HORMONSKA REGULAC INTERMEDIJERNOG METABOLIZMA 2H

• IMUNONEUROENDOKRINE INTERAKCIJE

• SPAVANJE I ENDOK SISTEM

Sleep disorders are common in many endocrine conditions, and endocrine diseases can have associated sleep disorders.

• acromegalic patients are at risk for sleep apnea.• Excessive androgens can worsen obstructive sleep apnea (OSA), as can hypothyroidism.• Thyrotoxicosis can contribute to insomnia. • Disruptive sleep is now known to be associated with increased risk for diabetes and obesity.

What are the stages of sleep?• Sleep is organized into non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep (Table 60-

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 predominately 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 number of delta waves, which are characterized by increased amplitude and slowed frequency. It may take up to 100 minutes for 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 to the slow eye movements (SEM) in Stage 1 sleep on the electrooculography (EOG). Also defining REM is muscle atonia, usually manifested in low electromyography (EMG) tone and absence of chin muscle movement. The only somatic muscles working in REM are the extraocular muscles and diaphragm!

What is the progression of sleep stages in a usual night of sleep?• In the human, NREM and REM sleep typically alternate in 90 to 120 minute cycles (Fig. 60-1). 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 predominately experienced in the first third of sleep and REM in the last half of sleep. Achieving SWS has neuroendocrine significance.

4. What are the fundamental changes in the nervous system in NREM versus REM sleep, and what other differences are noted between the phases of NREM and REM (See Table 60-1)?

• 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 and especially in REM. There is decrease in sympathetic nervous system (SNS) tone in NREM which is also usually the case in REM, but sympathetic tone in REM can be variable. In NREM, there are decreases in respiratory rate (RR), heart rate (HR), blood pressure (BP), and cardiac output. Normal REM 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 events. REM can have a few periods of decreased or absent breathing. Cerebral metabolic rates for glucose and oxygen decrease during NREM but increase to above waking levels in REM.

• 5. What are the two brain mechanisms responsible for anterior pituitary hormone cycling in a 24-hour period?• There are two separate but interrelated brain processes governing sleep and hormone release in a 24-hour

period. The first process is the brain’s master 24-hour clock, called Process-C, for circadian process. The other is sleep-wake homeostasis (SWH), also known as Process-S. SWH is dependent on Process-C but the circadian process in not dependent on SWH. Process-C is regulated in the hypothalamic suprachiasmatic nuclei (SCN). It receives a variety of input and works with the pineal gland melatonin from the pineal. Additionally, Process-C receives input from environmental cues, the strongest of which is light. The SCN uses autonomous, intrinsic electrical and molecular mechanisms to maintain a near 24-hour rhythm. 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, then there is increased pressure to sleep. The pressure to sleep is least when 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.

• 6. How do the sleep stages change during one’s life span?• As we age, total sleep time decreases and sleep begins to fragment (See Fig. 60-1). 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 and declines to 25% of sleep by the time he/she is one year old (25% is usual REM percent for an adult). There is also a progressive decrease in SWS with aging. This loss of SWS also has endocrine repercussions since there is anterior pituitary hormone release associated with SWS. This fact challenges the assertion that hormone release is solely based on a feedback loop.

• 7. Name the two hormones that are elevated early in sleep and the two hormones• that are elevated late in sleep.• Recall that SWS predominates in the first third of sleep, and that REM predominates in the last• half of sleep. Growth hormone (GH) and prolactin (PRL) are entrained to SWS (Table 60-2).• The nighttime GH and PRL surges are associated with the first period of SWS. Females have a• GH surge midday as well. 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 a.m.,• peaking between 6 and 9 am. The timing and amount of REM sleep are related to the late-sleep• rise of these two hormones in men. But the 24-hour rhythm for both testosterone and cortisol is• primarily controlled by circadian rhythmicity (Process-C) and not sleep-wake homeostasis• (Process-S).

• 8. How do the gonadotropins levels vary with sleep?• They vary with sleep according to gender and stage of maturity. Prior to 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 LH and FSH. Both• Process-S and Process-C contribute to this nocturnal surge in pubertal children. As the• pubescent male enters adulthood, there is increased daytime LH as well, so the variation on a• 24-hour cycle is less apparent. In adult men, LH has a low amplitude but testosterone is• markedly increased. This suggests the SWH process is involved. Indeed, plasma levels of free• testosterone are increased until the first REM occurs.

