Sleep and Hormonal Rhythms in Humans

Georges Copinschi, Rachel Leproult, and Eve Van Cauter

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Sleep and Hormonal Rhythms in Humans In the human, sleep and hormonal secretions are under the dual control of circadian rhythmicity and of a homeostatic process relating the depth of sleep to the duration of prior wakefulness. The circadian clock plays a major role in the timings of sleep onset and offset, sleep consolidation, and the distributions of rapid eye movement (REM) sleep. The temporal organization of the secretions of a number of hormones such as melatonin and the hormones of the hypothalamo±pituitary±adrenal axis are also primarily controlled by the circadian pacemaker. On the other hand, the temporal pro®le of non-REM sleep, in particular slow-wave sleep, and a number of hormones such as prolactin and growth hormone are primarily controlled by the homeostatic process. Normal aging is commonly associated with profound alterations of both the homeostatic process and the circadian pacemaker, which are, however, chronologically dissociated. Alterations of the homeostatic process, as assessed by exponential decreases in slow-wave sleep and in nocturnal growth hormone secretion, are essentially complete by midlife. In contrast, alterations of the circadian pacemaker, as assessed in particular by modi®cations of REM sleep and of the glucocorticoid secretory pro®les, occur essentially from 50 years onward. Strategies for preventing or limiting such alterations should take into account this dissociated chronology of aging. Pharmacological approaches to restore normal sleep could represent an indirect form of hormonal therapy with possible bene®cial health effects. # 2001 Academic Press.

I. Mechanisms Subserving Sleep and Hormonal Rhythms

tation of physiological and behavioral functions to environmental conditions. Otherwise, a clock with a period only a few minutes shorter or longer than 24 hr would soon be totally desynchronized from the environment. The light±dark cycle is the most important synchronizing environmental agent (Turek, 1998). Light±dark information is transmitted from the retina to the suprachiasmatic nuclei and then to the pineal gland, where it regulates melatonin secretion. In turn, melatonin exerts synchronizing effects on the circadian pacemaker as an indirect photic zeitgeber. There is increasing evidence that the rest± activity cycle may also participate in the synchronization of endogenous circadian rhythmicity independently of photic inputs (Turek, 1998). In the human, sleep is under the dual control of circadian rhythmicity and of a homeostatic process relating the depth of sleep to the duration of prior wakefulness. Thus, circadian rhythmicity plays an important role in the timings of sleep onset and offset, sleep consolidation, and the distribution of rapid eye movement (REM) sleep and sleep spindle activity (Czeisler et al., 1980; Dijk and Czeisler, 1995). On the other hand, non-REM sleep, in particular slow-wave sleep, is primarily controlled by the homeostatic process, which is thought to involve a putative neural sleep factor which increases during waking drops and exponentially during sleep (Achermann and BorbeÂly, 1990; BorbeÂly, 1998). Both sleep and the circadian clock are major regulators of endocrine function. Their relative contributions in the temporal organization of hormonal release differ from one endocrine

In the human as in all mammalian species, reproducible changes of essentially all physiological and behavioral variables occur over the course of the 24 hr day, in synchrony with the 24 hr periodicities in the physical environment. However, these daily or diurnal rhythms are not simply a response to the environmental periodicities imposed by celestial mechanics, but instead are generated by an internal time-keeping system, generally referred to as the circadian clock or pacemaker (Turek, 1998). Two small bilaterally paired nuclei in the anterior hypothalamus, called the suprachiasmatic nuclei, function as a master circadian pacemaker (Rusak and Zucker, 1979; Moore-Ede, 1982; Miller et al., 1996). In the absence of any environmental time cues, the intrinsic period of this master pacemaker, which is primarily responsible for the generation and entrainment of all circadian rhythms of the body, is rarely exactly 24 hr. In the human, this period is slightly longer than 24 hr. Estimations from early studies of subjects maintained for extended periods of time in temporal isolation, either in underground bunkers or in specially designed units, averaged 24.5± 25.0 hr (Wever, 1979; Aschoff, 1981). A recent reevaluation using a different experimental strategy has, however, suggested that the endogenous period of human circadian rhythmicity is actually very close to 24 hr, i.e. 24.18 hr (Czeisler et al., 1999). The endogenous pacemaker needs to be synchronized and entrained by environmental signal(s) to ensure adequate adapFunctional Neurobiology of Aging

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Copyright # 2001 by Academic Press. All rights of reproduction in any form reserved.

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SECTION V Homeostasis

axis to another. For most pituitary hormones, the 24 hr pro®les result from the interaction of the circadian clock with sleep± wake homeostasis and re¯ect the superposition of 24 hr periodicities on an ultradian, or pulsatile, pattern of release. Morphological and neuroanatomical alterations have been evidenced in the suprachiasmatic nuclei of older animals in some, but not all, studies (Wise et al., 1987, 1988; Swaab et al., 1988; Weiland and Wise, 1990). These alterations could, at least partially, be responsible for age-related changes in 24 hr rhythms which are primarily driven by the circadian pacemaker, such as reduced amplitude and earlier phase. It has been suggested that the phase-advance of circadian rhythmicity in the elderly could result from a shortening of the intrinsic period of the circadian pacemaker (Pittendrigh and Daan, 1974; Weitzman et al., 1982; Czeisler et al., 1986, 1992). However, a recent study performed under conditions of forced desynchronyÐwhere the subjects are maintained on a sleep± wake and dark±light cycle with a period outside the range of entrainment of the circadian systemÐfound similar durations of intrinsic periods of the circadian pacemaker in healthy young and older individuals (Czeisler et al., 1999). It is possible, however, that the relatively short duration of the protocol did not allow for the expression of the endogenous period and of a possible impact of age. Studies in blind subjects who have no photic input to their circadian system and therefore ``freerun'' naturally have indeed provided estimations of the human circadian period around 24.6 hr (Lewy and Newsome, 1983). Alternatively, changes in 24 hr rhythms could re¯ect agerelated modi®cations in entrainment mechanisms or exposure to entrainment agents, e.g., absence of constraining professional and social schedules and decreased exposure to the synchronizing effects of the dark±light and rest±activity cycles. Indeed, some older individuals maintain well-preserved circadian function into the later stages of adulthood (Monk et al., 1995). It has been suggested that individual differences in circadian function in the elderly could re¯ect individual differences in degree of exposure and responsivity to the synchronizing effects of both photic and nonphotic inputs in the course of aging (Campbell et al., 1988; Van Cauter et al., 1998). Decreased sleep quality is also a hallmark of aging and is likely to contribute to the development of hormonal alterations in the elderly (Van Cauter et al., 1998). The characteristics and the chronology of age-related changes in sleep duration and quality will be reviewed in the ®rst section of the present chapter. The following sections will be devoted to a review of age-related alterations in a number of hormonal rhythms classically considered to be mainly dependent on sleep±wake homeostasis (growth hormone, prolactin), on circadian rhythmicity (cortisol, melatonin), or on both processes (thyrotropin). Particular emphasis will be put on two hormones for which the chronology of aging has been clearly de®ned, namely growth hormone and cortisol.

