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  • OSA is a common sleep disordered breathing characterized by


    OSA is a common sleep disordered breathing, characterized by recurrent apneas (complete breathing cessation) or hypopneas (shallow breathing), upper airway constriction, hypoxemia, hypercapnia, autonomic activation, and EEG arousal and sleep fragmentation, leading to daytime fatigue and sleepiness [17]. As nocturnal awakening is associated with pulsatile norepinephrine bitartrate manufacturer release and autonomic activation, we can expect OSA to lead to HPA axis activation through the same mechanisms involved in arousal and sleep fragmentation [4]. However, the studies to date are contradictory. Some have shown that continuous positive airway pressure (CPAP) therapy for OSA does not lower cortisol while the acute withdrawal of CPAP does not change cortisol levels [18]. On the other hand, other authors have demonstrated that CPAP does reverse hypercortisolemia [19]. A systematic review revealed that only 2 studies showed statistically significant differences in cortisol levels after CPAP treatment [20]. Elevated cortisol levels were reported in patients with OSA by some studies [21], but not in others [22]. Responsiveness of ACTH to CRH administration was much higher in obese patients with OSA, possibly due to alterations in the central control of ACTH secretion and impairment in the negative feedback of glucocorticoids [23]. A recent study showed that serum basal and peak cortisol levels were lower in OSA patients when compared to the control group during 1μg ACTH and glucagon stimulation tests, showing an association between OSA and hypocortisolemia in the morning with reduced responses to ACTH and glucagon stimulation tests [24]. Many of the discrepancies observed in the literature are reflective of methodological differences. The majority of studies are limited by assessment of cortisol at a single time point. The available studies do not provide clear evidence regarding whether OSA is associated with alterations in cortisol levels or that treatment with CPAP changes cortisol levels. Methodological concerns such as infrequent sampling, failure to match comparison groups on demographic factors known to impact cortisol levels (age, body mass index etc.), and inconsistent control of confounding factors may have limited the findings. However, there is evidence that excessive HPA axis activation may be a result from sleep loss, hypoxemia, and autonomic activation, playing an important role in the metabolic alterations arising from OSA [17]. Many studies have shown increase in cortisol levels during the nighttime period of total sleep deprivation and in the prolonged wakefulness of the norepinephrine bitartrate manufacturer following day. This is likely a result of stress due to the effort of maintaining wakefulness, as high frequency EEG activity is correlated with indices of arousal and cortisol release [25,26]. However, some authors also reported no change [27,28] or a decrease in cortisol levels [29,30] after 1 or more nights of sleep deprivation. These discrepancies seem to be influenced by insufficient frequency of blood sampling, small sample size, and by fatigue and sleepiness. In animals, however, the results are more consistent. Adult rats subject to paradoxical sleep deprivation during 96h show increased levels of corticosterone, which are normalized after 48h of sleep rebound [31]. Notwithstanding, it is important to consider that animal models do not accurately reflect human physiology; and thus, it is difficult to compare these results. Studies using chronic protocols of sleep restriction, which model a widespread condition in modern society, have also addressed the role of HPA axis. The first study assessed the effect of 6 consecutive nights of 4h in bed in young men, showing increased levels of cortisol in the afternoon and early evening, and a shorter quiescent period, with onset delayed by 1.5h [16]. The rate of decrease of free cortisol in saliva was nearly 6 times slower in sleep restricted volunteers compared to fully rested condition. Notably, chronic short sleepers do present higher levels of cortisol compared to chronic long sleepers [32].