Impact of Sleep and Its Disturbances on Hypothalamo-Pituitary-Adrenal Axis Activity

“Retention of declarative memory critically depends on the integrity of the hippocampus and has been shown to benefit specifically from early nocturnal sleep, in which SWS predominates and cortisol concentrations are minimal [52, 53].”

“The first systematic study of HPA axis activity in a state of sleep debt assessed the effect of 6 consecutive nights of 4 hours in bed in eleven young men [83].”

“On the first day after the shift, profound disruptions in the 24-hour cortisol rhythm were found: a reduction of more than 3 hours in the duration of the quiescent period resulted in an increase of the 24-hour mean levels and in the advance of the circadian onset.”

“As a confirmation, lesions of the SCN in rats result in the loss of corticosteroid periodicity [15, 16].”

“In addition to the master clock in the SCN, circadian oscillators have been found in a number of peripheral tissues, such as liver, heart, lung, skeletal muscle, and adrenal glands [2, 3].”

“In addition to the master clock in the SCN, circadian oscillators have been found in a number of peripheral tissues, such as liver, heart, lung, skeletal muscle, and adrenal glands [2, 3].”

“On the first day after the shift, profound disruptions in the 24-hour cortisol rhythm were found: a reduction of more than 3 hours in the duration of the quiescent period resulted in an increase of the 24-hour mean levels and in the advance of the circadian onset.”

“Declarative memory for emotional events, although still hippocampusdependent, is under critical modulation by the amygdala [57].”

“Insomnia is a sleep disorder characterized by difficulties falling or staying asleep or having restorative sleep, associated with daytime impairment or distress [99].”

“In addition, it is detectable independently of the time and the mode of awakening (naturally or induced) [39], both in long and short sleepers [40].”

“Responsiveness of ACTH to CRH administration has been shown to be higher in obese patients without OSA compared with lean subjects and to be even higher in obese patients with OSA [145], probably as the result of an alteration in the central control of ACTH secretion, as well as of an impaired sensitivity to the negat…”

“Even though, until recently, it was unclear if alterations in glucose metabolism and hypertension were the results of obesity or of SDB per se, there is a growing evidence to indicate that SDB may represent an independent risk factor in the pathogenesis of these metabolic alterations [133–136].”

“The amplitude of the circadian oscillation is generally defined as 50% of the difference between the value of the acrophase and the value of the nadir [11–13] (Figure 1).”

“Even though, until recently, it was unclear if alterations in glucose metabolism and hypertension were the results of obesity or of SDB per se, there is a growing evidence to indicate that SDB may represent an independent risk factor in the pathogenesis of these metabolic alterations [133–136].”

“Retention of declarative memory critically depends on the integrity of the hippocampus and has been shown to benefit specifically from early nocturnal sleep, in which SWS predominates and cortisol concentrations are minimal [52, 53].”

“In times of stress, amygdala GRs may be preferentially activated, increasing CRH secretion, therefore promoting sleep disruption [8].”

“Further research to delineate the functional links between sleep and HPA axis activity is needed to fully understand the pathophysiology of these syndromes and to develop adequate strategies of prevention and treatment.”

“Indeed, in studies of real and simulated jet-lag, the synchronization of the acrophase to the new clocktime occurred faster than the adaptation of the quiescent period [14, 66].”

“Sleep complains in older adults are more common in women than in men and this could play a role in the greater female reduction of the quiescent period.”

“It is likely that an increase in the sympathetic activity, secondary to the respiratory distress [137] or to the sleep loss/fragmentation per se [91] plays”

“Moreover, a study that collected 24-hour plasma ACTH and cortisol profiles in young insomniacs and in matched healthy controls found mean ACTH and cortisol levels higher in insomniacs than in controls, with the stronger elevations observed in the afternoon, in the late evening and in the early part of the night [105]…”

“Even though, until recently, it was unclear if alterations in glucose metabolism and hypertension were the results of obesity or of SDB per se, there is a growing evidence to indicate that SDB may represent an independent risk factor in the pathogenesis of these metabolic alterations [133–136].”

“On the first day after the shift, profound disruptions in the 24-hour cortisol rhythm were found: a reduction of more than 3 hours in the duration of the quiescent period resulted in an increase of the 24-hour mean levels and in the advance of the circadian onset.”