• 9. Is the LH pattern the same in women?• In women, plasma LH is significantly influenced by the menstrual cycle. There is, however, some• modulation of LH levels, as the LH pulse frequency slows during sleep. In early follicular and• early luteal phases, the amplitude of LH pulses actually increases. The frequency, however,• decreases and the nocturnal LH pulse frequency slowing becomes evident. In mid and late• follicular and luteal phases, this slowing is less apparent to absent. In the postmenopausal• women there are elevated FSH and LH levels without circadian variation.

• 10. Do the gonadal steroid hormones follow the LH and FSH changes mentioned in• the question above?• Gonadotropins have pulse amplitude and frequency, which are not reflected in the gonadal• steroids (i.e., the gonadal steroids do not have pulsations). For pubertal girls, there is a daytime• estradiol elevation. For pubescent boys, the testosterone increase coincides with elevation of

the• gonadotropins, as described, with minimal testosterone levels in the late evening and highest• levels in early am. In post menopausal women, the gonadotropins increase in an attempt to• stimulate estradiol production, and there is no consistent circadian gonadotropin pattern.

• 11. What factors influence thyroid stimulating hormone (TSH) release?• TSH release is primarily related to the circadian rhythm, though there is Process-S influence.• TSH release in young healthy males shows a decline by late afternoon, an early evening circadian• elevation, then a decline in levels shortly after sleep onset. The inhibitory influence of sleep• on TSH is thought to be SWS, as it continues to chart a nocturnal decline to reach daytime• values. With acute sleep loss, TSH takes its usual early evening upturn at approximately• 6 pm, but then continues to rise to nearly twice normal maximum through the middle of the• usual sleep period. The loss of inhibitory effect of sleep on the circadian TSH elevation may• contribute to the elevated TSH values seen in acutely ill hospitalized patients.

• 12. Since TSH and cortisol release are circadian, are their levels parallel through the• night and day?• TSH is influenced by Process-C and, to a lesser extent, influenced by the SWH process. Cortisol• is primarily influenced by the circadian process with some influence from Process-S (see• Table 60-2). So a change to one’s sleep-wake cycle influences the release of these hormones but• to different extents. In general, TSH fluctuations precede cortisol, with cortisol peaking later and• staying up longer. TSH begins to rise under circadian rhythm, reaches maximum levels around• mid-sleep (midnight to 2 a.m.), and nadirs 1.5 microIU/milliliter by mid-afternoon. TSH then• levels off stopping a would-be ascent after sleep onset, reflecting sleep suppression of TSH. In a• study of healthy young man during nocturnal sleep deprivation between 10 p.m. to 6 a.m. (SWS• suppression removed) TSH more than doubled. That is, TSH went from its afternoon nadir of• approximately 1.5 microIU/ml to a new peak of approximately 3.8 microIU/ml at 2 a.m. In the• follow-on recovery sleep (10 a.m.– 6 p.m.) TSH returned to a mean of 1.25 microIU/ml. Cortisol,• on the other hand, rises abruptly after midnight, peaks around 6-9 am, then declines throughout• the day (reaching a nadir at midnight). It is well documented that interruptions to nocturnal sleep• are associated with short-term TSH elevations. TSH levels normalize when normal nocturnal• sleep is resumed. Repeated and prolonged nocturnal interruptions of sleep result in an elevation• of cortisol.

• 13. What changes in sleep will influence cortisol levels?• Insomniacs, whose total time asleep/total time in bed is less than 70% of normal, have• significantly higher evening and early sleep cortisol levels. In a study of young adults whose• circadian rhythms were perturbed by a flight from Europe to US, GH secretory patterns adjusted• within a few days to the new sleep-wake cycle but the cortisol levels remained disassociated for• two weeks. This dissociation is thought to contribute to the symptoms of jet lag syndrome.

• 14. How do circadian and sleep-wake processes influence glucose and insulin• levels?• Glucose and insulin levels are influenced by both processes. Studies in normal adults have• demonstrated a 30% increase in glucose and a 60% increase in insulin levels during nocturnal• sleep. In sleep deprivation, glucose and insulin secretion rates increase at habitual sleep time,• though to a much lesser degree, suggesting circadian modulation. In recovery sleep, however,• secretion of both insulin and glucose rates markedly increase, suggesting modulation by sleep• itself.

