ArticleLiterature Review

Melatonin deficiencies in women

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Abstract

The pineal hormone melatonin is the mediator of external light to physiologic adaptation to day and night rhythms, it regulates reproduction in animals but attempts to utilize melatonin in women for contraception have failed. Melatonin seems to be the natural hormone to facilitate sleep in insomniac patients and causes no hang over. When applied together with benzodiazepine it allows reduction of benzodiazepine without withdrawal effects. It should be applied 2 h before sleeping time in doses between 3 and 5 mg. Melatonin acts via the gamma-aminobutyric acid- and benzodiazepine receptor explaining its success in treatment of seizures in children and in adults. Constant application of benzodiazepine reduced the production of natural melatonin in rats, supporting the evidence that long-term application of benzodiazepine in humans does not restore sleeping habits but reduces natural sleeping habits even more. Low melatonin levels were seen in bulimia or neuralgia and in women with fibromyalgia; replacement reduced pain, sleeping disorders, and depression in fibromyalgia and bulimia. Melatonin profiles are a diagnostic tool to distinguish between several forms of depression, like major depression, winter depression (SAD), unipolar depression, delayed sleep phase syndrome (DSPS). In patients with a major depression success with antidepressants correlated with an increase in their melatonin profiles but only patients suffering from DSPS can be successfully treated with melatonin. In perimenopausal women melatonin administration did produce a change in LH, FSH and thyroid hormones. Some oncostatic properties are supported by cell culture work and studies in animals. In Nordic countries indigenous people suffer less from breast and prostate cancer, winter darkness seems to protect. The supposedly increased melatonin levels created the 'melatonin hypothesis'. Epidemiological studies did show that blind people indeed have half the rate of breast cancers, supporting the hypothesis. Controversial results concerning melatonin and insulin resistance and glucose tolerance have been published. In postmenopausal women application of melatonin reduced glucose tolerance and insulin sensitivity. Pregnant women should avoid melatonin, since its teratogenic effect is not known. Patients suffering from non-hormone dependent tumors, like leukemia, should avoid melanin, since tumor growth was promoted in animal experiments. It can be expected that melatonin will receive wide consideration for treatment of sleeping disturbances, jet lag, and fibromyalgia once an oral formulation becomes available in Europe.

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... It has been observed that blood glucose levels which increase after intravenous glucose supplementation decline during sleep. The fact that melatonin has been reported to play an important role in this decrease in blood glucose level (Rohr and Herold, 2002) can be cited as proof of a relation between carbohydrate mechanism and pineal gland. Melatonin's increasing the use of liver carbohydrates in rats (Anisimov, 2003) is a significant result supporting this relation. ...
... We were not able to find a study with which we could compare the reduced plasma glucose levels we obtained in the melatoninsupplemented swimming group (group 3). However, Rohr and Herold (2002) concluded in a study that blood glucose levels that increased after intravenous glucose supplementation declined during sleep and melatonin played a significant role in the decline of blood glucose level. Results of Rohr and Herold (2002) are consistent with the reduced glucose levels we found in group 3. ...
... However, Rohr and Herold (2002) concluded in a study that blood glucose levels that increased after intravenous glucose supplementation declined during sleep and melatonin played a significant role in the decline of blood glucose level. Results of Rohr and Herold (2002) are consistent with the reduced glucose levels we found in group 3. ...
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The aim of the present study is to examine how melatonin supplementation affects plasma glucose and liver glycogen levels in rats subjected to acute swimming exercise. Sprague-Dawley species thirty adult male rats were allocated to 3 groups with equal number of animals: general control group which was not subjected to any procedure (Group 1), the group subjected to a 30-minute acute swimming exercise (Group 2), and the group subjected to a 30-minute acute swimming exercise after intraperitoneal (i.p.) melatonin supplementation (3 mg/kg/day) for 4 weeks (Group 3). Blood samples collected from the experimental animals by decapitation method were analyzed in terms of plasma glucose, and glycogen levels were determined in liver tissue samples by histological method. The highest plasma glucose levels were obtained in group 2 (p < 0.05). Plasma glucose levels in groups 1 and 3 were not different. Mean liver glycogen level in group 3 was significantly higher than those in the other groups (p < 0.01), while there was no significant difference between group 1 and group 2 in terms of this parameter. Results of the study demonstrate that melatonin supplementation can have a protective effect on liver glycogen reserves in rats subjected to acute swimming exercise.
... Although sleep temporally coincides in humans with high nocturnal melatonin levels, persistent effects of melatonin on sleep maintenance are less evident. Nevertheless, low nocturnal melatonin is, independently of its specific causes, generally associated with sleep difficulties [65,128129130131. Elderly insomniacs exhibit strongly decreased levels and rhythm amplitudes of the excretion product, 6-sulfatoxyme- latonin, compared to individuals of same age without sleeping difficulties [128], but this phenomenon is not restricted to individuals of advanced age [3]. ...
... Nonetheless, the development of tumors from transformed cells may be favored under conditions of melatonin deficiency , when immunomodulation by the pineal hormone has declined. In humans, melatonin deficiency has been attributed to a higher incidence of prostate [65], endometrial [75, 166], and breast [65, 167] cancers. It has remained unclear whether the decreases in melatonin have occurred prior to the disease and are contributing factors to tumor development or represent secondary changes induced by the tumor. ...
... Nonetheless, the development of tumors from transformed cells may be favored under conditions of melatonin deficiency , when immunomodulation by the pineal hormone has declined. In humans, melatonin deficiency has been attributed to a higher incidence of prostate [65], endometrial [75, 166], and breast [65, 167] cancers. It has remained unclear whether the decreases in melatonin have occurred prior to the disease and are contributing factors to tumor development or represent secondary changes induced by the tumor. ...
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Melatonin is a highly pleiotropic signaling molecule, which is released as a hormone of the pineal gland predominantly during night. Melatonin secretion decreases during aging. Reduced melatonin levels are also observed in various diseases, such as types of dementia, some mood disorders, severe pain, cancer, and diabetes type 2. Melatonin dysfunction is frequently related to deviations in amplitudes, phasing, and coupling of circadian rhythms. Gene polymorphisms of melatonin receptors and circadian oscillator proteins bear risks for several of the diseases mentioned. A common symptom of insufficient melatonin signaling is sleep disturbances. It is necessary to distinguish between symptoms that are curable by short melatonergic actions and others that require extended actions during night. Melatonin immediate release is already effective, at moderate doses, for reducing difficulties of falling asleep or improving symptoms associated with poorly coupled circadian rhythms, including seasonal affective and bipolar disorders. For purposes of a replacement therapy based on longer-lasting melatonergic actions, melatonin prolonged release and synthetic agonists have been developed. Therapies with melatonin or synthetic melatonergic drugs have to consider that these agents do not only act on the SCN, but also on numerous organs and cells in which melatonin receptors are also expressed.
... This theory, known as the melatonin hypothesis, attributes increased cancer risk to decreased melatonin excretion due to the presence of light at night. Melatonin levels have a typical circadian rhythmicity, with the peak of circulating melatonin levels occurring in the middle of the night around 4am, a time at which natural light is rarely present and most humans are asleep (Healy and Waterhouse, 1995;Rohr and Herold, 2002;Stow and Gumz, 2011). However, with the advent of artificial light, sleep/wake and work cycles have become more malleable, and light exposure can easily occur during times that are atypical evolutionarily. ...
... However, with the advent of artificial light, sleep/wake and work cycles have become more malleable, and light exposure can easily occur during times that are atypical evolutionarily. It is important to note that melatonin production in the pineal gland can be suppressed by both natural and artificial light (Stevens et al., 1992;Rohr and Herold, 2002;Anisimov, 2003;Nakahara et al., 2003;Stow and Gumz, 2011), and plasma melatonin levels are often used as an indicator of circadian phase because of the interconnectedness of the pineal gland and the SCN. Anomalies in melatonin cycles are considered symptomatic of circadian disruption (Healy and Waterhouse, 1995;Rohr and Herold, 2002;Nakahara et al., 2003). ...
... It is important to note that melatonin production in the pineal gland can be suppressed by both natural and artificial light (Stevens et al., 1992;Rohr and Herold, 2002;Anisimov, 2003;Nakahara et al., 2003;Stow and Gumz, 2011), and plasma melatonin levels are often used as an indicator of circadian phase because of the interconnectedness of the pineal gland and the SCN. Anomalies in melatonin cycles are considered symptomatic of circadian disruption (Healy and Waterhouse, 1995;Rohr and Herold, 2002;Nakahara et al., 2003). While suppression of melatonin occurs as a result of exposure to visible light, melatonin synthesis remains rhythmic in the absence of light. ...
... Meanwhile, a relatively large body of evidence has accumulated for reductions of melatonin under stressful and painful conditions, however, with considerable interindividual variation. These include several forms of cardiac diseases (coronary heart disease, myocardial infarction, cardiac syndrome X)149150151152153154155, fibromyalgia [125,156], neuralgia [156], migraine [157,158], severe epilepsy [159,160], Menière's disease [161], bulimia [156], critical illness162163164, postoperative stress [165], acute intermittent porphyria, especially during seizures [166,167], and cases of cancer [168,169]. Decreases in melatonin have been also observed in diabetes type 2 [170,171]. ...
... Meanwhile, a relatively large body of evidence has accumulated for reductions of melatonin under stressful and painful conditions, however, with considerable interindividual variation. These include several forms of cardiac diseases (coronary heart disease, myocardial infarction, cardiac syndrome X)149150151152153154155, fibromyalgia [125,156], neuralgia [156], migraine [157,158], severe epilepsy [159,160], Menière's disease [161], bulimia [156], critical illness162163164, postoperative stress [165], acute intermittent porphyria, especially during seizures [166,167], and cases of cancer [168,169]. Decreases in melatonin have been also observed in diabetes type 2 [170,171]. ...
... Meanwhile, a relatively large body of evidence has accumulated for reductions of melatonin under stressful and painful conditions, however, with considerable interindividual variation. These include several forms of cardiac diseases (coronary heart disease, myocardial infarction, cardiac syndrome X)149150151152153154155, fibromyalgia [125,156], neuralgia [156], migraine [157,158], severe epilepsy [159,160], Menière's disease [161], bulimia [156], critical illness162163164, postoperative stress [165], acute intermittent porphyria, especially during seizures [166,167], and cases of cancer [168,169]. Decreases in melatonin have been also observed in diabetes type 2 [170,171]. ...
Article
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The mammalian circadian system is composed of numerous oscillators, which gradually differ with regard to their dependence on the pacemaker, the suprachiasmatic nucleus (SCN). Actions of melatonin on extra-SCN oscillators represent an emerging field. Melatonin receptors are widely expressed in numerous peripheral and central nervous tissues. Therefore, the circadian rhythm of circulating, pineal-derived melatonin can have profound consequences for the temporal organization of almost all organs, without necessarily involving the melatonin feedback to the suprachiasmatic nucleus. Experiments with melatonin-deficient mouse strains, pinealectomized animals and melatonin receptor knockouts, as well as phase-shifting experiments with explants, reveal a chronobiological role of melatonin in various tissues. In addition to directly steering melatonin-regulated gene expression, the pineal hormone is required for the rhythmic expression of circadian oscillator genes in peripheral organs and to enhance the coupling of parallel oscillators within the same tissue. It exerts additional effects by modulating the secretion of other hormones. The importance of melatonin for numerous organs is underlined by the association of various diseases with gene polymorphisms concerning melatonin receptors and the melatonin biosynthetic pathway. The possibilities and limits of melatonergic treatment are discussed with regard to reductions of melatonin during aging and in various diseases.
... It seems that stressful conditions generally have the potential for depressing melatonin. Low levels of melatonin were also observed in women with fibromyalgia (Rohr and Herold, 2002;Acuñ a-Castroviejo et al., 2006;Reiter et al., 2007) and pain has been reported to be reduced by replacement therapy (Citera et al., 2000;Reiter et al., 2007;Sá nchez-Barceló et al., 2010). Decreased melatonin has also been reported in patients with migraine (Claustrat et al., 1989(Claustrat et al., , 1997. ...