“An increasing number of epidemiological studies have reported an association between short sleep duration and higher risk of developing obesity and type II diabetes [86– 89].”

“Most early studies investigating this topic, limited by small sample sizes and heterogeneous composition, seemed to indicate that there are no major sex and age differences in basal functioning of the HPA axis [27–29].”

“Several studies have reported an elevation of cortisol levels both during the night of total sleep deprivation [13, 35, 72] and, if wakefulness was further prolonged, during the following day, particularly in the afternoon and evening [63, 73].”

“Sleep complains in older adults are more common in women than in men and this could play a role in the greater female reduction of the quiescent period.”

“Well-documented neuroendocrine changes in depressed patients include increased cortisol levels, in particular at the time of the cortisol nadir [112, 113], increased ACTH levels [113], lack of inhibition of cortisol to the suppression test with dexamethasone [114, 115] or exaggerated response of ACTH and cortisol to t…”

“A recent experiment of sleep fragmentation led to different findings [93].”

“When declarative memory for highly emotional rather than neutral material is assessed, the data point to a more beneficial influence of REM sleep which prevails during the late night, when cortisol concentrations rise [56].”

“Moreover, important metabolic impairments are part of the clinical features that characterize this syndrome: indeed, SDB is associated with elevated body mass index (BMI), hypertension, increased risk of diabetes, insulin resistance and dyslipidemia [132].”

“In addition, significant evidence now points to a neural SCN-adrenal gland connection, via the autonomic nervous system and independent from the HPA axis activation [19, 20]: this multisynaptic pathway from the SCN to the adrenal gland is able to transmit light information to the adrenal glands, modulating corticoster…”

“Well-documented neuroendocrine changes in depressed patients include increased cortisol levels, in particular at the time of the cortisol nadir [112, 113], increased ACTH levels [113], lack of inhibition of cortisol to the suppression test with dexamethasone [114, 115] or exaggerated response of ACTH and cortisol to t…”

“Circadian rhythms are generated by the endogenous master pacemaker located in the paired suprachiasmatic nucleus (SCN) of the hypothalamus and are kept entrained to the local conditions by environmental timing cues; the most important of these cues is light, that signaled to the SCN by direct input from the retina via…”

“On the contrary, in a more recent experiment, 24-hour urinary free cortisol excretion was positively correlated with polysomnographic indices of sleep disturbance in a group of adult insomniacs [104].”

“Indeed, some authors have reported no change [41, 43, 74, 75] or even a slight decrease in cortisol levels [76, 77] after one or several nights of total sleep deprivation.”

“One report documented a normalization of both ACTHcortisol profiles and REM sleep in adult patients after recovery [117], but in other studies, cortisol levels or the response to Dex-CRH test were improved after recovery, but pathological sleep-EEG persisted [121–123].”

“Some authors have reported that CPAP does not reduce cortisol levels [147] or that acute withdrawal of CPAP treatment does not result in an increase in cortisol levels [148].”

“An alteration of circadian rhythmicity, namely, a phase advance of the ACTH and cortisol nadir has been found in some studies [117, 118], but not in others [119, 120].”

“Even though, until recently, it was unclear if alterations in glucose metabolism and hypertension were the results of obesity or of SDB per se, there is a growing evidence to indicate that SDB may represent an independent risk factor in the pathogenesis of these metabolic alterations [133–136].”

“Themost common study protocols involve shifts of the sleep period (with volunteers kept awake at night and allowed to sleep at different times of the day), sleep deprivation, including constant routine conditions (in which human volunteers remain awake for 30–60 hours, in a semirecumbent position, in dim light and rec…”

“In fact, evening cortisol levels while awake correlate with the number of awakenings during the subsequent night in subjects with and without insomnia [106, 107].”

“An influence of sleep-wake transitions on cortisol secretion is also detectable during nocturnal awakenings which are consistently associated with a transient elevation of cortisol levels, followed by temporary inhibition of cortisol secretion [38].”

“This was evident in subjects undergoing a 3-hour sleep-wake cycle [34], in subjects reversing the phase of sleepwake cycle by 180◦ [35] and during temporal isolation (free running condition) [36].”

