Circadian system, sleep and endocrinology

Abstract

Levels of numerous hormones vary across the day and night. Such fluctuations are not only attributable to changes in sleep/wakefulness and other behaviors but also to a circadian timing system governed by the suprachiasmatic nucleus of the hypothalamus. Sleep has a strong effect on levels of some hormones such as growth hormone but little effect on others which are more strongly regulated by the circadian timing system (e.g., melatonin). Whereas the exact mechanisms through which sleep affects circulating hormonal levels are poorly understood, more is known about how the circadian timing system influences the secretion of hormones. The suprachiasmatic nucleus exerts its influence on hormones via neuronal and humoral signals but it is now also apparent that peripheral tissues contain circadian clock proteins, similar to those in the suprachiasmatic nucleus, that are also involved in hormone regulation. Under normal circumstances, behaviors and the circadian timing system are synchronized with an optimal phase relationship and consequently hormonal systems are exquisitely regulated. However, many individuals (e.g., shift-workers) frequently and/or chronically undergo circadian misalignment by desynchronizing their sleep/wake and fasting/feeding cycle from the circadian timing system. Recent experiments indicate that circadian misalignment has an adverse effect on metabolic and hormonal factors such as circulating glucose and insulin. Further research is needed to determine the underlying mechanisms that cause the negative effects induced by circadian misalignment. Such research could aid the development of novel countermeasures for circadian misalignment.

Figure 1

Independent influence of circadian phase (left panel) and time since start of sleep episode (right panel) on wakefulness in a scheduled sleep period. Reproduced with permission from Dijk and Czeisler (1994).

Figure 2

The interactive effect of the homeostatic and circadian systems on wakefulness during sleep. Percentage of wakefulness was assigned to the circadian phase (twelve 30-degree bins) and time into the sleep episode (five 112-min bins) that it occurred. Therefore, e.g., the ‘block’ at 0–112 min and 0 degrees represents wakefulness within the first 112 min of a sleep period that occurred between the circadian phases −15 to 15 degrees. Circadian phase is reported related to clock time under entrained conditions. The black dashed line represents the trajectory of circadian phase and time since the start of a scheduled sleep period, as would occur during nocturnal sleep in an entrained individual. Reproduced with permission from Dijk and Czeisler (1994).

Figure 3

The separate and interacting effects of circadian and homeostatic systems on occurrence of sleep stages during sleep. Sleep was measured via polysomnography during a forced desyncrhony protocol. To assess the effect of the homeostatic system, sleep opportunities were split into 3 tertiaries (left, middle, and right panel). Slow wave sleep is primarily regulated by the homeostatic system (decreasing from first to third tertiary) whereas REM sleep is primarily regulated by the circadian system (with the peak at 0° and 60°, and the trough at 240°). Furthermore, the Figure highlights that the homeostatic and circadian influence are not additive: the circadian influence on (especially) REM sleep and Stage 2 sleep are small when homeostatic sleep pressure is high (left panel) and large when homeostatic sleep pressure is low (right panel). It also shows that the amount of slow wave sleep is not noticeably decreased when sleeping during the biological day (e.g., 180°), as occurs in night-workers, consistent with the fact that SWS is primarily homeostatically driven. S1, S2, SWS and REM indicate Stage 1, 2, slow wave sleep and rapid eye movement sleep respectively. Gray bars in the background indicate the circadian phases corresponding to the average habitual sleep episode in these subjects. Data are double plotted to improve visibility of rhythmicity. The data are unpublished, were provided by F.A. Scheer, T.J. Shea, M.F. Hilton and S.A. Shea, and based on Scheer et al. (2008).

Figure 4

The effect of the sleep/wake cycle (solid line) and the endogenous circadian system (dotted line) on circulating levels of melatonin, cortisol, growth hormone (GH), prolactin and thyroid stimulating hormone (TSH). The solid line represents measurements taken whilst subjects maintained their habitual sleep/wake cycle including daytime activity and meals and nighttime rest and fasting. The dotted line represents data collected while subjects were under constant routine conditions including constant rest, semi-recumbent posture, wakefulness and hourly isocaloric snacks. For the sleep/wake cycle only, the vertical lines of the rectangle represent relative clock hour of habitual bed time (left line) and habitual wake time (right line) and thus the rectangle indicates scheduled nocturnal sleep. Note that the rectangle is not applicable to the constant routine conditions in which the subjects remained awake. The melatonin data were collected under dim light conditions (<3 lux during wakefulness and <1 lux during sleep periods) and are based on data from Gooley et al. (2011). Cortisol, GH and TSH data were collected under dim (<1 lux during sleep periods) and room light (~150 lux during wake periods) conditions and are based on data from Czeisler and Klerman (1999). The prolactin figure was based on data courteously provided by C.A. Czeisler. Copyright held by the Division of Sleep Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA. Reprinted with permission.

Figure 5

The effect of circadian misalignment on circulating levels of leptin, glucose and insulin. Gray area indicates scheduled sleep episode and short vertical grey bars represent meal times. The white strips within the scheduled sleep period indicate when participants were briefly awoken to perform pulmonary function tests. B, L, D and S indicate breakfast, lunch, dinner and snack respectively. Reproduced with permission from Scheer and colleagues (2009).