Article

The relationship between melatonin and cortisol rhythms: Clinical implications of melatonin therapy

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Abstract

Disturbances in circadian rhythm have been linked to chronic diseases such as insomnia, hypertension, diabetes, and depression. Here we review recent studies on the age-related changes in cortisol and melatonin rhythms and then present descriptive statistics on our preliminary findings on the rectification of the cortisol rhythms by melatonin therapy in elderly patients with insomnia. In adults, the melatonin onset typically occurs during low cortisol secretion. Administration of exogenous melatonin around dusk will shift the phase of the human circadian clock to earlier hours (advance phase shift) leading to phase advances in circadian rhythms (e.g., sleep, endogenous melatonin, cortisol). With aging, the production of melatonin declines and is shifted to later hours while the production of cortisol increases and its peak occurs earlier in the night. In a randomized placebo-controlled crossover study with 8 patients with insomnia aged 55 years and older, a group characterized by low and delayed melatonin production, administration of prolonged-release melatonin in the evening was able to rectify the early onset cortisol production. This delay in nocturnal cortisol onset may explain in part the improvement in sleep quality in elderly patients with insomnia, in schizophrenics, and in depressed patients. Support of circadian pacemaker function by melatonin may provide a new strategy in the treatment of disorders related to impairments in the internal temporal order. The clinical benefit from a decrease in cortisol during the early part of the night may lie beyond the improvement of sleep into a better control of blood pressure, metabolism, and mood. Drug Dev. Res. 65:119–125, 2005. © 2005 Wiley-Liss, Inc.

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... Cortisol, a major glucocorticoid, plays an important role in behavior, metabolism, growth, stress response, osmoregulation, reproduction and immune function. 92 It stimulates proteolysis and provides substrates for gluconeogenesis. However, the prolonged elevation of this hormone may induce muscle atrophy by increasing proteolysis and decreasing protein synthesis. ...
... 22 In elderly, melatonin production decreases and its peak is later at night while cortisol production increases and its highest level occurs early at night. 92 The loss in melatonin secretion and the increase in cortisol level in aged subjects could exacerbate age-related chronic diseases like hypertension and insulin resistance. Melatonin therapy could be clinically beneficial in controlling blood pressure and metabolism. ...
... Melatonin therapy could be clinically beneficial in controlling blood pressure and metabolism. 92 Therefore, more studies are needed to find out the exact mechanisms of beneficial effects of melatonin on the levels of cortisol in patients with CC. ...
Article
Heart failure (HF) is one of the prominent health concerns and its morbidity is comparable to many malignancies. Cardiac cachexia (CC), characterized by significant weight loss and muscle wasting, frequently occurs in progressive stage of HF. The pathophysiology of CC is multifactorial including nutritional and gastrointestinal alterations, immunological and neurohormonal activation, and anabolic/catabolic imbalance. Neurohormones are critically involved in the development of both HF and CC. Melatonin is known as an anti-inflammatory and antioxidant hormone. It seems that melatonin possibly regulates the neurohormonal signaling pathway related to muscle wasting in CC, but limited comprehensive data is available on the mechanistic aspects of its activity. In this, we reviewed the reports regarding the role of neurohormones in CC occurrence and possible activity of melatonin in modulation of HF and subsequently CC via neurohormonal regulation. In addition, we have discussed proposed mechanisms of action for melatonin considering its possible interactions with neurohormones. In conclusion, melatonin likely regulates the signaling pathways related to muscle wasting in CC by reducing tumor necrosis factor α levels and activating the gene expression of insulin-like growth factor-1. Also, this hormone inhibits the proteolytic pathway by inhibiting nuclear factor-κB (NF-κB), renin-angiotensin system and forkhead box protein O1 pathways and could increase protein synthesis by activating Akt and mammalian target of rapamycin. To elucidate the positive role of melatonin in CC and exact mechanisms related to muscle wasting more cellular and clinical trial studies are needed.
... When given at daytime the architecture of sleep induced by melatonin resembles to some extent the contribution of the endogenous circadian pacemaker to the spectral composition of the sleep EEG at night [37]. In preparation for sleep, melatonin acts to induce heat loss, reduce arousal and related brain activation and delay cortisol production [38,39]. ...
... Middleaged individuals not only have higher cortisol levels in the early portion of the night compared to younger adults, but also an increased vulnerability of sleep to stress hormones, possibly resulting in impairments in the quality of sleep [128,129]. PRM treatment delayed the nocturnal cortisol production in elderly insomnia patients towards the morning hours [38]; this delay may explain in part some of the beneficial effects of PRM on sleep and daytime alertness in elderly patients with insomnia [117,118]. No such effect was observed with FR-melatonin (unpublished data). ...
Article
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Melatonin is produced over the night in a process driven by the circadian clock that resides in the suprachiasmatic nuclei (SCN), and by ambient light. It is a time cue to tune the sleep-wake and other circadian rhythms with the day-night cycles and thus useful in circadian rhythm sleep disorders. In addition melatonin induces fatigue and concurrent sleep-like changes in brain activation patterns in humans. With age SCN activity and melatonin production capacity decline thus depriving the brain of an important regulator of the body's circadian rhythms. Melatonin substitution therapy with a prolonged-release formulation that mimics the physiological release profile of the hormone (PRM) may effectively treat insomnia in older patients. Large-scale, randomized, placebo-controlled clinical trials in insomnia patients aged 55 years and older indicated that PRM given for 3 weeks or more improved sleep quality, facilitated sleep onset and improved morning alertness, daytime functioning and quality of life and reduced hypnotic drug usage. Preliminary results of a 6-months long term placebo controlled study announced at the 2009 meeting of the Associated Professional Sleep Societies indicated that PRM efficacy was sustained. There were no main safety concerns and in particular, none of the risks associated with hypnotic drugs use (e.g. memory and cognitive impairments, falls and accidents, residual daytime or 'hangover' effects, rebound insomnia and withdrawal symptoms). There is clinical data showing efficacy of PRM in circadian rhythm sleep disorders in totally blind individuals and children with neurodevelopmental disabilities. PRM thus represents a new therapeutic principle for treating sleep disorders.
... A systematic review of published studies on exogenous melatonin (formulations and doses not standardized) for primary insomnia and circadian rhythm sleep disorders showed decrease in sleep onset latency in such patients compared with placebo, but quality of sleep was not significantly improved [66]. Exogenous melatonin simulates/mimics nocturnal circadian physiology (i.e., reduced body temperature, blood pressure and arousal and increased heat loss, fatigue and sleepiness during the night) in patients with low or abnormal melatonin production [61,[67][68][69][70][71][72] but these effects may depend on the formulation used. ...
... Melatonin replacement therapy may replenish the deficiency in the endogenous sleep-regulating hormone, thereby improving sleep quality. As part of its therapeutic effect, it can also reinforce the functioning of the circadian clock so that the sleep propensity rhythm is in tune with the societal activity cycle [61] and with the circadian rhythms in metabolism and blood pressure [67,72]. (Circadin) for the treatment of insomnia 2.2.1 Pharmacokinetics and metabolism Circadin (Box 1) is specifically developed to treat insomnia in patients aged ‡ 55 years to satisfy the unmet need for an appropriate treatment for this age group. ...
Article
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Introduction: Insomnia is common among the elderly. The use of hypnotic drugs in elderly patients is frequently criticized owing to dependency, cognitive impairments, falls and withdrawal effects. The production of melatonin, a physiological sleep and circadian rhythm regulator, declines with age. Prolonged-release melatonin (Circadin®), designed to mimic the endogenous pattern of melatonin production, is licensed for insomnia in patients aged ≥ 55 years. Areas covered: This review summarizes published studies on Circadin's efficacy and safety (Summary of Product Characteristics and Medline search on 'Circadin' and 'insomnia'). Expert opinion: The main significant and clinically relevant benefits are improvements in sleep quality and latency, next-day morning alertness and quality of life. The responses may develop over several days. An oral 2-mg dose once daily, for 3 months, has generally been well tolerated with no rebound, withdrawal or 'hangover' effects and no safety concerns on concomitant therapy with antihypertensive, antidiabetic, lipid-lowering or anti-inflammatory drugs. Untoward effects of hypnotics on cognition, memory, postural stability and sleep structure are not seen with Circadin. Given as a first-line prescription, with 13 weeks' posology and the lack of rebound effects, Circadin has the potential to improve quality of life in insomnia patients aged 55 years and older and avoid long-term use of hypnotics.
