INTRODUCTION
Melatonin (N-acetyl-5-methoxytryptamine [7]) is a lipophilic hormone, mainly produced and secreted at night by the pineal gland. Melatonin synthesis is under the control of postganglionic sympathetic fibers that innervates the pineal gland. Melatonin acts via high affinity G protein-coupled membrane receptors. To date, three different receptor subtypes have been identified in mammals: MT1 (Mel 1a) and MT2 (Mel 1b) and a putative binding site called MT3. [1]
Main and best-known effect of melatonin is restoring the natural cycle of organism functions. It is safe and non-addictive sleep-inducing drug, which can eliminate disruptions in our circadian rhythm, in such situations as shift working, changing of time zones (during intercontinental air travelling) or insomnia. It improves mood and quality of sleep. [10] However, researchers also have shown that melatonin has chronbiotic activities to resynchronize sleep and circadian rhythms disturbances and it is also involved in the regulation of seasonal reproduction, body weight and energy balance. [1]MELATONIN PHYSIOLOGY
In both diurnal and nocturnal vertebrates, its main product, the hormone melatonin, is synthesized and released in rhythmic fashion, during the dark portion of the day-night cycle. Melatonin production is controlled by an endogenous circadian timing system and is also suppressed by light. In lower vertebrates, the pineal gland is photosensitive, and is the site of a self-sustaining circadian clock. In mammals, including humans, the gland has lost direct photosensitivity, but responds to light via a multisynaptic pathway that includes a subset of retinal ganglion cells containing the newly discovered photopigment, melanopsin. The mammalian pineal also shows circadian oscillations, but these damp out within a few days in the absence of input from the primary circadian pacemaker in the suprachiasmatic nuclei (SCN). The duration of the nocturnal melatonin secretory episode increases with nighttime duration, thereby providing an internal calendar that regulates seasonal cycles in reproduction and other functions in photoperiodic species. Although humans are not considered photoperiodic, the occurrence of seasonal affective disorder (SAD) and its successful treatment with light suggest that they have retained some photoperiodic responsiveness. [5]
FUNCTIONS Drs Macchi MM and Bruce JN from Columbia University have suggested the multiple functions of melatonin. In humans, exogenous melatonin has a soporific effect, but only when administered during the day or early evening, when endogenous levels are low. Some types of primary insomnia have been attributed to diminished melatonin production, particularly in the elderly, but evidence of a causal link is still inconclusive. [5]
Melatonin administration also has mild hypothermic and hypotensive effects. A role for the pineal in human reproduction was initially hypothesized on the basis of clinical observations on the effects of pineal tumors on sexual development. More recent data showing an association between endogenous melatonin levels and the onset of puberty, as well as observations of elevated melatonin levels in both men and women with hypogonadism and/or infertility are consistent with such a hypothesis. [5]
A rapidly expanding literature attests to the involvement of melatonin in immune function, with high levels promoting and low levels suppressing a number of immune system parameters. The detection of melatonin receptors in various lymphoid organs and in lymphocytes suggests multiple mechanisms of action. [5]
Melatonin is a powerful antioxidant, and has oncostatic properties via its effects on reproductive hormones. Finally, there are reports of abnormal daily melatonin profiles in a number of psychiatric and neurological disorders, but it is still to early to draw any conclusions. [5, 21]
DEFICIENCIES The production of melatonin probably starts to slow at 40 year of ages. Researchers from China found that a step-wise decrease in the circadian rhythms of saliva melatonin occurred early in life, around 40 yr of ages, in a study of healthy human subjects. The middle-aged subjects had only 60% of the amplitude of the young subjects. In addition, the middle-aged subjects showed the longest peak levels duration and the lowest daytime melatonin levels. [2]
MELATONIN HEALTH BENEFITS
Melatonin is a potent antioxidant. Melatonin scavenges hydroxyl, carbonate and various organic radicals, peroxynitrite and other reactive nitrogen species. Melatonyl radicals formed by scavenging combine with and, thereby, detoxify superoxide anions in processes terminating the radical reaction chains. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes like superoxide dismutase, glutathione peroxidase and glutathione reductase, and by augmenting glutathione levels. Thus, it provides various health benefits on various conditions [4, 17] Melatonin plays a beneficial role in the biologic regulation of circadian rhythms, sleep, mood, reproduction, tumor growth and aging. It may also modulate the activity of various receptors in cancer cells. [18]
Population worldwide is aging and most of the baby boomers are actively seeking for various ways including using health supplements to improve their quality of life. One of the popular issues for these baby boomers is insufficient sleep, which is possibly related to reduced production of melatonin at older ages.