... In fact, elderly insomniacs exhibited strongly decreased levels and rhythm amplitudes of the excretion product, 6-sulfatoxymelatonin, compared to individuals of same age without sleeping difficulties (Haimov et al., 1994). The association of sleep difficulties with low levels of melatonin, often in conjunction with abnormal phasing of the residual secretion pattern, has been repeatedly observed (Haimov and Lavie, 1995;Zisapel, 1999;Haimov, 2001;Rohr and Herold, 2002;Lipton et al., 2009) and is not restricted to elderly individuals. Almost complete suppression of melatonin secretion after surgery in pediatric survivors of craniopharyngioma caused inappropriate daytime sleep and nocturnal awakenings, although the circadian rhythm of sleep/wakefulness was clearly discernible in the actograms (Lipton et al., 2009). ...
... It appears rather to represent a physiological chemopreventive action of the pineal hormone and may involve the tumor suppressor actions of some core oscillator genes, as discussed in a previous section. In various studies, melatonin deficiency has been attributed to a higher incidence of prostate (Rohr and Herold, 2002), endometrial (Chubb, 1999;Viswanathan et al., 2007) and breast (Rohr and Herold, 2002;Schernhammer et al., 2010) cancers. The precise mechanisms of cancer prevention remain to be elucidated (Stevens, 2009). ...
Article
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Melatonin, the neurohormone of the pineal gland, is also produced by various other tissues and cells. It acts via G protein-coupled receptors expressed in various areas of the central nervous system and in peripheral tissues. Parallel signaling mechanisms lead to cell-specific control and recruitment of downstream factors, including various kinases, transcription factors and ion channels. Additional actions via nuclear receptors and other binding sites are likely. By virtue of high receptor density in the circadian pacemaker, melatonin is involved in the phasing of circadian rhythms and sleep promotion. Additionally, it exerts effects on peripheral oscillators, including phase coupling of parallel cellular clocks based on alternate use of core oscillator proteins. Direct central and peripheral actions concern the up- or downregulation of various proteins, among which inducible and neuronal NO synthases seem to be of particular importance for antagonizing inflammation and excitotoxicity. The methoxyindole is also synthesized in several peripheral tissues, so that the total content of tissue melatonin exceeds by far the amounts in the circulation. Emerging fields in melatonin research concern receptor polymorphism in relation to various diseases, the control of sleep, the metabolic syndrome, weight control, diabetes type 2 and insulin resistance, and mitochondrial effects. Control of electron flux, prevention of bottlenecks in the respiratory chain and electron leakage contribute to the avoidance of damage by free radicals and seem to be important in neuroprotection, inflammatory diseases and, presumably, aging. Newly discovered influences on sirtuins and downstream factors indicate that melatonin has a role in mitochondrial biogenesis.
... Deficiency in the production of endogenous melatonin that results in specific functional losses are improved by supplementation with exogenous melatonin (52). There is ample evidence of reduced endogenous melatonin in various types of cardiac diseases (53)(54)(55)(56)(57), fibromyalgia (51,58), neuralgia (58), migraine (59,60), epilepsy (61,62), Menières disease (63), various cancers (64,65), attention-deficit hyperactivity disorder (66), recurrent depression (67), and bipolar disorder (68). Agorastos and Lindhorst describe potential pleiotropic benefits of melatonergic treatments to remediate problems with chronodisruption, hypothalamic pituitary adrenal-axis dysfunction, sympathoadrenal and autonomic dysregulation, neuroimmunomodulation, oxidative stress, brain injury, cognitive function, memory and neurocircuitry, mood and anxiety disorders (32). ...
... Deficiency in the production of endogenous melatonin that results in specific functional losses are improved by supplementation with exogenous melatonin (52). There is ample evidence of reduced endogenous melatonin in various types of cardiac diseases (53)(54)(55)(56)(57), fibromyalgia (51,58), neuralgia (58), migraine (59,60), epilepsy (61,62), Menières disease (63), various cancers (64,65), attention-deficit hyperactivity disorder (66), recurrent depression (67), and bipolar disorder (68). Agorastos and Lindhorst describe potential pleiotropic benefits of melatonergic treatments to remediate problems with chronodisruption, hypothalamic pituitary adrenal-axis dysfunction, sympathoadrenal and autonomic dysregulation, neuroimmunomodulation, oxidative stress, brain injury, cognitive function, memory and neurocircuitry, mood and anxiety disorders (32). ...
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Background: Sleep disturbances are a hallmark of posttraumatic stress disorder (PTSD), yet few studies have evaluated the role of dysregulated endogenous melatonin secretion in this condition. Methods: This study compared the sleep quality and nocturnal salivary melatonin profiles of Canadian Armed Forces (CAF) personnel diagnosed with PTSD, using the Clinician Administered PTSD Scale (CAPS score ≥50), with two healthy CAF control groups; comprising, a “light control” (LC) group with standardized evening light exposure and “normal control” (NC) group without light restriction. Participants were monitored for 1-week using wrist actigraphy to assess sleep quality, and 24-h salivary melatonin levels were measured (every 2h) by immunoassay on the penultimate day in a dim-light (< 5 lux) laboratory environment. Results: A repeated measures design showed that mean nocturnal melatonin concentrations for LC were higher than both NC (p = .03) and PTSD (p = .003) with no difference between PTSD and NC. Relative to PTSD, NC had significantly higher melatonin levels over a 4-h period (01 to 05 h), whereas the LC group had higher melatonin levels over an 8-h period (23 to 07 h). Actigraphic sleep quality parameters were not different between healthy controls and PTSD patients, likely due to the use of prescription sleep medications in the PTSD group. Conclusions: These results indicate that PTSD is associated with blunted nocturnal melatonin secretion, which is consistent with previous findings showing lower melatonin after exposure to trauma and suggestive of severe chronodisruption. Future studies targeting the melatonergic system for therapeutic intervention may be beneficial for treatment-resistant PTSD.
... It has been argued that physical activity might bring about a change in plasma melatonin levels [2] and that melatonin supplementation has a performance-enhancing effect in exercise [3,4]. It has been observed that blood glucose which increased after intravenous glucose administration dropped back during sleep [5]. A report that melatonin played a significant role in this decrease in the blood glucose level [5] can be considered to be sound evidence of the relationship between carbohydrate metabolism and pineal gland. ...
... It has been observed that blood glucose which increased after intravenous glucose administration dropped back during sleep [5]. A report that melatonin played a significant role in this decrease in the blood glucose level [5] can be considered to be sound evidence of the relationship between carbohydrate metabolism and pineal gland. Furthermore, the account that melatonin increased the use of carbohydrates in rats [6] is a crucial factor supporting this relationship. ...
Article
This study aimed to examine the effects of melatonin supplementation on liver glycogen levels in rats with streptozotocin- induced diabetes and subjected to acute swimming exercise. Eighty Sprague-Dawley type adult male rats were divided into eight groups: Group 1, general control; Group 2, melatonin-supplemented control; Group 3, melatonin-supplemented diabetes; Group 4, swimming control; Group 5, melatonin-supplemented swimming; Group 6, melatonin-supplemented diabetic swimming; Group 7, diabetic swimming; Group 8, diabetic control. Melatonin was supplemented at a dose of 3 mg/kg/day intraperitoneally for four weeks. Liver tissue samples were collected and evaluated using a Nikon Eclipse E400 light microscope. All images obtained from the light microscope were transferred to PC medium and evaluated using Clemex PE 3.5 image analysis software. The lowest liver glycogen levels in the study were found in group 4. Liver glycogen levels in groups 3, 6, 7 and 8 (the diabetic groups) were higher than group 4, but lower than those in groups 1 and 2. The lowest liver glycogen levels were obtained in groups 1 and 2. The study indicates that melatonin supplementation maintains the liver glycogen levels that decrease in acute swimming exercise, while induced diabetes prevents this maintenance effect in rats.
... In some patients the symptoms could be recurrent or there could be some subjects with mixed (IBS-M) or unsubtyped (IBS-U) IBS. Most studies have shown a female predominance in patients with IBS (12, 14, 15, 19, 20). Our results agree with the results obtained by Lu et al. who performed the study on female patients with IBS and found decreased salivary melatonin and urine 6-SMLT level compared to non-IBS volunteers (20). ...
... Our results agree with the results obtained by Lu et al. who performed the study on female patients with IBS and found decreased salivary melatonin and urine 6-SMLT level compared to non-IBS volunteers (20). Low melatonin levels were observed in women with eating disorders, moreover, the low melatonin concentrations were related to increased depressive symptomatology especially sadness, bodily discomfort, inner tension, difficulties in attention concentration and pain (19, 20). In the current study we observed the lower level of 6-SMLT/crea in men compared to women and the issue deserves further investigations, althought some differences concerning the function of serotonin and its receptors in male and female patients with IBS are known. ...
Article
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There is a substantial evidence that large quantities of melatonin are produced in gastrointestinal tract, however, is still unclear which is the role of melatonin in digestive system in human physiology and pathophysiology. In the present study we investigated urinary excretion of a main melatonin metabolite, 6-sulphatoxymelatonin, in patients with irritable bowel syndrome (IBS). The investigation was carried out in 67 persons, both sexes, aged 20-45 years old who according to Rome III Criteria were diagnosed as sufferers of constipation (C-IBS, n=21 persons) or diarrhoea (D-IBS, n=24 persons) form of irritable bowel syndrome and as healthy subjects (K, n=22), matched for control. Samples were obtained from the collected diurnal urine. The concentration of 6-sulphatoxymelatonin (6-SMLT) was measured with ELISA method, creatinine (crea) was automatically analyzed with biochemical analyzer and 6-SMLT/crea calculated. There were statistically significant differences between groups: the 6-SMLT/crea level was lower in C-IBS (103.86+/- 82.83 ng/mg) and D-IBS (112.72+/-85.29 ng/mg) groups compared to K group (202.7+/-89.28 ng/mg), respectively, p=0.002, p=0.003. There were no differences between C-IBS and D-IBS groups, however, there were observed differences between men and women with C-IBS. The 6-SMLT/crea. level was higher in women with C-IBS (139.31+/-96.45) compared to men with C-IBS (35.51+/-41.05) (p=0.04). These results suggest that different melatonin secretion and metabolism may be involved in the pathogenesis of irritable bowel syndrome.
... Gece saatlerinde serotonin miktarının azalması melatonin sentezinin artmasından yani serotoninin melatonine dönüştürülmesinden kaynaklanmaktadır. [8,11,[17][18][19][20][21] Hayvan deneylerinde NAT enzimi aktivitesinin ve dolayısıyla melatoninin kan düzeyinin karanlıkta zirve yaptığı gösterilmiştir. Bu periyod, pineal bezde norepinefrinin dönüşümünün ve bezi innerve eden sempatik sinir liflerinden kaynaklanan spontan aktivitenin tepe yaptığı saatlere rastlamaktadır. ...
... Ayrıca uykuya başlama hızının ve uyku kalitesinin artacağı da bildirilmektedir. [18,19,32,33] Dikkat eksikliği/hiperaktivite ve uyku başlangıcında bozukluğu (sleep-onset insomnia) olan çocuk hastalar için melatonin tedavisi önerilmektedir. [34] Ancak bazı araştırmalarda uyku problemi yaşayan erişkin kişilerdeki melatonin düzeyinin uyku problemi olmayan kişilerden düşük olmadığı bulunmuştur. ...
... Pain reduced by melatonin [129,130] [128] Bulimia [123] Critical illness [131][132][133] ...