“While sleep loss and sleep disruption are generally thought of as activating the HPA axis, there is in turn strong evidence that elevated CRH tone increases sleep EEG frequency, thereby decreasing SWS, and increasing light sleep and wakefulness [94].”

“Well-documented neuroendocrine changes in depressed patients include increased cortisol levels, in particular at the time of the cortisol nadir [112, 113], increased ACTH levels [113], lack of inhibition of cortisol to the suppression test with dexamethasone [114, 115] or exaggerated response of ACTH and cortisol to t…”

“Again contradictory results have been reported: while in some studies cortisol secretion seemed to be almost unaffected by recovery sleep following prolonged wakefulness [78–80], Vgontzas et al.”

“[81] found a significant decrease in plasma cortisol levels, that appeared to be negatively correlated with the rebound increase of SWS.”

“Elevated cortisol levels have been found in patients with OSA present in some studies [141, 142] but not in others [143, 144].”

“This was evident in subjects undergoing a 3-hour sleep-wake cycle [34], in subjects reversing the phase of sleepwake cycle by 180◦ [35] and during temporal isolation (free running condition) [36].”

“In a cross-sectional analysis of data collected from the Whitehall II study, the relationship between self-reported sleep duration, sleep disturbances, and salivary cortisol levels has been assessed in a cohort of more than 2700 middle-aged men and women [85].”

“An early study failed to show any difference in urinary cortisol excretion between control and self-reported poor sleepers [103].”

“minutes “day,” with 2/3 of the time awake and 1/3 of the time asleep) [5–7].”

“An association between REM sleep and periods of low adrenal cortex secretory activity has been reported [48] and it has been shown that a significant proportion of REM sleep phases starts at a time of stable or decreasing cortisol levels, but may persist after cortisol increases again [41].”

“The SCN shows, indeed, direct and indirect projections (mainly via the subparaventricular zone and the dorsomedial nucleus of the hypothalamus) to the PVN [17, 18].”

“As a confirmation, lesions of the SCN in rats result in the loss of corticosteroid periodicity [15, 16].”

“Consistent with a role for quiescent cortisol release in this process, hippocampusdependent declarative memory has been impaired by the infusion of a low dose of cortisol during a period of early SWS-rich sleep [54].”

“On the contrary, CPAP does reverse hypercortisolemia according to other authors [149, 150], particularly with prolonged use [142].”

“One report documented a normalization of both ACTHcortisol profiles and REM sleep in adult patients after recovery [117], but in other studies, cortisol levels or the response to Dex-CRH test were improved after recovery, but pathological sleep-EEG persisted [121–123].”

“Moreover, it is well known that activation of HPA axis plays an essential causative role in the pathogenesis of metabolic and mood disorders that are often also associated with sleep disturbances [97, 98].”

“Major sleep disturbances result from this condition when untreated: total sleep time and sleep efficiency are reduced and sleep is more fragmented; wake, stage 1 and stage 2 are increased, SWS and REM sleep are markedly reduced [129, 130].”

“Interestingly, it has been hypothesized that the nature and the extent of the alterations in HPA axis activity and in sleep architecture may help to identify distinct subtypes within major depression [124].”

“Well-documented neuroendocrine changes in depressed patients include increased cortisol levels, in particular at the time of the cortisol nadir [112, 113], increased ACTH levels [113], lack of inhibition of cortisol to the suppression test with dexamethasone [114, 115] or exaggerated response of ACTH and cortisol to t…”

“Even though it is one of the most commonly encountered sleep disorders in medical practice, the understanding of its neurobiological basis and etiology is still limited and therefore even the treatment of this condition is challenging and often unsatisfactory [100].”

“A reduction of SWS has been reported [46, 128].”

“In addition, significant evidence now points to a neural SCN-adrenal gland connection, via the autonomic nervous system and independent from the HPA axis activation [19, 20]: this multisynaptic pathway from the SCN to the adrenal gland is able to transmit light information to the adrenal glands, modulating corticoster…”

“On the contrary, CPAP does reverse hypercortisolemia according to other authors [149, 150], particularly with prolonged use [142].”