II. Sleep REM sleep and non-REM sleep both correlate with speci®c changes in brain activity, muscle tone, and autonomic activity. Non-REM sleep is subdivided, relatively arbitrarily, into four

precisely de®ned stages: stages 1, 2, 3, and 4. Stage 1 sleep is a transitional stage between wakefulness and sleep, and is followed after a few minutes of sleep by stage 2 sleep, which is generally considered to be the onset of true sleep. This is successively followed by stages 3 and 4, which are generally referred to as slow-wave sleep or ``deep sleep.'' During stages 3 and 4, the electroencephalogram is characterized by slow waves in the range 0.5±4.0 Hz, often referred to as ``delta waves.'' REM sleep, also referred to as ``paradoxical sleep,'' is a state in which the brain is highly activated but the body is paralyzed, and is preferentially associated with dreaming and eye movements. Under normal conditions, sleep starts with non-REM stages, followed by the ®rst period of REM sleep. As the night progresses, REM sleep increases in duration with each successive cycle, which lasts approximately 90 min, while slow-wave sleep decreases (Fig. 60.1, top). Thus, in a young normal adult, normal sleep architecture typically consists of four to ®ve alternating non-REM and REM cycles, with REM sleep occupying approximately 25% and non-REM sleep approximately 75% of the total sleep time. Profound disruptions of the daily sleep±wake cycle are commonly observed in normal aging. Elderly individuals frequently complain of sleep problems, usually reporting shallow, unrefreshing sleep, frequent awakenings during the night, early morning awakenings and unwanted daytime naps (Prinz, 1995). Consistent with this decrease in sleep quality with aging, regular use of sedative and hypnotic medications also increases in elderly. Numerous studies have demonstrated that these age-related changes in subjective sleep quality re¯ect marked alterations in polysomnographically de®ned sleep architecture (Prinz et al., 1990; Bliwise, 1993, 1994; Prinz, 1995). While the sleep period (i.e., the interval separating sleep onset from ®nal morning awakening) remains relatively constant across adulthood, signi®cant sleep fragmentation occurs after 50 years of age, resulting in a decrease in total sleep time (i.e., the sleep period minus the total duration of awakenings) and therefore in a reduction of sleep ef®ciency. Morever, aging exerts differential effects on the different sleep stages (Fig. 60.1). The most spectacular age-related change is the decrease in slow-wave (stages III and IV) sleep and in delta wave activity. This decrease appears to be more pronounced in men than in women. The decline in REM time, while less marked, is accompanied by a redistribution of REM stages across sleep. Indeed, REM stages are shifted toward the early part of the night. This is illustrated in Fig. 60.2, which shows that following sleep onset, the time necessary to accumulate 50% of the total amount of REM sleep is 75 min shorter in normal old men than in young controls. Since the distribution of REM sleep is mainly controlled by the circadian pacemaker, these alterations suggest that a phase advance of the circadian clock could be a hallmark of aging. The chronology of age-related changes in sleep quality is illustrated in Fig. 60.3. From young adulthood (16±25 years) to midlife (35±50 years), the duration of slow-wave sleep decreases rapidly (almost 30 min per decade) so that by midlife slow-wave sleep represents less than 10% of the sleep period, with practically no more stage IV sleep. This decrease in deep sleep is compensated by an increase in light non-REM sleep (i.e., stages I and II) while the durations of REM sleep and

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60. Sleep and Hormonal Rhythms in Humans

FIG. 60.2. Cumulated distribution of REM stages (mean  SEM) in

normal men ages 20±27 years (solid lines) and 67±84 years (dashed lines). Adapted from van Coevorden et al. (1991).

III. Hormones Primarily Controlled by Sleep±Wake Homeostasis: Prolactin and Growth Hormone A. Prolactin

FIG. 60.1.

Sleep scores at 30 sec intervals throughout the night in three normal men ages 20 years (top), 54 years (middle), and 67 years (bottom).

of wake and the total sleep time remain stable. In contrast, from midlife to old age (70±83 years), there is no additional decline in slow-wave sleep, but the duration of REM sleep decreases and the duration of wake increases, resulting in a progressive decline in total sleep time. This differential pattern of age-related changes in slow-wave sleep, primarily controlled by the homeostatic process, and in REM sleep, mainly dependent on the circadian pacemaker, suggests that an alteration in sleep±wake homeostasis may constitute an early biological marker of aging in normal men.