SLEEP Melatonin may facilitate sleep........Administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. Successful use of melatonin's chronobiotic properties has been reported in other sleep disorders associated with abnormal timing of the circadian system: jetlag, shiftwork, delayed sleep phase syndrome, some sleep problems of the elderly. [27-29]
According to a paper issued by HHS' Agency for Healthcare Research and Quality, sleep disorders are grouped into two catalogs. Disorders due to sleep schedule alterations can stem from flying across time zones or working night shifts. Primary sleep disorders, which include insomnia, can be caused by factors such as stress or drinking too much caffeinated coffee. Secondary sleep disorders can also include insomnia, but patients in this category also have underlying mental disorders, such as psychoses or mood and anxiety disorders, neurological conditions such as dementia and Parkinson's disease, or chronic pulmonary disease. Melatonin supplements do not appear to have much health benefits on people with secondary sleep disorder, but it does appear to increase sleep efficiency modestly. Sleep efficiency refers to the percent of time a person is asleep after going to bed. [11] Furthermore, Turk J from St. George's Hospital Medical School, UK, points out that intractable sleep disturbance is associated to behavioral problems of children. Melatonin, as a sleep inducer, may also be beneficial and safe adjunct to psychological and social approaches for severe sleep disturbance in this client group. [31] In an attempt to take advantages of the beneficial opportunities available through the brain's melatonin system, researchers have developed several melatonin agonists with improved properties in comparison to melatonin. Some of these agents are now in clinical trials (or even in markets) for treatment of insomnia or circadian rhythm sleep disorders. [30]
POISON Melatonin prevents poisoning induced by elements like chromium (III) and (VI), iron and copper, through levelling toxic actions of these ions on organism. The beneficial role of melatonin in these processes relies mainly on scavenging of arisen free radicals, detoxification of hydrogen peroxide and combining excess of toxic ions into compounds harmless for organism. [26]
STROKE Melatonin may benefit people suffered from strokes.. Macleod MR and co-workers from National Stroke Research Institute, Melbourne, Australia, reviewed 14 studies on how melatonin benefited 432 animal models suffered from focal cerebral ischaemia. They concluded an improvement in outcome with melatonin treatment. [24]
When given at the time of ischemia or reperfusion onset, melatonin reduces neurophysiological deficits, infarct volume, the degree of neural edema, lipid peroxidation, protein carbonyls, DNA damage, neuron and glial loss, and death of the animals. Reiter RJ and co-workers from University of Texas Health Science Center suggested that melatonin's protective actions against these adverse changes are related to its direct free radical scavenging and indirect antioxidant activities, possibly from its ability to limit free radical generation at the mitochondrial level and because of yet-undefined functions. [8]
CARDIC CONDITIONS Melatonin may have benefits of heart protection.... Sewerynek E from Medical University of Lodz, Poland suggested that melatonin may have benefits of heart protection. People with hypertension have lower melatonin levels than those with normal blood pressure. Researchers reported that melatonin, even in a dose 1 mg, reduced blood pressure and decreased catecholamine level after 90 min in human subjects. There are evidences of the presence of vascular melatoninergic receptors/binding sites. Melatonin may reduce blood pressure via the following mechanisms: 1) by a direct effect on the hypothalamus; 2) as an antioxidant which lowers blood pressure; 3) by decreasing the level of catecholamines, or 4) by relaxing the smooth muscle in the aorta wall. [9]
People with high LDL-cholesterol levels are also found to have low levels of melatonin. Melatonin was shown to suppress the formation of cholesterol by 38% and reduce LDL accumulation by 42%. Even a 10-15% reduction in blood cholesterol concentration resulted in a 20 to 30% decrease in the risk of coronary heart disease, in a study. [9]
