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The relationship between melatonin and cortisol rhythms: Clinical implications of melatonin therapy
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.
... 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. ...
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.
... It is worth noting that prior to exercise, the treated group exhibited lower cortisol levels compared to the control group. This observation aligns with the inversely proportional relationship between cortisol and melatonin, wherein elevated melatonin corresponds to diminished cortisol levels (Zisapel et al., 2005). The temporal dynamics of these hormones are elucidated by research that highlights the precedence of plasma cortisol surge before the decline in plasma melatonin concentration, accentuating the intertwined relationship (Monteleone et al., 1992). ...
... In addition, the finding that cortisol levels decreased post-exercise in the treated group could be attributed to the temporal relationship between cortisol and melatonin (Zisapel et al., 2005). It is possible that the melatonin supplementation in the treated group helped to balance the cortisol levels after exercise, leading to a decrease in cortisol levels compared to the control group. ...
... 17 However, the effect of melatonin on cortisol rhythm and production is still inconclusive as previous studies reported melatonin to either increase, decrease, or have no effect on cortisol levels. Zisapel et al. 18 reported that administration of exogenous melatonin for a week delayed the endogenous cortisol rhythm in the elderly with insomnia. While an experiment on fibromyalgia patients found 9 mg of melatonin administration for 10 days reduced urinary cortisol levels. ...
... 15 Melatonin might not simply affect sCort levels in terms of stress reduction but it could also modulate the rhythm of sCort secretion or cortisol awakening response or cortisol slope throughout the 24-h diurnal pattern. 18 As the change in circadian rhythm affected cortisol awakening response, 33 it could be possible that melatonin administration at a particular time point as in the current study shifted the diurnal rhythm of sCort. Also, an increase in sCort level does not always mean more stress as an increase in cortisol awakening response possibly reflects better sensitivity to coping with stress during the day. ...
This study aimed to examine the effect of acute exogenous melatonin administration on salivary cortisol and alpha‐amylase (sCort and sAA) as representatives of the HPA axis and the sympathetic nervous system, respectively. A single‐dose prolonged‐release melatonin (2 mg) or a placebo tablet was given to healthy volunteers (n = 64) at 20:00 h in a crossover design. The saliva was collected at six time points (20:00, 21:00, awakening, 30 min after awakening, 10:00, and 12:00 h) and was measured for sCort, sAA, and salivary melatonin (sMT) levels. Pulse rates and sleep parameters were also collected. Melatonin was effective in improving sleep onset latency by 7:04 min (p = .037) and increasing total sleep time by 24 min (p = .006). Participants with poor baseline sleep quality responded more strongly to melatonin than participants with normal baseline sleep quality as they reported more satisfaction in having adequate sleep (p = .017). Melatonin administration resulted in higher sCort levels at awakening time point (p = .023) and a tendency of lower sAA levels but these were not significant. Melatonin ingestion at 20:00 h resulted in a marked increase in sMT levels at 21:00 h and remained higher than baseline up to at least 10:00 h (p < .001). Melatonin increases sCort levels at certain time point with a tendency to lower sAA levels. These opposing effects of melatonin suggested a complex interplay between melatonin and these biomarkers. Also, the results confirmed the positive acute effect of a single‐dose melatonin on sleep quality.
... 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). ...
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.
... 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). ...
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.
... 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. ...
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.
... In individuals with alcohol use disorder, acute ethanol withdrawal causes altered plasma melatonin and cortisol concentrations with loss of circadian periodicity [199]. As people age, melatonin production declines and the peak shifts to late-night hours, whereas cortisol production increases, peaking earlier in the night, exacerbating sleep difficulties [200]. Melatonin can be potentially used for the management of substance use disorders because of its anti-inflammatory, analgesic, and neuroprotective properties via influencing gut microbiota and epigenetic modifications [201]. ...
Substance use disorder is a major global health concern, with a high prevalence among adolescents and young adults. The most common substances of abuse include alcohol, marijuana, cocaine, nicotine, and opiates. Evidence suggests that a mismatch between contemporary lifestyle and environmental demands leads to disrupted circadian rhythms that impair optimal physiological and behavioral function, which can increase the vulnerability to develop substance use disorder and related problems. The circadian system plays an important role in regulating the sleep–wake cycle and reward processing, both of which directly affect substance abuse. Distorted substance use can have a reciprocal effect on the circadian system by influencing circadian clock gene expression. Considering the detrimental health consequences and profound societal impact of substance use disorder, it is crucial to comprehend its complex association with circadian rhythms, which can pave the way for the generation of novel chronotherapeutic treatment approaches. In this narrative review, we have explored the potential contributions of disrupted circadian rhythms and sleep on use and relapse of different substances of abuse. The involvement of circadian clock genes with drug reward pathways is discussed, along with the potential research areas that can be explored to minimize disordered substance use by improving circadian hygiene.
... Considering all nurses, a negative correlation was also observed between salivary morning cortisol levels and morning melatonin levels. These reported observations are in line with existing scientific evidence [52]. Indeed, as shown in Supplementary Figure S2, within the nurse population, a small subgroup of 12 subjects (12% of the total) with high cortisol and low melatonin who might be considered at higher potential risk of developing stress and/or sleep disturbances could be identified. ...
Currently, about one in five workers is employed in night shift work in Europe. Shift work including nighttime hours is essential in several activities, especially the healthcare sector. Importantly, night working may be associated with the occurrence of sleep disorders or work-related stress, both potentially augmenting the risk of errors and accidents at work. This study aims to examine the presence of neurobehavioral alterations that can be a consequence of shift working and concurrent misalignment of the sleep times and circadian rhythms. Nurses (n = 102) employed at a University Hospital located in North-Eastern Sicily, Italy, voluntarily participated in this pilot study. During medical surveillance, morning and evening salivary samples were collected, and seven psychodiagnostics questionnaires were administered to all the subjects. On one hand, the salivary levels of stress-related biomarkers (cortisol and alpha-amylase) and a circadian biomarker (melatonin) were evaluated. On the other hand, several neurobehavioral features were assessed, including depression, anxiety, work-related, and sleep issues. Interestingly, a positive relationship between salivary morning cortisol and depression scale, as well as a negative relationship between salivary morning alpha-amylase and work ability scale, were observed. Based on these results, the integration of subjective questionnaire outcomes and objective salivary biomarker quantification can help to identify workers with increased susceptibility to developing neurobehavioral alterations. This approach may contribute to ameliorating preventive strategies towards sensitive categories, such as nurses working rotation shifts.
... The CAR usually lasts for about 30-45 minutes immediately after waking. Thereafter, cortisol levels decrease throughout the day, to half of its peak value in the afternoon, with the lowest production at midnight (84). ...
Stress is viewed as a state of real or perceived threat to homeostasis, the management of which involves the endocrine, nervous, and immune systems. These systems work independently and interactively as part of the stress response. The scientific stress literature, which spans both animal and human studies, contains heterogeneous findings about the effects of stress on the brain and the body. This review seeks to summarise and integrate literature on the relationships between these systems, examining particularly the roles of physiological and psychosocial stress, the stress hormone cortisol, as controlled by the hypothalamic-pituitary-adrenal (HPA) axis, and the effects of stress on cognitive functioning. Health conditions related to impaired HPA axis functioning and their associated neuropsychiatric symptoms will also be considered. Lastly, this review will provide suggestions of clinical applicability for endocrinologists who are uniquely placed to measure outcomes related to endocrine, nervous and immune system functioning and identify areas of intervention.