In normal young adults, the 24 hr pro®le of circulating prolactin levels is characterized by a major nocturnal elevation starting shortly after sleep onset and culminating around midsleep (Sassin et al., 1972, 1973; Van Cauter et al., 1981). Sleep onset has a stimulatory effect on prolactin release, irrespective of the time of the day, but the amplitude of the prolactin rise associated with daytime sleep may be dampened as compared with nocturnal sleep (Van Cauter and Refetoff, 1985). Conversely, modest elevations of prolactin levels may persist during waking around the time of the usual sleep onset, particularly in women. Thus, prolactin secretion appears to be also modulated by circadian rhythmicity, and maximal stimulation occurs only when sleep and circadian effects are superimposed (Desir et al., 1982; Spiegel et al., 1994; Waldstreicher et al., 1996). The circadian component of prolactin secretion is much more pronounced in women than in men (Waldstreicher et al., 1996). In addition, two studies have indicated that elevations of nocturnal prolactin levels in the absence of sleep could also depend on other factors. In one study, prolactin increased when the subjects were kept awake in total darkness but not in the presence of light (Okatani and Sagara, 1993). Therefore, the authors suggested that the nocturnal elevation of prolactin may be partially dependent on melatonin. Indeed, administration of low doses of melatonin during the daytime results in an

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SECTION V Homeostasis

elevation of plasma prolactin concentrations. In the other study, elevations of prolactin during nocturnal wakefulness occurred only when subjects were in a state of ``quiet rest'' but not if they expected to be disturbed (Wehr et al., 1993). The relationship between sleep stages and prolactin release has been investigated in a few studies. A close temporal relationship has been evidenced between slow-wave activity (estimated by spectral analysis) and sleep-associated prolactin secretion (Spiegel et al., 1995). Conversely, awakenings inhibit nocturnal prolactin release (Spiegel et al., 1995). Thus, fragmented sleep will generally be associated with lower nocturnal levels of prolactin. As illustrated in Fig. 60.4, the night time prolactin rise is generally dampened in elderly subjects (van Coevorden et al., 1991). This could be due to increased sleep fragmentation. When considered in relation to the time of the sleep onset, the timings of the nocturnal rise and of the early morning decline are not modi®ed (van Coevorden et al., 1991). Daytime levels remain essentially unchanged. No data are available concerning the time course of the occurrence of prolactin alterations with aging. B. Growth Hormone

FIG. 60.3.

Percentages of the sleep period spent in wake, slow-wave (SW) sleep, and REM sleep as a function of age in normal men (mean  SEM). Data source: Van Cauter et al. (2000).

It was recognized more than 30 years ago that GH secretion is markedly stimulated during sleep (Quabbe et al., 1966; Takahashi et al., 1968; Honda et al., 1969; Sassin et al., 1969). In normal young adults, the 24 hr pro®le of circulating GH levels consists of stable low concentrations abruptly interrupted by secretory pulses. In normal young adult males, the largest and most reproducible pulse occurs shortly after sleep onset (Takahashi et al., 1968; Sassin et al., 1969; Van Cauter et al., 1992), while in normally cycling young women, this sleep-onset-associated pulse, while also present, does not generally account for the majority of the 24 hr secretion, since daytime pulses are far more frequent and of higher amplitude than in men. The increased daytime GH secretion in women appears to be correlated with circulating free estradiol levels (Ho et al., 1987). The close association between sleep onset and GH secretory bursts is still present in subjects submitted

FIG. 60.4. Mean 24 hr (  SEM) pro®les of plasma prolactin in normal men ages 67±84 years (left) and 20±27 years (right). Black bars denote the bedtime periods. Adapted from van Coevorden et al. (1991).

60. Sleep and Hormonal Rhythms in Humans

to various manipulations of the sleep±wake cycle, including recovery sleep following sleep deprivation, sleep interruptions followed by reinitiations of sleep, phase advances, and phase delays (Takahashi et al., 1968; Sassin et al., 1969; Beck et al., 1975; Golstein et al., 1983; Davidson et al., 1991; Van Cauter et al., 1991, 1992; Pietrowsky et al., 1994; Weibel et al., 1997). Thus, shifts of the sleep±wake cycle are immediately followed by parallel shifts of the GH rhythm. This is observed after transmeridian shifts (Golstein et al., 1983), in shift work conditions (Weibel et al., 1997), and in subjects living in free-running conditions, i.e., in temporal isolation without any environmental time cues (Weitzman et al., 1981; Moline et al., 1986). However, modest GH secretory pulses may persist during waking in the late evening and in the early part of the night following abrupt delays of the sleep period, indicating the existence of a modulation of the somatotropic axis by circadian rhythmicity (Aschoff, 1979; Van Cauter et al., 1992). It has been shown that during nocturnal sleep, the major GH pulse occurring following sleep onset is caused by a sleep-associated surge of hypothalamic GH-releasing hormone (GHRH) which coincides with a circadian period of relative somatostatin disinhibition (Jaffe et al., 1995; Ocampo-Lim et al., 1996). The relationship between sleep stages and nocturnal GHRH surgesÐresulting in GH secretory burstsÐcan be investigated using a deconvolution procedure to estimate GH secretory rates. This procedure provides an accurate estimation of the amount of GH released during each secretory pulse and allows to delineate precisely the temporal limits of each pulse. A robust relationship has been evidenced between slow-wave sleep and nocturnal GH secretion (Holl et al., 1991; Van Cauter et al., 1992). Thus, maximal GH release occurs within minutes of the onset of slow-wave sleep; the longer the slow-wave episode, the more likely it is to be associated with a GH pulse; the amount of GH secreted during pulses occurring during slow-wave sleep is quantitatively correlated with the duration of the slow-wave episode. Similar correlations have been evidenced between GH secretion and concomitant values of spectral power density of the electroencephalogram in the delta range, i.e., 0.5±4.0 Hz (Gron®er et al., 1996). However, this relationship between slow-wave sleep and GH secretion, although strong and consistent, is not obligatory, since nocturnal GH secretion may also occur in the absence of slow-wave sleep, and approximately one-third of the slow-wave periods are not associated with detectable GH secretion (Van Cauter et al., 1992). These dissociations could re¯ect variations in the somatostatinergic tone which exerts an inhibitory action on GH secretion (Jaffe et al., 1995). The mechanisms underlying the relationship between slowwave sleep and GH release are still a matter of speculation. Based on rodent data, it has been suggested that the promotion of slow-wave sleep and the stimulation of GH release are two separate processes which involve GHRH neurons situated in two distinct areas of the hypothalamus (ObaÂl et al., 1991; Krueger and ObaÂl, 1993; Bredow et al., 1996). Daytime pituitary GH release would primarily involve GHRH neurons in the arcuate nucleus, while promotion of slow-wave sleep would implicate GHRH neurons of other hypothalamic area(s) (Meister and HoÈkfelt, 1992; Toppila et al., 1997). The association between slow-wave sleep and GH release would re¯ect syn-