DIABETES Melatonin may have benefits on diabetes. Nishida S from Nihon University School of Medicine, Japan suggested the beneficial use of melatonin for the treatment of cholesterol/lipid and carbohydrate disorders. Melatonin reduces serum lipid levels and helps to prevent oxidative stress in diabetic subjects. Long-term melatonin administration to diabetic rats reduced their hyperlipidemia and hyperinsulinemia, and restored their altered ratios of polyunsaturated fatty acid in serum and tissues. In a study, melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the potential existence of signaling pathway cross-talk between melatonin and insulin. Because TNF-alpha has been shown to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-alpha-associated insulin resistance in type 2 diabetes. [23]
Cancer Melatonin may benefit people at risk of certain cancers.....Some researchers believe that melatonin may have a benefit-role in preventing and treating some types of cancers, especially, the hormone-dependent mammary cancer. [12-14] In various experimental studies, Physiological and pharmacological blood concentrations of melatonin inhibit tumorigenesis. Studies indicate that melatonin's anticancer effects are exerted via inhibition of cell proliferation and a stimulation of differentiation and apoptosis. In which, melatonin suppresses cAMP formation and inhibits tumor uptake of linoleic acid and its metabolism to 13-hydroxyoctadecadienoic acid via a melatonin receptor-mediated mechanism in both tissue-isolated rat hepatoma 7288 CTC and human breast cancer xenografts. [13]
Researchers found that Nocturnal dietary supplementation with melatonin, at levels contained in a melatonin-rich diet, inhibits rat hepatoma growth. [13] Thus, one may suggest that light at night may suppress melatonin production and pose a risk for breast cancer development. However, more studies are needed to confirm this idea.
Infertility Melatonin may benefit people suffered from infertility...Melatonin may benefit male and female infertility in couples with abnormal melatonin metabolism. Seasonal change may lead to circadian disturbances in reproduction. Melatonin may also be considered essential to both spermatogenesis and folliculogenesis. Melatonin may exert an inhibitory effect on the GnRH pulse generator to decrease gonadotropin secretion. Consequently, it may have effects on the pubertal onset and timing of ovulation. Studies are needed to understand how melatonin used in infertility. [15]
Neural Issues
Melatonin may have benefits of neuroprotection. The etiology of the neurodegenerative diseases which are characterized by the progressive and irreversible destruction of specific neuronal populations is complex and multifactorial.
Mayo JC and co-workers from University of Oviedo, Spain suggested that melatonin has potent endogenous antioxidant actions, which may be beneficial to neurodegenerative disorders. It is because neurodegenerative disorders are mainly caused by oxidative damage, and melatonin has been tested successfully in both in vivo and in vitro models of Parkinson's disease. Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is characterized by a progressive loss of dopamine in the substantia nigra and striatum. However, over 70% of dopaminergic neuronal death occurs before the first symptoms appear, which makes either early diagnosis or effective treatments extremely difficult. Only symptomatic therapies have been used, including levodopa (l-dopa), to restore dopamine content; however, the use of l-dopa leads to some long-term pro-oxidant damage. [16]
Melatonin has been shown to have benefits of neuroprotection in several degenerative disorders, because of its antioxidant properties. [18] Therapeutic trials with melatonin have been effective in slowing the progression of Alzheimer's disease. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases, e.g., Alzheimer's disease. [17]
BONE CONDITIONS Melatonin has benefits on bone healthBone formation proceeds through a remodeling process that runs continuously, involving the resorption of old bone by osteoclasts, and the subsequent formation of new bone by osteoblasts. This is controlled by growth factors and cytokines produced in bone marrow microenvironment and by the action of systemic hormones, like parathyroid hormone, estradiol or growth hormone (GH). Cardinali DP and co-workers from Universidad de Buenos Aires, Argentina suggest that melatonin can be a candidate for hormonal modulation of osteoblast and osteoclast formation. [19]
Melatonin through its free radical scavenger and antioxidant properties may impair osteoclast activity and bone resorption. At least in one study melatonin was both inhibitory to osteoclastic and osteoblastic cells. Additionally, melatonin may impair development of osteopenia associated with senescence by improving non-rapid eye movement sleep and restoring GH secretion. [19] Nevertheless, more studies are needed to confirm its beneficial role in bone health.