Article
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Melatonin is a pleiotropically acting regulator molecule, which influences numerous physiological functions. Its secretion by the pineal gland progressively declines by age. Strong reductions of circulating melatonin are also observed in numerous disorders and diseases, including Alzheimer's disease, various other neurological and stressful conditions, pain, cardiovascular diseases, cases of cancer, endocrine and metabolic disorders, in particular diabetes type 2. The significance of melatonergic signaling is also evident from melatonin receptor polymorphisms associated with several of these pathologies. The article outlines the mutual relationship between circadian oscillators and melatonin secretion, the possibilities for readjustment of rhythms by melatonin and its synthetic analogs, the consequences for circadian rhythm-dependent disorders concerning sleep and mood, and limits of treatment. The necessity of distinguishing between short-acting melatonergic effects, which are successful in sleep initiation and phase adjustments, and attempts of replacement strategies is emphasized. Properties of approved and some investigational melatonergic agonists are compared.
... Большинство как экспериментальных, так и клинических работ указывают на противосудорожные свойства мелатонина. Существуют и другие данные, указывающие, что бензодиазепины обладают противосудорожным действием и снижают уровень мелатонина в крови, с другой стороны мелатонин действует посредством гамма-аминомасляной кислоты (ГАМК) и на бензодиазепиновые рецепторы [40]. Катамениальные приступы прекращаются в менопаузу, которая является индикатором старения и, соответственно, снижения содержания мелатонина, с другой стороны патогенез катамениальной эпилепсии связан с половыми гормонами [5,34]. ...
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The effect of the epiphysis hormone melatonin on the brain bioelectrical activity is understudied: the data of experimental and clinical studies of melatonin effects are inconclusive and related mostly to exogenous administration. We studied 43 patients with focal epilepsy, 25 patients with cryptogenic epilepsy and 18 with symptomatic epilepsy. Carbamazepine and valproate were used as anticonvulsive drugs. Morning and evening urine concentrations of 6-sulfatoxymelatonin (6-COM), the main melatonin metabolite, were determined twice using immunoassay method: in autumn at the inclusion in the study and beginning of the anticonvulsant treatment and after 6 months, in spring, when anticonvulsant doses had been adjusted. The presence of epileptic seizures was associated with the reduction of melatonin concentration in the body that was supported by the decrease of urine 6-COM, in particular in the morning, in non-treated patients. Prescription of anticonvulsant treatment resulted in the increase of 6-COM. The concentration of the morning urine 6-COM was higher in patients with focal epilepsy receiving anticonvulsant treatment with valproate compared to those receiving carbamazepine: 49.28±6.71 and 37.09±5.43 ng/ml versus 20.00±3.6 and 13.11±2.08 ng/ml in patients treated with valproate and carbamazepine, respectively, before and after the adjustment.
... Amara. disorders includes: Schizophrenia (Only in a subpopulation) [134]; Multiple sclerosis [135], Primary obsessive-compulsive disorder [136], Menière's disease [137], Fibromyalgia, Pain [138,139], Migraine [140], Cancer [141] Critical illness [142] and, other forms. There are a respective number of diseases associated with the melatonin disorder. ...
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This review is a "Food For Thought" about the role of the DNA repair genes, Food and, our genes in health maintaining. From the different kind of diseases could be happening (including the degenerative diseases) because of the defect or leakage in the DNA repair system; facts will be pointed about its role in protecting us against "the major human killer" the "Cancer". The different types of interaction between our genes and, our Food have been addressed. There is a need for systematic rearrangement of the information in our hand for better understanding for the role of the DNA repair genes and, better use of our Food. I direct this review content to prove the "Inevitability of Balanced lives" for good health and, safe life.
... The time of the nocturnal melatonin peak secretion was significantly delayed in depressive subjects compared to healthy controls [79], although both groups showed no significant difference in the mean level of melatonin. Interestingly, in patients with major depression, positive response to antidepressants correlated with an increase in their melatonin profiles, but only patients suffering from delayed sleep phase syndrome were successfully treated with melatonin [80]. ...
Article
As the mainstream medical world is confronted with the dramatic increases in the utilization of complementary and alternative medicine (CAM) therapies, much is unknown regarding how to adequately consider these alternative treatments. There is little scientific justification to support the use of the vast array of alternative options, but these treatments are readily available to the public and CAM pro- fessionals. The public has been choosing to use dietary supplements, which has driven the increased utilization of CAM treatments in the past decade. This chapter discusses CAM treatments for major depression, but the primary focus is on dietary supplements. It is important to discuss how CAM clinicians ascertain that alternative treatment modalities are appropriate and then ascertain factors/symptoms in depressive illness that are most relevant when choosing from a myriad of treatment options available. It is important to mention that a substantial portion of the public has been utilizing dietary supplements without consulting CAM or non-CAM clinicians.
... It can be expected that melatonin will receive wide consideration for treatment of sleeping disturbances, jet lag, and fibromyalgia. 64 External magnetic fields have also been found to synchronize melatonin secretion in experimental animals and humans and may be beneficial in the treatment of post-menopausal osteoporosis. Pineal melatonin has been shown in animals to be involved in the regulation of calcium and phosphorus metabolism by stimulating the parathyroid glands and by inhibiting calcitonin release and prostaglandin synthesis Menopause is associated with a decline in melatonin secretion and increased pineal calcification. ...
... It is responsible for regulating sleep cycle and helping with insomnia and jet lag. Melatonin only helps with depressed patients that are suffering from delayed sleep that are on antidepressant [33]. It is an excellent supplement or insomnia with no co-morbidities to maintain sleep, as well as SAD in winter months. ...
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Complementary and Alternative Medicine (CAM) has been used for a wide variety of disease states including psychiatric disorders. Herbal and nutritional supplements play an important role in CAM therapy and therefore their efficacy and safety should be explored, especially in psychiatric disorders. The Food and Drug Administration (FDA) does not regulate herbals and supplements and therefore caution must be used before making a decision. A careful overview of products with good scientific evidence will enable clinicians and patients to make a more informative decision. Even though herbals and nutritional supplements are usually safe, some may interact with a patient’s current medication(s) and produce unwanted adverse event(s) that could potentially be fatal. It is not only important to determine if an herbal or supplement is effective, but also consider their possible interactions, overall safety and toxicity and other drawbacks. Keywords: CAM, psychiatric disorders, herbal supplement, nutritional supplement
... Abnormal regulation of sex-hormones (122), thyroid hormones (123,124), and melatonin (125,126) is observed in patients with anxiety disorder and depression. ...
... These include various cases in which there is no reason to assume dysfunction of the SCN. In particular, such reductions have been found to accompany several stressful or painful conditions, such as Menièreʼs disease [374], fibromyalgia and neuralgia [375], migraines [376,377], heart diseases [378][379][380][381][382][383][384], critical illness [109,385,386] and cases of cancer [387,388], in which the contribution of stress and pain has remained unclear, as well as in some metabolic diseases, such as acute intermittent porphyria [389,390], and notably, diabetes type 2 [391,392]. In some neurological disorders, decreases in melatonin are only observed in subpopulations of affected individuals or in a very limited number of subjects studied [364]. ...
Article
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Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under natural conditions. In spite of the positive impact of artificial light, we pay a price for the easy access to light during the night: disorganization of our circadian system or chronodisruption (CD), including perturbations in melatonin rhythm. Epidemiological studies show that CD is associated with an increased incidence of diabetes, obesity, heart disease, cognitive and affective impairment, premature aging and some types of cancer. Knowledge of retinal photoreceptors and the discovery of melanopsin in some ganglion cells demonstrate that light intensity, timing and spectrum must be considered to keep the biological clock properly entrained. Importantly, not all wavelengths of light are equally chronodisrupting. Blue light, which is particularly beneficial during the daytime, seems to be more disruptive at night, and induces the strongest melatonin inhibition. Nocturnal blue light exposure is currently increasing, due to the proliferation of energy-efficient lighting (LEDs) and electronic devices. Thus, the development of lighting systems that preserve the melatonin rhythm could reduce the health risks induced by chronodisruption. This review addresses the state of the art regarding the crosstalk between light and the circadian system.
... One of the most important mediators involved in the performance of melatonin in improving the psychological symptoms is Gamma-aminobutyric acid (GABA) which affects the regulation of humans' behavioral function. GABA reaches its maximum level during the night when melatonin secretion increases and has similar effects to clonazepam and sedatives (36). Beneficial effects of melatonin for treatment of certain insomnias are also able to improve the psychological symptoms (37). ...
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Menopause is one of the most critical periods of woman's life. With reducing of ovarian estrogen; women are more prone to psychological and physical symptoms. The present study aimed to investigate the effect of melatonin on the climacteric symptoms. The present double blind, placebo randomized controlled clinical trial was conducted on 240 menopausal women (40 - 60 years old) referring to the gynecology clinics of Shiraz University of Medical Sciences (January - November 2012). The participants were randomly divided into two groups through sortition. Demographic characteristics, Goldberg's general health questionnaire (GHQ), Greene Climacteric Scale and level of Follicle Stimulating Hormone (FSH) were determined for both groups before the intervention. The intervention group received one 3mg melatonin tablet each night for 3 months and the control group received the placebo in the same period. Changes of climacteric symptoms and drug complications were measured 1, 2 and 3 months after the intervention. We analyzed the data of 99 postmenopausal women in the intervention group and 101 postmenopausal women in the control group. In the melatonin group, the climacteric symptoms score decreased from 35.73+11.6 to 17.09+10.22 during the 3-month study period and regardless of time, a significant difference was observed between the two groups (P<0.001). In addition, a significant difference was found between the two groups regarding various dimensions of the climacteric symptoms over time (P<0.001). No significant difference was found regarding side effects between the two groups (P= 0.135). The study findings showed that using melatonin improved the climacteric symptoms.
... Regarding the first subtype of menopause-related sleep disturbances that is associated with depression, it should be noted that some subtypes of depression, including bipolar disorder (BP), lead to decreases in melatonin 31,32 . Reduced levels and atypical secretion patterns of melatonin have been also observed in obstructive sleep apnea syndrome (OSAS) 33,34 and chronic obstructive pulmonary disease (COPD) 35 , findings that may indicate a possible relationship to the second type of sleepdisordered breathing. ...
Article
One of the core symptoms of the menopausal transition is sleep disturbance. Peri-menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings. Factors that may play a role in this type of insomnia include vasomotor symptoms, changing reproductive hormone levels, circadian rhythm abnormalities, mood disorders, coexistent medical conditions, and lifestyle. Other common sleep problems in this age group, such as obstructive sleep apnea and restless leg syndrome, can also worsen the sleep quality. Exogenous melatonin use reportedly induces drowsiness and sleep and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age and the menopausal transition. Recently, more potent melatonin analogs (selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonists) with prolonged effects and slow-release melatonin preparations have been developed. They were found effective in increasing total sleep time and sleep efficiency as well as in reducing sleep latency in insomnia patients. The purpose of this review is to give an overview on the changes in hormonal status to sleep problems among menopausal and postmenopausal women.
... This may be explained by an increase in carbohydrate use during exercise (Trionfante et al., 2017). In addition, Rohr and Herold (2002) found that GL, which increases after intravenous glucose supplementation, decreases during sleep. This has been related to a hypoglycemic role of MEL and elucidated a relationship between the pineal gland and the mechanisms of carbohydrate use. ...
Article
Background: While the promotion of the beneficial effects of melatonin (MEL) ingestion on the modulation of oxidative stress is widespread, less attention is given to the biological influence that it could exert on the results of hematology and clinical chemistry parameters. This study was undertaken to assess the effects of acute MEL ingestion on these parameters during a maximal running exercise. Methods: In double blind randomized design, 12 professional soccer players [age: 17.54 ± 0.78 yrs, body mass: 70.31 ± 3.86 kg, body height: 1.8 ± 0.08 m; maximal aerobic speed (MAS): 16.85 ± 0.63 km/h; mean ± standard deviation], all males, performed a diurnal (17:00 h ± 30 h) running exercise test (RET) at 100% of their MAS following either MEL or placebo ingestion. Blood samples were obtained at rest and following the RET. Results: Compared to placebo, MEL intake decreased post-exercise biomarkers of liver damage (aspartate aminotransferase, p<0.001; alanine aminotransferase, p<0.001; gamma-glutamyltransferase; p<0.05) and improved post-exercise renal function markers (i.e., creatinine, p<0.001). However, lipid profile, glucose, lactate and leukocyte were not affected by MEL ingestion. Regarding the time to exhaustion, no difference was found between MEL (362.46 ± 42.06 s) and PLA (374.54 ± 57.97 s) conditions. Conclusion: The results of this investigation clearly attest that MEL ingestion before a maximal running exercise might protect athletes from liver damage and perturbation in renal function biomarkers. However, this study comprises an acute MEL supplementation and no assessment on chronic effects or circadian rhythm the day before was done.