... Older individuals appear to be more prone to internal desynchronization than younger subjects, suggesting a weakening of the internal coupling among various rhythms. Among the rhythms that appear to change considerably with age are the rhythms in the production and secretion of serotonin, melatonin and cortisol (Zisapel et al. 2005). In previous studies we have noted a significant decline in circulating melatonin levels in old ringdoves compared with the concentration observed in both mature and young animals (Terrón et al. 2002(Terrón et al. , 2004 as well as a significant decline in the amplitude and mean levels of melatonin (Paredes et al. 2006). ...
... Again, melatonin contained in the product or its precursors, once converted into the indoleamine after being assimilated by the organism, may be involved in this effect. In fact, melatonin treatment has been repeatedly reported to decrease blood corticosterone levels in mammals and birds (Saito et al. 2005, Zisapel et al. 2005, Detanico et al. 2009). ...
Article
Impaired daily rhythms in vertebrate physiology occur with age. Particularly, age-related changes in melatonin and serotonin rhythms and hypercortisolemia have been reported to be linked to age-related disorders. This study was aimed at assessing the effect of a Jerte Valley cherry-based nutraceutical product (patent no ES 2342141 B1), which contains high levels of tryptophan, serotonin, and melatonin, on the serum melatonin, serotonin, corticosterone, and total antioxidant capacity (TAC) levels in young and old ring doves (Streptopelia risoria) and rats (Rattus norvegicus) as representatives of animals with diurnal and nocturnal habits, respectively. The animals consumed the cherry product for 10 days. Serum melatonin, serotonin, corticosterone, and TAC were measured with commercial ELISA kits. The consumption of the cherry product induced a significant increase in the circulating levels of melatonin and serotonin, as well as in the serum TAC and a significant decrease in the circulating levels of corticosterone in both species and groups of age as compared to their respective values in the control groups. The consumption of a Jerte Valley cherry-based nutraceutical product may help to counteract the decrease in melatonin and serotonin and the increase in oxidative stress, suggesting a potential health benefit especially in aged populations where these parameters have been found to be altered.
... Elevated nocturnal plasma and urinary cortisol levels correlated with impaired sleep in patients with severe primary insomnia (Rodenbeck et al., 1998). Exploratory studies in patients with insomnia aged 55 years and older, suggested that administration of PRmelatonin in the evening was able to rectify the early onset cortisol production (Zisapel et al., 2005). This delay in nocturnal cortisol onset may explain in part the improvement in sleep quality and morning alertness in elderly patients with insomnia. ...
Article
Full-text available
Melatonin, secreted nocturnally by the pineal gland, is an endogenous sleep regulator. Impaired melatonin production and complaints on poor quality of sleep are common among the elderly. Non-restorative sleep (perceived poor quality of sleep) and subsequently poor daytime functioning are increasingly recognized as a leading syndrome in the diagnostic and therapeutic process of insomnia complaints. The effects of 3-weeks prolonged-release melatonin 2 mg (PR-melatonin) versus placebo treatment were assessed in a multi-center randomized placebo-controlled study in 170 primary insomnia outpatients aged > or =55 years. Improvements in quality of sleep (QOS) the night before and morning alertness (BFW) were assessed using the Leeds Sleep Evaluation Questionnaire and changes in sleep quality (QON) reported on five categorical unit scales. Rebound insomnia and withdrawal effects following discontinuation were also evaluated. PR-melatonin significantly improved QOS (-22.5 versus -16.5 mm, P = 0.047), QON (0.89 versus 0.46 units; P = 0.003) and BFW (-15.7 versus -6.8 mm; P = 0.002) compared with placebo. The improvements in QOS and BFW were strongly correlated (Rval = 0.77, P < 0.001) suggesting a beneficial treatment effect on the restorative value of sleep. These results were confirmed in a subgroup of patients with a greater symptom severity. There was no evidence of rebound insomnia or withdrawal effects following treatment discontinuation. The incidence of adverse events was low and most side-effects were judged to be of minor severity. PR-melatonin is the first drug shown to significantly improve quality of sleep and morning alertness in primary insomnia patients aged 55 years and older-suggesting more restorative sleep, and without withdrawal symptoms upon discontinuation.
... Because of the role of melatonin in circadian system functioning, the decline in melatonin with age may be causally related to low evening sensitivity to cortisol in the elderly and therefore to blunted and delayed inhibition of ACTH secretion and consequently sustained activation of the HPA axis during the early night. Such an explanation is compatible with phase delay in cortisol acrophases despite a phase advance in melatonin that is seen in older subjects with insomnia upon melatonin replacement therapy [115]. ...
Article
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Sleep is a neurochemical process involving sleep promoting and arousal centers in the brain. Sleep performs an essential restorative function and facilitates memory consolidation in humans. The remarkably standardized bouts of consolidated sleep at night and daytime wakefulness reflect an interaction between the homeostatic sleep need that is manifested by increase in sleep propensity after sleep deprivation and decrease during sleep and the circadian pacemaker. Melatonin, the hormone produced nocturnally by the pineal gland, serves as a time cue and sleep-anticipating signal. A close interaction exists between the sleep-wake, melatonin, core temperature, blood pressure, immune and hormonal rhythms leading to optimization of the internal temporal order. With age the robustness of the circadian system decreases and the prevalence of sleep disorders, particularly insomnia, increases. Deviant sleep patterns are associated with increased risks of morbidity, poor quality of life and mortality. Current sleep pharmacotherapies treat insufficient sleep quantity, but fail to improve daytime functioning. New treatment modalities for sleep disorders that will also improve daytime functioning remain a scientific and medical challenge.
... More likely, we suspect that the increase in melatonin levels determined in our experiment can be mainly attributed to the reduced cortisol levels. Actually, a relationship between cortisol and melatonin rhythms has been observed [95], indicating that melatonin onset typically occurs during low cortisol secretion. In addition, Monteleone et al. [96] found that exercise-induced increases in plasma cortisol preceded Evidence-Based Complementary and Alternative Medicine 7 the lower night-time melatonin secretion, thus suggesting a connection between the metabolisms of these two hormones. ...
Article
This work monitored changes in oxidative stress and antioxidant defence during an endurance exercise in over 40 years old athletes. Subjects were monitored during the 24-hours mountain bike Idro Lake (North of Italy) competition which took place in June 2008. The race lasted for 24 h, starting at 10.00 a.m., ending at 10.00 a.m. of the following day and was based upon riding for as many kilometers as possible in the 24-hours time schedule in a 5.5 km circuit trail. The study included 6 men bikers, aged 44.8 +/- 2 years, who raced on an individual basis. Blood samples were collected and the oxidative stress was measured performing the d-ROMs test which determined the reactive oxygen metabolites (ROMs), whereas the antioxidant defence status was assessed determining the biological antioxidant potential (BAP test). The ROMs levels significantly increased after 8 h from the beginning of the competition (122 %), at the end of the race (162%), 24 h (158%) and 48 h (144%) post-race. The biological antioxidant potential significantly increased at the end of the race (128%) and remained elevated 48 h later (114%). After 72 h post-race, ROMs and BAP levels differed significantly amongst subjects, thus showing an individual response to oxidative stress. In conclusion, exposure to intense and prolonged exercise induced a marked increase in dROMs levels in master athletes, only partially counterbalanced by antioxidants in blood plasma. The long-term effects of oxidative agents on the human body requires further studies, but it is likely that a diet potentially rich in antioxidants would help preventing oxidative damage of body cells and tissues and enhancing recovering from the endurance performance.
... More likely, we suspect that the increase in melatonin levels determined in our experiment can be mainly attributed to the reduced cortisol levels. Actually, a relationship between cortisol and melatonin rhythms has been observed [95], indicating that melatonin onset typically occurs during low cortisol secretion. In addition, Monteleone et al. [96] found that exercise-induced increases in plasma cortisol preceded the lower night-time melatonin secretion, thus suggesting a connection between the metabolisms of these two hormones. ...