HEADACHE Melatonin may help headache, a study suggests.Melatonin has a role in the biological regulation of circadian rhythms, sleep, mood, and ageing. Altered melatonin levels in cluster headache and migraine have been documented. [20] Peres MF from Albert Einstein Hospital, Brazil, suggests that Melatonin mechanisms are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of proinflammatory cytokine up-regulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilization, GABA and opioid analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation, serotonin modulation, and the similarity of chemical structure to that of indomethacin. Treatment of headache disorders with melatonin and other chronobiotic agents is promising. A double-blind, placebo-controlled trial shows that melatonin is effective in cluster headache prevention. [20]
PANCREATIC AND GASTRIC ULCERS Melatonin may be a beneficial agent on the pancreatic damage and gastric ulcers. Melatonin is found to be discharged into the gut lumen and may stimulate pancreatic enzyme secretion, via melatonin-induced release of cholecystokinin. Melatonin exhibits similar highly protective actions as its precursor L-tryptophan against the damage of both the stomach and the pancreas and promotes the healing of chronic gastric ulcerations via stimulation of the microcirculation and cooperation with prostaglandins, nitric oxide, and/or sensory nerves and with their neuropeptides. The beneficial effects of melatonin results in gastro- and pancreato-protection, prevents various forms of gastritis and pancreatitis through the activation of specific MT2-receptors and scavenges reactive oxygen species (ROS). Melatonin also counteracts the increase in the ROS-induced lipid peroxidation and preserves, at least in part, the activity of key anti-oxidizing enzymes such as superoxide dismutase. [33]
Among various causes of gastric ulceration, lesions caused by stress, alcohol consumption, Helicobacter pylori infection and use of nonsteroidal antiinflammatory drugs have been shown to be mediated largely through the generation of reactive oxygen species especially hydroxyl radical (*OH). A number of excellent drugs have been proved useful in controlling hyperacidity and ulceration but their long term uses are not devoid of disturbing side-effects. Hence, melatonin may be a beneficial agent to cure gastric hyperacidity and ulcer. [32]
SKIN CONDITIONS Melatonin may have benefits of skin protection Slominski A et al from University of Tennessee, Memphis proposed that melatonin (synthesized locally or delivered topically) could counteract or buffer external (environmental) or internal stresses to preserve the biological integrity of the organ and to maintain its home-ostasis. They also suggest that melatonin could have an beneficial role in protection against solar radiation or even in the management of skin diseases. Melatonin has been experimentally implicated in skin functions such as hair growth cycling, fur pigmentation, and melanoma control, and melatonin receptors are expressed in several skin cells including normal and malignant keratinocytes, melanocytes, and fibroblasts. Melatonin is also able to suppress ultraviolet (UV)-induced damage to skin
cells and shows strong antioxidant activity in UV exposed cells. [22]
IMMUNO-ACTIVITY Melatonin may have benefits of immuno-stimulatory activities. Melatonin has been shown to prevent paralysis and death in mice infected with the encephalomyocarditis virus and to decrease viremia. Melatonin also delays the onset of the disease produced by Semliki Forest virus inoculation and reduces the mortality of West Nile virus-infected mice stressed by either isolation or dexamethasone injection. Bonilla E and co-workers from Universidad del Zulia, Maracaibo, Venezuela consider that these observations are related to an increase in the host resistance to the virus via a peripheral immuno-stimulating activity
Studies have shown that melatonin protects some strains of mink against Aleutian disease, and prevents the reduction of B- and T-cells as well as Th1 cytokine secretion in mice infected with leukemia retrovirus. In VEE-infected mice, melatonin postpones the onset of the disease and death for several days and reduces the mortality rate. [34]
MELATONIN SIDE EFFECTS
Melatonin supplements, which people often take for problems sleeping, appear to be safe when used over a period of days or weeks, at recommended doses and in conventional formulations. However, the safety and side effects of melatonin supplements used over months or even years is unclear. [11]