... These findings introduce creatine supplementation as useful dietary intervention to improve muscle function in fibromyalgia patients (45). Lower levels of melatonin and urinary metabolites as 6-sulphatoxymelatonin (6-SMT) were found in FM patients (46)(47)(48)(49) and the more recent works seem to agree on the efficacy of melatonin in the management of pain in fibromyalgia (50,51). In the last few years, many authors have suggested an association between chronic muscular pain and vitamin D deficiency and these observations have stimulated a great deal of research exploring whether a relationship exists between muscle pain and low vitamin D serum levels (52)(53)(54)(55)(56)(57). ...
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Camillo Giacomelli,* Francesca Sernissi,* Alessandra Rossi, Stefano Bombardieri, Laura BazzichiRheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy *These authors contributed equally to the manuscript Abstract: Fibromyalgia is a common syndrome diagnosed by clinical criteria. The main symptom of fibromyalgia is pain, but patients frequently also complain about other nonspecific symptoms, such as headache, sleep disturbance, mood disorder, and cognitive impairment. In the light of the multifactorial origin of the disease and of the lack of objective diagnostic findings, several attempts have been made to find a reliable biomarker. For this reason, over the years, a number of patients and various biological samples have been studied, using many different approaches and techniques. Despite this, none of these studies has been able to find the proper biomarker. The aim of this review is to provide a critical overview of the current environment characterizing the search for fibromyalgia biomarkers. Keywords: genetics, proteomics, oxidative stress, fibromyalgia
... Notably, these changes in melatonin are also observed in some symptoms linked to menopause. Regarding the first subtype of menopause-related sleep disturbances that is associated with depression, it should be noted that some subtypes of depression, including bipolar disorder (BP), lead to decreases in melatonin [31,32]. Reduced levels and atypical secretion patterns of melatonin have been also observed in obstructive sleep apnea syndrome (OSAS) [33,34] and chronic obstructive pulmonary disease (COPD) [35], findings that may indicate a possible relationship to the second type of sleep-disordered breathing. ...
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The pineal hormone Melatonin plays an important role in the regulation of the circadian sleep/wake cycle, mood, and perhaps immune functions, carcinogensis and reproduction. The human circadian rhythm of melatonin release from the pineal gland is tightly synchronized with the habitual hours of sleep. Peri- and postmenopausal women often complain of difficulties initiating and/or maintaining sleep, with frequent nocturnal and early morning awakenings. In this review we discuss the pathophysiology of melatonin function as it relates to sleep disorders in menopausal women, highlighting the potential use of exogenous melatonin during the menopausal transition and beyond.
... In humans, melatonin secretion decreases with age [22]. These changes are particularly apparent in perimenopausal women [23,24]. Some researchers believe that the reduction in melatonin secretion in women begins around the age of 40 years and may initiate menopause [25]. ...
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Background Dyspeptic syndrome is particularly common in postmenopausal women in the form of epigastric pain. The aim of the study was to assess the role of melatonin in chronic dyspepsia in this group of women, and examine the role of Helicobacter infection. Methods The study comprised 152 subjects including 30 healthy women (Group I), 60 women with asymptomatic H.pylori infection (Group II), and 64 women with H. pylori infection with chronic dyspepsia (Group III). Endoscopic examination was performed, as well as histological assessment of gastric end duodenal mucosa, urease breath test (UBT-13C), and immunoenzymatic assessment of serum 17-β-estradiol, follicle stimulating hormone and melatonin, and urinary 6-sulfatoxymelatonin. In Group III, 14-day antibacterial treatment was introduced with pantoprazole, amoxicillin and levofloxacin followed a six-month treatment with placebo in 32 women (Group IIIa), and melatonin 1 mg/morning and 3 mg/at bedtime in the other 32 women (Group IIIb). Results No significant differences were found between serum level of female hormone. Serum melatonin levels were similar between Group I (12.5 ± 2.72 pg/ml) and Group II (10.5 ± 3.73 pg/ml; p > 0,05). The level was significantly lower in Group III (5.72 ± 1.42 pg/ml; p < 0.001). Eradication of H.pylori was obtained in 75.0% women in Group IIIa, and in 84.3% in Group IIIb (p > 0.05). After six months, dyspeptic symptoms resolved in 43.7% patients in Group IIIa and 84.3% in Group IIIb (p < 0.001). Conclusion Melatonin supplementation is useful in treating H. pylori-associated dyspepsia, particularly in postmenopausal women with lower levels of this hormone. Trial registration NCT04352062, date of registration: 15.04.2020.
... Melatonin as a regulator of daily and annual cycles of physiological functions of the body and, in particular, the reproductive system of animals and humans in recent years has increasingly attracted the attention of researchers. [1][2][3][4][5] However, not only changes in melatonin production depending on the length of the light and the dark time of day is determined by seasonal and daily rhythms of reproduction system restructuring, but its unique antioxidant, immunomodulating properties as well as participate in the metabolic processes at the cellular and tissue levels provide reproductive health. [6][7][8][9][10] Melatonin is synthesized in the pineal gland, 11 which is the physiological control of the endocrine function to a large extent is light regime. ...
... Amara. disorders includes: Schizophrenia (Only in a subpopulation) [134]; Multiple sclerosis [135], Primary obsessive-compulsive disorder [136], Menière's disease [137], Fibromyalgia, Pain [138,139], Migraine [140], Cancer [141] Critical illness [142] and, other forms. There are a respective number of diseases associated with the melatonin disorder. ...
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This review is a "Food For Thought" about the role of the DNA repair genes, Food and, our genes in health maintaining. From the different kind of diseases could be happening (including the degenerative diseases) because of the defect or leakage in the DNA repair system; facts will be pointed about its role in protecting us against "the major human killer" the "Cancer". The different types of interaction between our genes and, our Food have been addressed. There is a need for systematic rearrangement of the information in our hand for better understanding for the role of the DNA repair genes and, better use of our Food. I direct this review content to prove the "Inevitability of Balanced lives" for good health and, safe life.
... Many authors reported the therapeutic usefulness of melatonin in different fields of medicine, e.g., the treatment of FMS suggesting that it is an alternative and safe treatment for patients with this pathology since it determines an improvement in severity of pain [14][15][16]. Moreover, serum levels of melatonin and its precursors were reported to be low in patients with FMS affecting sleep and perception and therefore, the melatonin supplementation, responsible for reducing the oxidative stress burden during aging and/or pathological conditions [16][17][18], may be a novel approach for the management of patients with FMS [19,20]. Furthermore, considering the oxidative damage associated with FMS, the use of powerful antioxidants such as melatonin, alone or in combination with other therapies, may improve the outcome of this pathology [21][22][23]. ...
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Fibromyalgia syndrome (FMS) is considered a musculoskeletal disorder associated to other symptoms including chronic pain. Since the hypothesis of FMS etiogenesis is consistent with mitochondrial dysfunction and oxidative stress, we evaluated the pathophysiological correlation among these factors studying some proteins involved in the mitochondrial homeostasis. We focused our attention on the roles of peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1α), mitofusin2 (Mfn2), and coenzyme Q10 (CoQ10) in reserpine-induced myalgic (RIM) rats that manifest fibromyalgia-like chronic pain symptoms. First, we underlined that RIM rats are a good model for studying the pathophysiology of FMS and moreover, we found that PGC-1α, Mfn2, and CoQ10 are involved in FMS. In fact, their expressions were reduced in gastrocnemius muscle determining an incorrect mitochondrial homeostasis. Today, none of the currently available drugs are fully effective against the symptoms of this disease and they, often, induce several adverse events; hence, many scientists have taken on the challenge of searching for non-pharmacological treatments. Another goal of this study was therefore the evaluation of the potential benefits of melatonin, an endogenous indoleamine having several functions including its potent capacity to induce antioxidant enzymes and to determine the protective or reparative mechanisms in the cells. We observed that melatonin supplementation significantly preserved all the studied parameters, counteracting oxidative stress in RIM rats and confirming that this indoleamine should be taken in consideration for improving health and/or counteract mitochondrial related diseases.
... In contrast, other studies (31,37) have found that MEL attenuates the decrease of plasma [Gl] observed after exercise. Else, Rohr and Herold (36) found that [Gl], which increases after intravenous glucose supplementation, decreases during sleep. This has been related to a hypoglycemic role of MEL and elucidated the relationship between the pineal gland and the mechanisms of carbohydrate use. ...
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OBJECTIVES: Fatigue is a limiting factor for sport performance. For this reason, optimal recovery after training is just as critical as the training program itself, if not more. Indeed, there is a need for strategies that can facilitate recovery after training, and one such strategy is the ingestion of supplements like melatonin (MEL). This study aimed to evaluate if MEL intake could improve recovery of athletes after an intermittent training session (ITS). METHODS: Fifteen elite female athletes (17.4 ± 0.4 years, 76.4 ± 5.6 kg, 1.76 ± 0.04 m; mean ± standard deviation) participated in two testing campaigns. During each period, they performed a battery of physical and cognitive tests before and after an ITS, as well as after ingesting MEL (6 mg tablet) or placebo in a randomized design. The ITS comprised the modified agility T-test, squat jump, counter movement jump, maximum standing ball-throw velocity test, maximum jump ball-throw velocity test, and 20-m sprint. Oral temperature (OT) and vigilance were evaluated before and after the ITS. Rating of perceived exertion (RPE), blood lactate [La], and glucose [Gl] were recorded after each ITS. RESULTS: Short-term performance, recovery of physical performance, and OT were not affected by MEL ingestion after the ITS. Moreover, MEL did not affect cognitive performance or RPE scores after the ITS. However, [La] and [Gl] (p < 0.05 for both) were decreased after MEL ingestion. CONCLUSION: MEL has no effect on the recovery of physical performance but may affect glucose utilization and lactate metabolism during the team-handball training session.
... Однако исследователями установлено, что изменения секреции мелатонина в перименопаузальный период носят неоднозначный характер -у 13 % обследуемых женщин имел место высокий уровень мелатонина при повышенных концентрациях пролактина в крови [9]. Влияние пролактина на уровень мелатонина было подтверждено работами зарубежных исследователей [37]. E. Toffol et al. (2014) в своём исследовании о влиянии мелатонина на настроение, сон, вазомоторные симптомы и качество жизни у женщин в зависимости от фазы менопаузы показали, что женщины в постменопаузе имеют более низкие концентрации мелатонина в сыворотке в ночное время, чем женщины в перименопаузе. ...
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The aim of this review is analyze the literature data on the role of the circadian system key element - melatonin in the regulation of the sleep-wake cycle in menopausal women. It is shown that the melatonin level defined in a variety of biological fluids (blood, saliva, urine) depends on age, sex, race, and chronotype. It is detected that morning melatonin can be used as a biological marker for determining human chronotype. Most studies indicate that melatonin decreases with age, and that in women this hormone level is lower than in men. For sleep disorders, lower values of melatonin are revealed, although the results of the studies are ambiguous. Also, the studies show the shift of hormone secretion peaks in the early morning hours. The dependence of circadian rhythm of melatonin secretion on the climacteric phase has been revealed. This determines different approaches to the therapy of sleep disorders. It is extremely important to study the role of melatonin as an adaptogen of the female reproductive system because climacteric syndrome is the realization of a violation of the adaptation of the woman's organism in conditions requiring increased activity of the adaptive system of the body and sleep disorders are common in menopausal women.