859 chronous activity of GHRH neurons in these distinct regions. However, the existence of a quantitative relationship between various measures of slow-wave activity and the amount of GH secreted (Van Cauter et al., 1992, 1997; Gron®er et al., 1996) suggests that the GHRH neurons which are implicated in the promotion of slow-wave sleep also participate in the control of nocturnal pituitary GH secretion. Aging is associated with dramatic decreases in circulating levels of GH and insulin-like growth factor I (IGF-I) (Ho et al., 1987; van Coevorden et al., 1991; Landin-Wilhelmsen et al., 1994). This is illustrated in Fig. 60.5, which shows individual 24 hr GH pro®les in young, middle aged, and old adult men. In normal men over 65 years, daily GH secretion is only about one-third of the amount secreted by young adults (Finkelstein et al., 1972; Ho et al., 1987; Vermeulen, 1987; Iranmanesh et al., 1991; van Coevorden et al., 1991; Frank

FIG. 60.5. 24 hr pro®les of plasma GH in three normal men ages 26 years (top), 51 years (middle), and 64 years (bottom). Black bars denote the bedtime periods.

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FIG. 60.6.

(Top) Growth hormone secretion in early sleep (black bars) and minutes of slow-wave sleep (dashed bars) as a function of age in normal men. (Bottom) Value of cortisol nadir (black bars) and minutes of REM sleep (dashed bars) as a function of age in normal men. All values are mean  SEM. Data source: Van Cauter et al. (2000).

et al., 1995). This reduction is achieved by a decrease in amplitude, rather than in frequency, of GH pulses (Vermeulen, 1987; Veldhuis et al., 1995). Moreover, it has recently been suggested that the orderliness of GH secretion decreases with aging (Veldhuis et al., 1997). Interestingly, it has been shown that in men aging affects GH release Ðboth during sleep and during wakeÐwith a similar chronology to that observed for slow-wave sleep (Fig. 60.6, top), the age-related GH decrease is exponential, and despite the persistence of high levels of sex steroid hormones, circulating GH concentrations and pulsatile GH secretion rates fall in midlife to less than half the values achieved in young adulthood. This decrease is followed by further more progressive decrements from midlife to old age. In a cross-sectional study performed in 114 normal men (Van Cauter et al., 2000), the 24 hr GH secretion for ages 25±35 years and 60±70 years averaged around 50 and 30%, respectively, of the secretion for ages 16±25 years. These age effects are independent of modi®cations in the body mass index. Decreases in GH secretion rates and circulating levels are followed by a more gradual decline in plasma IGF-I levels (Clemmons and Van Wyk, 1984; Landin-Wilhelmsen et al., 1994). In the elderly, IGF-I levels are about 50% of the values in young adults, but there is a wide individual variation. About 20% of normal men beyond 60 years old have IGF-I values within the normal range of young (20±30 years old) men. Conversely, there is a considerable overlap between healthy elderly subjects and patients with GH de®ciency due to pituitary disease.

SECTION V Homeostasis

The origin of this decrease in GH-IGF-I axis activity in aging is very probably multifactorial but the underlying mechanisms remain largely speculative. The major primary alteration appears to be an increase of hypothalamic secretion of somatostatin (Muller et al., 1995). The ability of the hypothalamus to synthesize and release GHRH and the intrinsic secretory capacity of somatotroph cells do not appear to be altered, but the secretion rate of GHRH is decreased, at least partly, because of the increased somatostatinergic tone (Martin et al., 1997). Thus, the reduction of GH secretion would result from increased somatostatin inhibitory activity and decreased GHRH responsiveness (Martin et al., 1997). In addition, the decrease in the orderliness of GH pulses suggests that the ®ne coordination of the GHRH±somatostatin interaction at the pituitary level may be impaired in the elderly and contribute to the blunting of GH secretion (Veldhuis et al., 1995). A possible increased negative feedback by GH and/or IGF-I in the elderly has been evoked to explain the increase in somatostatin, but a recent study suggests on the contrary that the negative feedback exerted by IGF-I on GH secretion is blunted in old age (Chapman et al., 1997). It has also been suggested that diminished cholinergic tone could be, at least partly, responsible for the somatostatin increase (Martin et al., 1997). The parallelism between GH and slow-wave sleep alterations in the elderly suggests the involvement of common mechanisms. Decreased physical activity as well as decreased sex steroid hormone concentrations in older men and women certainly contribute to the reduction in GH secretion (Veldhuis et al., 1997). Normal elderly subjects display a number of features similar to those observed in young adults with GH de®ciency due to pituitary disorders: increased body fat, reduced protein synthesis and protein turnover, reduced lean body mass, muscle strength and exercise capacity, decreased bone mass and bone mineral content, reduced renal blood ¯ow and glomerular ®ltration, reduced cellular immunity (Cuneo et al., 1992; Corpas et al., 1993; Rosen et al., 1993). Since in young adults with GH de®ciency, these features can be partly reversed by longterm treatment with GH (Marcus and Hoffman, 1998), it has been suggested that in older healthy subjects, they may result from relative GH-IGF-I de®cit and represent a syndrome that has been named somatopause (Hoffman et al., 1993). However, the causal link between decreased GH-IGF-I activity and these somatic features in the elderly has not been proven. Nevertheless, the effects of sustained recombinant human GH therapy in healthy older subjects have been investigated in a limited number of clinical trials, with mixed results (Rudman et al., 1991; Holloway et al., 1994; Papadakis et al., 1996). Though circulating IGF-I values were restored within the normal range for young adults and despite signi®cant increases in lean body mass, no consistent improvement in functional capacities, as assessed by grip strength and endurance, could be demonstrated. Similarly, there was no consistent improvement in cognitive performances. Only slight bene®cial effects on bone mineral density were evidenced. Moreover, there was a high prevalence of side effects, mainly edema, carpal tunnel syndrome, gynaecomastia, and hyperglycemia, possibly because the recombinant human GH dosages used were excessive. Treatment with rhGH, which needs dailyÐor at least three weeklyÐsubcutaneous injections, does not actually restore a