• 15. How does aging change hormonal release?• Changes to sleep architecture with aging lead to hormonal change. Recall that GH and PRL rise• primarily in relation to the SWS of NREM, whereas TSH, cortisol, and testosterone have• increases that are primarily circadian. Since there is less SWS with aging (see Fig. 60-1), there• are decreases in nocturnal GH and PRL secretion. In general, the extent of hormone release• decreases from young to old. The extent of circadian changes in cortisol and TSH are less• dramatic with aging. Day-night TSH fluctuations also dampen with age.

• 16. What is the definition of sleep disordered breathing (SDB) and how does this• differ from obstructive sleep apnea (OSA)?• Confusion arises when the terms sleep related breathing disorders (SRBD), SDB, and OSA are• used interchangeably in the literature and in sleep lab reports. SRBD and SDB are disease• headings under which other diseases are arranged (much like COPD comprises a general• reference for other specific disease entities). SRBD on the one hand contains for example adult• and pediatric central apnea syndromes and obstructive sleep apnea syndromes. OSA on the• other hand is a specific disorder that is diagnosed with polysomnography (PSG). It can be• suspected on the basis of patient or bed partner complaints. Such complaints include:• unintentional sleep episodes during wakefulness, daytime sleepiness, unrefreshing sleep, fatigue• or insomnia, waking from sleep with breath holding, gasping or choking, loud snoring, and• breathing interruptions. The PSG criteria are not as stringent if associated with patient or bed• partner complaints. Accompanied by complaints, the PSG must have five or more respiratory• events per hour of sleep associated with increased respiratory effort. Without a history of• complaints, the PSG instead must contain 15 or more such respiratory events. In either case,• rendering the diagnosis of OSA includes ruling out current medical, neurological, and/or• substance abuse disorders. Of note, some prescribed medications can also increase risk for OSA.

• 17. What are respiratory events?• Respiratory events are apneas, hypopneas and respiratory effort-related arousals (RERA). An• apneic episode is an airflow decrease of at least 90% from baseline which lasts at least 10 seconds• (Try holding your own breath for 10 seconds!). Hypopnea is defined as 10 seconds of at least a• 30% decrease in airflow which results in 4% or more of desaturation on pulse oximetry. On the• other hand, RERA criteria should be sought if an observed event does not meet apnea or hypopnea• criteria. RERA is defined as a sequence of breaths greater than 10 seconds in duration that is• associated with increased respiratory effort and results in an arousal from sleep. AASM directs• apneas, hyopopneas and RERAs, if present, to be scored in the routine PSG interpretation. The• average number of apneas and hypopneas in one hour is referred to as the apnea-hypopnea index• (AHI). But if RERAs are present then the average number of apneas, hyopopneas and RERAs• should be calculated. This is called respiratory disturbance index (RDI). Note AHI does not equal• RDI, but one does see these used interchangeably—such an interchange could create confusion.

• 18. What is the prevalence of OSA?• The prevalence is dependent on the definition of OSA. Earliest epidemiological investigations,• primarily of white men, estimated that up to 4% had OSA (60-90% were obese). The classic• prevalence of OSA for adults aged 30–60 is 24% in men and 9% in women. In non-obese• patients, genetic craniofacial features like retrognathy are correlated with OSA. As OSA data• matures, prevalence may become unique to populations or ethnicities. In Asian non-obese male• office workers, BMI and age were positively correlated with OSA, but weight was less so than in• white, non-Asian subjects. Risk factors for OSA other than adiposity, such as pharyngeal• narrowing, retrognathia or micrognathia, and pharyngeal collapsibility, are thought to assume• greater pathologic significance in Chinese subjects.

• 19. Define sleep deprivation. How common is it?• Sleep deprivation can be acute or chronic. By definition, going without sleep for 24 hours is acute• sleep loss, whereas sleeping less than six hours a night for six nights or greater is considered• chronic sleep deprivation. Patients in industrialized nations are sleeping less. In the United• States, for example, over 30% of adults less than 64 years of age report sleeping less than six• hours per night, leaving no doubt that many patients are accumulating chronic sleep deprivation.