“In a recent study that measured nocturnal cortisol profiles, sleep apnea in obese men compared with nonapneic obese controls was associated with an elevation of cortisol levels, which was corrected after 3 months of CPAP use [151].”

“The SCN shows, indeed, direct and indirect projections (mainly via the subparaventricular zone and the dorsomedial nucleus of the hypothalamus) to the PVN [17, 18].”

“metyrapone on sleep-associated consolidation of memory for texts of either neutral and emotional valence [58].”

“Several studies have reported an elevation of cortisol levels both during the night of total sleep deprivation [13, 35, 72] and, if wakefulness was further prolonged, during the following day, particularly in the afternoon and evening [63, 73].”

“A reduction of SWS has been reported [46, 128].”

“An association between REM sleep and periods of low adrenal cortex secretory activity has been reported [48] and it has been shown that a significant proportion of REM sleep phases starts at a time of stable or decreasing cortisol levels, but may persist after cortisol increases again [41].”

“Nevertheless, some authors have questioned the direction of the inverse link found between cortisol and SWS, suggesting that a decreased HPA tone may promote sleep deepening and, conversely, that increasing cortisol levels may prevent the occurrence of SWS [13, 46].”

“minutes “day,” with 2/3 of the time awake and 1/3 of the time asleep) [5–7].”

“Correspondingly, mild transient hyperglycemia has been shown to suppress HPA secretory activity in rats [25].”

“An alteration of circadian rhythmicity, namely, a phase advance of the ACTH and cortisol nadir has been found in some studies [117, 118], but not in others [119, 120].”

“In addition, the HPA axis receives relevant feedback from other areas of the brain, such as the hippocampus and amygdala [8].”

“Moreover, it is well known that activation of HPA axis plays an essential causative role in the pathogenesis of metabolic and mood disorders that are often also associated with sleep disturbances [97, 98].”

“Treatment with continuous positive airway pressure (CPAP), that represents at the moment the most efficacious therapy for sleep apnea, has been shown to improve sleep architecture in SDB patients [131].”

“In response to HPA axis activation, both liver and kidney increase endogenous glucose production, ensuring sufficient glucose supply to glucose-dependent organs, in particular the brain [24].”

“One report documented a normalization of both ACTHcortisol profiles and REM sleep in adult patients after recovery [117], but in other studies, cortisol levels or the response to Dex-CRH test were improved after recovery, but pathological sleep-EEG persisted [121–123].”

“The secretory regularity of ACTH and cortisol was also evaluated with approximate entropy (ApEn) statistic; the univariate ApEn quantifies the orderliness of a single hormone release, while the bivariate crossApEn quantitates the relative pattern synchrony of coupled time series: increased randomness of coupled hormon…”

“A similar result has been achieved with the administration of the glucocorticoid receptor (GR) agonist dexamethasone [55].”

“One report documented a normalization of both ACTHcortisol profiles and REM sleep in adult patients after recovery [117], but in other studies, cortisol levels or the response to Dex-CRH test were improved after recovery, but pathological sleep-EEG persisted [121–123].”

“a challenge (resiliency), rather than the rate of the initial response or the magnitude of the response [29, 30].”

“In addition, significant evidence now points to a neural SCN-adrenal gland connection, via the autonomic nervous system and independent from the HPA axis activation [19, 20]: this multisynaptic pathway from the SCN to the adrenal gland is able to transmit light information to the adrenal glands, modulating corticoster…”

“Again contradictory results have been reported: while in some studies cortisol secretion seemed to be almost unaffected by recovery sleep following prolonged wakefulness [78–80], Vgontzas et al.”

“Spectral analysis further reveals lower slow-wave activity during the first non-REM period [111].”

“The HPA axis plays a key role in mobilizing energy resources in conditions of reduced energy supply, such as during hypoglycemia [23].”

“has recently demonstrated the rhythmic expression of clock genes in the adrenal cortex of a diurnal primate [22].”

“correlation found between high frequency EEG activity in wake, indices of arousal, and cortisol release [63].”

“Some authors have reported that CPAP does not reduce cortisol levels [147] or that acute withdrawal of CPAP treatment does not result in an increase in cortisol levels [148].”

