The 24-hour profile of nearly all pituitary hormones is related to the presence and quality of sleep. Stereotypical changes in nearly all hormonal and metabolic variables are observed in and around sleep, especially the transition to and from sleep. This fact challenges the assertion that hormone release is solely based on feedback loops. Understanding these reproducible changes in view of sleep-wake cycling is fundamental to recognizing normal and early abnormal endocrine processes. For example, appreciation of hormone changes during the day and night provides insight into a patient’s laboratory values drawn at varied times through a 24-hour period.

Both are true. Sleep experts have dubbed sleep symptoms as the “canary in the mine” for serious medical and psychological disease. Sleep quality can be a tool for assessment of disease. Additionally, sleep disorders are common in many endocrine diseases. For example, acromegalic patients are at risk for sleep apnea (also see question 26). Excessive androgens can worsen OSA, as can hypothyroidism. Thyrotoxicosis can contribute to debilitating insomnia, with profound daytime fatigue accompanying other presenting complaints. Disruptive sleep is now associated with increased risk for diabetes and obesity.

Sleep is organized into non–rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep (Table 59-1). In classic teaching, NREM was organized into four stages. Typically, adults enter sleep through stage 1, which is characterized on electroencephalogram (EEG) by low-amplitude mixed-frequency waves. As one enters stage 2, the EEG displays predominantly sleep spindles and K complexes. The 2007 American Academy of Sleep Medicine (AASM) manual combines stages 3 and 4 into one stage, N3, or slow wave sleep (SWS). In SWS, the EEG slows and is associated with a progressive increase in the number of delta waves, which are characterized by increased amplitude and slowed frequency. It may take up to 100 minutes for the first NREM sleep cycle to finish, but once completed, it heralds the first REM period. Although REM is not defined by characteristic EEG patterns, the EEG can look like that of stage 1. The true hallmark of REM sleep, however, is rapid movement of the eyes in all directions compared with the slow eye movement (SEM) seen on electrooculography (EOG) in stage 1 sleep. Also defining REM is muscle atonia, usually manifested by low electromyography (EMG) tone and absence of chin muscle movement. The only somatic muscles working in REM are the extraocular muscles and the diaphragm.

In the human, NREM sleep and REM sleep typically alternate in 90- to 120-minute cycles (Fig. 59-1). Four to six cycles occur during a normal sleep period, depending on the length of sleep. Each cycle is similar, with sleep onset initiating in stage 1, progressing to stage 2, then to SWS, and without significant arousal back to stage 2. In a typical night of adult sleep, stage 1 will comprise up to 5% of total sleep, stage 2 up to 50%, SWS up to 20%, and REM up to 25%. SWS is predominantly experienced in the first third of sleep and REM in the last half of sleep. Achieving predominant SWS or predominant REM sleep likely has neuroendocrine significance.

As we age, total sleep time decreases, and sleep begins to fragment (see Fig. 59-1). The time in sleep declines with age from 16 to 18 hours a day in a newborn to 9 to 10 hours in a 10 year old to 7 ½ to 8 hours in the average adult, to 6 hours in an 80 year old. A newborn’s sleep is up to 50% REM sleep, which declines to 25% of sleep by adulthood. There is also a progressive decrease in SWS with aging. This loss of SWS also has endocrine repercussions because anterior pituitary hormone release is associated with SWS.

Sleep is characterized by reversible unconsciousness and variable responsiveness to stimuli. There is a shift in the autonomic nervous system (ANS) in sleep, with parasympathetic nervous system (PNS) predominance in NREM sleep and especially in REM sleep. Sympathetic nervous system (SNS) tone decreases in NREM sleep and usually in REM sleep, but sympathetic tone in REM sleep can be variable. In NREM sleep, there are decreases in respiratory rate (RR), heart rate (HR), blood pressure (BP), and cardiac output. Normal REM sleep is characterized by fluctuations in BP, HR, and RR. Dreaming and somatic muscle hypotonia to atonia (which includes reduced to absent upper airway muscle tone) are also REM sleep events. REM sleep can have a few periods of decreased or absent breathing. Cerebral metabolic rates for glucose and oxygen decrease during NREM sleep, but they increase to above waking levels in REM sleep.

The first process is called Process-C, for circadian process (circadian from Latin “approximately a day”). It regulates the timing of sleep. Process-C is regulated in the hypothalamic suprachiasmatic nuclei (SCN), which receives input from environmental cues, the strongest of which is light. Process-C does not just coordinate hormone release; it is the broader of the two processes and transmits circadian output to coordinate behavioral, physiologic, and genetic rhythms. Research has uncovered core molecular clock machinery responsive to Process-C in most tissues. For further discussion of the circadian clock field, please see appropriate references.

The second process is sleep-wake homeostasis (SWH), also known as Process-S. SWH is dependent on Process-C but the circadian process is not dependent on SWH.

The SWH process relates the amount and intensity of sleep to the duration of prior wakefulness. So, if one has 24 hours with no sleep, there is increased pressure to sleep. The pressure to sleep is least when one is most rested. This pressure increases during the day and peaks just before midnight. The interaction of these two processes, Process-C and Process-S, influences the hypothalamic generators of releasing or inhibiting hormones that influence anterior pituitary function.