... Melatonin and cortisol are well-known circadian rhythm-related hormones that have opposite functions toward sleep [45]. However, when stress activates the hypothalamicpituitary-adrenal axis leading to high levels of serum cortisol in humans, melatonin release is suppressed and its antioxidant mechanism is impaired, which can then cause neuronal mitochondrial dysfunction and is related to numerous neurodegenerative diseases [46][47][48]. Consistent with these studies, this study revealed that glucocorticoid-induced mitophagy impairment and mitochondrial dysfunction, followed by neuronal cell apoptosis, were well reversed by melatonin treatment in both SH-SY5Y cells and mouse hippocampal tissue. ...
The physiological crosstalk between glucocorticoid and melatonin maintains neuronal homeostasis in regulating circadian rhythms. However, the stress-inducing level of glucocorticoid triggers mitochondrial dysfunction including defective mitophagy by increasing the activity of glucocorticoid receptors (GRs), leading to neuronal cell death. Melatonin then suppresses glucocorticoid-induced stress-responsive neurodegeneration; however, the regulatory mechanism of melatonin, i.e., associated proteins involved in GR activity, has not been elucidated. Therefore, we investigated how melatonin regulates chaperone proteins related to GR trafficking into the nucleus to suppress glucocorticoid action. In this study, the effects of glucocorticoid on suppressing NIX-mediated mitophagy, followed by mitochondrial dysfunction, neuronal cell apoptosis, and cognitive deficits were reversed by melatonin treatment by inhibiting the nuclear translocation of GRs in both SH-SY5Y cells and mouse hippocampal tissue. Moreover, melatonin selectively suppressed the expression of FKBP prolyl isomerase 4 (FKBP4), which is a co-chaperone protein that works with dynein, to reduce the nuclear translocation of GRs among the chaperone proteins and nuclear trafficking proteins. In both cells and hippocampal tissue, melatonin upregulated melatonin receptor 1 (MT1) bound to Gαq, which triggered the phosphorylation of ERK1. The activated ERK then enhanced DNA methyltransferase 1 (DNMT1)-mediated hypermethylation of FKBP52 promoter, reducing GR-mediated mitochondrial dysfunction and cell apoptosis, the effects of which were reversed by knocking down DNMT1 . Taken together, melatonin has a protective effect against glucocorticoid-induced defective mitophagy and neurodegeneration by enhancing DNMT1-mediated FKBP4 downregulation that reduced the nuclear translocation of GRs.
... It reaches its peak at the midpoint of the sleeping period, then bright light firmly decreases melatonin levels and promotes cortisol production by the adrenocorticotropic hormone (ACTH) via an independent sympathetic mechanism. 39 The consequence of the activation of the hypothalamic-pituitary-adrenal axis is a daily rhythmic production of ACTH and a slow decrease during the day, reaching its nadir at the beginning of the sleeping phase. An increasing pattern between 2 AM and 4 AM is shown to lead to a maximal hormonal rise from the adrenal gland in the morning, which provokes vigilance and initiates catabolic processes in adipose and muscle cells. ...
Circadian rhythm refers to the daily physiologically fluctuating patterns of systemic processes that occur within a circa 24-hour timeframe, independently of external factors. There is evidence that in time, external and internal cycle misalignment leads to severe health consequences, resulting in the development of cardiometabolic disturbances. Desynchronized hormonal fluctuations along with daily specific macronutrient utilization patterns are also discussed, which by consequence, are all predictors of metabolic syndrome. The aim of this paper is to provide insight on the circadian clock’s organization throughout the human body and to explain the underlying genetic background. By understanding these well-established molecular mechanisms and processes, we believe this paper will provide accuracy regarding the importance of the circadian clock’s integrity and will highlight its role in the etiopathology of cardiometabolic syndrome.
... Cortisol, like melatonin, plays an important role in the human circadian system [1]. It is an essential hormone, synthesized by the cortex of the adrenal gland and regulated via the hypothalamic-pituitary-adrenal (HPA) axis [2][3][4], that is associated with waking, alertness, and stress response [5]. ...
Cortisol secretion has a fundamental role in human circadian regulation. The cortisol awakening response (CAR) can be observed as a daily recurring sharp increase in cortisol concentration within the first hour after awakening and is influenced by environmental light conditions. The current work provides the study protocol for an ongoing research project that is intended to explore the spectral dependencies and to discuss measures of emotional state and cognitive functioning potentially related to the CAR. Based on a controlled within-subjects sleep laboratory study, the impact of a two-hour, (quasi-)monochromatic, post-awakening light exposure of different peak wavelength (applied from 6:00 to 8:00 am) on resulting CAR levels should be investigated in a systematic manner to eventually derive a corresponding spectral sensitivity model. As a secondary outcome, it should be explored whether a potentially light-enhanced cortisol secretion might also impact different measures of sleepiness, mood, and vigilance for certain wavelengths. The study protocol described in the present work discusses the various protocol steps using pilot data collected for two different wavelength settings (i.e., short-wavelength blue-light at λmax = 476 nm and long-wavelength red-light at λmax = 649 nm) experienced by a group of four healthy male adults at an average ± SD age of 25.25 ± 3.59 years.
... When the melatonin concentration rises at night, the cortisol concentration is reduced to its trough values, and when the cortisol concentration reaches its peak value in the early morning, the melatonin concentration drops to its lowest. It is well known that abnormal concentration-time profiles of melatonin and cortisol rhythm results in problems with sleep [14]. Interestingly, the GI tract is the greatest source of extra-pineal melatonin, where it is synthesized by the enterochromaffin cells [15]. ...
A well-functional intestinal mucosal barrier can be compromised as a result of various diseases, chemotherapy, radiation, and chemical exposures including surfactants. Currently, there are no approved drugs targeting a dysfunctional intestinal barrier, which emphasizes a significant medical need. One candidate drug reported to regulate intestinal mucosal permeability is melatonin. However, it is still unclear if its effect is primarily receptor mediated or antioxidative, and if it is associated with enteric neural pathways. The aim of this rat intestinal perfusion study was to investigate the mechanisms of melatonin and nicotinic acetylcholine receptors on the increase in intestinal mucosal clearance of 51Cr-labeled ethylenediaminetetraacetate induced by 15 min luminal exposure to the anionic surfactant, sodium dodecyl sulfate. Our results show that melatonin abolished the surfactant-induced increase in intestinal permeability and that this effect was inhibited by luzindole, a melatonin receptor antagonist. In addition, mecamylamine, an antagonist of nicotinic acetylcholine receptors, reduced the surfactant-induced increase in mucosal permeability, using a signaling pathway not influenced by melatonin receptor activation. In conclusion, our results support melatonin as a potentially potent candidate for the oral treatment of a compromised intestinal mucosal barrier, and that its protective effect is primarily receptor-mediated.
... An example of these types of medications could be Melatonin. In the literature, it has been indicated that excessive cortisol secretions associated with Cushing's disease may lead to an irregular Melatonin rhythm (Zisapel et al., 2005;James et al., 2007). So, taking the advantages of Melatonin in improving sleep cycles, we can suggest using this medication for inhibitory effects. ...