Atkinson G et al from Loughborough University, UK, points out that the administration of melatonin leads to hypnotic and hypothermic responses in humans, which can be linked to immediate reductions in short-term mental and physical performance. Depending on the dose of melatonin, these effects may still be apparent 3-5 hours after administration for some types of cognitive performance, but effects on physical performance seem more short-lived. [25]
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. [3]
Melatonin may reduce side effects of some drugs and metal poisoning. Melatonin has been shown to reduce the toxicity and increase the efficacy of a large number of drugs which side effects are well documented. Researchers from University of Texas Health Science Center, San Antonio, summarize the beneficial effects of melatonin when combined with the following drugs: doxorubicin, cisplatin, epirubicin, cytarabine, bleomycin, gentamicin, ciclosporin, indometacin, acetylsalicylic acid, ranitidine, omeprazole, isoniazid, iron and erythropoietin, phenobarbital, carbamazepine, haloperidol, caposide-50, morphine, cyclophosphamide and L-cysteine. The majority of these studies were conducted using animals, a number of the investigations also used man. [7]
Further, researchers also worry that melatonin may play a role in rheumatoid arthritis. It is because melatonin may stimulate the immune system via activating the immature and mature immuno-competent cells, and consequently promote autoimmune diseases such as rheumatoid arthritis. Clinical studies have shown that subjects suffered from rheumatoid arthritis have an elevated serum level of melatonin. [6] In one of the early studies, Italian researchers from University of Genova evaluated melatonin serum levels in 10 rheumatoid arthritis patients and six healthy subjects. They found that melatonin level was higher in the rheumatoid arthritis patients than in controls. Melatonin progressively increased from 8 p.m. to the first hours of the morning in both groups. However, melatonin serum level reached the peak at least two hours before in rheumatoid arthritis patients than in controls. And the melatonin concentration became steadily high lasting 2-3 hours in the rheumatoid arthritis patients. This melatonin concentration plateau did not happen in the healthy controls. Since several symptoms of rheumatoid arthritis, such as morning gelling, stiffness, and swelling happen in the early morning, some researchers believe that rheumatoid arthritis (synovitis) may be related to melatonin's neuro-immunomodulatory effects. [8] However, more studies are needed to show if there is a cause-effect relationship.
CONCLUSION
Further, researchers also worry that melatonin may play a role in rheumatoid arthritis. It is because melatonin may stimulate the immune system via activating the immature and mature immuno-competent cells, and consequently promote autoimmune diseases such as rheumatoid arthritis. Clinical studies have shown that subjects suffered from rheumatoid arthritis have an elevated serum level of melatonin. [6] In one of the early studies, Italian researchers from University of Genova evaluated melatonin serum levels in 10 rheumatoid arthritis patients and six healthy subjects. They found that melatonin level was higher in the rheumatoid arthritis patients than in controls. Melatonin progressively increased from 8 p.m. to the first hours of the morning in both groups. However, melatonin serum level reached the peak at least two hours before in rheumatoid arthritis patients than in controls. And the melatonin concentration became steadily high lasting 2-3 hours in the rheumatoid arthritis patients. This melatonin concentration plateau did not happen in the healthy controls. Since several symptoms of rheumatoid arthritis, such as morning gelling, stiffness, and swelling happen in the early morning, some researchers believe that rheumatoid arthritis (synovitis) may be related to melatonin's neuro-immunomodulatory effects. [8] However, more studies are needed to show if there is a cause-effect relationship.
CONCLUSION
Melatonin has been proved to have multiple benefits, however, its long-term safety or side effects are unclear. Since prolonged high melatonin serum level is associated to rheumatoid arthritis, selection of a proper dosage form (ie melatonin release) becomes very important. Discuss with your doctor before taking any supplement.