The bilaterally paired SCN of the hypothalamus has been regarded as the sole master 24-hour pacemaker. Research since 2000, however, has shown the circadian process to be a decentralized hierarchy of oscillations within the SCN and downstream oscillations within the brain and other tissues. Interactions among several hypothalamic nuclei are also involved in Process-C. SCN timing is genetically determined to be slightly greater than 24 hours and must be modified or reset (synchronized) to the 24-hour day-night cycle by environmental stimuli (zeitgebers, German for time givers or time cues). SCN cytoarchitecture reveals functional organization. The SCN projects into the periventricular hypothalamic nucleus (PVH), mediating melatonin and corticosteroid synthesis. SCN projections to other hypothalamic nuclei are also critical to sleep-wake cycling.

Circadian rhythms are synchronized to the 24-hour day through the process of entrainment. The SCN is the neural pacemaker for biologic rhythms, but it is set at greater than 24 hours. Entrainment is the phase shift caused by daily stimuli. This phase shift corrects for the difference between the intrinsic period of the pacemaker (slightly greater than 24 hours) and the environmental cycle. For example, light is the dominant time cue, capable of inducing sleep phase or wake phase changes. Aside from photic stimuli, there are other nonphotic stimuli or time cues, such as exercise, social interaction, temperature variation, and even feeding, all capable of shifting circadian rhythms. The interaction between photic and nonphotic clues is complex. The magnitude of contributions to the human system remains to be determined. At this point, it can be said that stable entrainment likely reflects integration of both central and peripheral parameters.

Melatonin levels in the pineal gland are inhibited by light; they increase at sundown and peak at mid-darkness. This makes the neurohormone, melatonin, the chemical message communicating a photoperiod “fine tuning” to the autonomous master clock in the SCN. Melatonin also communicates a chemical message of light-dark cycling to the remainder of the body. This communication occurs through specific melatonin receptors. The MT1 and MT2 melatonin receptors are G-protein coupled, with characteristic seven transmembrane domains. These two receptor families are distributed throughout the brain and peripheral tissues, for example, in the SCN itself, the adipocytes, macrophages, platelets, gastrointestinal tract, liver, heart, kidneys, and adrenals. The melatonin receptors are only receptive at the light-/dark transitions, so exogenous administration of melatonin is most effective at these transitions.

The SWS predominates in the first third of sleep, and REM predominates in the last half of sleep. Growth hormone (GH) and prolactin (PRL) are entrained to SWS (Table 59-2). Regardless of age and gender, most of the PRL released occurs when the individual is asleep. The nighttime GH and PRL surges are associated with the first period of SWS. In fact, the GH surge immediately after sleep onset is the largest of the 24-hour period for both genders, although girls and women burst less than boys and men. Girls and women have two evening GH bursts; the first is before sleep onset late in evening, and a second is with SWS. Boys and men have few daytime GH pulses compared with girls and women. The surge of PRL and GH is lost if the patient goes sleepless and returns if the patient gets recovery sleep. It is the onset of sleep and not the time of day that triggers the release of these hormones. The hormones that increase later in sleep are cortisol and testosterone. Testosterone rises just after midnight and cortisol begins its rise at 2 am, peaking at 6 to 9 am. The timing and amount of REM sleep are related to the late-sleep rise of these two hormones in men. However, the 24-hour rhythm for both testosterone and cortisol is primarily controlled by circadian rhythmicity (Process-C) and not SWH (Process-S).

They vary with sleep according to gender and stage of maturity. Before puberty, there is daytime pulsatile gonadotropin release, which is augmented with sleep onset. One of the hallmarks of puberty for the child is increased nocturnal amplitude of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulses. Both Process-S and Process-C contribute to this nocturnal surge in pubertal children. As the pubescent boy enters adulthood, there is increased daytime LH as well, thus making the variation on a 24-hour cycle less apparent. Accumulating evidence in adult men indicates that the testosterone profile is significantly influenced by NREM-REM cycling. The nighttime LH surges of puberty dampen in height and decrease in frequency in adulthood. The early morning male testosterone rise starts with sleep onset and increases to maximum levels during last half of sleep (REM predominant). This surge of testosterone is different from that of cortisol, which is quiescent in early sleep. In addition, during the early phase of sleep, there is no corresponding LH surge. The characteristic nighttime LH bursts occur later on, in the last half of sleep. A testosterone surge was observed during adult daytime recovery sleep, and a testosterone decrease followed as the patient remained awake after the daytime recovery sleep. All this suggests that sleep itself, and not only the LH bursts, is contributing to testosterone release. The mechanisms for this increase are not yet known. The 24-hour testosterone profile and its response to sleep deprivation and daytime recovery sleep are more like PRL (Fig. 59-2). For example, when the sleep-deprived male internal medicine resident finally gets some sleep, his testosterone will surge during his recovery sleep; during the normal day and in one who has not slept, testosterone levels are on a decline. To take this example to clinical application, if low testosterone is found in an individual, it may be from sleep deprivation, OSA, or even shift work. It is fair to tell our patients to have their testosterone levels drawn first thing in the morning in a rested state, based on the observations that sleep increases testosterone, wakefulness decreases it, and the circadian influence may be less potent than SWH.