60. Sleep and Hormonal Rhythms in Humans

physiological GH-IGF-I pro®le, even if circulating IGF-I levels are carefully monitored and rhGH doses adjusted accordingly. Indeed, because of the very broad range of normal IGF-I values, the goal to be reached in each individual cannot be de®ned with precision. Morever, it is impossible to preserve the normal pulsatile pattern of GH secretion. In addition, GH injections inhibit GHRH secretion and are therefore likely to have detrimental effects on slow-wave sleep, since GHRH is involved in the generation of slow-wave sleep (Kerkhofs et al., 1993). Preliminary investigations suggest that orally active pharmacological GH secretagogues might potentially be used during the somatopause to both stimulate GH secretion and enhance slow-wave sleep. Prolonged oral administration of an experimental GH secretagogue, MK-0677, was found to stimulate pulsatile GH release and to increase IGF-I levels in normal young and old subjects (Chapman et al., 1996; Copinschi et al., 1996). Moreover, it was also found to have bene®cial effects on sleep, with signi®cant increases in the duration of stage IV and of REM sleep (Copinschi et al., 1997). Interestingly, in normal young subjects, the rise in GH levels appeared to be less important than the enhancement of IGF-I values (Copinschi et al., 1996), possibly because elevated IGF-I levels exert a negative feedback effect on GH secretion. This relative dissociation between increases in GH and IGF-I levels might reduce the occurrence of negative side effects of the treatment, although MK-0677 had an adverse effect on glucose tolerance in older subjects (Chapman et al., 1996). Two recent studies indicate that compounds known to stimulate slow-wave sleep could represent a novel class of GH secretagogues and be potentially useful for the treatment of somatopause. Reliable stimulation of both slow-wave sleep and GH secretion has been obtained in normal young subjects with oral administration of ritanserin, a selective serotonin 2 receptor antagonist (Gron®er et al., 1996), as well as with low doses of -hydroxybutyrate (Van Cauter et al., 1997), a simple four-carbon fatty acid which is used as an investigational drug for the treatment of narcolepsy. Thus, experimental approaches which might mimic natural GH secretory patterns and improve sleep quality would appear more promising than recombinant human GH administration. The question still remains, however, as to whether the aim of restoring GH and IGF-I levels to the normal young range is legitimate. If that was the case, such interventions should target early midlife rather than subjects over 60 years of age, in whom peripheral tissues have been continuously exposed to very low GH and IGF-I levels for at least two decades. Indeed, initiating in subjects over 60 years old a treatment aiming at restoring GH secretion to the normal young range of may be compared to starting an estrogen replacement therapy in postmenopausal women when they are 70 years old.

IV. Thyrotropin: A Hormone Controlled by Both Sleep±Wake Homeostasis and Circadian Timing The 24 hr pattern of circulating thyrotropin levels appears to be generated by frequency as well as amplitude modulation of secretory pulses (Veldhuis et al., 1990). Daytime levels are low

861

FIG. 60.7. Mean (  SEM) thyrotropin pro®les in normal young men

ages 22±27 years and normal old men ages 59±72 years during a 52 hr period including 8 hr of nocturnal sleep, 28 hr of sleep deprivation, and 8 hr of daytime sleep. Black bars denote the bedtime periods.

and relatively stable. In normal young adults, the nocturnal rise starts in the early evening and the maximum occurs around the beginning of the sleep period. This presleep elevation is interrupted by sleep onset and levels progressively decline throughout the sleep period toward low daytime values (Brabant et al., 1990). Because the onset of the nocturnal rise occurs well before sleep onset, it is considered to re¯ect a circadian effect. Conversely, the decline in thyrotropin levels observed following sleep onset is thought to re¯ect an inhibitory in¯uence of sleep on thyrotropin secretion (Parker et al., 1976). Indeed, during sleep deprivation, the nocturnal decline does not occur and thyrotropin levels continue to increase until the middle of the usual sleep period, as illustrated in Fig. 60.7, left). The sleep-related thyrotropin inhibition appears to be associated with slow-wave stages (Goichot et al., 1992). Conversely, awakenings are frequently associated with thyrotropin increments (Hirschfeld et al., 1996). Interestingly, thyrotropin levels are not suppressed signi®cantly below normal daytime levels when sleep occurs during daytime hours (Hirschfeld et al., 1996). Thus, the inhibitory action of sleep on thyrotropin secretion appears to be operative only when the circadian elevation has occurred. While the onset of the thyrotropin nocturnal rise may be considered as a robust marker of the circadian clock, the diurnal thyrotropin pro®le appears to be a good illustration of the interaction between sleep and circadian rhythmicity. Aging is associated with a progressive decrease in overall thyrotropin secretion (which is achieved by a decrease in amplitude, rather than in frequency, of secretory pulses) and in circulating thyrotropin levels, and with a dampening of the amplitude of the circadian variation (van Coevorden et al., 1991). This is illustrated in Fig. 60.7 (right) and 60.8. Figure 60.7 shows a comparison of thyrotropin pro®les obtained during a 53 hr study period including 8 hr of nocturnal sleep, 28 hr of sleep deprivation, and 8 hr of daytime sleep in normal young men ages 22±27 years and normal old men ages 59±72 years, while Fig. 60.8 shows a comparison of 24 hr thyrotropin pro®les in normal young men ages 20±27

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SECTION V Homeostasis

FIG. 60.8. Mean (  SEM) 24 hr thyrotropin pro®les in normal young men ages 20±27 years (solid lines) and normal old men ages 67±84 years (dashed lines). From van Coevorden et al. (1991).

years and normal old men ages 67±83 years. In the older elderly (Fig. 60.8), thyrotropin levels are clearly lower than in young adults thoughout the 24 hr span, although the difference is more marked during sleep than during the daytime period. In the younger elderly (Fig. 60.7), age-related decreases in thyrotropin levels are apparent only during the period of nocturnal sleep deprivation. Thus, it appears that the thyrotropin secretory capacity declines progressively with aging. The timing of the onset of the nocturnal rise was found to be advanced by approximately 1.5 hr in a group of normal old men ages 67±84 years, as compared to subjects under 20 years of age (van Coevorden et al., 1991). This ®nding is consistent with a phase advance of the circadian clock in the elderly.