Hypercortisolism or Cushing's disease, which corresponds to the excessive levels of cortisol hormone, is associated with tiredness and fatigue during the day and disturbed sleep at night. Our goal is to employ a wearable brain machine interface architecture to regulate one's energy levels in hypercortisolism. In the present simulation study, we generate multi-day cortisol profile data for ten subjects both in healthy and disease conditions. To relate an internal hidden cognitive energy state to one's cortisol secretion patterns, we employ a state-space model. Particularly, we consider circadian upper and lower bound envelopes on cortisol levels, and timings of hypothalamic pulsatile activity underlying cortisol secretions as continuous and binary observations, respectively. To estimate the hidden cognitive energy-related state, we use Bayesian filtering. In our proposed architecture, we infer one's cognitive energy-related state using wearable devices rather than monitoring the brain activity directly and close the loop utilizing fuzzy control. To model actuation in the real-time closed-loop architecture, we simulate two types of medications that result in increasing and decreasing the energy levels in the body. Finally, we close the loop using a knowledge-based control approach. The results on ten simulated profiles verify how the proposed architecture is able to track the energy state and regulate it using hypothetical medications. In a simulation study based on experimental data, we illustrate the feasibility of designing a wearable brain machine interface architecture for energy regulation in hypercortisolism. This simulation study is a first step toward the ultimate goal of managing hypercortisolism in real-world situations.
... Advanced age, neuro-degenerative diseases, diabetic neuropathy, brain tumors, Alzheimer's disease and administration of some drugs i.e. β-blockers and non steroid anti-inflammatory drugs inhibit melatonin synthesis at night and can cause sleep disorders (85,63). Day-time intake of melatonin when its endogenous rate of production is almost absent induces events such as fatigue and sleepiness seen in early night time in response to the physiological dim-light melatonin onset (86)(87)(88).The sleeppromoting effects of melatonin appears about 2 hours after exogenous administration which is in line with the physiological sequence at night caused by endogenous melatonin -heat loss, reduced arousal activity and delay in cortisol secretion (89)(90)(91)(92). In addition, exogenous melatonin intake induces similar architecture of sleep as during natural sleep detected by EEG (89). ...
Sleep and wakefulness are two main types of human and animal behavior. On the average human beings spend about one-third of their lives asleep. The sleep-wake cycle is the most important circadian rhythms which alternates in a periodic manner lasting for about 24 hours. Sleep is determined as the natural periodic suspension of consciousness characterized by relative immobility
and reduced responsiveness to external stimuli. The researchers have found and identified many special brain structures and systems controlling waking, rapid eye movement (REM) sleep and nonrapid eye (NREM) sleep and the transitions among these states. Currently, there is an enhanced interest of researchers toward sleep and its neurophysiological mechanisms of regulation because the number of people suffering from various sleep disturbance such
as insomnia, delayed sleep onset, duration and propensity of sleep, worldwide dramatically increases. In addition to the next day drowsiness, nervousness, tiredness and decreased workability, it has been suggested that sleep is important also for the maintaining of mood, memory and cognitive function of
the brain and is essential for the normal functioning of the endocrine and immune systems. More recently, new studies show a sustained link between sleep disorders and different serious health problems, including obesity, insulin resistance, type 2 diabetes mellitus, cardio-vascular diseases and
depression.
Therefore, the purpose of this review is to summarize and analyze the available data about the neurological control of wakefulness, non-rapid-eye-movement (NREM) sleep and rapid- eyemovement (REM) sleep creating a substantial basis for better understanding different sleep disorders.
Special attention is paid on the pharmacological aspects and use of some new classes of sleep promoting agents – melatonin, melatonin receptor agonists and orexin receptor antagonists.
... 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. ...
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.
... 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]. ...
Background:
Circadian rhythm plays an important role as our internal body's clock that synchronizes behavior and physiology according to the external 24-h light-dark cycle. Past studies have associated disrupted circadian rhythm with higher risk of miscarriages, preterm birth and low birth weights. This paper described the protocol of a prospective cohort study which aims to determine the circadian rhythm in pregnant women, identify its association with maternal factors during pregnancy, gestational weight gain, birth and infant outcomes.
Methods:
Ten government maternal and child health clinics in Kuala Lumpur, Malaysia will be randomly selected. Sample size of 438 first-trimester pregnant women will be followed-up until the birth of their infant. Salivary melatonin and cortisol concentration among subsample will be determined using enzyme-linked immunosorbent assay. Data on sleep quality, psychological distress and morningness/eveningness chronotype of pregnant women will be collected using validated questionnaires. Pedometer will be used to measure 5-day physical activity data. Total gestational weight gain will be determined at the end of pregnancy. Utilization of 3-day food record is to capture meal timing and nutrient intake. All measurements will be done in 2nd and 3rd trimester. Birth outcomes will be collected through clinic records and Centers for Disease Control and Prevention (CDC) Neonatal questionnaire. Infants will be followed-up at 6 and 12 months old to obtain anthropometric measurements.
Discussion:
There is a growing recognition of the role of maternal circadian rhythm, which entrains fetal circadian rhythms that may subsequently have long-term health consequences. The present study will identify the effect of circadian rhythm on pregnancy outcomes and infant growth in the first year of life.
... 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). ...
Melatonin and cortisol are the main hormones of the circadian rhythm, which effect cognitive decline during aging. An imbalance of circadian rhythm hormones serves as an early sign of the progress of age-related disease and brain pathology in aging. The aim of this study was to determine the cortisol-melatonin ratio in relation to brain activity and cognitive function in aging. Sixty-four aging subjects were recruited from the brain healthy project. The morning salivary of all subjects was collected for cortisol and melatonin levels analysis. The brain activity was recorded for 5 minutes in the eyes open condition and seven cognitive functions were assessed by the MoCA. The results were divided into a low ratio group and a high ratio group of cortisol-melatonin ratio. The low ratio group and the high ratio group differed in the delta-beta ratio at the left temporal lope (p < .05), and the delayed recall in the high ratio group was markedly higher than in the low ratio group. Moreover, the cortisol-melatonin ratio was strongly correlated with delayed recall (p < .05), the delta-beta ratio in the left temporal lope (p <.05), the theta alpha ratio in the left temporal lope (p < .05), and right temporal lope (p < .05). We found that a low cortisol-melatonin ratio corresponded to a high delta-beta ratio and a high thetaalpha ratio at the left temporal lobe with a low score of delayed recall function, but a high cortisol-melatonin ratio corresponded to a low delta-beta ratio and a low theta-alpha ratio at the left temporal lobe with a high score of delayed recall. The imbalance of the circadian hormone related to cognitive function and brain activity in aging could serve as a biomarker of age-related diseases.
... 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). ...
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). ...
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
... 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]. ...
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.
... 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. ...
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.
... 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. ...
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.
... 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]. ...
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.
... 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. ...
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.
... 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]. ...
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.
... 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. ...
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.
... 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. ...
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.
... 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]. ...
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.
... 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. ...
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.
