivation, the increased amplitude of the TSH rhythm may result in a detectable increase in plasma triiodothyronine levels, paralleling the nocturnal TSH rise,³⁰⁰ although negative findings also have been reported.³⁰³ If sleep deprivation is prolonged for a second night, the nocturnal rise in TSH is markedly diminished as compared with that occurring during the first night.³⁰³ It is likely that, following the first night of sleep deprivation, elevated thyroid hormone levels, which persist during the daytime period because of the prolonged half-life of these hormones, limit the subsequent TSH rise. A study involving 64 hours of sleep deprivation demonstrated, during the second night of sleep deprivation, a nocturnal increase in both triiodothyronine and thyroxine levels, contrasting with the decreases seen during normal sleep.³⁰⁴ These data suggest that prolonged sleep loss may be associated with upregulation of the thyroid axis. Consistent findings have been reported in a study of 6 days of partial sleep loss (4 hours in bed per night) wherein the nocturnal TSH rise was strikingly decreased and overall mean TSH levels were reduced by more than 30%, probably as the result of increased levels of thyroid hormones caused by TSH elevation at the beginning of sleep curtailment (see Fig. 4-8).¹⁹⁴

Because inhibitory effects of sleep on TSH secretion are time dependent, elevations in plasma TSH levels may occur in conditions of misalignment of sleep and circadian timing. This is illustrated in Fig. 4-11, which shows the mean profiles of plasma TSH observed in a group of normal young men in the course of adaptation to a simulated jet lag involving an abrupt 8-hour advance of the sleep-wake cycle and the dark period, following a 24-hour baseline period.³⁰⁰ In the course of adaptation, TSH levels increased progressively because nighttime wakefulness was associated with large circadian-dependent TSH elevations, and daytime sleep failed to inhibit TSH. As a result, mean TSH levels were more than twofold higher following awakening from the second shifted period than during the same time interval after normal nocturnal sleep. This study indicates that the subjective discomfort and fatigue associated with jet lag may involve prolonged elevation of a hormonal concentration in the peripheral circulation.

Aging is associated with a progressive decrease in overall TSH secretion (which is achieved by a decrease in amplitude, rather than in frequency, of secretory pulses) and in circulating TSH levels, and with dampening of the amplitude of the circadian variation.¹²⁶ In subjects in the seventh and eighth decades, TSH levels are lower than in young adults throughout the 24-hour span, although the difference is more marked during sleep than during the daytime period (see Fig. 4-4). In middle-aged subjects, age-related decreases in TSH levels may be evidenced only in response to nocturnal sleep deprivation. Thus, it appears that TSH secretory capacity declines progressively with aging.

Alterations in Disease States: A decreased or absent nocturnal rise in TSH has been observed in a wide variety of nonthyroidal illnesses,³⁰⁵ which suggests that hypothalamic dysregulation generally will affect the circadian TSH surge. This contrasts with the circadian variation of plasma cortisol, which persists in a wide variety of disease states. The nocturnal TSH surge is diminished or absent in various conditions of hypercortisolism,³⁰⁶ as well as in hyperthyroidism and in primary and secondary hypothyroidism.^307,308 In poorly controlled diabetic states, whether insulin-dependent or non–insulin-dependent, the surge also disappears.³⁰⁹ Correction of hyperglycemia is associated with a reappearance of the nocturnal elevation.³⁰⁹ It is interesting to note that morning TSH values in hyperglycemic patients do not differ from those of control subjects, and the TSH response to TRH is only marginally reduced.³⁰⁹ Obesity is associated with an increase in overall TSH secretion (which is achieved by an increase in amplitude, rather than in frequency, of secretory pulses) without alteration of the diurnal variation. TSH profiles tend to return toward normal levels after body weight loss induced by caloric restriction.³¹⁰