• 20. What are the key features of sleep deprivation versus sleep apnea?• In sleep deprivation, one doesn’t sleep but breaths normally. In OSA, one sleeps but doesn’t• breathe well during sleep. The AASM classifies volitional sleep deprivation as Behaviorally• Induced Insufficient Sleep Syndrome as long as it is associated with daytime sleepiness. One can• objectively measure excessive daytime sleepiness (EDS) with a standardized tool (Table 60-3),• such as the Epworth Sleepiness Scale (ESS). An ESS score of greater than 9 is consistent with• EDS. Patients with acute or chronic shortening of sleep resist the drive to sleep with no• impairment of gas exchange. In OSA, there is a repetitive collapse of the upper airway, which• induces apneic and hypopneic episodes despite persistent thoracic and abdominal respiratory• effort. This leads to increased mechanical load on the upper airway, chest wall, and diaphragm.• What follows are hypoxia, hypercarbia, and a marked increase in adrenergic tone. OSA often leads• to a disruption or fragmentation of the usual sleep wake cycle and endocrine responsiveness. Both• can contribute to fatigue and daytime sleepiness. If EDS is secondary to sleep deprivation, the• patient’s sleep continuity is normal and is often associated with an increase in SWS. Recall the• inhibitory influence of daytime recovery sleep (TDRS) on TSH, which occurred if TDRS followed• nocturnal sleep deprivation (see question 12).

• 21. In view of increased SNS tone in OSA, (see question 4), does the co-morbidity of• OSA interfere with the assessment of metanephrines and catecholamines when• screening for pheochromocytoma?• Yes. OSA results in an appropriate release of catecholamines in response to physiologic stress• or disease, just as a myocardial infarctions, cerebral vascular accidents, and acute heart failure• are associated with appropriate catecholamine increases. If a 24-hour urinary collection is• performed in the setting of undiagnosed or poorly treated OSA, it would likely contain elevated• levels of metanephrines and catecholamines. This may falsely suggest a diagnosis of• pheochromocytoma.

24. How does sleep deprivation influence glucose tolerance?• In one study, after one week of sleeping 4 hour per night, there were increases in post-breakfast• insulin resistance. During sleep restriction, glucose tolerance is nearly 40% worse than when• compared to a group with sleep extension. Interestingly, it was the first phase of insulin release• that was found to be markedly reduced. When the sleep deprived individuals go into recovery• sleep (sleeping during the day due to their sleep deprivation), there are marked elevations of• glucose and insulin levels, indicating that sleep also exerts modulatory influences on glucose• regulation independent of the circadian rhythm.

• 25. What is the evidence linking OSA to abnormal glucose metabolism?• Snoring, sleep deprivation, and OSA have all been linked to type 2 diabetes mellitus (DM2) risk.• Data gathered from diverse patient populations suggest that OSA severity is a risk for DM2• development. At present, available data does not definitively prove direct causation. Snoring, in• the nonobese Asian and especially in the obese, has been independently associated with• abnormal oral glucose tolerance tests and higher HbA1c percentages. In epidemiologic studies,• sleep quality has been positively correlated with the risk of developing DM2. Observational• studies have shown that patients who report less than 6 hours of sleep per night have an• increased prevalence of glucose intolerance and DM2. Very recently, it was found that the• duration of sleep (<6 and >8 hours per night) was predictive of an increased incidence of DM2.• OSA, as diagnosed by PSG, is independently associated with abnormal glucose metabolism.• Another recent paper extends this independent association through rigorous assessment of the• potential confounders of overweight/obesity. In this cross-sectional analysis of 2,588 patients, it• was shown that impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and occult• diabetes are associated (but to different degrees) with OSA in both the normal-weight (BMI < 25• kg/m2) and overweight/obese subgroups. This suggests that individuals with OSA are at special• risk for diabetes and its cardiovascular complications.

• 26. What are the two main mechanisms underlying the development abnormal• glucose metabolism in sleep apnea patients?• The hallmark of OSA is airflow reduction, which is typically associated with intermittent• hypoxemia and sleep fragmentation. In animal studies, insulin sensitivity has been shown to• vary with intermittent hypoxemia, independent of activation of the SNS. Additionally, it has been• shown that in the non-diabetic overweight to mildly obese male, every 4% decrease in oxygen• saturation is associated with an odds ratio that approaches 2 for worsened glucose tolerance.• Sleep fragmentation has also been associated with abnormal glucose metabolism. In one study• of healthy adults, selective suppression of SWS (without decreasing total sleep time) was• associated with decreases in insulin sensitivity by nearly 25%. This suggests the low levels of• SWS in the elderly and obese may contribute to the increased incidence of DM2.