Background: Recent research underscores a crucial connection between circadian rhythm disruption and cancer promotion, highlighting an urgent need for attention. Objectives: Explore the molecular mechanisms by which modern lifestyle factors—such as artificial light exposure, shift work, and dietary patterns—affect cortisol/melatonin regulation and cancer risk. Methods: Employing a narrative review approach, we synthesized findings from Scopus, Google Scholar, and PubMed to analyze lifestyle impacts on circadian health, focusing on cortisol and melatonin chronobiology as molecular markers. We included studies that documented quantitative changes in these markers due to modern lifestyle habits, excluding those lacking quantitative data or presenting inconclusive results. Subsequent sections focused solely on articles that quantified the effects of circadian disruption on adipogenesis and tumor microenvironment modifications. Results: This review shows how modern habits lead to molecular changes in cortisol and melatonin, creating adipose microenvironments that support cancer development. These disruptions facilitate immune evasion, chemotherapy resistance, and tumor growth, highlighting the critical roles of cortisol dysregulation and melatonin imbalance. Conclusions: Through the presented findings, we establish a causal link between circadian rhythm dysregulation and the promotion of certain cancer types. By elucidating this relationship, the study emphasizes the importance of addressing lifestyle factors that contribute to circadian misalignment, suggesting that targeted interventions could play a crucial role in mitigating cancer risk and improving overall health outcomes.
There are currently no effective treatments to prevent, halt, or reverse Alzheimer’s disease (AD), the most common cause of dementia in older adults. Melatonin, a relatively harmless over-the-counter supplement, may offer some benefits to patients with AD. Melatonin is known for its sleep-enhancing properties, but research shows that it may provide other advantages as well, such as antioxidant and anti-amyloidogenic properties. Clinical trials for melatonin use in AD have mixed results but, overall, show modest benefits. However, it is difficult to interpret clinical research in this area as there is little standardization to guide the administration and study of melatonin. This review covers basic biology and clinical research on melatonin in AD focusing on prominent hypotheses of pathophysiology of neurodegeneration and cognitive decline in AD (i.e., amyloid and tau hypotheses, antioxidant and anti-inflammation, insulin resistance and glucose homeostasis, the cholinergic hypothesis, sleep regulation, and the hypothalamic-pituitary-adrenal axis and cortisol). This is followed by a discussion on pending clinical trials, considerations for future research protocols, and open questions in the field.
Uyku sorunları ve ağrı kişinin yaşam kalitesini olumsuz etkileyen durumlardır. Bu iki durumun hastaların iyileşmesinde zamansal ve düzeysel olarak etkili olduğu düşünülmektedir. Bu bölümün amacı, uyku ve ağrının birbiri ile olan ilişkisini farklı mekanizmalar üzerinden değerlendirmektir. Bu amaçla ‘Uykusuz birey ağrılı birey midir ya da ağrılı birey uykusuz birey midir?’ Sorularının varlığı ve nedenselliği farklı mekanizmalar üzerinden açıklanmaya çalışılacaktır. Ağrı ile uyku arasındaki ilişkinin dinamiklerinin neler olabileceğini anlamak için hangi ortak alanlarda kesiştiklerini anlamaya çalışmak önemlidir. Bu kapsamda öncelikle uyku sorunlarının çerçevesi çizilmeye çalışılmıştır. Daha sonra ağrı kavramı ve ağrı üzerinde etkili unsurlar farklı bakış açıları ile değerlendirilmiştir. Sirkadian ritmin ne olduğu ve metabolizma üzerindeki geniş etkisinden bahsedilmiştir. Uyku
hormonu olan melatoninin ve kortizolün ağrı ile ilişkisi inflamatuvar süreçler ve stres üzerinden açıklanmaya çalışılmıştır. Ağrı nöromatriksinin uyku ile ilişkili faktörler ile olan statik ve dinamik ilişkisi, beynin yeterli ve yetersiz uyku durumundaki farklılaşan çalışma sisteminden ve temporal sumasyondan bahsedilmiştir.
The circadian system is an intricate molecular network of coordinating circadian clocks that organize the internal synchrony of the organism in response to the environment. These rhythms are maintained by genetically programmed positive and negative auto-regulated transcriptional and translational feedback loops that sustain 24-hour oscillations in mRNA and protein components of the endogenous circadian clock. Since inter and intracellular activity of the central pacemaker appears to reduce with aging, the interaction between the circadian clock and aging continues to elude our understanding. In this review article, we discuss circadian clock components at the molecular level and how aging adversely affects circadian clock functioning in rodents and humans. The natural decline in melatonin levels with aging strongly contributes to circadian dysregulation resulting in the development of neurological anomalies. Additionally, inappropriate environmental conditions such as Artificial Light at Night (ALAN) can cause circadian disruption or chronodisruption (CD) which can result in a variety of pathological diseases, including premature aging. Furthermore, we summarize recent evidence suggesting that CD may also be a predisposing factor for the development of age-related neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), although more investigation is required to prove this link. Finally, certain chrono-enhancement approaches have been offered as intervention strategies to prevent, alleviate, or mitigate the impacts of CD. This review thus aims to bring together recent advancements in the chronobiology of the aging process, as well as its role in NDDs.
Objective: The aim of this study was to investigate the effects of exogenous melatonin on the quality of sleep in patients undergoing dialysis and to investigate its mechanism for the regulation of total circadian rhythm and salivary levels of cortisol in hemodialysis patients admitted to Pange Azar hospital in Gorgan in winter of 2017.
Method: This was a double-blind randomized clinical trial. Samples were transferred to the laboratory by maintaining the cold chain. Then, the patients were divided into two groups. In a double-blind trial, one group received three mg melatonin and another group received placebo for two weeks at 10 PM. At the end of two weeks, sampling was performed to investigate the salivary level of cortisol under the same conditions. The research instrument was Pittsburgh questionnaire. Data were analyzed before and after intervention using SPSS 16 software.
Results: Salivary levels of cortisol decreased significantly after the intervention in the melatonin group (melatonin: 1.40 ± 1.82 and placebo: 4.94 ± 4.43; P = 0.008). Salivary levels of cortisol in the morning after intervention were also lower in the melatonin group, but were not statistically significant (melatonin 3.99 ± 3.45 and placebo: 5.35 ± 4.9; P = 0.93). Also, the difference in salivary levels of cortisol at night and before and after intervention significantly decreased in melatonin group. PSQI difference (interventional dimension) and PSQI (before intervention) were significantly decreased in melatonin group (P = 0.0001). The rate of change in the subscales of sleep latency, sleep efficiency, and sleep disorders in the melatonin group than in the placebo group was significantly higher.
Conclusion: Melatonin can be used as a safe and cost-effective treatment to improve sleep quality and can also reduce salivary cortisol increased in hemodialysis patients at night.
Chronobiology is defined as the temporal fluctuations occurring in the human physiology due to the circadian cycle. These fluctuations are good indicators of the functioning of the Hypothalamic-Pituitary-Adrenal axis (HPA axis) and can be tracked by using biomarkers: cortisol and DHEA. Low volume tracking systems will be beneficial for patients exposed to chronic stress, patients suffering from endocrine conditions manifested by circadian disruption and act as a lifestyle monitoring tool. The sensor system demonstrated in this work was an affinity-based system, characterized using EIS (Electrochemical Impedance Spectroscopy).The sensor can detect cortisol and DHEA in the physiologically relevant ranges i.e. 8–200 ng ml⁻¹ and 2–131 ng ml⁻¹ respectively. Thus, the senor is a non-invasive, label free, cost-effective solution for tracking chronobiology for circadian diagnostics.