Article
Full-text available
Diaphragmatic breathing is relaxing and therapeutic, reduces stress, and is a fundamental procedure of Pranayama Yoga, Zen, transcendental meditation and other meditation practices. Analysis of oxidative stress levels in people who meditate indicated that meditation correlates with lower oxidative stress levels, lower cortisol levels and higher melatonin levels. It is known that cortisol inhibits enzymes responsible for the antioxidant activity of cells and that melatonin is a strong antioxidant; therefore, in this study, we investigated the effects of diaphragmatic breathing on exercise-induced oxidative stress and the putative role of cortisol and melatonin hormones in this stress pathway. We monitored 16 athletes during an exhaustive training session. After the exercise, athletes were divided in two equivalent groups of eight subjects. Subjects of the studied group spent 1 h relaxing performing diaphragmatic breathing and concentrating on their breath in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. Results demonstrate that relaxation induced by diaphragmatic breathing increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol and the increase in melatonin. The consequence is a lower level of oxidative stress, which suggests that an appropriate diaphragmatic breathing could protect athletes from long-term adverse effects of free radicals.
... Consequently, there is disorganization of the internal temporal order [12,44]. PRM treatment has been shown to delay the nocturnal cortisol production in elderly insomnia patients towards the morning [45], improve blood pressure rhythms [46] and, as shown here, progressively advance time to bed in those aged 65-80 years old in addition to the shortening of sleep latency. Improvement in internal temporal order with PRM may explain why the treatment effects are more prominent in older patients and there is a gradual development of response over days or weeks [25]. ...
Article
Full-text available
Melatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment. Adult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit. On the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] <or=8 microg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome. The results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. The age cut-off for response warrants further investigation.
... The authors therefore propose that besides sleep induction, PRM replacement therapy acts to reinstate the internal temporal order that appears to dissipate in older age 16 . This notion is compatible with the change in cortisol peak time and improvement in nocturnal blood pressure rhythm seen with this formulation 27,28 . Another plausible explanation for the gradual evolution of response is recovery of responsiveness to melatonin that is diminished in aging. ...
Article
Full-text available
The authors recently reported on efficacy and safety of prolonged-release melatonin formulation (PRM; Circadin 2  mg) in elderly insomnia patients. The age cut-off for response to PRM and the long-term maintenance of efficacy and safety were further evaluated by looking at the total cohort (age 18-80 years) from that study and subsets of patients aged 18-54 and 55-80 years (for whom the drug is currently indicated). Randomised, double-blind, placebo controlled trial. Setting: Multicentre, outpatients, primary care setting. A total of 930 males and females aged 18-80 years with primary insomnia who reported mean nightly sleep latency (SL) >20  min were enrolled and 791 entered the active phase of the study. The study comprised a 2-week, single-blind placebo run-in period followed by 3 week's double-blind treatment with PRM or placebo, one tablet per day at 2 hours before bedtime. PRM patients continued whereas placebo completers were re-randomised 1:1 to PRM or placebo for 26 weeks followed by 2-weeks run-out on placebo. Main outcome measures: SL and other sleep variables derived from sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of life (WHO-5), Clinical Global Impression of Improvement (CGI-I) and adverse effects, recorded each visit, withdrawal and rebound effects during run-out. In all, 746 patients completed the 3-week and 555 (421 PRM, 134 placebo) completed the 6-month period. The principal reason for drop-out was patient decision. At 3 weeks, significant differences in SL (diary, primary variable) in favour of PRM vs. placebo treatment were found for the 55-80-year group (-15.4 vs. -5.5  min, p = 0.014) but not the 18-80-year cut-off which included younger patients. Other variables (SL-PSQI, PSQI, WHO-5, CGI-I scores) improved significantly with PRM in the 18-80-year population, more so than in the 55-80-year age group. Improvements were maintained or enhanced over the 6-month period with no signs of tolerance. No withdrawal symptoms or rebound insomnia were detected. Most adverse events were mild with no significant differences between PRM and placebo groups in any safety outcome. The results demonstrate short- and long-term efficacy of PRM in insomnia patients aged 18-80 years, particularly those aged 55 and over. PRM was well-tolerated over the entire 6-month period with no rebound or withdrawal symptoms following discontinuation. Study Registry No: ClinicalTrials.gov ID: NCT00397189.
... It is an endogenous sleep regulator and signal of darkness in humans [32]. In preparation for sleep, melatonin induces heat loss, reduces arousal and related brain activation and delays cortisol production [33,34]. Melatonin acts on its own receptors (MT1 and MT2), which are members of the G-protein-linked receptor family [35]. ...
Article
Full-text available
Prolonged-release (PR) melatonin (Circadin®, Neurim Pharmaceuticals, Tel-Aviv, Israel) is a nonbenzodiazepine licensed to treat primary insomnia in patients aged 55 years and older. It exerts its effects by mimicking endogenous melatonin, a hormone which regulates sleep. PR-melatonin has been shown to be effective in improving quality of sleep and morning alertness. An oral dose of 2 mg once-daily for 3 weeks has generally been well tolerated, and does not cause 'hangover' effects or impair memory and psychomotor skills.
... There are the reasons to believe that the circadian periodicity in the functioning of the HPA axis in humans and nonhuman primates deteriorates with aging f6, 16,79,20-22,25-2J,30,31,35,48,65,69,'TT,T2landthatthesedisturbancesplayanimportantrol related changes of glucocorticoid-sensitive tissues functioning, inadequate reaction to stress and high frequency stress-related pathology in aged individuals f '7,9,17,76,2J,31,32,33, 65,7 tl. Circadian periodicity is characteristic not only for basal levels of ACTH and cotticosteroids in peripheral blood f6, 16,20,22,30,31,34,48,69,80] but, apparently, and for magnitude of their rise in response to the acute psycho-emotional stress imposed at variotts times of day 112,15,23,29,331. At aging, smoothing of circadian rhythms in stress responsiveness of the HPA axis was observed. ...
Chapter
Full-text available
The hypothalamic-pituitary-adrenal (HPA) axis is all-important adaptive neuroendocrine system with the circadian periodicity in the activity. There is some evidence to suggest that the circadian periodicity in functioning of the HPA deteriorates with aging and that these disturbances play an important role in age-related changes of glucocorticoid-sensitive tissue functioning, inadequate reaction to stress and high frequency stress-related pathology in aged individuals. Unfortunately, up to now there have been some unclarities in the character and mechanisms of age-related disturbances in circadian rhythms of codicosteroid production. One of the possible causes of this unsolved problern is the use of inadequate experimental nocturnal models - laboratory rodents - in which the circadian rhythm of HPA activity is in contrast to that in humans and nonhuman primates. The purpose of this chapter was to investigate changes of circadian rhythrns of HPA axis activity under stress and during aging as well as to evaluate the role of age-related disturbances in melatoninergic and vasopressinergic regulation in their development. Female Macaca mulatta monkeys of 6-8 years (young) and 20-27 years (old) were subjected to acute psycho-emotional stress (two hours irnmobilization), corticotropin-releasing hormone (CRH) or arginine vasopressin (AVP) injection at 0900h or 1500h on the background of placebo or a pineal tetrapeptide Ala-Glu-Asp-Gly (epitalon) administration (10 microgram/lanimal/day, 10-14 days) as stimulator of the pineal rnelatonin secretion. In response to the stress imposed at 1500h, young monkeys demonstrated much higher increase in ACTH and cortisol than to the stress at 0900h. This stress difference attenuates with aging. Compared to old animals, young ones demonstrated much higher responsiveness of the HPA axis to the afternoon stress and a tendency toward lower responsiveness to the morning stress. In response to CRH, young and old monkeys demonstrated the well-defined circadian rhythms in dynamics of ACTH and cortisol. AVP injection did not induce any circadian periodicity in the ACTH and cortisol responsiveness neither in young animals, nor in old ones. However, in response to the afternoon injection of AVP, old monkeys by comparison to the young ones demonstrated lower accretions of ACTH and cortisol without increase in melatonin. The deteriorations of the circadian rhythms of the HPA axis responsiveness to AVP and stress were restored by epitalon. Thus, age-related changes in circadian rhythms of HPA stress reactivity are associated with age-related disturbances in melatoninergic and vasopressinergic regulation. The functioning of the HPA is restored through correction of the melatonin secretion by treatment with epitalon.