V. Hormones Primarily Controlled by the Circadian Clock A. Melatonin Not surprisingly, in view of the neuroanatomical connection between the hypothalamic suprachiasmatic nuclei and the pineal gland, the 24 hr pro®le of plasma melatonin is a robust marker of the human circadian clock (Rosenthal, 1991). During daytime, circulating levels are low and stable. In normal young adults, the circadian rise starts in the evening, between 21:00 and 23:00 hr, and the maximum occurs around the middle of the sleep period. Thereafter, melatonin levels progressively decrease to return to low daytime values in the morning, between 08:00 and 09:00 hr. Although a recent study indicated that high-intensity exercise may have acute stimulatory effects on melatonin secretion when applied during the night (Buxton et al., 1997), melatonin rhythmicity is otherwise primarily dependent on the circadian pacemaker and does not appear to be directly affected by sleep and nonphotic stimuli (Geoffriau et al., 1998). In contrast, exposure to light of suf®cient intensity (>200±500 lux) exerts immediate direct inhibitory effects on the melatonin secretion, resulting in a dosedependent suppression of nocturnal melatonin levels (Lewy et al., 1980). Daytime levels of melatonin are similar in young and old normal adults as illustrated in Fig. 60.9. The nocturnal eleva-

tion is markedly dampened in the elderly (van Coevorden et al., 1991), although some old people may have melatonin peak values within the normal range for young adults. This is illustrated in Fig. 60.8. Moreover, as shown in Fig. 60.10, the circadian rise occurs almost 1.5 hr earlier in older than in young adults (van Coevorden et al., 1991). B. Cortisol Diurnal pro®les of plasma cortisol re¯ect the circadian pattern of adrenocorticotropic activity (which, in turn, results from periodic changes in level of pituitary stimulation by corticotropin-releasing hormone). The 24 hr rhythm of plasma cortisol is a good model for estimating the circadian temporal organization of the corticotropic axis because of its reproducibility and large amplitude. Mathematical procedures (Cleveland, 1979; Van Cauter, 1979) have been used to quantify the 24 hour pro®le of plasma cortisol and to determine times of occurrence and values of the maximum (acrophase) and the minimum (nadir) of the circadian rhythm as well as its amplitude. In young normal adults, plasma cortisol pro®les show an early morning maximum around 07:00±08:00 hr, declining levels during the daytime, followed by a prolonged period of minimal levels (sometimes referred to as the quiescent period) centered around midnight and an abrupt elevation (referred to as the circadian rise) during the later part of the night (Fig. 60.11) (Van Cauter and Spiegel, 1999). This pattern is primarily controlled by the circadian pacemaker and is produced by modulation of the height of successive secretory pulses (Veldhuis et al., 1989). However, modulatory effects are also exerted by sleep±wake homeostasis. Indeed, sleep onset is consistently associated with a short-term inhibition of cortisol secretion (Weitzman et al., 1983; Born et al., 1988; Van Cauter et al., 1991; Bierwolf et al., 1997). This inhibitory effect of sleep appears to be related to slow-wave stages (Follenius et al., 1992). Conversely, during the second part of the night, awakeningsÐand particularly the ®nal morning awakeningÐare consistently followed by bursts of cortisol secretion (Van Cauter et al., 1990, 1991; Spath-Schwalbe et al., 1991; Pruessner et al., 1997). Nevertheless, adaptation of the 24 hr pattern of cortisol to abrupt shifts of the sleep±

863

60. Sleep and Hormonal Rhythms in Humans

FIG. 60.9. Mean (  SEM) 24 hr pro®les of plasma melatonin in normal men ages 20±27 years (left) and 67±84 years (right). Adapted from van Coevorden et al. (1991).

wake cycle needs several days to be complete and therefore the 24 hr pro®le of plasma cortisol, especially the timing of the onset of the early morning circadian rise, may be considered as a robust marker of circadian timing (Van Cauter and Turek, 1995). This morning rise represents a response to an endogenous stimulatory signal timed by the circadian clock. On the other hand, the subsequent decline of cortisol levels and the occurrence and the maintenance of the quiescent period all partially re¯ect the recovery of the corticotropic axis from this endogenous challenge. Aging is associated with marked gender-speci®c effects on the levels and diurnal variation of plasma cortisol. This was

FIG. 60.10.

examined in a retrospective analysis of 24 hr cortisol pro®les recorded in 90 normal men and 87 normal women, with ages spanning seven decades, from 18 to 83 years (Van Cauter et al., 1996). This study indicates that although diurnal rhythmicity is preserved in old age, alterations of the cortisol pro®les, which essentially develop from 50 years of age onward, are present in the elderly, as illustrated for men in Fig. 60.11. A modest but signi®cant increase in 24 hr cortisol levels from young adulthood to old age is observed for both sexes. Between 20 and 80 years of age, basal cortisol levels increase by 20±50%, more in women than in men, so that cortisol levels, which are slightly higher in young men than in young women, become

Mean (  SEM) pro®les of the circadian rises of cortisol (left) and melatonin (right) in normal men ages 20±27 years (solid lines) and 67±84 years (dashed lines). Adapted from van Coevorden et al. (1991).

864

SECTION V Homeostasis

FIG. 60.11.