... The low toxicity of MLT administration has encouraged studies to examine the effects of MLT, alone or in combination with other drugs, in different type of tumors, and also, in patients having low MLT production and secretion [16]. The studies conducted in the last decades exhibited a significant correlation between MLT deficiency and a higher incidence of some cancer types [17] such as prostate [18], endometrial [19], and breast cancers [20]. ...
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This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland secretory product, an evolutionarily highly conserved molecule; it is also an antioxidant and an impressive protector of mitochondrial bioenergetic activity. MLT is characterized by an ample range of activities, modulating the physiology and molecular biology of the cell. Its physiological functions relate principally to the interaction of G protein-coupled MT1 and MT2 trans-membrane receptors (GPCRs), a family of guanidine triphosphate binding proteins. MLT has been demonstrated to suppress the growth of various tumours both, in vivo and in vitro. In this review, we analyze in depth, the antioxidant activity of melatonin, aiming to illustrate the cancer treatment potential of the molecule, by limiting or reversing the changes occurring during cancer development and growth.
... It is also known that the pineal gland plays a modulating role in the female reproductive system regulation. The decay of the activity of the pineal gland as the circadian system humoral effector may, in turn, desynchronize main signals that are necessary for the reproductive function realization [37]. Administration of melatonin to experimental animals, according to some data, is able to correct the age-associated impairments of the reproductive function regulation hypothalamo-pituitary link [38]. ...
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Industrial xenobitics, as well as endogenous damaging factors, such as L-homocysteine, are a well-known source of reactive oxygen species that disrupt biological processes. Among many others, luteinizing hormone releasing hormone synthesis and secretion mediated by a variety of neurotransmitters, which are under control of the hypothalamus and pineal gland, may be put in peril by reactive oxygen species. Their formation can be one of the reasons for the reproductive function shutdown in ageing as the generic response to the damaging factors independent of their nature. We review recent findings demonstrating the role of reactive oxygen species in disrupting the circadian signal originated in the main pacemaker of the organism, the suprachiasmatic nuclei of the hypothalamus, on its way to the hypothalamic areas responsible for the luteinizing hormone preovulatory surge.
... 20 Disruptions in sleeping pattern or menstrual cycle during flights across several time zones have been suspected to increase breast cancer risk. 21 This is believed to be due to excess exposure to light during normal sleeping hours and thus impaired pineal secretion of melatonin. 22 The melatonin hypothesis is supported by epidemiological studies on blind people. ...
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Overview Breast Cancer Epidemiology Hormones And Breast Cancer Pharmacologic Approaches To Breast Cancer Prevention Dietary Chemopreventive Strategies A Role For Inflammatory Prostaglandin Blockade The Pineal Hormone Melatonin And Breast Cancer Building Evidence Conclusion
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Melatonin is a neurohormone secreted mainly by the pineal gland that controls circadian rhythm, which is primarily regulated by light. Although melatonin levels are known to be altered in individuals with sleep disorders, melatonin also has modulatory effects on other body systems, including the skeletal and immune systems. In addition, melatonin has been shown to interfere with carbohydrate and lipid metabolism and to have significant antioxidant effects, both directly and via its metabolites. Melatonin levels vary throughout human life and are known to decrease with age but the effects of declining melatonin levels are poorly understood. In women, this age-related decrease in melatonin levels coincides with the menopause. This review aims to summarize the impact of altered melatonin levels in ageing women and the outcomes of exogenous replacement therapies.
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The CNS is both source and target of melatonin. This methoxyindole formed in the pineal gland is also produced in other CNS regions and additionally enters the brain by uptake from the circulation as well as via the pineal recess. The mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN), not only controls the pineal, but also receives a feedback information on darkness. Two G protein-coupled melatonin receptors, MT1 and MT2, are responsible for the transduction of many melatonergic actions. High receptor densities are especially found in the SCN, but their presence at lower expression levels in other areas is functionally important. Various metabolites and analogs are formed in the CNS, such as N-acetylserotonin, 5-methoxytryptamine, 5-methoxytryptophol, 5-methoxylated kynuramines, and even 6-sulfatoxymelatonin. The chronobiological effects of melatonin go beyond the resetting of a single circadian oscillator. They contribute to phase relationships between oscillatory subsets and are required for robust rhythm amplitudes. CNS effects of melatonin comprise sleep initiation, antiexcitatory, antiepileptic, antinociceptive, anxiolytic, proneurotrophic, antiinflammatory, antioxidant and other neuroprotective actions. The role as a sleep-promoting compound, which is limited by its short half-life in the circulation, has led to the development of controlled-release formulations and of various synthetic agonists, such as ramelteon, agomelatine, tasimelteon, TIK-301, UCM765 and UCM924. Their differences concerning receptor affinities, preferences for receptor subtypes, and pharmacokinetics are discussed, as well as additional antidepressive actions of agomelatine and TIK-301 based on properties as antagonists of the serotonergic 5-HT2C receptor. Indirect antidepressive effects by melatonergic drugs are largely explained by circadian readjustments.
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North-America and northern European countries exhibit the highest incidence rate of breast cancer, whereas women in southern regions are relatively protected. Immigrants from low cancer incidence regions to high-incidence areas might exhibit similarly higher or excessive cancer risk as compared with the inhabitants of their adoptive country. Additional cancer risk may be conferred by incongruence between their biological characteristics and foreign environment. Many studies established the racial/ethnic disparities in the risk and nature of female breast cancer in United States between African-American and Caucasian women. Mammary tumors in black women are diagnosed at earlier age, and are associated with higher rate of mortality as compared with cancers of white cases. Results of studies on these ethnic/racial differences in breast cancer incidence suggest that excessive pigmentation of dark skinned women results in a relative light-deficiency. Poor light exposure may explain the deleterious metabolic and hormonal alterations; such as insulin resistance, deficiencies of estrogen, thyroxin and vitamin-D conferring excessive cancer risk. The more northern the location of an adoptive country the higher the cancer risk for dark skinned immigrants. Recognition of the deleterious systemic effects of darkness and excessive melatonin synthesis enables cancer protection treatment for people living in light-deficient environment. Recent patents provide new methods for the prevention of hormonal and metabolic abnormities.
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Sleep disturbances (SD) represent one of the main symptoms of menopause and they are caused by several factors. Hormonal changes such as the reduction of oestrogen levels and the consequent vasomotor symptoms (VMS) along with psychiatric disorders such as depression and anxiety could contribute to the onset of SD. Furthermore, obesity per sè or through the obstructive sleep apnoea (OSA) could blunt sleep. Moreover, in menopause is usual a reduction in melatonin, that could contribute to SD. Nutritional strategies are paramount because they could contribute to manage menopause-related SD, in particular tackling obesity and overweight. Furthermore, some foods, such as soy, fish, whole grains, vegetables and fruit could decrease symptoms like depression and VMS, correlated with SD in postmenopausal women. Therefore, the aim of this review is to provide an overview of the current evidence on SD in menopause and to provide nutritional strategies for managing SD in this context.
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This review describes the role of biogenic amines in the hypothalamic regulation of ovarian cycles in female rats. The mechanisms of action of industrial xenobiotics and experimental hyperhomocysteinemia, which induces premature aging of the reproductive function, are discussed. The point of view that the damaging action of reactive oxygen species is the basis of the unified response of hypothalamic regulation of reproductive cycles to external and internal neurotoxic impacts is substantiated. We describe the involvement of melatonin and short regulatory peptides in antioxidant protection of the reproductive system during aging.
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It is well-established that human nocturnal melatonin secretion is suppressed by presentation of artificial light >2,000 lux, a level that is also therapeutically effective in alleviating winter depression symptoms of Seasonal Affective Disorder [SAD]. Furthermore, early-morning bright light induces phase advances of the melatonin cycle in SAD patients (Lewy et al., 1987 a). The functional significance of melatonin in SAD remains unclear. With plasma melatonin sampled at 20-min intervals in a series of overnight studies, we found marked phase delays of the cycle, relative to that previously reported for normals, in 4/5 depressed SAD patients. 2,500 lux light exposure at 6–8a.m. resulted in exponentially declining melatonin levels that approached low daytime baselines within two hours (t1/2 = 45.52 min). All five patients showed clinical remissions as well as phase advances of the melatonin cycle of 0.75 to 3.27 hours (mean, 1.94 0.84hours) after one week of daily exposure from 6–8a.m. and p.m. These results suggest that the combination of early morning and early evening light exposures induces circadian phase adjustments similar to those of morning light alone, by impacting a photosensitive interval when, in SAD, melatonin secretion overshoots its normal nocturnal phase.
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The effect of melatonin (5 mg, p.o.) on electroencephalographic (EEG) activity during sleep was investigated in eight men in a placebo-controlled cross-over design. Melatonin was administered immediately prior to a Ph daytime sleep episode (13-17 h) after a partial sleep deprivation. The non-REM sleep stages and REM sleep duration were not significantly affected. Melatonin enhanced EEG power density in non-REM sleep in the 13.75-14.0 Hz bin (i.e., within the frequency range of sleep spindles), and reduced activity in the 15.25-16.5 Hz band. In the first 2 h spectral values within the 2.25-5.0 Hz range were reduced. These changes in the EEG are to some extent similar to those induced by benzodiazepine hypnotics and to the contribution of the endogenous circadian pacemaker to the spectral composition of the sleep EEG when sleep occurs at night.
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The acute soporific effect of melatonin in humans has been demonstrated in a range of studies. How alertness and performance are changed after melatonin given in the morning is not yet known. In a double-blind, placebo-controlled study of nine healthy young men, melatonin was given at 0700 h under controlled conditions of a modified constant routine protocol lasting 56 h (2 days, 3 nights with sleep). A clear decrement in neurobehavioral functions as measured by the Psychomotor Vigilance Test lasted for 6 h after melatonin administration (particularly in the lapse domain and median of the reaction time) without any effect on a letter cancellation task. A subjective soporific effect was present but less pronounced. Thus, melatonin taken in the morning requires caution in situations where high attention is needed.
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Two normal control populations, separated by 8,000 miles and 24 degrees of latitude, had similar six-month mean values for overnight urinary melatonin concentrations. These values were significantly higher than six-month values for depressed subjects and abstinent alcoholic subjects, while the means for the two clinical populations were similar. Age and urinary melatonin concentration in the control and clinical populations were inversely related, but the slopes of the linear regression equations were ten times steeper for the control populations than for the clinical populations. Differences in age and sex distributions accounted for some of the differences in values between controls and the clinical populations, although controls still differed from the clinical populations, even after sex and age were factored out. The disparate slopes for age and melatonin concentrations may contribute to some of the conflicting findings of studies comparing populations of different ages. The total melatonin content in the samples from alcoholic subjects, but not the depressed subjects, was lower than that for controls. The difference in the urinary melatonin concentration between the controls and the two patient groups was not accounted for by difference in duration of urine collection period, hours of sleep or body weight.
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This case-control study addressed the hypothesis that uninterrupted exposure to light is associated with increased rates of breast cancer. We compared the odds of profound binocular blindness among women with a diagnosis of breast cancer with the odds of profound binocular blindness among women with diagnoses of coronary heart disease or stroke. All hospital discharges in the National Hospital Discharge Survey from 1979 through 1987 were analyzed, after exclusion of women with diabetes. Profoundly blind women were half as likely to have breast cancer as women who were not profoundly blind. This effect diminished substantially with increasing age.
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It is well-established that human nocturnal melatonin secretion is suppressed by presentation of artificial light greater than 2,000 lux, a level that is also therapeutically effective in alleviating winter depression symptoms of Seasonal Affective Disorder [SAD]. Furthermore, early-morning bright light induces phase advances of the melatonin cycle in SAD patients (Lewy et al., 1987a). The functional significance of melatonin in SAD remains unclear. With plasma melatonin sampled at 20-min intervals in a series of overnight studies, we found marked phase delays of the cycle, relative to that previously reported for normals, in 4/5 depressed SAD patients. 2,500 lux light exposure at 6-8 a.m. resulted in exponentially declining melatonin levels that approached low daytime baselines within two hours (t1/2 = 45.52 min). All five patients showed clinical remissions as well as phase advances of the melatonin cycle of 0.75 to 3.27 hours (mean, 1.94 +/- 0.84 hours) after one week of daily exposure from 6-8 a.m. and p.m. These results suggest that the combination of early morning and early evening light exposures induces circadian phase adjustments similar to those of morning light alone, by impacting a photosensitive interval when, in SAD, melatonin secretion overshoots its normal nocturnal phase.