... We therefore propose that besides the soporific effect leading to improvement in sleep per se, PRM therapy may act to reinstate the internal temporal order that appears to dissipate in older age (Czeisler et al., 1992;Mirmiran et al., 1992;Hofman and Swaab, 1994). This notion is compatible with the change in cortisol peak time, improvement in nocturnal blood pressure rhythm, and advance in bedtime hours observed with this formulation (Zisapel et al., 2005;Grossman et al., 2006;Wade et al., 2010Wade et al., , 2011. ...
Article
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Surveillance studies are useful to evaluate how a new medicinal product performs in everyday treatment and how the patient who takes it feels and functions, thereby determining the benefit/risk ratio of the drug under real-life conditions. Prolonged-release melatonin (PRM; Circadin) was approved in Europe for the management of primary insomnia patients age 55 years or older suffering from poor quality of sleep. With traditional hypnotics (e.g. benzodiazepine-receptor agonists), there are concerns about rebound insomnia and/or withdrawal symptoms. We report data from a postmarketing surveillance study in Germany on the effects of 3 weeks of treatment with PRM on sleep in patients with insomnia during treatment and at early (1-2 days) and late (around 2 weeks) withdrawal. In total, 653 patients (597 evaluable) were recruited at 204 sites (mean age 62.7 years, 68% previously treated with hypnotics, 65% women). With PRM treatment, the mean sleep quality (on a scale of 1-5 on which 1 is very good and 5 is very bad) improved from 4.2 to 2.6 and morning alertness improved from 4.0 to 2.5. The improvements persisted over the post-treatment observation period. Rebound insomnia, defined as a one-point deterioration in sleep quality below baseline values, was found in 3.2% (early withdrawal) and 2.0% (late withdrawal). Most of the patients (77%) who used traditional hypnotics before PRM treatment had stopped using them and only 5.6% of naive patients started such drugs after PRM discontinuation. PRM was well tolerated during treatment and the most frequently reported adverse events were nausea (10 patients, 1.5%), dizziness, restlessness and headache (five patients each, <1%). There were no serious adverse events and no adverse events were reported after discontinuation. The persisting treatment effect and very low rebound rate suggest a beneficial role of sleep-wake cycle stabilization with PRM in the treatment of insomnia.
... Although serotonin is produced in the brain, where its primary functions is performed there but 90 percent of our serotonin supply is found in the digestive tract and in blood platelets. Serotonin can help the regulation of other neurotransmitter and hormone systems; decreased serotonin activity may let these systems to act in unusual and irregular ways [18]. ...
Article
According to the world health organization, major depressive disorder (MDD) is considered as the fourth main cause of death and premature weakness in the whole world. Abnormality in the hormones and neurotransmitters level is the one of the main factors which may result in this disorder. In this article melatonin is chosen among these hormones, which is the most implicated to control sleep and depression. Because the measurement of melatonin is crucial important, the fuzzy logic approach as the mathematical method is utilized to making melatonin behavior model. In this paper, two effective factors on melatonin are modeled by fuzzy logic. This model is only a part of our project which is performed for modeling of the major depression.
... Thus, the releases of melatonin, serotonin, glutamates or endorphins in different rhythms are naturally controlled. Due to the body's hormone concentrations certain times of the day fit better to particular activities than others [2,[5][6][7]22]. The internal intervals vary from person to person. ...
Preprint
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Time and its lack of play a central role in our everyday lives. Despite increasing productivity, many people experience time stress, exhaustion and a longing for time affluence, and at the same time, a fear of not being busy enough. All this leads to a neglect of natural time, especially the patterns and rhythms created by physiological processes, subsumed under the heading of chronobiology. The present paper presents and evaluates a calendar application, which uses chronobiological knowledge to support people s planning activities. Participants found our calendar to be interesting and engaging. It especially made them think more about their bodies and appropriate times for particular activities. All in all, it supported participants in negotiating. external demands and personal health and wellbeing. This shows that technology does not necessarily has to be neutral or even further current (mal-)practices. Our calendar cares about changing perspectives and thus about enhancing users wellbeing.
... Analyzing advanced HD we have found that the patterns of circadian changes for both, melatonin and cortisol, are similar to the changes that occur with ageing, when the production of melatonin declines and is shifted to later hours while the production of cortisol increases and its peak occurs earlier in the night (31). Several studies suggest that different neuronal dysfunctions linked with increased basic level of cortisol may result from disinhibition of HPA-axis due to declined levels of melatonin indicating its role as an antiadrenocortical or antistress factor (32)(33)(34)(35). ...
Article
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Recent studies indicate disruptions to the circadian system in brain injury and neurodegeneration. The results, however, are often not consistent and limited by measurement of only one circadian marker and by infrequent sampling rates. In this study, we examined diurnal rhythmicity in different stages of Huntington (HD) disease and in patients with acute moderate ischemic stroke (AIS) outside the retinohypothalamic pathway by evaluating serum concentrations of melatonin and cortisol at twelve timepoints. All study participants were subjected to the same study protocol of 12-hour light/dark cycle and controlled room conditions. Using cosinor analysis of data and comparing the results with the controls we found melatonin phase delay with lowered amplitude and mesor in stage III HD patients. These changes coexisted with phase advanced rhythm and elevated values of mesor and amplitude for cortisol. Early and mid-stages of HD showed only a phase advance in cortisol secretion. In AIS the circadian rhythm of serum melatonin was sustained without any phase shift and exhibited more flattened profile (lowered mesor and amplitude values), while advanced rhythm with higher mesor for cortisol was present. In conclusion, (1) abnormal pattern of melatonin release in the late stages of HD and in moderate AIS occurs in conjunction with phase-advanced rhythm of cortisol; (2) changes observed in late stages of HD are similar to those that occur with ageing; (3) brain regions other than the presumptive retinopineal neural pathway may play an important role in the pineal production of melatonin in humans; (4) lesion in extrahippocampal region is related to the strong adrenal stimulation in response to AIS. Key words: Huntington disease, acute stroke, melatonin, cortisol, circadian rhythm
... Analyzing advanced HD we have found that the patterns of circadian changes for both, melatonin and cortisol, are similar to the changes that occur with ageing, when the production of melatonin declines and is shifted to later hours while the production of cortisol increases and its peak occurs earlier in the night (31). Several studies suggest that different neuronal dysfunctions linked with increased basic level of cortisol may result from disinhibition of HPA-axis due to declined levels of melatonin indicating its role as an antiadrenocortical or antistress factor (32)(33)(34)(35). ...
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... Furthermore, the relationship between melatonin and cortisol rhythms improves sleep quality in aging patients with insomnia, schizophrenics, and depression and helps controls blood pressure, metabolism, and mood. (Zisapel, Tarrasch, & Laudon, 2005). Both hormone profiles in late midlife are associated with age-related changes in cognitive changes (Waller et al., 2016). ...
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... Melatonin and cortisol are the most widely used biological phase markers to examine circadian rhythm [4,5]. The secretions of these hormones are highly rhythmic, with melatonin exhibiting maximal level in the middle of night and gradual decline towards dawn while cortisol peaks in the second half of the night toward early morning, and declines to half of the peak value in the afternoon [6,7]. Both melatonin and cortisol play a role in synchronizing the circadian rhythms in peripheral tissues to the 24-h pattern and likely provide feedback to the SCN [8]. ...