• 27. With respect to causality, does the use of CPAP improve abnormal glucose• metabolism parameters?• Yes. Trials reporting CPAP adherence definitions and the trials demonstrating no change in BMI• during the study period do show improvement. A study of nondiabetic patients with moderate to• severe OSA reported that CPAP significantly improved insulin sensitivity after only 2 days of• treatment and that the improvement persisted at the three-month follow-up with no significant• changes in body weight. Interestingly, this influence was most pronounced in the non-obese• population. In contrast, this same lab showed no improvement in insulin sensitivity in the obese• DM2 patients.

• 28. Does the effective use of CPAP in the OSA patient lead to weight loss?• Yes it does, apparently working through two distinct mechanisms. First, the patient with treated• sleep apnea usually wakes more rested and with a sense of improved vitality or energy. Once on• treatment, patients with treated OSA have even been shown to exercise more. Secondly,• treatment of sleep apnea results in normalization of leptin, the so-called satiety hormone. As will• be elaborated below, leptin is suppressed during sleep deprivation and untreated sleep apnea.• 29. What are the effects of sleep deprivation on leptin (the satiety hormone) and• ghrelin (hunger hormone)?• With sleep deprivation, leptin (from the Greek word leptos, meaning ‘‘thin’’) decreases and• ghrelin (from the original root ghre meaning ‘‘to grow’’) increases. In longer than average sleep,• leptin increases and ghrelin decreases. It has been documented that leptin release is blunted in• the sleep deprived patient such that over a six month period of time the patient with sleep• deprivation gains an average of 10 pounds more than rested patients.• 30. Is the testosterone decline observed with aging related to the changes• associated with sleep pattern of aging?• As discussed previously, aging is associated with less time in sleep and less time in slow wave• sleep. In older men, the amplitude of LH pulses are less but the frequency is increased. The• sleep-related rise of testosterone is still seen, though the amplitude is less. The rise of nocturnal• testosterone leading up to the first REM, however, is no longer seen in the elderly patient.• Furthermore, the relationship of LH levels with latency to the first REM period is less prominent• with aging.

• 31. How does androgen influence sleep?• Exogenous testosterone may worsen existing OSA or lead to changes associated with sleep• apnea. One randomized controlled trial revealed that high dose testosterone administration in• hypogonadal, otherwise healthy, elderly men shortened total sleep time and worsened• coexisting undiagnosed sleep apnea. Though there have been no substantiated reports of• decreased cognition and impaired driving ability with hypogonadism, it is incumbent on the• prescriber to screen the patient for the possibility of undiagnosed OSA.• 32. How does the testosterone panel change with OSA and does OSA treatment• influence the panel?• The androgen changes of OSA are distinct from those seen in aging and obesity (Table 60-4). In• OSA, there are decreases in the sex hormone binding globulin and free and total testosterone• without concomitant increases in gonadotropins. In fact, one study showed LH pulse• disturbances with untreated OSA. Interestingly, testosterone levels improve with OSA treatment,• whether by CPAP or with UPPP. These findings point to a hypothalamic abnormality related to• the low testosterone levels of untreated OSA.

• 33. How well are providers in diabetes clinics screening their patients for OSA?• What are good tools for screening historically and on physical exam?• A study of diabetic patients, using a validated clinical measurement and questionnaire to• quantify OSA risk and sleepiness, revealed that 56% of patients reported snoring, 29% had• fatigue upon awakening, and 34% reported feeling tired during wake time. The authors of the• study concluded that 56% of those questioned were at high risk of OSA. This finding supports a• call for greater vigilance in screening for OSA in diabetics given the high prevalence of SDB• found in that patient population. Certain screening tools may be helpful towards this end. BMI is• proportional to OSA, and neck size greater than 17 inches is the most sensitive physical finding.• Some craniofacial changes, such as retrognathia, also place a patient at high-risk. Keep in mind• that a patient with OSA is often unaware of the neurocognative changes that have developed• slowly over time, and thus he or she may not volunteer history consistent with OSA unless• directly queried.

• 8. Short-term sleep deprivation increases cortisol levels, suppresses insulin secretion and• diminishes glucose tolerance. Leptin increases and ghrelin decreases and such patients• gain weight compared to non sleep deprived patients.

• 9. OSA results in less predictable hormone changes depending on the extent of sleep• fragmentation, elevation of adrenergic tone, and hypoxia. It is associated with decreased• insulin sensitivity and worsening glucose tolerance proportional to severity of OSA.• 10. Effective treatment of OSA improves sleep architecture, normalizes hormone release,• improves abnormal glucose metabolism.