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The effects of the pineal hormone, melatonin, and of pinealectomy on the incidence of mammary adenocarcinoma in Sprague-Dawley rats treated with 7,12-dimethylbenz(alpha)-anthracene (DMBA) were investigated. Melatonin (2.5 mg/kg), begun on the same day as DMBA (5 mg) treatment and given daily in the afternoon for 90 days, significantly reduced the incidence of mammary tumors from 79% (control) to 20% (treated) (p less than 0.002). Rats pinealectomized at 20 days of age and treated with 7 mg of DMBA at 50 days of age had a higher incidence of tumors (88%) compared to control animals (22%). Fifteen mg of DMBA, which resulted in a higher incidence of tumors, reduced the difference between pinealectomized and control animals. Melatonin only partially reversed the effects of pinealectomy, reducing the incidence from 87% (pinealectomy alone) to 63% (pinealectomy plus melatonin); however, the tumor incidence was still lower (27%) in nonpinealectomized, melatonin-treated animals. Assessment of plasma prolactin, luteinizing hormone, follicle-stimulating hormone, estradiol, and cortisol in DMBA-treated tumor-free and tumor-bearing animals revealed a significantly lower plasma prolactin concentration [27 +/- 5 (S.E.) ng/ml] in melatonin-treated animals as compared to vehicle-treated animals [65 +/- 8 ng/ml]. The concentration of plasma prolactin was less in melatonin-treated, pinealectomized rats (55 +/- 10 ng/ml) as compared to vehicle-treated, pinealectomized animals (101 +/- 13 ng/ml). Other hormones were not affected by melatonin treatment. These data support the hypothesis that melatonin inhibits the development of DMBA-induced mammary tumors in the rat while removal of the pineal gland stimulates development of such tumors. Additionally, these experiments provide evidence that these effects may be mediated by a suppression of plasma prolactin levels.
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Circadian changes in plasma levels of melatonin, prolactin, LH and FSH were studied in four groups: seven healthy young men, six elderly men, six elderly women and six elderly demented patients (two men and four women). The daily activities of the subjects were synchronous and blood samples were taken every 4 h. The 24-h mean concentrations of prolactin in plasma were the same in all groups, whereas those of LH and FSH were twice as high in the elderly as in the young men and eight and 23 times higher respectively in the elderly women. The 24-h mean plasma levels of melatonin in the elderly were half those in the young, but were not influenced by the sex or mental condition of the subjects. A statistically significant circadian rhythm for melatonin was defined in the four groups, for prolactin in all groups except the elderly men and for LH only in the demented patients and in the young men. No circadian rhythm could be detected for FSH in any of the four groups. The acrophases of melatonin and prolactin ranged between 02.30 and 04.00 h, those of LH (when a rhythm was validated) clustered around 01.00 h. The circadian rhythms of plasma levels of melatonin, prolactin and LH are not modified in old age nor in dementia. A positive correlation has been demonstrated in young men between melatonin and LH and between melatonin and prolactin, but no such correlation could be found in the elderly.
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Seasonal changes in adaptations associated with winter coping strategies have been frequently studied. Central among the suite of energy-saving, winter-coping strategies is the suspension of reproductive activities. The inhibition of reproduction by nontropical rodents is mediated by daylength changes. Although balanced annual energy budgets are critical, survival and subsequent reproductive success also require avoiding predators, illness, and early death. Because the stressors of winter could lead to suppressed immune function, we hypothesized that animals should have evolved survival strategies involving immunoenhancement. Short daylengths provide a predictive cue to individuals that could be used to enhance immune function in advance of stress-induced immunosuppression. In Experiment 1, adult female deer mice (Peromyscus maniculatus) were housed in either long (LD 16:8) or short (LD 8:16) days for 8 weeks, then injected with the chemical carcinogen 9,10-dimethyl-1,2-benzanthracene (DMBA) dissolved in dimethyl sulfoxide (DMSO) or with the DMSO vehicle alone. Animals were evaluated weekly for 8 weeks after injection. None of the animals treated with DMSO developed tumors in any of the experiments. Nearly 90% of the long-day deer mice injected with DMBA developed squamous cell carcinoma. None of the short-day deer mice injected with DMBA developed tumors. Small lesions developed at the site of injection; short-day females had less severe lesions and healed faster than long-day females. Immunoglobulin G (IgG) response to i.p. injection of sheep red blood cells (SRBC) did not differ photoperiodic conditions. The role of estrogens in the photoperiodic responses was evaluated in Experiment 2: Ovariectomized or sham-ovariectomized deer mice received estradiol benzoate replacement therapy or a control procedure in long daylengths for 8 weeks prior to injection of DMBA or DMSO, then were monitored for 8 additional weeks. Females treated with DMBA developed tumors at the same rate, regardless of estrogen manipulation. Estrogen did not affect healing rates. In Experiment 3, female deer mice were injected with a slurry of microspheres that either contained bromocriptine or were empty. Suppression of prolactin with bromocriptine resulted in a decrease of tumor incidence from 55.6% to 24% in long-day females 8 weeks after injection with DMBA. Healing rates were not affected by prolactin manipulations. Silastic capsules that were filled with either melatonin or cholesterol were implanted into long-day female deer mice in Experiment 4; 8 weeks later, females received an injection of either DMBA or DMSO, then were monitored for 8 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)
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Blood levels of the pineal hormone melatonin are high at night and low during the day. Its secretion is regulated by a rhythm-generating system located in the suprachiasmatic nucleus of the hypothalamus, which is in turn regulated by light. Melatonin is regulated not only by that circadian oscillator but acts as a darkness signal, providing feedback to the oscillator. Melatonin has both a soporific effect and an ability to entrain the sleep-wake rhythm. It also has a major role in regulating the body temperature rhythm. Melatonin rhythms are altered in a variety of circadian rhythm disorders. Melatonin treatment has been reported to be effective in treatment of disorders such as jet lag and delayed sleep phase syndrome.
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In winters 1990-1991 and 1991-1992 women with and without seasonal affective disorder, winter type, were treated by light at 2500 lux either in the morning (0800h-1000h) or afternoon (1600h-1800h). In winter before light treatment, melatonin levels in serum in daytime (1200h and 1600h) were higher in patients compared to controls (p < 0.05). This difference disappeared in the summer or after light treatment in the winter. Also, light treatment and change in season resulted in a phase advance shift of melatonin rhythm in patients. The decline in melatonin levels correlated with the decline in specific SAD symptoms of hyperphagia and carbohydrate craving. In winter, neither patients nor controls showed significant diurnal variations in levels of whole blood serotonin. In both patients and controls, levels of serotonin were higher in summer as compared with winter, especially at 2000h. Our data suggest that elevated daytime melatonin can be a state marker of winter depression, and that seasonal change of photoperiod may also affect the circadian amplitude and daytime levels of blood serotonin.
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We tested the hypothesis that phase-delayed circadian rhythms underlie seasonal affective disorder (SAD) by measuring phase position of 6-sulfatoxymelatonin excretion and comparing antidepressant response to morning or evening light given as a first treatment. Randomized controlled trial. Ambulatory. Thirty-two women and seven men with SAD. Light therapy (2500 lux for 1 hour for 1 week) was administered either at 7 AM or 10 PM, preceded by a baseline week and followed by a withdrawal week. Our SAD patient sample was moderately depressed (Hamilton Depression Scale [HAM-D] score 18); a HAM-D reduction of 50% or more was found in 12 of 18 patients given morning and in 15 of 21 patients given evening light (70% response rate). Response was not dependent on age, gender, stage of the menstrual cycle, time of year, or on the timing or duration of sleep. Urinary 6-sulfatoxymelatonin was measured in 30 patients; 22 had phase-delayed circadian rhythms. However, phase position was correlated neither with depth of depression nor with a preferential response to morning or evening light. Both morning and evening light therapy improved depressive symptoms in patients with SAD independent of their circadian phase or sleep timing. These findings argue against a circadian phase-delay hypothesis of the pathophysiology of SAD, or the necessity of a phase-advance by morning light for clinical efficacy. They additionally suggest more practicable and flexible schedules for light therapy in SAD, since time of day is not crucial.
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The hypotensive effect of a short term intranasal application of melatonin (2.0 mg/day for 1 week) in 20 untreated patients with essential hypertension (36 ± 3.8 years) was tested in a double-blind experiment. The melatonin treatment was successful in 85% of patients: the systolic and diastolic blood pressure decreased significantly from 182 ± 19 to 124 ± 9 mmHg and from 112 ± 3 to 79 ± 8 mmHg respectively (p <0.001). The intranasal application of melatonin increased, the very low melatonin serum concentration at 14.00 hours (12.7 ± 2.1 pg/ml) to the normal range (24.6 ± 6.3 pg/ml, p <0.001) within a week. Mild side effects (tiredness and sedation in 7 and diarrhoea in 2 patients) disappeared after 2-3 day of treatment; no sleep induction by melatonin was recognized. These results suggest that the essential hypertension is also due to pathological melatonin secretion. Melatonin is a new natural anti-hypertensive drug in the therapy of the essential hypertension in man.
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Background Previous studies have suggested that bipolar patients are supersensitive to light suppression of melatonin and that this may be a trait marker for genetic vulnerability. The present study was an attempt to replicate and extend this observation. Propranolol hydrochloride effects were compared with light effects because of the documented influence of β-adrenergic receptors on melatonin production. Nighttime levels of corticotropin and cortisol were also examined as potential trait vulnerability markers. Methods Melatonin levels in euthymic bipolar patients (n=29) were tested before and after 500-lux light was administered between 2 and 4 AM and on a separate night in the dark. Results were compared with those of a group of patients with unipolar depression (n=24) and with those of a group of non–psychiatrically ill control subjects (n=50). Lithium effects and propranolol effects were tested in subgroups. Results No group differences were seen in light suppression among bipolar patients, unipolar patients, and controls; an analysis of the whole group did not reveal differences in propranolol effect, differences in corticotropin or cortisol levels, or evidence for a lithium effect. However, patients with bipolar I affective disorder showed the following: (1) significantly lower melatonin levels on the light night, at baseline and following light exposure; and (2) a later peak time for melatonin on the dark night. Conclusions The general hypothesis of increased light sensitivity in bipolar patients was not supported. However, melatonin secretion abnormalities were confirmed in the subgroup with bipolar I disorder. Further assessments of circadian rhythm disruption as a vulnerability marker in bipolar illness are indicated.
Article
Objective: We tested the hypothesis that phase-delayed circadian rhythms underlie seasonal affective disorder (SAD) by measuring phase position of 6-sulfatoxymelatonin excretion and comparing antidepressant response to morning or evening light given as a first treatment. Design: Randomized controlled trial. Setting: Ambulatory. Patients: Thirty-two women and seven men with SAD. Intervention: Light therapy (2500 lux for 1 hour for 1 week) was administered either at 7 AM or 10 PM, preceded by a baseline week and followed by a withdrawal week. Results: Our SAD patient sample was moderately depressed (Hamilton Depression Scale [HAM-D] score 18); a HAM-D reduction of 50% or more was found in 12 of 18 patients given morning and in 15 of 21 patients given evening light (70% response rate). Response was not dependent on age, gender, stage of the menstrual cycle, time of year, or on the timing or duration of sleep. Urinary 6-sulfatoxymelatonin was measured in 30 patients; 22 had phase-delayed circadian rhythms. However, phase position was correlated neither with depth of depression nor with a preferential response to morning or evening light. Comment: Both morning and evening light therapy improved depressive symptoms in patients with SAD independent of their circadian phase or sleep timing. These findings argue against a circadian phase-delay hypothesis of the pathophysiology of SAD, or the necessity of a phaseadvance by morning light for clinical efficacy. They additionally suggest more practicable and flexible schedules for light therapy in SAD, since time of day is not crucial.