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Thesis
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IL-6 and TNF alpha secretion is increased by sleep loss or restriction. IL-6 secretion progressively increases with age, yet its association with decreased quality and quantity of sleep in old adults is unknown. This study examined the alteration of 24-h secretory pattern of IL-6, TNF alpha, and cortisol in 15 young and 13 old normal sleepers who were recorded in the sleep laboratory for four consecutive nights. Serial 24-h plasma measures of IL-6, TNF alpha, and cortisol were obtained during the fourth day, and daytime sleepiness was assessed with the multiple sleep latency test. Old adults, compared with young subjects, slept poorly at night (wake time and percentage stage 1 sleep were increased, whereas their percentage slow wave sleep and percentage sleep time were decreased, P < 0.05). Accordingly, their daytime sleep latency was longer than in young adults (P < 0.05). The mean 24-h IL-6 and cortisol levels were significantly higher in old than young adults (P < 0.05). In both groups, IL-6 and cortisol plasma concentrations were positively associated with total wake time, with a stronger association of IL-6 and cortisol with total wake time in the older individuals (P < 0.05); their combined effect was additive. IL-6 had a negative association with rapid eye movement (REM) sleep only in the young (P < 0.05), but cortisol was associated negatively with REM sleep both in the young and old, with a stronger effect in the young. We conclude that in healthy adults, age-related alterations in nocturnal wake time and daytime sleepiness are associated with elevations of both plasma IL-6 and cortisol concentrations, but REM sleep decline with age is primarily associated with cortisol increases.
Article
While living under constant conditions and complete isolation from environmental time cues for about 4 weeks, 9 male subjects exercised on a bicycle ergometer seven times per 'day' during two weeks and refrained from physical activities during the other 2 weeks. The freerunning circadian rhythms of wakefulness and sleep and of rectal temperature showed, on the average, no difference between the two sections with regard to the autonomous period and the tendency towards internal desynchronization. Even in the one experiment in which the two rhythms became internally desynchronized, the periods of the rhythms remained unchanged during the time the subject worked on the bicycle. Only in one out of the nine subjects, the autonomous period was considerably longer under the influence of work than without it. The hypothesis is advanced that the period of an autonomous rhythm becomes normally independent of physical workload by way of a compensation mechanism.
Article
In previous studies, we found that many totally blind people have free-running melatonin rhythms, but that free-running melatonin rhythms were not necessarily associated with periodic insomnia and daytime sleepiness. Thus, it was not clear if the circadian sleep propensity rhythm was free-running with the other circadian rhythms. In the present study, we report that the sleep propensity rhythm (as defined by an ultrashort sleep-wake schedule) free-ran with the melatonin, temperature and cortisol rhythms in a 44-year-old totally blind man even though he maintained a conventional sleep schedule and did not complain of clinically significant insomnia or excessive daytime sleepiness.
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The relationship between the temporal organization of cortisol secretion and sleep structure is controversial. To determine whether the cortisol profile is modified by 4 hours of sleep deprivation, which shifts slow-wave sleep (SWS) episodes, 12 normal men were studied during a reference night, a sleep deprivation night and a recovery night. Plasma cortisol was measured in 10-minute blood samples. Analysis of the nocturnal cortisol profiles and the concomitant patterns of sleep stage distribution indicates that the cortisol profile is not influenced by sleep deprivation. Neither the starting time of the cortisol increase nor the mean number and amplitude of pulses was significantly different between the three nights. SWS episodes were significantly associated with declining plasma cortisol levels (p less than 0.01). This was especially revealed after sleep deprivation, as SWS episodes were particularly present during the second half of the night, a period of enhanced cortisol secretion. In 73% of cases, rapid eye movement sleep phases started when cortisol was reflecting diminished adrenocortical activity. Cortisol increases were not concomitant with a specific sleep stage but generally accompanied prolonged waking periods. These findings tend to imply that cortisol-releasing mechanisms may be involved in the regulation of sleep.
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Six healthy adult male volunteers underwent serial blood drawings at 4-hour intervals over 24 hours for the definition of melatonin (MT), prolactin (PRL), cortisol, and testosterone circadian patterns. Serum levels of triiodotironine (T3) and thyroxine (T4) were determined at 0800. Systolic and diastolic blood pressure and heart rate were automatically recorded every 30 minutes for 24 hours. The responses of luteinizing hormone (LH), follicle stimulating hormone (FSH), PRL, thyroid stimulating hormone (TSH), cortisol, and aldosterone to a stimulation test with gonadotrophin-releasing hormone (Gn-RH), thyrotrophin-releasing hormone (TRH), adrenocorticotrophin (ACTH), and testosterone to human chorionic gonadotrophin (HCG) were also evaluated. The same protocol was repeated after a two-month course of treatment with MT, 2 mg per os daily at 1800. After treatment, we recorded a marked elevation of mean serum MT levels with a significant phase-advance of its circadian rhythm. The 24-hour patterns of cortisol and testosterone displayed an anticipation of the morning acrophase of about 1.5 hour (not significant) for cortisol and three hours (P less than 0.05) for testosterone. PRL pattern was unchanged as well as serum levels of thyroid hormones. The circadian organization of the cardiovascular variables did not show any changes after MT supplementation; the pituitary, adrenal, and testicular responses to specific stimuli were comparable before and after treatment. These results are compatible with the view that the MT signal may provide temporal cues to the neuroendocrine network for the organization of testicular circadian periodicity.
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One-hundred and ninety-four children (11 +/- 1.5 years of age), 43 young adult subjects (21 +/- 2 years of age) and 149 elderly subjects studied in 278-24 hour profiles (77 +/- 8 years of age) were studied over one or several 24-hour spans. All subjects followed a diurnal activity pattern with rest during the night. Blood and urine were collected at 4-hour intervals over a 24-hour span (6 samples). The circadian rhythms of 22 endocrine parameters were explored in plasma and five in urine. In the children and the elderly subjects, the investigations extended over all four seasons allowing also the study of seasonal variations or circannual rhythms. The circadian rhythms were characterized by population mean cosinor for each group of subjects. The circannual rhythms were explored by single cosinor, by one and two way analysis of variance applied to the circadian means obtained during each season and by comparison of the circadian rhythm parameters obtained during the four seasons by the parameter test described by Bingham et al. Circadian rhythms were found in most and circannual rhythms in many parameters. The rhythm characteristics are presented as cosinor summaries and acrophase charts. Although there were certain differences in some rhythm parameters between the age groups, the elderly showed a remarkable maintenance of their circadian time structure. In the circannual frequency range, the elderly men showed more circannual periodicity as group phenomenon than the women. Many endocrine rhythms show high amplitude rhythms which have to be taken into account in the selection of the time for endocrine testing and in the interpretation of the results.
Article
The relationship of age to the circadian rhythms of melatonin and cortisol was investigated in 44 men and 27 women (age range 19-89 years). Subjects were physically and psychiatrically normal. Four hourly serial blood samples were drawn from 8:00 AM until 8:00 AM the next day, with additional samples at 10:00 PM and 2:00 AM. The indoor illumination was restricted to 300 lux during day and 50 lux during the night. Plasma melatonin and cortisol were estimated by radioimmunoassay. Results show that the means of melatonin and cortisol values decreased significantly with age when the subjects were divided into three age groups, i.e., 19-25 years, 42-65 years, and 66-89 years. They also showed a significant negative correlation with age. The acrophases of the two hormonal rhythms, however, showed different relationships to age. The acrophase of melatonin rhythm showed a positive correlation with age (r = 0.38, p less than 0.001), and cortisol showed a negative correlation with age (r = -0.56, p greater than 0.001). It is suggested that this may indicate a weakened responsiveness of the circadian system in the elderly to the day-night cycle and an altered relationship between the pacemakers driving melatonin and cortisol circadian rhythms. This may thus represent a biomarker for the intrinsic process of the aging of the brain.
Article
Using a recently developed model for investigating the neuroendocrine role of melatonin in man, we studied melatonin's effect on the nocturnal secretion of thyrotropin and cortisol in 17 normal male volunteers. The model consists of sleep in the dark and all-night sleep deprivation in conditions of: bright light with and without a melatonin infusion, and dim light. We have improved our infusion paradigm so that levels of melatonin during infusion are now indistinguishable from those occurring during sleep in the dark or dim light sleep deprivation. Sleep deprivation per se raised TSH levels compared to normal sleep. However, the three conditions of sleep deprivation could not be distinguished from each other, which suggests that the suppression of TSH by sleep (or the stimulation of TSH by sleep deprivation) is not mediated by melatonin. Cortisol secretion was unaffected by sleep deprivation regardless of melatonin's presence or absence. However, a difference in the pattern of secretion of cortisol in the sleep condition in the early morning (compared to the sleep deprivation conditions) was noted. These data do not implicate melatonin in the acute regulation of TSH or cortisol in normal man. These data also provide a method of melatonin infusion that replicates the pattern and levels seen in sleep.