Méthode : Nous avons réalisé une étude rétrospective de polysonographies (PSG) et de dossiers médicaux de patients ayant une maladie de Parkinson (MP) idiopathique ou un syndrome parkinsonien dégénératif non idiopathique (SPNI) et se plaignant de troubles du sommeil. Les patients ont été subdivisés en 3 groupes (diagnostic à la dernière visite) : MP sans démence (MPI, n=58), MP plus démence ou démence à corps de Lewy (MPD, n=15), SPNI (6 patients atrophie multi-systématisée, 5 patients paralysie supranucléaire progressive, 3 patients SPNI d'origine non déterminée). Nous avons réalisé une subanalyse de patients MPI lors de la PSG et qui ont développé une démence ultérieurement au cours du suivi après la PSG (n=7). Une subanalyse de données de PSG de patients MPI en fonction de la maladie a également été réalisée. Résultats : Les données architecturales du sommeil des patients PMD étaient moins bien préservées que celles des autres groupes. Néanmoins, la différence était seulement significative pour la présence d'un syndrome d'apnées du sommeil (SAS) (p=0.01) et ils présentaient plus d'hallucinations visuelles (HV) (p inférieur à 0.01). On n'a pas retrouvé de lien entre la présence de trouble du comportement en sommeil paradoxal (TCSP) et la présence d'HV. Les données PSG étaient incapables de prévoir l'apparition ultérieure d'un syndrome démentiel. On ne retrouvait pas non plus de relation directe entre fatigue diurne excessive et qualité du sommeil nocturne. Aucune différence de survenue de TCSP, de mouvements périodique et de SAS n'a été retrouvée en fonction de la durée de la maladie. Conclusion : Les perturbations du sommeil ne permettent pas de différencier les patients parkinsoniens idiopathiques des patients non idiopathiques ni de prévoir l'évolution de la maladie. Les troubles du sommeil sont une partie intégrale de la maladie de Parkinson.
Memories are the glue of one’s existence; unfortunately sometimes memories are more transitory then we would like. Aging and various disease states can induce memory impairments, but for the most part the mechanisms for these memory impairments are largely unknown. Circadian rhythms increase an organism’s biological fitness by synchronizing its physiology and behaviour to their environment. Sometimes circadian rhythms become desynchronized from the environment and this circadian misalignment elicits memory impairments in both humans and rodents. Circadian rhythm dysfunction and memory impairments are hallmarks of both aging and chronic shiftwork, therefore it is pertinent to untangle the nature of the relationship between these processes. Epigenetics allow one’s environment to influence gene expression without changing the genome itself. The plasticity of both memory and circadian rhythms are mediated in part by epigenetic modifications. While epigenetics is necessary for both circadian rhythm generation and memory, very little is known about how circadian rhythm disruption affects the epigenome. Epigenetics will be discussed as a mediator between circadian rhythms and memory in conditions where circadian rhythms are in or out of synch with the environment.
Earlier we have discribed the role of glucocorticoids in aging and age-related diseases. In present paper the proposal was analysed for possible counteraction of glucocorticoid ontogenetic influence by melatonin and neuroactive steroids. At first, the data are discussed on antistress or antiglucocorticoid actions of these hormones. Thereafter, the evidence is evaluated for contributions of melatonin and neuroactive steroids to ontogenetic bioregulation, especially in aging. It is concluded that ontogenetic approach may be of great value for estimating the physiopathologic role of hormonal interactions. However, due to complexity of such interactions, the employment of systems biology and medicine will be urgently needed in future studies. 158 Ранее мы описали роль глюкокортикоидов в возраст-зависимых заболеваниях и при старении. В настоящей работе проведен анализ предположения о возможном противодействии онтогенетическому влиянию глюкокортикоидов посредством мелатонина и нейроактивных стероидов. Вначале обсуждаются данные об антистрессорных или антиглюкокортикоидных эффектах этих гормонов. Затем осуществлена оценка сведений о вкладе мелатонина и нейроактивных стероидов в онтогенетическую биорегуляцию, особенно при старении. Сделано заключение о том, что онтогенетический подход может иметь большое значение для выяснения физиопатологической роли гормональных взаимодействий. Однако, из-за сложности таких взаимодействий, в будущих исследованиях может оказаться весьма необходимым применение системной биологии и медицины. Ключевые слова: мелатонин, нейроактивные стероиды, глюкокортикоиды, онтогенез.
Sleep is affected by a number of the symptoms related to stress. Sleep complaints and disturbances in arousal are continuing symptoms in patients with post-traumatic stress disorder (PTSD). This article reviews the effects of neurobiological mechanisms of stress on sleep with emphasis on the role of the amygdala in regulating sleep in PTSD.
The complete synchronization of the internal circadian clock of our body cycle day - night helps the body in equilibrium. For maintaining the day-night cycle is responsible melatonin. Melatonin is also called hormone of darkness because the sunset starts secretion, which causes drowsiness. The effect of this makes it particularly useful for the treatment of insomnia and the jet lag, after oral administration of a drug can synchronize external rhythms with internal (the organization). Investigations showed that the biological roles of melatonin-go-be exempt from its primary function in an excellent antioxidant. In the evening the skin refreshed, cells are regenerated and restored damages arising in cells. When the body is in balance then the skin is resistant in time to this effort skin ally is melatonin. Main cause of aging is the free radicals produced from foods low in nutrients and oxidative stress. So the antioxidant activity of melatonin corrects damage. While studies have shown that constitutes the drug against hair loss and baldness. Like everything in life, presents and negative elements so the hypersecretion of melatonin accompanied by low estrogen so look hirsutism.
frequently accompany natural aging. Circadian rhythms and memory are intertwined, rodents. Although, the precise relationship between circadian rhythms and memory is still largely unknown, it is hypothesized that circadian rhythm disruption, which memory loss. While there are a variety of mechanisms that could mediate this effect, changes in the epigenome that occur during aging has been proposed as a potential candidate. Interestingly, epigenetic mechanisms, such as DNA methylation and sirtuin1 (SIRT1) are necessary for both circadian rhythms and memory. During aging, similar alterations of epigenetic mechanisms occur in the suprachiasmatic nucleus (SCN) and hippocampus, which are necessary for circadian rhythm generation and memory, respectively. Recently, circadian rhythms have been linked to epigenetic function in the hippocampus, as some of these epigenetic mechanisms oscillate in the hippocampus and are disrupted by clock gene deletion. The current paper will review how circadian rhythms and memory change with age, and will suggest how epigenetic changes in these processes might contribute to age-related cognitive decline.
There is a vast literature dealing with various aspects of the circadian clock. This review provides examples of the multifaceted nature, of namely redox, oxidative stress, melatonin, antioxidants, nitric oxide, hypoxia, anesthetics, cortisol and cocaine. The redox and oxidative stress features reflect the involvement of electron transfer and radical species, which can exert either beneficial or deleterious effects. The harmful aspects can be countered by antioxidants. Melatonin is a brain hormone that is known to play a widespread role in the biochemistry of the circadian clock. Nitric oxide is widespread in the human body and plays a variety of roles. Hypoxia has been broadly discussed in relation to circadian rhythm, e.g., in high altitude flight. The anesthetic topic completes the list.