Article
• Seasonal affective disorder (SAD) is a syndrome characterized by recurrent depressions that occur annually at the same time each year. We describe 29 patients with SAD; most of them had a bipolar affective disorder, especially bipolar II, and their depressions were generally characterized by hypersomnia, overeating, and carbohydrate craving and seemed to respond to changes in climate and latitude. Sleep recordings in nine depressed patients confirmed the presence of hypersomnia and showed increased sleep latency and reduced slow-wave (delta) sleep. Preliminary studies in 11 patients suggest that extending the photoperiod with bright artificial light has an antidepressant effect.
Article
We investigated the relationship between body mass (i.e., wet mass) at nest-leaving and lipid content in 372 European Starling Sturnus vulgaris chicks in New Zealand to test the hypothesis that heavier chicks have greater lipid stores than lighter chicks, thereby enhancing their chances of surviving stressful periods after leaving the nest. Mass at nest-leaving ranged from 63 to 92 g. Total lipid content varied from 1.8 to 10.2 g, and increased as chick body mass increased up to 80 g, after which it leveled off. The lipid index (g lipid/g lean dry mass) varied from 0.106 to 0.470. The daily energy expenditures of fledglings of different masses were calculated to estimate the maximum number of hours that they could be sustained by their lipid stores after leaving the nest. Although the estimated fasting capability of the lightest chicks is only seven hours, most chicks (92%) had similar capacities of 15 to 20 h. This similarity in estimated fasting capability of most chicks is inconsistent with the hypothesis and may result from a compromise between the risks associated with carrying large lipid stores and the likelihood of encountering poor feeding conditions shortly after leaving the nest.
Article
This open-label, short-term pilot study was designed to assess the efficacy and tolerability of melatonin in the treatment of sleep disturbances in elderly patients. The 41 patients (28 women and 13 men; mean age [±SD], 74 ± 12 years) were separated into three groups: (1) patients with sleep disturbances alone (n = 22); (2) patients with sleep disturbances and signs of depression (n = 9); and (3) patients with sleep disturbances and dementia of the degenerative or vascular type (n = 10). All patients received 3-mg gelatin capsules of melatonin orally 30 minutes before expected sleep time for 21 days. Overall sleep quality and daytime alertness were assessed by means of structured clinical interviews and sleep logs completed by the patients (or their caregivers in the case of dementia patients). Starting from day 2 or 3 of treatment, melatonin significantly improved sleep quality and decreased the number of awakenings in patients with sleep disturbances with or without associated depression. Patients with dementia did not show significant improvement of sleep quality. Estimates of next-day function (ie, alertness in the morning and during the day) improved significantly only in patients exhibiting sleep disturbances alone. Clinical assessment indicated that symptoms improved in 16 (73%) of the patients with sleep disturbances alone and 4 (44%) of those with sleep disturbances associated with depression, and that agitated behavior at night (sundowning) decreased significantly in 7 (70%) of the patients with dementia. This was reflected by the coefficient of variation of bedtime, which averaged 58% in patients with dementia compared with 27% and 33% in nondepressed and depressed patients, respectively, on days 0 to 2 of treatment, and which decreased significantly only in dementia patients when reassessed on days 19 to 21. Four (31%) of the 13 patients with primary insomnia who were receiving benzodiazepines concomitantly reduced their benzodiazepine use (by 50% to 75% of initial doses) and 4 (31%) discontinued use of these agents; of the 7 patients with depression and 7 with dementia who were receiving benzodiazepines concomitantly, 2 (29%) in each group reduced benzodiazepine use by up to 50%. No side effects considered to be attributable to treatment were reported. The results of this trial suggest that melatonin may be useful for the treatment of primary sleep disturbances in elderly patients.
Article
Our objective was to investigate the effects of melatonin on the free radical-induced oxidative damage to mitochondria in fetal rat brain. Female Wistar rats on day 19 of pregnancy were used. Melatonin (10 mg/kg) or vehicle (control) was injected intraperitoneally 60 min prior to laparotomy for removal of the fetuses. The mitochondrial fraction was isolated from the fetal rat brain of each group. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were measured. As indicators of mitochondrial respiratory activity, we determined the respiratory control index (RCI) and the adenosine 5-diphosphate/oxygen (ADP/O) ratio in the presence and absence of 2.5 μM hypoxanthine and 0.02 units/mL xanthine oxidase. Mitochondrial lipid peroxidation was determined by measuring the concentration of thiobarbituric acid reactive substances in fetal brain mitochondria in the presence or absence of 2.5 μM hypoxanthine, 0.02 units/mL xanthine oxidase, and 50 μM FeSO4. The free radical-induced rates of inhibition of mitochondrial RCI and the ADP/O ratio were both significantly lower in the fetal rat brains treated with melatonin compared with those of the controls (RCI, 44.25±15.02% vs. 25.18±5.86%, P<0.01; ADP/O ratio, 50.74±23.05% vs. 13.90±7.80%, P<0.001). The mitochondrial lipid peroxidation induced by free radicals was significantly reduced in the melatonin-treated group compared with the controls (484.2±147.2% vs. 337.6±61.0%, P<0.01). Pretreatment with melatonin significantly increased the activity of GSH-Px (20.35±5.27 to 28.93±11.01 mU/min mg−1 protein, P<0.05) in fetal rat brain mitochondria, but the activity of SOD did not change significantly. Results indicate that the administration of melatonin to the pregnant rat may prevent the free radical-induced oxidative mitochondrial damage to fetal rat brain by a direct antioxidant effect and the activation of GSH-Px.
Article
Previous human stuthes have indicated that daytime melatonin levels increase when the organism is subjected to the stress of fasting and exercise. Melatonin, epinephrine, and norepinephrine levels were measured during a mock run and in the course of treadmill exercise performed before (T-l), during (T-2), and following (T-3) a progressive conditioning (running) program. Hormonal responses to the training program were determined by comparing values at T-l and T-3. Plasma melatonin, epinephrine, and norepinephrine levels rose significantly (P < .01) from baseline values for each exercise intensity during all three treadmill runs. While a dose-response trend was observed in each of the norepinephrine and epinephrine trials, there appeared to be a progressive diminution of this relationship in melatonin between intensities. Further, as training progressed, the peak melatonin concentration was decreased by 52% from T-l to T-3, while peak epinephrine and norepinephrine values diminished only 19% and 8%, respectively. These results suggest that vigorous exercise training may attenuate rather than augment the secretion of pineal melatonin. Development of a human model of pineal responsiveness to exercise may contribute to the elucidation of exercise-associated reproductive disorders.
Article
The effect of melatonin on human carbohydrate metabolism is not yet clear. We investigated whether melatonin influences glucose tolerance and insulin sensitivity in aged women. Twenty-two postmenopausal women of whom 14 were on hormone replacement therapy. After an overnight fast, at 0800 hours on two nonconsecutive days, placebo or melatonin (1 mg) were administered randomly and in a double blind fashion. Forty-five minutes later, an oral glucose tolerance test (75 g; OGTT) was performed in 13 women. In another nine women insulin-dependent (Si) and -independent (Sg) glucose utilization was tested by a frequently sampled intravenous glucose tolerance test (FSIGT). Areas under the response curve to OGTT (AUC) for glucose (1420 ± 59 vs. 1250 ± 55 mmol × min/l; P < 0·01), and C-peptide (420980 ± 45320 vs. 33528 ± 15779 pmol × min/l; P < 0·02) were higher following melatonin than placebo, while Si values were lower (2·6 ± 0·28 units vs. 3·49 ± 0·4 units; P < 0·03). Si modifications induced by melatonin were inversely related to Si values of the placebo day (r2 = 0·538; P < 0·025). The present results indicate that in aged women administration of 1 mg of melatonin reduces glucose tolerance and insulin sensitivity. The present data may have both physiological and clinical implications.
Article
The temporal organization of plasma melatonin. cortisol. growth hormone (GH) and prolactin secretion was examined in healthy rested controls and in patients suffering from episodic cluster headache. Eleven patients with typical cluster headache (10 men, 1 female) and 8 male controls were studied over a 24-h period: blood was collected at 2-h intervals during the day and at l-h intervals at night. Plasma melatonin. cortisol, GH and prolactin levels were determined by radioimmunoassay. Most of the cluster headache patients showed a decrease in nocturnal melatonin secretion and the melatonin rhythm was even completely abolished in one patient. Chronobiological analysis of the cluster headache patients' 24-h plasma melatonin profile showed a significant decrease in amplitude and mesor: these were 58.7 pg/ml and 34.4 pg/ml respectively in control subjects, versus 18.7 pg/ml and 17.6 pg/ml for the patients. In addition. patients showed a significant phase-advance in their melatonin rhythm For cortisol, the rhythm appeared slightly blunted in the cluster headache group and was significantly phase-advanced. The plasma prolactin profile showed no significant alteration, but for plasma GH the nocturnal peak was advanced in some patients: in the absence of sleep recording, however, no conclusion could be drawn. Results from this study suggest a neuroendocrine dysregulation in cluster headache in the endogenous clock which controls the pineal rhythmicity.
Article
The pineal gland serves the function of a neuroendocrine transducer converting information about day length into the nocturnal release of melatonin. Melatonin acts on the brain, particularly on the hypothalamus, to affect several biological rhythms. By employing autoradiography and 2-[125I]melatonin as a radioligand, the hypothalamic suprachiasmatic nucleus (SCN) and the pars tuberalis of the adenohypophysis have been identified as sites for melatonin binding exhibiting dissociation constants (Kds) in the 10−10 M range. These sites were also revealed in test-tube binding assays employing crude membrane fractions. Additionally, studies in either membrane or cytosol fractions using tritiated or radioiodine-labelled melatonin indicated location of another population of presumptive melatonin binding sites with Kds in the 10−8 −10−9 M range in several other brain areas, including the hippocampus, cerebral and cerebellar cortexes, as well as the pineal gland. Signal transduction processes for melatonin presumably involve interaction with G proteins to inhibit adenylate cyclase. Also, a decrease of Ca2+ uptake, stimulation of guanylate cyclase and inhibition of cyclooxygenase occur at 10−8 M melatonin concentrations. The time of administration of melatonin is critical for hormone action. In rodents and humans, a major late afternoon-early evening period of sensitivity is found for several central and peripheral effects of melatonin. Results in rats suggest that central synapses employing τ-aminobutyric acid (GABA) as an inhibitory transmitter are a target for pineal melatonin activity because: (a) pinealectomy (Px) disrupts circadian rhythmicity of brain GABA and benzodiazepine (BZP) binding; (b) low doses of melatonin counteract Px-induced modifications of BZP and GABA binding; (c) chronic melatonin treatment increases brain BZP and GABA binding; (d) melatonin administration accelerates brain GABA turnover rate; (e) melatonin increases glutamic acid decarboxylase activity and Cl− ion conductance in the medial basal hypothalamus-preoptic area, with maximal activity in the evening. As BZP, melatonin could affect circadian rhythmicity by modifying GABAergic mechanisms in the endogenous oscillator. Additionally, the epileptoid state described after Px and the mild sedation and torpor that follow administration of pharmacological amounts of melatonin can be explained by an effect on central GABAergic circuits.
Article
In normal subjects, the secretion of melatonin, the pineal hormone that regulates the rhythm of many functions, exhibits a circadian pattern synchronized with the day–night cycle. An alteration of this secretory pattern has been found in various psychiatric disorders (seasonal affective disorder, bipolar disorder, unipolar depression, bulimia, anorexia, schizophrenia, panic disorder, obsessive compulsive disorder). At present, it is not known if such alterations have an etiological role or are secondary to the dysfunctions underlying the different disorders. In addition, we do not know if the involvement of melatonin in several disorders has the same significance in the pathophysiology of each disorder. An understanding of the role of the pineal hormone and of its alterations in psychiatric diseases could help to identify the biological mechanisms underlying such disorders.