Article
We studied the effect of age on the circadian rhythm of plasma cortisol in 34 normal subjects, aged 18-75 yr. Blood was sampled at 20-min intervals beginning at 2000 h, and the data were analyzed using the PULSAR program and the cosinor method. There was a negative correlation between age and the time of the maximum cortisol concentration (r = -0.548; P = 0.001), the time of the nadir cortisol concentration (r = -0.543; P = 0.001), and the acrophase (r = 0.528; P = 0.001). When the subjects were divided into those 39 yr of age and younger and 40 yr of age and older, the times of the cortisol nadir, maximum, and acrophase were significantly earlier in the older group. The interval between the nadir and peak cortisol levels was not significantly different, consistent with an age-related phase advance of the cortisol circadian rhythm. Quantitative indices of adrenal function, including the 24-h mean cortisol concentration and the number of cortisol peaks as well as their amplitude and duration, were not different in the two groups. There was a significant negative correlation between age and customary bedtime (r = -0.686; P = 0.001) that may explain, in part, the phase advance in the older subjects. This observation strengthens the evidence that sleep onset is a major factor contributing to synchronization of the cortisol rhythm. Alternative explanations are that age-related changes in the control of hormonal and other rhythms have important influences on sleep and activity schedules, or that sleep and cortisol variables do not influence each other, but are both the final expression of some central change.
Article
: Psychologic stress is known to be associated with both sleep disturbances and increased adrenocortical activity. In this experiment, 2 groups of male medical students were selected as poor or good sleepers on the basis of their responses to a sleep questionnaire. The poor sleepers had significantly greater levels of adrenocortical activity than did the good sleepers throughout the day and night. This difference was related to psychologic characteristics. The general level of activation of the central nervous system, largely reflecting one's personality and life situation, may determine one's usual sleep habits as well as the level of adrenocortical activity. Copyright (C) 1971 by American Psychosomatic Society
Article
Melatonin, produced by the pineal gland at night, has a role in regulation of the sleep-wake cycle. Among elderly people, even those who are healthy, the frequency of sleep disorders is high and there is an association with impairment of melatonin production. We investigated the effect of a controlled-release formulation of melatonin on sleep quality in 12 elderly subjects (aged 76 [SD 8] years) who were receiving various medications for chronic illnesses and who complained of insomnia. In all 12 subjects the peak excretion of the main melatonin metabolite 6-sulphatoxymelatonin during the night was lower than normal and/or delayed in comparison with non-insomniac elderly people. In a randomised, double-blind, crossover study the subjects were treated for 3 weeks with 2 mg per night of controlled-release melatonin and for 3 weeks with placebo, with a week's washout period. Sleep quality was objectively monitored by wrist actigraphy. Sleep efficiency was significantly greater after melatonin than after placebo (83 [SE 4] vs 75 [3]%, p < 0.001) and wake time after sleep onset was significantly shorter (49 [14] vs 73 [13] min, p < 0.001). Sleep latency decreased, but not significantly (19 [5] vs 33 [7] min, p = 0.088). Total sleep time was not affected. The only adverse effects reported were two cases of pruritus, one during melatonin and one during placebo treatment; both resolved spontaneously. Melatonin deficiency may have an important role in the high frequency of insomnia among elderly people. Controlled-release melatonin replacement therapy effectively improves sleep quality in this population.
Article
To define the chronobiology of glucose tolerance and insulin secretion in obesity, nine obese men and nine lean men were studied during constant glucose infusion for 53 h, including 8 h of nocturnal sleep, 28 h of continuous wakefulness, and 8 h of daytime sleep. Blood samples were collected at 20-min intervals to assay glucose, insulin, C-peptide, cortisol, and GH. Sleep was polygraphically monitored. Abnormal temporal profiles of glucose regulation were observed during wakefulness and sleep in obese subjects. During daytime hours, the normal profile of glucose tolerance was reversed, as an improvement, rather than a deterioration, was observed from morning to late evening. This reversal of the daytime pattern appeared to be caused by a dual defect in glucose regulation during the previous night. Indeed, during early sleep, GH secretion was markedly reduced, and the nocturnal rises of glucose and insulin secretion were dampened. During late sleep, obese subjects failed to suppress insulin secretion and plasma glucose, resulting in high morning levels. Comparisons of metabolic and hormonal patterns during nocturnal and daytime sleep suggest that the failure to suppress insulin secretion in late sleep may reflect a relative insensitivity of the beta-cell to acute inhibitory effects of cortisol in addition to insulin resistance.
Article
Changes in sleep-wake patterns are among the hallmarks of biological aging. Previously, we reported that impaired melatonin secretion is associated with sleep disorders in old age. In this study we investigated the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs. The study comprised a running-in, no-treatment period and four experimental periods. During the second, third and fourth periods, subjects were administered tablets for 7 consecutive days, 2 hours before desired bedtime. The tablets were either 2 mg melatonin administered as sustained-release or fast-release formulations, or an identical-looking placebo. The fifth period, which concluded the study, was a 2-month period of daily administration of 1 mg sustained-release melatonin 2 hours before desired bedtime. During each of these five experimental periods, sleep-wake patterns were monitored by wrist-worn actigraphs. Analysis of the first three 1-week periods revealed that a 1-week treatment with 2 mg sustained-release melatonin was effective for sleep maintenance (i.e. sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved by the fast-release melatonin treatment. Sleep maintenance and initiation were further improved following the 2-month 1-mg sustained-release melatonin treatment, indicating that tolerance had not developed. After cessation of treatment, sleep quality deteriorated. Our findings suggest that for melatonin-deficient elderly insomniacs, melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep.
Article
Polysomnographic sleep patterns and melatonin secretion were investigated in 10 patients (age: 41.3 +/- 9.5 years) who suffered from chronic primary insomnia and complained predominantly about difficulties in maintaining sleep and in five healthy controls (age 27.2 +/- 0.7 years). Nocturnal plasma melatonin concentrations were obtained hourly, measured by direct radioimmunoassay and statistically compared between insomniacs and controls with age as a covariate. Plasma melatonin levels in the patient group tended to begin increasing earlier in the evening and were significantly (P < or = 0.01) lower during the middle of the night (peak value 82.5 +/- 26.5 pg/ml) than in the healthy controls (peak value 116.8 +/- 13.5 pg/ml). Among the patients, the most severely reduced nocturnal plasma melatonin levels were found in those patients with a history of sleep disturbance lasting for longer than five years (N = 6; age 41.8 +/- 11.7 years; duration 15.3 +/- 5.9 years; peak value 72.1 +/- 25.0 pg/ml); whereas those chronic insomniacs affected for fewer than five years had relatively higher nocturnal levels (N = 4; age 40.6 +/- 6.5 years; duration 3.8 +/- 1.5 years; peak value 98.2 +/- 23.9 pg/ml). These results show that the circadian rhythm of melatonin secretion is disturbed in patients with chronic primary insomnia, and that the nocturnal plasma melatonin secretion is increasingly more affected the longer the patients are unable to maintain a regular sleep pattern.
Article
Prolonged hypothalamic-pituitary-adrenocortical (HPA) axis overactivity occurs at all levels of this axis during stress in normals and some depressed patients. This can induce enlargement of the pituitary and adrenals. Various reports showed that cortisol can affect mood and behavior, and disrupt memory and recall. The integrity of the hippocampus is essential for memory function and, via the high density of its cortisol receptors, cortisol induced inhibitory feedback to the HPA axis. Animal data suggest that over time aging and stress can permanently downregulate hippocampal cell receptors, produce chronic hippocampal inflammation (astroglial), and kill cells. Cushing's syndrome patients (high cortisol) show diminished hippocampal size and verbal recall inversely related to cortisol levels. All the above is consistent with the 'cascade hypothesis' of cortisol induced hippocampal damage with resultant diminished inhibition to HPA hyperactivity in a circular manner. High cortisol is associated with altered neurotransmitter function, e.g., diminished brain serotonin synthesis, low CSF 5HIAA, and increased noradrenergic activity.