Clinical data show that poor quality, rather than quantity, of sleep corresponds negatively to measures of health, well-being and satisfaction with life. However, until now treatment of insomnia has primarily targeted quantity of sleep. PR (prolonged release)-melatonin offers a new treatment option in insomnia.
To provide an overview of PR-melatonin, the first melatonin receptor agonist to be granted marketing authorisation in Europe as monotherapy for the treatment of primary insomnia in patients aged > 55 years.
Review data published in peer review journals and the EMEA (European Medicines Agency) website.
PR-melatonin significantly improves morning alertness and quality of sleep compared with placebo. There are no safety concerns.
Although insomnia is, by far, the most commonly encountered sleep disorder in medical practice, our knowledge in regard to its neurobiology and medical significance is limited. Activation of the hypothalamic-pituitary-adrenal axis leads to arousal and sleeplessness in animals and humans; however, there is a paucity of data regarding the activity of the hypothalamic-pituitary-adrenal axis in insomniacs. We hypothesized that chronic insomnia is associated with increased plasma levels of ACTH and cortisol. Eleven young insomniacs (6 men and 5 women) and 13 healthy controls (9 men and 4 women) without sleep disturbances, matched for age and body mass index, were monitored in the sleep laboratory for 4 consecutive nights, whereas serial 24-h plasma measures of ACTH and cortisol were obtained during the fourth day. Insomniacs, compared with controls, slept poorly (significantly higher sleep latency and wake during baseline nights). The 24-h ACTH and cortisol secretions were significantly higher in insomniacs, compared with normal controls (4.2 +/- 0.3 vs. 3.3 +/- 0.3 pM, P = 0.04; and 218.0 +/- 11.0 vs. 190.4 +/- 8.3 nM, P = 0.07). Within the 24-h period, the greatest elevations were observed in the evening and first half of the night. Also, insomniacs with a high degree of objective sleep disturbance (% sleep time < 70), compared with those with a low degree of sleep disturbance, secreted a higher amount of cortisol. Pulsatile analysis revealed a significantly higher number of peaks per 24 h in insomniacs than in controls (P < 0.05), whereas cosinor analysis showed no differences in the temporal pattern of ACTH or cortisol secretion between insomniacs and controls. We conclude that insomnia is associated with an overall increase of ACTH and cortisol secretion, which, however, retains a normal circadian pattern. These findings are consistent with a disorder of central nervous system hyperarousal rather than one of sleep loss, which is usually associated with no change or decrease in cortisol secretion or a circadian disturbance. Chronic activation of the hypothalamic-pituitary-adrenal axis in insomnia suggests that insomniacs are at risk not only for mental disorders, i.e. chronic anxiety and depression, but also for significant medical morbidity associated with such activation. The therapeutic goal in insomnia should be to decrease the overall level of physiologic and emotional arousal, and not just to improve the nighttime sleep.
Although melatonin treatment has been shown to phase shift human circadian rhythms, it still remains ambiguous as to whether exogenous melatonin can entrain a free-running circadian system. We have studied seven blind male subjects with no light perception who exhibited free-running urinary 6-sulphatoxymelatonin (aMT6s) and cortisol rhythms. In a single-blind design, five subjects received placebo or 5 mg melatonin p.o. daily at 2100 h for a full circadian cycle (35-71 days). The remaining two subjects also received melatonin (35-62 days) but not placebo. Urinary aMT6s and cortisol (n=7) and core body temperature (n=1) were used as phase markers to assess the effects of melatonin on the During melatonin treatment, four of the seven free-running subjects exhibited a shortening of their cortisol circadian period (tau). Three of these had taus which were statistically indistinguishable from entrainment. In contrast, the remaining three subjects continued to free-run during the melatonin treatment at a similar tau as prior to and following treatment. The efficacy of melatonin to entrain the free-running cortisol rhythms appeared to be dependent on the circadian phase at which the melatonin treatment commenced. These results show for the first time that daily melatonin administration can entrain free-running circadian rhythms in some blind subjects assessed using reliable physiological markers of the circadian system.
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.
Biological aging is often associated with problems with sleep and daytime napping.1 There is considerable evidence linking melatonin, produced by the pineal gland, with the sleep-wake cycle. When administered orally to humans or animals it enhances sleep2 and has a synchronising effect on circadian rhythms. Circulating melatonin concentrations decrease in old age, and its time of secretion is delayed.3 We examined whether sleep disorders in old age were associated with changes in concentration of 6-sulphatoxymelatonin, the major urinary measure of melatonin.
The study population comprised four groups: (a) eight independently living patients with insomnia (four men, four women, mean age 73.1 (SD 3.9)); (b) 15 patients with insomnia (five men, 10 women, mean age 82.1 (8.8)) who had lived a minimum of six months in a nursing home; (c) 25 elderly patients without sleep disorders (19 …
Cagnacci A, Soldani R, Yen SSC. Melatonin enhances Cortisol levels in aged women: Reversible by estrogens. J. Pineal Res. 1997; 22:81–85. © Munksgaard, Copenhagen
Abstract
The administration of melatonin increases Cortisol levels in postmenopausal women. Aging and hypoestrogenism are believed to impair the regulation of the hypothalamo‐pituitary‐adrenal axis and may participate in the determination of this altered response. In this study the implications of hypoestrogenism were tested. Seven postmenopausal women were studied. At 08.00 hr for 2 consecutive days, each woman received randomly and in a double blind fashion a pill of placebo or melatonin (100 mg). Serum melatonin and Cortisol levels were evaluated at 20 min intervals, for 48 hr. Measurements were performed in the same subjects both during no estrogen supplementation and at least two cycles of conjugated estrogens administration (0.625 mg/day). During estrogen supplementation, postmenopausal women showed slightly lower Cortisol levels at lunch and early night (20.00–01.00 hr). The onset of the nocturnal melatonin rise was not modified, but that of Cortisol was delayed of about 60 min ( P <0.02). The administration of melatonin elicited a marked increase in daytime Cortisol levels in postmenopausal women ( P <0.02), but this stimulus completely disappeared during estrogen administration. Mean nighttime (20.00–08.00 hr) Cortisol levels were not modified by daytime administration of melatonin. The present data reveal that in aged postmenopausal women, reversal of hypoestrogenism, resulting from supplemental estrogens, may improve the regulation of the hypothalamo‐pituitary‐adrenal axis.
Cortisol production is increased during stress, and the actions of cortisol on receptors in the brain and other body organs are involved in allostasis, the process of adaptation to stress, as well as in allostatic load, the wear and tear associated with excessive exposure to cortisol. Using data from a community-based longitudinal study of older men and women, aged 70-79 yr, we tested the hypothesis that exposure to increasing levels of cortisol is associated with declines in memory performance. Associations between 12-h urinary free cortisol excretion and performance on tests of memory (delayed verbal recall and spatial recognition), abstraction, and spatial ability were examined. Among the women, greater cortisol excretion was associated with poorer baseline memory performance, independent of socio-demographic, health status, health behavior, and psychosocial characteristics. Moreover, women who exhibited increases in cortisol excretion over a 2.5-yr follow-up period were more likely to show declines in memory performance. By contrast, women who experienced declines in cortisol exhibited improvements in memory performance. No significant associations were found among the men. The results for the women suggest that decrements in memory performance associated with increases in cortisol may not represent irreversible effects, as declines in cortisol were associated with improvements in memory.