Mean (  SEM) 24 hr pro®les of plasma cortisol in normal men ages 17±24 years (left) and over 70 years (right).

similar in older men and women. With advancing age, both evening and morning cortisol levels increase in women, while only evening levels rise in men. Typically, the cortisol nadir in a subject over 70 years of age is three- to four-fold higher than in a young adult. As a result, a dampening of the amplitude of the circadian variation is observed with aging in both sexes. While there is no effect of age on the timing of the morning acrophase, the timing of the nadir and the timing of the onset of the circadian rise advance markedly with aging, similarly in men and in women. Between 20 and 80 years of age, the timing of the onset of the circadian riseÐa marker of the circadian phaseÐadvances 1.5 to 3 hr, as illustrated in Fig. 60.11. The quiescent period starts later and ends earlier in older sub-

FIG. 60.12.

jects than in young adults. As a result, the duration of the quiescent period is markedly shortened and increasingly fragmented, as illustrated in Fig. 60.12. Between 25 and 65 years of age, the reduction in the duration of the quiescent period averages almost 3 hr in men and approximately 4.5 hr in women, so that the quiescent period, which is somewhat longer in young women than in young men, has a similar duration in older men and women. These data con®rm that in late adulthood, aging is associated with an advance of circadian phase and a dampening of the amplitude of the circadian variations which suggests that the strength of the signal originating from the hypothalamic pacemaker decreases with advancing age. The major and

Individual quiescent periods (represented by black bars) in young (ages 19±29 years; left) and old (ages 50±83 years; right) normal men. Vertical lines at 18:00 and 02:00 hr serve to facilitate the visual estimation of onsets and offsets of quiescent periods. Note the later onset, the earlier offset, and the increased fragmentation of quiescent periods in older subjects. Adapted from Van Cauter et al. (1996).

865

60. Sleep and Hormonal Rhythms in Humans

most consistent age-related alteration in cortisol levels is an elevation of the evening nadir. Both animal and human studies have indicated that deleterious effects of hyperactivity of the hypothalamo±pituitary±adrenal axis, especially at the hippocampal level, are more pronounced at the time of the nadir of the rhythm than at the time of the peak (Dallman et al., 1993; Plat et al., 1999). Thus, even modest elevations in evening cortisol levels could facilitate the development of central and peripheral disturbances associated with glucocorticoid excess, such as insulin resistance and memory de®cits (McEwen and Stellar, 1993; McEwen, 1998a). The age-related increase in evening cortisol levels is likely to re¯ect a loss of resiliency of the hypothalamo±pituitary±adrenal axis (i.e. ability to recover from challenge), consistent with the concept of ``wear and tear'' of lifelong exposure to stress, and is likely to re¯ect neuronal loss in the hippocampus (McEwen, 1998b). Such hippocampal defects may underlie some of the memory de®cits that occur in many older adults. In addition, the loss of resiliency could also contribute to the increased sleep fragmentation in the elderly, since elevated cortisol levels promote awakenings. Interestingly, REM sleep is characterized by highly synchonized electroencephalographic activity in the 4- to 10-Hz ``theta frequency'' range in the hippocampus (Siegel, 1994). Whether hippocampal theta waves during REM sleep re¯ect a restorative action on neuronal mechanisms underlying the negative feedback regulation of glucocorticoid secretion is not known, but this hypothesis would be consistent with the fact that age-related alterations in REM sleep and in evening cortisol levels occur in a mirror image, as illustrated in Fig. 60.6 (bottom). Thus, decreased sleep quality could contribute to the allostatic load, i.e. to the wear and tear resulting from overactivity of stress-responsive systems (McEwen, 1998b).

VI. Conclusion The transition from early adulthood to midlife is associated with profound alterations of sleep±wake homeostasis, resulting in particular in exponential decreases in slow-wave sleep and in GH secretion. Statistical analysis of the data shown in Fig. 60.6 indicates that the reduction in GH secretion was signi®cantly associated with the reduction in amount of slowwave sleep, independently of age. In contrast, alterations of the circadian pacemaker exert their effects more progressively, essentially during the transition from midlife to old age, resulting in particular in modi®cations of REM sleep and of the glucocorticoid pro®les. Reduced amounts of REM sleep could be related to increased evening cortisol levels. Strategies for preventing or limiting such alterations should take into account this dissociated chronology. Pharmacological approaches to restore normal sleep could represent an indirect form of hormonal therapy with possible bene®cial health effects.

Acknowledgments This work was supported in part by grants from the Belgian Fonds de la Recherche Scienti®que MeÂdicale (FRSM), the Universite Libre de

Bruxelles and the U.S. National Institutes of Health (NIDDK DK41814 and NIA AG11412).