Article
Interactions between the hypothalamic-pituitary-adrenocortical (HPA) system and melatonin secretion have been demonstrated, but only the effects of melatonin on the activity of the HPA system have been studied in man. Alterations of melatonin secretion described as low-melatonin syndrome have been demonstrated in patients suffering from a major depressive episode, and an inhibitory factor on melatonin secretion has been postulated. We investigated whether corticotropin-releasing hormone (CRH), which is thought to be involved in HPA abnormalities in depressed patients, can also suppress melatonin secretion in healthy volunteers. Ten healthy male human volunteers in a double-blind study design received randomized hourly intravenous injections from 08.00 to 18.00 h that contained 10 micrograms human CRH, 1 microgram adrenocorticotropic hormone (ACTH), or placebo to simulate pulsatile hormone secretion. Plasma melatonin and cortisol responses during the treatment and nocturnal sleep electroencephalograms after the treatment were recorded. Administration of CRH reduced melatonin secretion significantly below values obtained after administration of placebo and ACTH. Cortisol secretion was significantly enhanced by ACTH in comparison to both placebo and CRH. Electroencephalographic sleep parameters revealed no treatment effects. Our findings suggest that CRH has an inhibitory effect on the pineal secretion of melatonin in normal man. A mechanism via a release of cortisol was not supported by our results. Secondary hormonal effects from changes in nocturnal sleep architecture were excluded. Further investigation of the action of CRH on melatonin secretion as well as the mutual feedback between the HPA system and the pineal gland may extend our knowledge of neuroendocrine alterations mediating the adaptive response to stress and the eventual involvement in the pathogenesis of depression.
Article
Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The present data suggest, however, that although sleep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.
Article
The authors' goal was to examine the hypnotic effects of slow-release melatonin during the initial 4 weeks of treatment with fluoxetine in 19 patients with major depressive disorder. Twenty-four outpatients with major depressive disorder were included in the study; 19 completed the study. Ten patients were treated with fluoxetine plus slow-release melatonin and nine were given fluoxetine plus placebo in a double-blind protocol for 4 weeks. Response was assessed by using rating scales for depression and sleep. The 10 patients given slow-release melatonin reported significantly better scores on the Pittsburgh Sleep Quality Index than the nine patients given placebo. No significant differences in the rate of improvement in depressive symptoms were noted between the two groups. No particular side effects were noted from the combination of fluoxetine and slow-release melatonin. Slow-release melatonin was effective in improving the sleep of patients with major depressive disorder. Slow-release melatonin had no effect on the rate of improvement in symptoms of major depressive disorder. The authors conclude that the role of slow-release melatonin for sleep disturbances in major depressive disorder should be investigated further.
Article
The aim of this study was to assess whether there is an association between chronic insomnia and the activity of the stress system. Fifteen young adult insomniacs (<40 years) were studied. After an adaptation night, each subject was recorded in the sleep laboratory for three consecutive nights. During this period, 24-hour urine specimens were collected for measurements of urinary free cortisol (UFC), catecholamines, and growth hormone (GH). The 24-hour UFC levels were positively correlated with total wake time (p=0.05). In addition, 24-hour urinary levels of catecholamine metabolites, DHPG, and DOPAC were positively correlated with percent stage 1 sleep (p<0.05) and wake time after sleep onset (WTASO) (p<0.05). Norepinephrine tended to correlate positively with percent stage 1 sleep (p=0.063) and WTASO (p=0.074), and negatively with percent slow-wave sleep (p=0.059). Twenty-four-hour urinary GH excretion was detectable in only three insomniacs, two of whom had low indices of sleep disturbance. We conclude that, in chronic insomnia, the activity of both limbs of the stress system (i.e., the HPA axis and the sympathetic system) relates positively to the degree of objective sleep disturbance.
Article
With the advent of RIAs capable of measuring the melatonin onset (60), the DLMO has been increasingly utilized as a marker for the phase of the ECP. Measurement of melatonin not only helps assess circadian phase but also has been important in developing the use of bright light to assess light sensitivity, as well as to shift the ECP in the treatment of circadian phase disorders. Physiological doses of melatonin have been used to describe a PRC that is about 12 hours out of phase with the PRC to light. Melatonin treatment of winter depression may eventually provide conclusive proof of the PSH for this disorder. One function of endogenous melatonin may be to augment entrainment of the ECP by the light/dark cycle. Another function may be to serve as a nighttime darkness discriminator. The fact that melatonin is generally made only at night and can be suppressed by light have been the guiding principles behind these developments. The early studies were also made possible because of the highly accurate and sensitive GCMS assay for melatonin (61).
Article
Accumulating evidence indicates decreased melatonin levels in patients with schizophrenia. Insomnia, mainly difficulty in falling asleep at night, is commonly reported in this population. Association of insomnia with low or abnormal melatonin rhythms has been repeatedly documented. Melatonin is an endogenous sleep promoter in humans. We hypothesized that insomnia in patients with schizophrenia may be partially due to diminished melatonin output. In this study, we measured melatonin output in patients with chronic schizophrenia and assessed the effects of melatonin replacement on their sleep quality. In a randomized, double-blind, cross-over, clinically based trial, 19 patients with DSM-IV schizophrenia who were treated with the normal treatment regimen were given melatonin (2 mg, controlled release) or placebo for 2 treatment periods of 3 weeks each with 1 week washout between treatment periods (7 weeks total). For measuring endogenous melatonin production, urine was collected from each patient every 3 hours between 9:00 p.m. and 9:00 a.m. Actigraphy was performed for 3 consecutive nights at the end of each period. Activity- and rest-derived sleep parameters were compared for the whole population with treatment arm as the intervening variable. A separate analysis was performed for patients subgrouped into high versus low sleep efficiency. All patients had low melatonin output. Melatonin replacement significantly improved rest-derived sleep efficiency compared with placebo (83.5% vs. 78.2%, p = .038) in this population. Improvement of sleep efficiency was significantly greater (p < .0014) in low-efficiency (80% vs. 67%) than high-efficiency sleepers (88% vs. 90%). In addition, during melatonin therapy, tendencies toward shortened sleep latency (by 40 minutes, p < .056) and increased sleep duration (by 45 minutes, p < .078) were observed in low- but not high-efficiency sleepers. Melatonin improves sleep efficiency in patients with schizophrenia whose sleep quality is low.
Article
The objective of this study was to evaluate the effects of nocturnal sleep, partial night sleep deprivation, and sleep stages on circulating concentrations of interleukin-6 (IL-6) in relation to the secretory profiles of GH, cortisol, and melatonin. In 31 healthy male volunteers, blood samples were obtained every 30 min during 2 nights: uninterrupted, baseline sleep and partial sleep deprivation-early night (awake until 0300 h). Sleep was measured by electroencephalogram polysomnography. Sleep onset was associated with an increase in serum levels of IL-6 (P < 0.05) during baseline sleep. During PSD-E, the nocturnal increase in IL-6 was delayed until sleep at 0300 h. Sleep stage analyses indicated that the nocturnal increase in IL-6 occurred in association with stage 1-2 sleep and rapid eye movement sleep, but levels during slow wave sleep were not different from those while awake. The profile of GH across the 2 nights was similar to that of IL-6, whereas the circadian-driven hormones cortisol and melatonin showed no concordance with sleep. Loss of sleep may serve to decrease nocturnal IL-6 levels, with effects on the integrity of immune system functioning. Alternatively, given the association between sleep stages and IL-6 levels, depressed or aged populations who show increased amounts of REM sleep and a relative loss of slow wave sleep may have elevated nocturnal concentrations of IL-6 with implications for inflammatory disease risk.