Sleep curtailment constitutes an increasingly common condition in industrialized societies and is thought to affect mood and performance rather than physiological functions. There is no evidence for prolonged or delayed effects of sleep loss on the hypothalamo-pituitary-adrenal (HPA) axis. We evaluated the effects of acute partial or total sleep deprivation on the nighttime and daytime profile of cortisol levels. Plasma cortisol profiles were determined during a 32-hour period (from 1800 hours on day 1 until 0200 hours on day 3) in normal young men submitted to three different protocols: normal sleep schedule (2300-0700 hours), partial sleep deprivation (0400-0800 hours), and total sleep deprivation. Alterations in cortisol levels could only be demonstrated in the evening following the night of sleep deprivation. After normal sleep, plasma cortisol levels over the 1800-2300-hour period were similar on days 1 and 2. After partial and total sleep deprivation, plasma cortisol levels over the 1800-2300-hour period were higher on day 2 than on day 1 (37 and 45% increases, p = 0.03 and 0.003, respectively), and the onset of the quiescent period of cortisol secretion was delayed by at least 1 hour. We conclude that even partial acute sleep loss delays the recovery of the HPA from early morning circadian stimulation and is thus likely to involve an alteration in negative glucocorticoid feedback regulation. Sleep loss could thus affect the resiliency of the stress response and may accelerate the development of metabolic and cognitive consequences of glucocorticoid excess.
To determine whether human hypothalamo-pituitary-adrenal axis activity is related to the alertness level during wakefulness, 10 healthy young men were studied under resting conditions in the daytime (0900–1800 h) after an 8-h nighttime sleep (2300–0700 h). A serial 70-sec gaze fixation task was required every 10 min throughout the daytime experimental session. The corresponding waking electroencephalographic (EEG) segments were submitted to quantitative spectral analysis, from which EEG β activity (absolute power density in the 13–35 Hz frequency band), an index of central alertness, was computed. Blood was collected continuously through an indwelling venous catheter and sampled at 10-min intervals. Plasma cortisol concentrations were measured by RIA, and the corresponding secretory rates were determined by a deconvolution procedure.
Analysis of individual profiles demonstrated a declining tendency for EEG β activity and cortisol secretory rate, with an overall temporal relationship indicated by positive and significant cross-correlation coefficients between the two variables in all subjects (average r= 0.565, P < 0.001). Changes in cortisol secretion lagged behind fluctuations in EEG β activity, with an average delay of 10 min for all the subjects. On the average, 4.6 ± 0.4 cortisol secretory pulses and 4.9 ± 0.5 peaks in EEG β activity were identified by a detection algorithm. A significant, although not systematic, association between the episodes in the two variables was found: 44% of the peaks in EEG β activity (relative amplitude, near 125%; P < 0.001) occurred during an ascending phase of cortisol secretion, cortisol secretory rates increasing by 40% (P < 0.01) 10-min after peaks in EEG β activity. However, no significant change in EEG β activity was observed during the period from 50 min before to 50 min after pulses in cortisol secretion.
In conclusion, the present study describes a temporal coupling between cortisol release and central alertness, as reflected in the waking EEGβ activity. These findings suggest the existence of connections between the mechanisms involved in the control of hypothalamo-pituitary-adrenal activity and the activation processes of the brain, which undergoes varying degrees of alertness throughout daytime wakefulness.
To examine antidepressant augmentation with and hypnotic effects of slow-release melatonin (SR-melatonin) in patients with treatment-resistant depression.
Open-label trial.
Tertiary care outpatient depression clinic.
Nine outpatients who had failed to respond to 2 or more 8-week trials of antidepressant medication.
Patients received SR-melatonin 5 mg per day for the first 2 weeks and 10 mg per day for the final 2 weeks, in addition to their antidepressant medication.
Structured Clinical Interview for DSM-IV, Axis 1 Disorders, Hamilton Rating Scale for Depression (HRSD), Beck Depression Inventory, Response Style Questionnaire, sleep and fatigue measures.
One patient was excluded after 1 week because of the development of a mixed affective state. In the remaining 8 patients there was a 20% mean decrease in HRSD scores after 4 weeks of treatment, with no individual achieving an improvement of 50% or more. There was a 36% decrease on the 3-item HRSD related to insomnia, with 4 of 8 patients showing at least a 50% improvement on this measure. The greatest decrease in insomnia occurred during the last 2 weeks of the study, following the increase in dosage to 10 mg per day of SR-melatonin. Patients also reported significantly lower levels of fatigue post-treatment.
SR-melatonin may be a useful adjunct for sleep, but does not substantially augment existing antidepressant therapies in some patients with treatment-resistant depression.
In young adults, sleep affects the regulation of growth hormone (GH) and cortisol. The relationship between decreased sleep quality in older adults and age-related changes in the regulation of GH and cortisol is unknown.
To determine the chronology of age-related changes in sleep duration and quality (sleep stages) in healthy men and whether concomitant alterations occur in GH and cortisol levels.
Data combined from a series of studies conducted between 1985 and 1999 at 4 laboratories.
A total of 149 healthy men, aged 16 to 83 years, with a mean (SD) body mass index of 24.1 (2.3) kg/m( 2), without sleep complaints or histories of endocrine, psychiatric, or sleep disorders.
Twenty-four-hour profiles of plasma GH and cortisol levels and polygraphic sleep recordings.
The mean (SEM) percentage of deep slow wave sleep decreased from 18.9% (1.3%) during early adulthood (age 16-25 years) to 3.4% (1.0%) during midlife (age 36-50 years) and was replaced by lighter sleep (stages 1 and 2) without significant increases in sleep fragmentation or decreases in rapid eye movement (REM) sleep. The transition from midlife to late life (age 71-83 years) involved no further significant decrease in slow wave sleep but an increase in time awake of 28 minutes per decade at the expense of decreases in both light non-REM sleep (-24 minutes per decade; P<.001) and REM sleep (-10 minutes per decade; P<.001). The decline in slow wave sleep from early adulthood to midlife was paralleled by a major decline in GH secretion (-372 microg per decade; P<.001). From midlife to late life, GH secretion further declined at a slower rate (-43 microg per decade; P<.02). Independently of age, the amount of GH secretion was significantly associated with slow wave sleep (P<.001). Increasing age was associated with an elevation of evening cortisol levels (+19. 3 nmol/L per decade; P<.001) that became significant only after age 50 years, when sleep became more fragmented and REM sleep declined. A trend for an association between lower amounts of REM sleep and higher evening cortisol concentrations independent of age was detected (P<.10).
In men, age-related changes in slow wave sleep and REM sleep occur with markedly different chronologies and are each associated with specific hormonal alterations. Future studies should evaluate whether strategies to enhance sleep quality may have beneficial hormonal effects. JAMA. 2000;284:861-868
Most totally blind people have circadian rhythms that are "free-running" (i.e., that are not synchronized to environmental time cues and that oscillate on a cycle slightly longer than 24 hours). This condition causes recurrent insomnia and daytime sleepiness when the rhythms drift out of phase with the normal 24-hour cycle. We investigated whether a daily dose of melatonin could entrain their circadian rhythms to a normal 24-hour cycle.