Article
The objectives of this study were to test the sensitivity of the short form 36 health survey questionnaire (SF 36) to sleep disruption in patients with obstructive sleep apnoea (OSA) and assess its use as an outcome measure for treatment with nasal continuous positive airway pressure (CPAP). Two hundred and twenty-three subjects under investigation for snoring and/or daytime somnolence completed the questionnaire at presentation and again after a six month period. Subjects with OSA requiring treatment scored lower on all dimensions of the SF 36 (P < 0.05) than normative scores for the general population. The largest differences were for vitality (24%) and social functioning (27.9%). After six months of treatment with CPAP there was an improvement in all scores and the score for vitality was no longer significantly different from that of the general population. The SF 36 is sensitive to the effects of sleep disruption in subjects with obstructive sleep apnoea, is a useful outcome measure for treatment with CPAP and its value in other sleep disorders should be assessed.
Article
The hypothesis that diminished function of the pineal gland may promote the development of breast cancer in human beings is suggested by the relation between breast cancer and prolonged oestrogen excess, and by the observation that the pineal secretion, melatonin, inhibits ovarian oestrogen production, pituitary gonadotrophin production, and sexual development and maturation. The hypothesis is supported by the following points. (1) Pineal calcification is commonest in countries with high rates of breast cancer and lowest in areas with a low incidence; the incidences of pineal calcification and of breast cancer are moderate among the black population in the United States. (2) Chlorpromazine raises serum-melatonin; there are reports that psychiatric patients taking chlorpromazine have a lower incidence of breast cancer. (3) Although information is lacking on breast cancer, the pineal and melatonin may influence tumour induction and growth in experimental animals. (4) The demonstration of a melatonin receptor in human ovary suggests a direct influence of this hormone on the ovarian function, and possibly oestrogen production. (5) Impaired pineal secretion is believed to be an important factor triggering puberty (early menarche is a risk factor for breast cancer).
Article
Melatonin was measured in human daytime CSF samples originating in the lumbar sac and basal cisterns. No gradient was found for melatonin, although significantly more 5-hydroxyindoleacetic acid was found in the cisternal samples. This suggests that, in the daytime, melatonin is not released directly from the pineal into the third ventricle, as that would produce a CSF gradient. Presumably daytime CSF melatonin is derived from blood and the original sources may include the retina, intestine and pineal.Daytime human CSF melatonin showed a significant negative correlation with age over the age range 8 to 70 years.
Article
The effects of behaviorally nonactive doses of melatonin and diazepam were investigated in two test models for anxiolytics in mice to see whether mutual enhancement could be observed when the two treatments were combined. The test models used were the four plates test and the tail suspension test. In the former test anxiolytics increase the number of punished crossings and in the latter increase the duration of immobility of mice suspended by the tail. In the four plates test combined treatment with melatonin (128 and 256 mg/kg IP) and diazepam (0.5 mg/kg PO) caused a significant increase in the number of punished crossings, whereas each treatment alone was without effect. Similarly, in the tail suspension test, a clear increase in the duration of immobility was observed after combined treatment (256 mg/kg IP melatonin + 0.5 mg/kg PO diazepam), whereas no effects were observed with the individual treatments alone. These results suggest that melatonin can enhance the anxiolytic actions of diazepam.
Article
Responses of isolated, 60 mmHg 'pressurized' segments of the distal caudal artery of adult and juvenile Wistar rats to melatonin and the selective alpha 2-adrenoceptor agonist 5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate (UK-14304) were examined using the Halpern pressure myograph. Melatonin showed no direct vasoconstrictor activity in vessels from adult rats, whereas UK-14304 produced moderate vasoconstriction (pD2-7.43 +/- 0.09). In the presence of phenylephrine-induced tone, melatonin produced a variable but small constrictor response (less than 10 microns reduction in diameter) in some vessels; the response to 1 mumol/l UK-14304 was less than in the absence of tone. In vessels isolated from juvenile rats, melatonin caused concentration-dependent vasoconstriction with a maximum response about 70% of the maximum response elicited by UK-14304. Vessels from juvenile rats were more sensitive to melatonin (pD2-9.40 +/- 0.07) than they were to UK-14304 (pD2-8.12 +/- 0.14). In the presence of phenylephrine-induced tone, the vasoconstrictor responses to both melatonin and IK-14304 were markedly less; the sensitivity to melatonin was not different from that seen in the absence of tone. These findings indicate that 'pressurized' segments of the isolated distal caudal artery may provide a simple and convenient, functional model of melatonin receptors. The findings also appear to implicate melatonin in thermoregulatory processes in juvenile rats.
Article
A potentially confounding variable inherent in studies designed to examine the effect of melatonin administration in humans is the presence of an endogenous melatonin rhythm in the experimental subjects. The effects of exogenous melatonin administration on serum hormone rhythms was recently examined in a male patient who lacked detectable circulating levels of endogenous melatonin. The patient's pineal gland had been destroyed five years previously in the course of treatment for a pineal astrocytoma. On three separate occasions, over approximately a one-year period, the patient was given daily oral melatonin replacement (2 mg/day, 1 mg/day and 0.5 mg/day). These experiments were designed to assess the effects of exogenous melatonin on serum growth hormone, prolactin, cortisol and testosterone rhythms. Analysis of blood samples collected every 2-4 hours periods both before and during melatonin replacement revealed that the exogenous melatonin rhythm was associated with improvements in self-reported sleep and mood ratings. Melatonin administration produced robust nocturnal peaks in serum growth hormone and prolactin levels immediately following ingestion of the hormone, while serum cortisol and testosterone rhythms were not influenced. These results suggest that melatonin may modulate the coordination and enhancement of selected biological rhythms in man.
Article
Serum melatonin and its main metabolic product 6-sulfatoxymelatonin were determined in 17 patients with breast cancer (BC) with either a fresh primary tumor (nine) or a secondary tumor (eight) as well as in four patients with untreated benign breast disease (controls). Circadian rhythms were detected in all groups with acrophases around 2 AM for melatonin and around 3 AM for 6-sulfatoxymelatonin. The nocturnal melatonin and 6-sulfatoxymelatonin concentrations were significantly depressed in the group of patients with primary breast cancer compared with controls (P less than 0.01, P less than 0.025). The circadian amplitudes of melatonin and 6-sulfatoxymelatonin were also depressed by 81% (P less than 0.01) and 63% (P less than 0.01). In contrast, patients with secondary BC had nocturnal melatonin and 6-sulfatoxymelatonin concentrations and amplitudes similar to controls. These results demonstrate that the depression of circulating melatonin in patients with primary BC is not due to an enhanced degradation to 6-sulfatoxymelatonin in the liver but must be due to a reduced activity of the pineal gland.
Article
The annual rhythm of human reproduction was analyzed on the basis of more than 3000 years of monthly birth rates covering 166 regions of the globe. The following variables were used to characterize the annual rhythm of human conception (birth minus 9 months): amplitude, phase of maximum and minimum, phase and length of the time span when rates are above the annual mean (alpha), and the steepest upward slope (delta max) of the curve fitted to the rates. The waveform of the annual rhythm is characteristic for geographical regions (e.g., unimodal or bimodal) and persists as such for many years. In most countries, the onset of alpha coincides with delta max and lies close to the spring equinox. This phase of the rhythm is the most stable over time. In many populations, the rhythm has changed in recent years, specifically in amplitude and phase. The phase of the rhythm depends on latitude, with a 6-month difference between the Northern and Southern Hemispheres. The latitudinal distribution of amplitudes is less systematic. In spite of the many social influences on timing of conceptions, we conclude that the seasonal component in human reproduction is based on biological factors.
Article
Eighteen patients with seasonal affective disorder (SAD) participated in a double-blind, placebo-controlled crossover study in 1986-1987. Each received, in random order, d-fenfluramine (15 mg p.o. twice daily)-a serotonin-releasing drug previously shown to suppress carbohydrate craving-or a placebo; these were given for 4 weeks separated by a 2-week washout period. Symptoms were assessed by means of clinical interviews and the Hamilton Rating Scale for Depression (HAM-D) with a special SAD addendum (AAD). Patients were also weighed. Depression scores (mean +/- SE) were identical before treatment with drug (20.9 +/- 1.3, HAM-D; 13.3 +/- 0.8, AAD) or placebo (21.4 +/- 1.2, HAM-D: 13.2 +/- 0.6, AAD). During placebo treatment, mean HAM-D scores declined by 22% (p less than .02) and AAD scores by 9% (p greater than .2). During d-fenfluramine treatment, HAM-D scores fell by 71% (p less than .001) and AAD scores by 73% (p less than .001). Thirteen (72%) of the patients demonstrated complete reversal of their abnormal test scores while taking d-fenfluramine. The group as a whole lost weight (mean = 1.2 kg) while receiving d-fenfluramine (p less than .033) but not when taking placebo. A second study, conducted in 1987-1988 with nine subjects who had previously responded to d-fenfluramine, showed that the drug remains effective for the full 3-month annual period of symptoms. These results indicate that d-fenfluramine may be useful in treating SAD and suggest that serotonin is involved in both SAD's affective and appetitive symptoms.
Article
SYNOPSIS We determined by radioimmunoassay plasma melatonin levels on blood samples drawn at 11 p.m. in migraine patients and control subjects. Ninety-three cephalalgic outpatients (75 females, 18 males) were compared to a control group (24 females, 22 males) matched according to age. Patients were divided into subgroups presenting common migraine (n = 38); ophthalmic migraine (n = 12); and tension headache associated with ophthalmic or common migraine (n = 24), and associated depressive status (n = 19). Statistical analysis revealed a decrease in plasma melatonin levels for the entire migraine population, compared to the control one, and a heterogeneity in both controls and patients; this heterogeneity was found mainly in the depressive and tension headache subgroups. When the migraine population-from which the depressive patients were excluded-was divided into male and female subgroups, a decrease in plasma melatonin levels was observed only for the female subgroups. Results are discussed with reference to the role of the pineal gland in the synchronization of the organism with the environmental conditions.
Article
Fifty-one patients were recruited into a descriptive study of the putative syndrome of seasonal affective disorder (SAD), diagnosed according to strict criteria. Some differences were found between this sample and those previously reported but there were many more similarities. Comparisons were made between self-referrals and psychiatrists' referrals, between patients who had previously been treated by psychiatrists and those who had never been treated, and between those who became depressed on follow-up through the winter of 1985/1986 and those who remained well. The syndrome of SAD was broadly supported.
Article
To test the hypothesis that the antidepressant effects of bright light in seasonal affective disorder are mediated by the suppression of melatonin, 19 patients with this disorder were given atenolol, which suppresses melatonin secretion, and placebo in a double-blind crossover study. No difference in antidepressant efficacy was found between drug and placebo in the sample as a whole, which argues against the melatonin hypothesis of phototherapy. However, in three of the patients atenolol provided repeated, marked, and sustained relief of symptoms, suggesting that it may be useful in treating the winter depressive symptoms of some patients with seasonal affective disorder.
Article
In 16 healthy volunteers, 16 patients with neurogenic pain syndromes, 37 patients with idiopathic pain syndromes, and 30 depressed patients, melatonin in serum was determined at 2 a.m. when the peak concentration was expected. In a somewhat larger series comprising 53 healthy volunteers, 14 patients with neurogenic pain syndromes, and 35 patients with idiopathic pain syndromes, melatonin was measured in urine collected during the night in a standardized manner. Chronic pain patients (with neurogenic or idiopathic pain disorders) and depressed patients had significantly lower melatonin in serum at 2 a.m. than healthy volunteers. Chronic pain patients also had significantly lower melatonin in urine than healthy volunteers, even when age, sex, and body weight were taken into account. The low melatonin concentrations were related to increased depressive symptomatology, especially sadness, bodily discomfort, inner tension, concentration difficulties, and pain. As low concentrations of melatonin in serum and urine also are found in patients with depressive disorders, the results are in line with the suggestion that the chronic idiopathic pain syndrome may be a variant of depressive disease, or the two syndromes may share a common pathogenic mechanism.