Circadian Misalignment: Circadian rhythms provide synchronization with pronounced periodic fluctuations in the external environment and organize the internal milieu so that coordination and synchronization of internal processes are evident. External synchronization is of obvious importance for the survival of the species and ensures that the organism does the “right thing” at the right time of the day. Of equal importance is the fact that the circadian clock system provides internal temporal organization (i.e., internal synchrony) between the myriad of biochemical and physiologic systems in the body. The concept of internal synchrony had to be reevaluated in recent years in view of the discovery that circadian clock genes, which are part of the transcription-translation feedback loop that generates self-sustained oscillations in the central master circadian clock in the SCN, also are expressed rhythmically in other regions of the brain and in a variety of peripheral tissues, including adipocytes, hepatocytes, pancreatic β cells, cardiomyocytes, and vascular smooth muscle cells.20,419 Under normal conditions, the central SCN pacemaker maintains synchrony between central and peripheral oscillators. In conditions of circadian misalignment, such as those that occur in jet lag and shift work, the alignment of central and peripheral oscillators is disrupted. Thus, the concept of internal desynchrony has to include desynchrony between different centrally controlled rhythms (e.g., cortisol vs. GH) and desynchrony between central and peripheral rhythms. Lack of synchrony within the internal environment may lead to chronic difficulties with serious consequences for the health and well-being of the organism. The physical and mental malaise that occurs following rapid travel across time zones (i.e., the jet lag syndrome) and the pathologies associated with long-term shift work are assumed to be due in part to alterations in the normal phase relationships between various internal rhythms. In addition, it has been speculated that alterations in internal phase relationships between rhythms underlie certain forms of affective illness.

Jet Lag: Subjects who travel rapidly across time zones are confronted with a desynchronization between their internal circadian rhythms and the periodicity of the new external environment. Upon arrival, the timings of the light-dark cycle, social schedule, and meals are abnormally matched to the phase of physiologic rhythm of the traveler. Associated with this lack of synchronization are symptoms of fatigue, subjective discomfort, sleep disturbances, reduced mental and psychomotor performance, and gastrointestinal disorders.

The rate of adaptation is generally slower for overt rhythms that are strongly dependent on the circadian system, such as those of cortisol and melatonin secretions, than for those that are markedly modulated by sleep-wake homeostasis, such as prolactin and GH secretions. As a result, during the period of adaptation, abnormal phase relationships between overt rhythms occur. Thus, the jet lag syndrome involves not only desynchronization between internal and external rhythms but also perturbation of internal temporal organization of physiologic functions. Depending on the strength of the zeitgebers, the rate of adaptation can be as low as half an hour a day or as high as 3 hours a day. The rate of adaptation is not constant: Adaptation to a large shift occurs at a faster rate during the first few days and progresses at a slower pace thereafter.⁴²⁰ The rate of adaptation is also dependent on the direction of the shift, with adaptation generally occurring faster after a delay (i.e., westward) shift than after an advance (i.e., eastward) shift.⁴²⁰ This eastward-westward difference in rate of adaptation is believed to be due to the fact that the endogenous circadian period of the human is slightly longer than 24 hours, and thus adjustment by delays is achieved more easily than adjustment by advances. Strong evidence suggests that reentrainment after a transmeridian flight is facilitated by exposure to bright light at appropriate circadian phases. It is widely believed that adherence to the local social and meal schedule upon arrival will accelerate adaptation to jet lag, but this has not been rigorously demonstrated. Laboratory studies suggest that physical exercise scheduled during the period corresponding to the nighttime before travel will facilitate adaptation to a delay (i.e., westward) shift.^57,421

Shift Work: Shift work, which is—voluntarily or not—accepted by millions of workers, is a major health hazard, involving increased risks for cardiometabolic illness, gastrointestinal disorders, infertility, and insomnia.422–424 Epidemiologic studies have indicated that shift work is a risk factor for weight gain,⁴²⁵ dyslipidemia,^426,427 and insulin resistance.^427,428 The medical consequences of shift work are associated with chronic misalignment of physiologic circadian rhythms and the activity-rest cycle. In addition, shift work almost invariably results in substantial sleep loss because daytime sleep generally is shorter and more fragmented than nocturnal sleep. Shift work usually creates conditions in which some zeitgebers (e.g., an artificial light-dark cycle) and additional phase-setting factors such as the rest-activity cycle are shifted, while others (e.g., the natural light-dark cycle, the routines of family life) remain unaltered. Shift workers thus live in a situation of conflicting zeitgebers that almost never allow a complete shift of the circadian system. Indeed, several studies have shown that workers on permanent or rotating night shifts do not adapt to these schedules, even after several years.^227,429,430

Besides its health implications, this misalignment with the circadian system has important social and economic implications, because night work is associated with substantial decrements in performance and vigilance, resulting in diminished productivity and increased accident rates. Scheduled exposure to bright light during night work and complete darkness during daytime sleep following night work can accelerate adjustment to the new schedule and improve nighttime alertness and performance; exogenous melatonin may facilitate sleep at abnormal circadian phases.⁴³¹