Article
The first-night effect (FNE) is the tendency for individuals to sleep worse than normal during their first night of polysomnographic sleep evaluation. FNE reflects the adaptive increase of alertness and perhaps the stress resulting from an unfamiliar sleeping environment. This effect is usually absent in patients with chronic schizophrenia. Melatonin (N-acetyl-5-methoxy-tryptamine), the hormone secreted by the pineal gland at night, has been found to improve sleep in elderly patients with insomnia and recently in patients with chronic schizophrenia. The authors used FNE as a marker to explore the neurobehavioral responses of patients with chronic schizophrenia to melatonin treatment. In a randomized, double-blind, crossover trial, 14 patients with chronic schizophrenia were administered melatonin (2 mg in a controlled-release formulation) or placebo for 3 weeks with a 1-week washout between treatment periods. Polysomnography was performed during the last two consecutive nights of each treatment period. The following significant FNEs were observed with melatonin treatment: (1) rapid eye movement sleep latency was longer; (2) sleep efficiency was lower; and (3) the duration of wakefulness during sleep was lower on the first night than on the second night. These effects were not found when the patients received a placebo. The FNE was manifested regardless of whether melatonin was administered before or after the placebo treatment period. For the first time, these results show that melatonin treatment exaggerates FNE in patients with chronic schizophrenia, thereby suggesting an improved ability of these patients to mobilize alertness in unfamiliar surroundings.
Article
Using a 10-min blood sampling procedure, we established 24-h plasma melatonin and cortisol rhythms in 11 night workers and determined whether the extent in the shift of the melatonin onset, highly variable among night workers, was reflected in the shift of the markers of the cortisol rhythm, i.e. the quiescent period of secretion and the acrophase. In all day-active subjects, the melatonin onset occurred during low cortisol secretion, with a time lag between the start of the quiescent period and the melatonin onset of 1 h 28+or-27 min. In night workers, whatever the shift of the melatonin surge, the start of the quiescent period of cortisol secretion remained phase locked to the melatonin onset with a similar time lag (1 h 25+or-27 min). There was a significant correlation between the timing of the melatonin onset and the timing of the start of the quiescent period (r=0.88; P=0.0072). No preserved time lag was found between the melatonin onset and the other cortisol phase markers, either with the end of the quiescent period or with the acrophase. These results settle the start of the quiescent period of cortisol and the melatonin onset as two coordinate markers, and suggest that each of them are reliable to assess circadian phase in humans.
Article
Recent research provides evidence for an interaction between sleep and the activation of the hypothalamic-pituitary-adrenal (HPA)-axis, but detailed studies in patients are still missing. We investigated hourly evening and nocturnal plasma cortisol secretion and sleep in seven male patients with severe chronic primary insomnia and age- and gender-matched controls. Evening and nocturnal cortisol levels were significantly increased in patients. Evening cortisol correlated with the number of nocturnal awakenings in patients and controls. Additionally, patients showed significant correlations between sleep parameters and the first 4 h of nocturnal cortisol secretion. These results are indicative of changes in the HPA system in insomnia and may reflect a pathophysiological mechanism of chronic insomnia resulting in a vicious cycle of both disturbed HPA functions and chronic insomnia according to the arousal hypothesis of insomnia.
Article
In a previous longitudinal study of basal cortisol levels and cognitive function in humans, we showed that elderly humans with 4- to 7-yr cumulative exposure to high levels of cortisol present memory impairments, compared with elderly humans with moderate cortisol levels over years. Here, we measured whether memory performance in two groups of elderly humans separated on the basis of their cortisol history over a 5-yr period could be modulated by a hormone-replacement protocol in which we inhibited cortisol secretion by the administration of metyrapone and then restored baseline cortisol levels by infusion of hydrocortisone. We showed that in elderly subjects with a 5-yr history of moderate cortisol levels (n = 8), metyrapone treatment significantly impaired memory performance, a deficit that was reversed following hydrocortisone replacement. In the elderly subjects with a 5-yr history of high cortisol levels and current memory deficits (n = 9), metyrapone treatment did not have any significant effect on memory performance, but hydrocortisone treatment significantly decreased delayed memory. These results suggest that memory function in elderly humans can be intensely modulated by pharmacological manipulation of glucocorticoids, although the direction of these effects depends on the cortisol history of each individual.
Article
The present study investigated evening and nocturnal serum cortisol and melatonin concentrations in patients with primary insomnia to test if this clinical condition is accompanied by an increase of cortisol secretion and a simultaneous decrease of nocturnal melatonin production. Ten drug-free patients (4 males, 6 females) with primary insomnia (mean age+/-S.D.: 39.2+/-9.1 years) and 10 age- and gender-matched healthy controls participated in the study. All subjects spent three consecutive nights in the sleep laboratory with polysomnography. Measurement of cortisol and melatonin (from 19:00 h to 09:00 h) was performed prior to and during the last laboratory night. Contrary to expectation, cortisol secretion did not differ between healthy controls and insomniac patients. On the other hand, nocturnal melatonin production was significantly diminished in insomniac patients. Polysomnographically determined sleep patterns, in contrast to subjective ratings of sleep, demonstrated only minor alterations of sleep in the insomniac group. The lack of increased cortisol secretion in the patients with primary insomnia indicates that results from studies on the biological consequences of experimental sleep loss in healthy subjects cannot be applied to primary insomnia in general, especially if there are only minor objective sleep alterations. In spite of the negligible objective sleep disturbances in the present sample, nocturnal melatonin production was reduced, which tentatively suggests a role for this hormone in primary insomniacs. The pathophysiological significance of this finding is, however, still a matter of debate.
Article
The effects of night-time exposure to traffic noise (TN) or low frequency noise (LFN) on the cortisol awakening response and subjective sleep quality were determined. Twelve male subjects slept for five consecutive nights in a noise-sleep laboratory. After one night of acclimatisation and one reference night, subjects were exposed to either TN (35dB L(Aeq), 50dB L(Amax)) or LFN (40dB L(Aeq)) on alternating nights (with an additional reference night in between). Salivary free cortisol concentration was determined in saliva samples taken immediately at awakening and at three 15-minute intervals after awakening. The subjects completed questionnaires on mood and sleep quality. The awakening cortisol response on the reference nights showed a normal cortisol pattern. A significant interaction between night time exposure and time was found for the cortisol response upon awakening. The awakening cortisol response following exposure to LFN was attenuated at 30 minutes after awakening. Subjects took longer to fall asleep during exposure to LFN. Exposure to TN induced greater irritation. Cortisol levels at 30 minutes after awakening were related to "activity" and "pleasantness" in the morning after exposure to LFN. Cortisol levels 30 minutes after awakening were related to sleep quality after exposure to TN. This study thus showed that night time exposure to LFN may affect the cortisol response upon wake up and that lower cortisol levels after awakening were associated with subjective reports of lower sleep quality and mood.
Article
The hypothalamo-pituitary-adrenal (HPA) system is a most important mediator of the organism's response to stress. Secretory activity of this endocrine system displays a specific regulation during normal nocturnal sleep in humans. Pituitary release of adrenocorticotropin (ACTH) as well as adrenocortical release of cortisol decreases to a minimum during early sleep which is simultaneously characterized by maximum release of growth hormone (GH) and a predominance of slow wave sleep (SWS). In contrast, release of ACTH and cortisol reaches a maximum during late sleep which is simultaneously characterized by minimum plasma concentrations of GH and a predominance of rapid eye movement (REM) sleep. The nadir activity of the pituitary-adrenal system during early sleep reflects an active inhibition of this 'stress' system. One of the factors mediating this inhibition presumably is the sleep associated hypothalamic secretion of a release inhibiting factor of ACTH. In addition, limbic-hippocampal neuronal networks contribute to the inhibitory control over HPA activity during early sleep. Those structures appear to coordinate HPA inhibition and cortical activity (with prevalent SWS) during early sleep, thereby facilitating the formation of memories in sleep. As indicated by studies testing the effects of elevated plasma glucocorticoid levels, the inhibition of HPA activity during early sleep is an essential prerequisite for the memory function of sleep. Possibly, immunological memory formation likewise benefits from this inhibition. The suppression of pituitary-adrenal secretory activity during early sleep can be significantly weakened after profound acute stress as well as in states of chronic stress (including normal aging) which thereby disturb regular memory formation in sleep.
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