We performed a crossover study involving seven totally blind subjects who had free-running circadian rhythms. The subjects were given 10 mg of melatonin or placebo daily, one hour before their preferred bedtime, for three to nine weeks. They were then given the other treatment. The timing of the production of endogenous melatonin was measured as a marker of the circadian time (phase), and sleep was monitored by polysomnography.
At base line, the subjects had free-running circadian rhythms with distinct and predictable cycles averaging 24.5 hours (range, 24.2 to 24.9). These rhythms were unaffected by the administration of placebo. In six of the seven subjects the rhythm was entrained to a 24.0-hour cycle during melatonin treatment (P<0.001). After entrainment, the subjects spent less time awake after the initial onset of sleep (P=0.05) and the efficiency of sleep was higher (P=0.06). Three subjects subsequently participated in a trial in which a 10-mg dose of melatonin was given daily until entrainment was achieved. The dose was then reduced to 0.5 mg per day over a period of three months; the entrainment persisted, even at the lowest dose.
Administration of melatonin can entrain circadian rhythms in most blind people who have free-running rhythms.
We have previously shown that when tested in the morning, older men and women, pretreated with metyrapone to block endogenous cortisol synthesis, exhibit delayed suppression of plasma ACTH in response to cortisol infusion. To confirm this finding and to determine whether aging-related changes in feedback responsiveness are exaggerated near the time of the circadian nadir in adrenocortical secretion, we performed a similar study in the evening. Healthy young (20-35 yr, n = 22) and old (>65 yr, n = 21) men and women were administered metyrapone orally (750 mg) at 1600 and 1900 h, followed by a cortisol infusion of 0.06 mg/kg/h for 150 min. Blood samples were taken at 15-min intervals for 4 h following infusion onset for measurement of plasma ACTH, cortisol, 11-deoxycortisol, and corticosteroid binding globulin. When corrections were made for differences in circulating cortisol concentrations achieved among age and gender subgroups, feedback inhibition of ACTH was found to be significantly greater in young than in old subjects of both genders. Our studies support the hypothesis that glucocorticoid responses to stress in aging individuals are likely to be prolonged due to blunted and delayed inhibition of ACTH secretion, thus increasing the total exposure to glucocorticoids.
The prevalence of insomnia associated with emotional stress increases markedly in middle-age. Both the top and end hormones of the hypothalamic-pituitary-adrenal axis, i.e. CRH and glucocorticoids, stimulate arousal/wakefulness and inhibit slow wave (deep) sleep in experimental animals and man. The objective of this study was to test the hypothesis that middle-age is characterized by increased sensitivity to the sleep-disturbing effects of the hypothalamic-pituitary-adrenal axis. We studied 12 healthy middle-aged (45.1 +/- 4.9) and 12 healthy young (22.7 +/- 2.8) men by monitoring their sleep by polysomnography for 4 consecutive nights, including in tandem 1 adaptation and 2 baseline nights and a night during which we administered equipotent doses of ovine CRH (1 microg/kg, iv bolus) 10 min after sleep onset. Analyses included comparisons within and between groups using multiple ANOVA and regression analysis. Although both middle-aged and young men responded to CRH with similar elevations of ACTH and cortisol, the former had significantly more wakefulness and suppression of slow wave sleep compared with baseline sleep; in contrast, the latter showed no change. Also, comparison of the change in sleep patterns from baseline to the CRH night in the young men to the respective change observed in middle-aged men showed that middle-age was associated with significantly higher wakefulness and significantly greater decrease in slow wave sleep than in young age. We conclude that middle-aged men show increased vulnerability of sleep to stress hormones, possibly resulting in impairments in the quality of sleep during periods of stress. We suggest that changes in sleep physiology associated with middle-age play a significant role in the marked increase of prevalence of insomnia in middle-age.
Although insomnia is, by far, the most commonly encountered sleep disorder in medical practice, our knowledge in regard to its neurobiology and medical significance is limited. Activation of the hypothalamic-pituitary-adrenal axis leads to arousal and sleeplessness in animals and humans; however, there is a paucity of data regarding the activity of the hypothalamic-pituitary-adrenal axis in insomniacs. We hypothesized that chronic insomnia is associated with increased plasma levels of ACTH and cortisol. Eleven young insomniacs (6 men and 5 women) and 13 healthy controls (9 men and 4 women) without sleep disturbances, matched for age and body mass index, were monitored in the sleep laboratory for 4 consecutive nights, whereas serial 24-h plasma measures of ACTH and cortisol were obtained during the fourth day. Insomniacs, compared with controls, slept poorly (significantly higher sleep latency and wake during baseline nights). The 24-h ACTH and cortisol secretions were significantly higher in insomniacs, compared with normal controls (4.2 +/- 0.3 vs. 3.3 +/- 0.3 pM, P = 0.04; and 218.0 +/- 11.0 vs. 190.4 +/- 8.3 nM, P = 0.07). Within the 24-h period, the greatest elevations were observed in the evening and first half of the night. Also, insomniacs with a high degree of objective sleep disturbance (% sleep time < 70), compared with those with a low degree of sleep disturbance, secreted a higher amount of cortisol. Pulsatile analysis revealed a significantly higher number of peaks per 24 h in insomniacs than in controls (P < 0.05), whereas cosinor analysis showed no differences in the temporal pattern of ACTH or cortisol secretion between insomniacs and controls. We conclude that insomnia is associated with an overall increase of ACTH and cortisol secretion, which, however, retains a normal circadian pattern. These findings are consistent with a disorder of central nervous system hyperarousal rather than one of sleep loss, which is usually associated with no change or decrease in cortisol secretion or a circadian disturbance. Chronic activation of the hypothalamic-pituitary-adrenal axis in insomnia suggests that insomniacs are at risk not only for mental disorders, i.e. chronic anxiety and depression, but also for significant medical morbidity associated with such activation. The therapeutic goal in insomnia should be to decrease the overall level of physiologic and emotional arousal, and not just to improve the nighttime sleep.
Stress and depression are characterized by elevation of circulating cortisol, as well as by changes in physiological functions. In this study, we addressed the possibility that elevated cortisol is also associated with the origin and development of depression. We report here that cortisol at the nM-microM concentration range induces a substantial increase in serotonin uptake both in vitro, by human peripheral blood lymphocytes (PBLs) and cortical neuronal cells, and in vivo, by rabbit PBLs, owing to promotion of synthesis of the serotonin transporter. These findings offer a novel molecular mechanism for depression associated with stress. Accordingly, the elevated cortisol induced by stress increases serotonin uptake, under both rest and nerve stimulation, which is overtly expressed in symptoms of depression.
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.
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.
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.
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.
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.
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.
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.
An assessment of the rhythmic characteristics of melatonin secretion in man and other species requires the determination of 24-h secretion profiles. Measurement of a major excreted metabolite would allow noninvasive study of pineal function, applicable in particular to pediatric and long term circadian rhythm studies. This report describes a simple and rapid RIA for 6-hydroxymelatonin sulfate in human plasma and urine. Physiological studies revealed that both plasma and urinary levels of 6-hydroxymelatonin sulfate were closely related to plasma melatonin, and that the urinary 24-h rhythm was abolished by the beta 1-adrenergic anagonist atenolol.
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.
: 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
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.
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.
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.
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.
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.
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.
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.
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.