“Characteristic sleep-EEG findings in depressed patients include disturbed sleep continuity, increased wakefulness, shorter REM latency, and increased REM density [108–110].”

“Major sleep disturbances result from this condition when untreated: total sleep time and sleep efficiency are reduced and sleep is more fragmented; wake, stage 1 and stage 2 are increased, SWS and REM sleep are markedly reduced [129, 130].”

“Further research to delineate the functional links between sleep and HPA axis activity is needed to fully understand the pathophysiology of these syndromes and to develop adequate strategies of prevention and treatment.”

“Responsiveness of ACTH to CRH administration has been shown to be higher in obese patients without OSA compared with lean subjects and to be even higher in obese patients with OSA [145], probably as the result of an alteration in the central control of ACTH secretion, as well as of an impaired sensitivity to the negat…”

“Cortisol levels have been shown to decrease in the first 20 minutes after the onset of SWS [41]; in addition, a study that compared morning sleep after a regular night of sleep, with morning recovery sleep after a night of sleep deprivation, found increased SWS and decreased cortisol levels in the…”

“The effect of an abrupt 8hour delay of the sleep-wake cycle on plasma cortisol profiles was investigated in a study designed to mimic westward travel across eight time zones [67].”

“In a recent study the existence of a mild hypercortisolism in OSA patients has been suggested by the finding of a blunted response of cortisol to the dexamethasone suppression test [146].”

“Elevated cortisol levels have been found in patients with OSA present in some studies [141, 142] but not in others [143, 144].”

“Indeed, some authors have reported no change [41, 43, 74, 75] or even a slight decrease in cortisol levels [76, 77] after one or several nights of total sleep deprivation.”

“Another recent protocol investigated the effect of age, gender and BMI on the pulsatile pattern of secretion of ACTH and cortisol [32].”

“These authors showed that, during the period of pulsatile release, the cortisol secretory variations were concomitant with or anticipated opposite variations in SWA, by 10–20 minutes [47], suggesting the existence of a common central control.”

“An additional activating factor could be hypoxia, able to stimulate ACTH and cortisol secretion both in animals and in humans [138–140].”

“Well-documented neuroendocrine changes in depressed patients include increased cortisol levels, in particular at the time of the cortisol nadir [112, 113], increased ACTH levels [113], lack of inhibition of cortisol to the suppression test with dexamethasone [114, 115] or exaggerated response of ACTH and cortisol to t…”

“In addition, it is detectable independently of the time and the mode of awakening (naturally or induced) [39], both in long and short sleepers [40].”

“Cortisol levels have been shown to decrease in the first 20 minutes after the onset of SWS [41]; in addition, a study that compared morning sleep after a regular night of sleep, with morning recovery sleep after a night of sleep deprivation, found increased SWS and decreased cortisol levels in the latter condition [43…”

“The rate of re-entrainment of the biological rhythms to the new environmental time has been recognized to be different among physiologic variables, being slower for those mainly controlled by the circadian process, and faster for those mainly under the sleep-wake homeostasis control [65].”

“Decreased cortisol levels have been reported in a study of REM suppression [92].”

“Given that high-frequency EEG over 20 Hz is considered a marker of daytime arousal [64], a functional link between the regulatory mechanisms controlling the HPA activity and the level of central arousal has been hypothesized.”

“An additional activating factor could be hypoxia, able to stimulate ACTH and cortisol secretion both in animals and in humans [138–140].”

“It is well known that a central cognitive function of sleep is to consolidate newly acquired memories for long-term storage [50] and, moreover, different sleep stages seem to be implicated in the consolidation of different types of memory [51].”

“Thus, even though the normal nocturnal circadian oscillation of pituitary-adrenal activity is absent or markedly blunted in Cushing patients, a link between pituitary-adrenal activity and the ultradian rhythmicity of REM-non REM sleep appears to be preserved [127].”

“Secondly, sustained arousal and chronic activation of hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, the major neuroendocrine mediator of stress response, have been suggested as playing a vital role in the development of depression in insomniacs with objective short sleep duration [14, 61].”

“Severe fatigue is present in about half of the patients and is associated with sleep disturbances (339, 361).”

“[17] Balbo M, Leproult R, Van Cauter E.”