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867 Rudman, D., Feller, A. G., Cohn, L., Shetty, K. R., Rudman, I. W., and Draper, M. W. (1991). Effects of human growth hormone on body composition in elderly men. Horm. Res. 36 (Suppl. 1), 73±81. Rusak, B., and Zucker, I. (1979). Neural regulation of circadian rhythms. Physiol. Rev. 59, 449±526. Sassin, J. F., Frantz, A. G., Weitzman, E. D., and Kapen, S. (1972). Human prolactin: 24-hour pattern with increased release during sleep. Science 177, 1205±1207. Sassin, J. F., Frantz, A. G., Kapen, S., and Weitzman, E. D. (1973). The nocturnal rise of human prolactin is dependent on sleep. J. Clin. Endocrinol. Metab. 37, 436±440. Sassin, J. F., Parker, D. C., Mace, J. W., Gotlin, R. W., Johnson, L. C., and Rossman, L. G. (1969). Human growth hormone release: Relation to slow-wave sleep and sleep-waking cycles. Science 165, 513±515. Siegel, J. M. (1994). Brainstem mechanisms generating REM sleep. In ``Principles and Practice of Sleep Medicine'' (M. H. Kryger, T. Roth, and W. C. Dement, eds.), pp. 125±144. Saunders, Philadelphia. Spath-Schwalbe, E., Gofferje, M., Kern, W., Born, J., and Fehm, H. L. (1991). Sleep disruption alters nocturnal ACTH and cortisol secretory patterns. Biol. Psychiatry 29, 575±584. Spiegel, K., Follenius, M., Simon, C., Saini, J., Ehrhart, J., and Brandenberger, G. (1994). Prolactin secretion and sleep. Sleep 17, 20±27. Spiegel, K., Luthringer, R., Follenius, M., Schaltenbrandt, N., Macher, J. P., Muzet, A., and Brandenberger, G. (1995). Temporal relationship between prolactin secretion and slow-wave electroencephalographic activity during sleep. Sleep 18, 543±548. Swaab, D. F., Fisser, B., Kamphorst, W., and Troost, D. (1988). The human suprachiasmatic nucleus; neuropeptide changes in senium and Alzheimer's disease. Basic Appl. Histochem. 32, 43±54. Takahashi, Y., Kipnis, D. M., and Daughaday, W. H. (1968). Growth hormone secretion during sleep. J. Clin. Invest. 47, 2079±2090. Toppila, J., Alanko, L., Asikainen, M., Tobler, I., Stenberg, D., and PorkKa-Heiskanen, T. (1997). Sleep deprivation increases somatostatin and growth hormone-releasing hormone messenger RNA in the rat hypothalamus. J. Sleep Res. 6, 171±178. Turek, F. W. (1998). Circadian rhythms. Horm. Res. 49, 103±113. Van Cauter, E. (1979). Method for characterization of 24-h temporal variation of blood constituents. Am. J. Physiol. 237, E255±E264. Van Cauter, E., and Refetoff, S. (1985). Multifactorial control of the 24hour secretory pro®les of pituitary hormones. J. Endocrinol. Invest. 8, 381±391. Van Cauter, E., and Spiegel, K. (1999). Circadian and sleep control of endocrine secretions. In ``Regulation of Sleep and Circadian Rhythms'' (F. W. Turek and P. C. Zee, eds.), pp. 397±426. Marcel Dekker, Inc., New York. Van Cauter, E., and Turek, F. W. (1995). Endocrine and other biological rhythms. In ``Endocrinology'' (L. J. DeGroot, ed.), pp. 2487±2548. Saunders, Philadelphia. Van Cauter, E., L'Hermite, M., Copinschi, G., Refetoff, S., Desir, D., and Robyn, C. (1981). Quantitative analysis of spontaneous variations of plasma prolactin in normal man. Am. J. Physiol. 241, E355±E363. Van Cauter, E., van Coevorden, A., and Blackman, J. D. (1990). Modulation of neuroendocrine release by sleep and circadian rhythmicity. In ``Advances in Neuroendocrine Regulation of Reproduction'' (S. Yen and W. Vale, eds.), pp. 113±122. Serono Symposia USA, Norwell, MA. Van Cauter, E., Blackman, J. D., Roland, D., Spire, J. P., Refetoff, S., and Polonsky, K. S. (1991). Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep. J. Clin. Invest. 88, 934±942. Van Cauter, E., Kerkhofs, M., Caufriez, A., Van Onderbergen, A., Thorner, M. O., and Copinschi, G. (1992). A quantitative estimation of GH secretion in normal man: Reproducibility and relation to sleep and time of day. J. Clin. Endocrinol. Metab. 74, 1441±1450. Van Cauter, E., Leproult, R., and Kupfer, D. J. (1996). Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J. Clin. Endocrinol. Metab. 81, 2468±2473.

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SECTION V Homeostasis Waldstreicher, J., Duffy, J. F., Brown, E. N., Rogacz, S., Allan, J. S., and Czeisler, C. A. (1996). Gender differences in the temporal organization of prolactin (PRL) secretion: Evidence fort a sleep-independent circadian rhythm of circulating PRL levelsÐA Clinical Research Center study. J. Clin. Endocrinol. Metab. 81, 1483±1487. Wehr, T., Moul, D., Barbato, G., Giesen, H., Seidel, J., Barker, C., and Bender, C. (1993). Conservation of photoperiod-responsive mechanisms in humans. Am. J. Physiol. 265, R846±R857. Weibel, L., Follenius, M., Spiegel, K., Gron®er, C., and Brandenberger, G. (1997). Growth hormone secretion in night workers. Chronobiol. Int. 14, 49±60. Weiland, N. G., and Wise, P. M. (1990). Aging progressively decreases the densities and alters the diurnal rhythms of alpha-1 adrenergic receptors in selected hypothalamic regions. Endocrinology (Baltimore) 126, 2392±2397. Weitzman, E. D., Czeisler, C. A., Zimmerman, J. C., and Ronda, J. M. (1981). The sleep-wake pattern of cortisol and growth hormone secretion during non-entrained (free-running) conditions in man. In ``Human Pituitary Hormones. Circadian and Episodic Variations'' (E. Van Cauter and G. Copinschi, eds.), pp. 29±41. Martinus Nijhoff, The Hague. Weitzman, E. D., Moline, M. L., Czeisler, C. A., and Zimmerman, J. C. (1982). Chronobiology of aging: Temperature, sleep-wake cycle rhythms and entrainment. Neurobiol. Aging 3, 299±309. Weitzman, E. D., Zimmerman, J. C., Czeisler, C. A., and Ronda, J. M. (1983). Cortisol secretion is inhibited during sleep in normal man. J. Clin. Endocrinol. Metab. 56, 352±358. Wever, R. A. (1979). ``The Circadian System of Man: Results of Experiments Under Temporal Isolation.'' Springer-Verlag, New York. Wise, P. M., Walovitch, R. C., Cohen, I. R., Weiland, N. G., and London, D. E. (1987). Diurnal rhythmicity and hypothalamic de®cits in glucose utilization in aged ovariectomized rats. J. Neurosci. 7, 3469± 3473. Wise, P. M., Cohen, I. R., Weiland, N. G., and London, D. E. (1988). Aging alters the circadian rhythm of glucose utilization in the suprachiasmatic nucleus. Proc. Natl. Acad. Sci. U. S. A. 85, 5305±5309.