REFERENCE: [1] Barrenetxe J et al, Physiological and metabolic functions of melatonin. J Physiol Biochem. 2004 Mar;60(1):61-72. [2] Zhou JN et al, Alterations in the circadian rhythm of salivary melatonin begin during middle-age. J Pineal Res. 2003 Jan;34(1):11-6. [3] Rohr UD and Herold J, Melatonin deficiencies in women. Maturitas. 2002 Apr 15;41 Suppl 1:S85-104. [4] Karasek M Melatonin, human aging, and age-related diseases. Exp Gerontol. 2004 Nov-Dec;39 (11-12):1723-9. [5] Macchi MM and Bruce JN Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol. 2004 Sep-Dec;25(3-4):177-95. [6] Maestroni GJ et al, Does melatonin play a disease-promoting role in rheumatoid arthritis? J Neuroimmunol. 2005 Jan;158(1-2):106-11. [7] Reiter RJ et al, Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol. 2002 Oct;54(10):1299-321. [8] Sulli A et al, Melatonin serum levels in rheumatoid arthritis. Ann N Y Acad Sci. 2002 Jun;966:276-83. [8] Reiter RJ et al, When melatonin gets on your nerves: its beneficial actions in experimental models of stroke. Exp Biol Med (Maywood). 2005 Feb;230(2):104-17. [9] Sewerynek E Melatonin and the cardiovascular system. Neuro Endocrinol Lett. 2002 Apr;23 Suppl 1:79-83. [10] Boguszewska A and Pasternak K Melatonin and its biological significance. Pol Merkuriusz Lek. 2004 Nov;17(101):523-7. [11] AHRQ Issues New Report on the Safety and Effectiveness of Melatonin Supplements. Press Release, December 8, 2004. Agency for Healthcare Research and Quality, Rockville, MD. [12] Sanchez-Barcelo EJ et al, Melatonin-estrogen interactions in breast cancer, J Pineal Res. 2005 May;38(4):217-22. [13] Blask DE et al, Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine. 2005 Jul;27(2):179-88. [14] Mills E et al, Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005 Nov;39(4):360-6. [15] Wojtowicz M and Jakiel G, from Kliniki Rozrodczosci i Andrologii Katedry Macierzynstwa i Prokreacji AM w Lublinie, Melatonin and its role in human reproduction Ginekol Pol. 2002 Dec;73(12):1231-7. [16] Mayo JC et al Melatonin and Parkinson's disease. Endocrine. 2005 Jul;27(2):169-78. [17] Srinivasan V et al, Role of melatonin in neurodegenerative diseases. Neurotox Res. 2005;7(4):293-318. [18] Olakowska E et al, The role of melatonin in the neurodegenerative diseases. Bratisl Lek Listy. 2005;106(4-5):171-4. [19] Cardinali DP et al, Melatonin effects on bone: experimental facts and clinical perspectives. J Pineal Res. 2003 Mar;34(2):81-7. [20] Peres MF Melatonin, the pineal gland and their implications for headache disorders. Cephalalgia. 2005 Jun;25(6):403-11. [21] Cuzzocrea S and Reiter RJ Pharmacological actions of melatonin in acute and chronic inflammation. Curr Top Med Chem. 2002 Feb;2(2):153-65. [22] Slominski A et al On the role of melatonin in skin physiology and pathology. Endocrine. 2005 Jul;27(2):137-48. [23] Nishida S. Metabolic effects of melatonin on oxidative stress and diabetes mellitus. Endocrine. 2005 Jul;27(2):131-6. [24] Macleod MR and co-workers, Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke. J Pineal Res. 2005 Jan;38(1):35-41. [25] Atkinson G et al The relevance of melatonin to sports medicine and science. Sports Med. 2003;33(11):809-31. [26] Boguszewska A and Pasternak K Melatonin and bio-elements Pol Merkuriusz Lek. 2004 Nov;17(101):528-9. [27] Cajochen C et al, Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol. 2003 Apr;15(4):432-7. [28] Claustrat B et al, The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005 Feb;9(1):11-24. [29] Arendt J et al, Melatonin as a chronobiotic. Sleep Med Rev. 2005 Feb;9(1):25-39. [30] Turek FW et al, Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med. 2004 Nov;5(6):523-32. [31] Turk J Melatonin supplementation for severe and intractable sleep disturbance in young people with genetically determined developmental disabilities: short review and commentary. J Med Genet. 2003 Nov;40(11):793-6. 32 Bandyopadhyay D et al, Involvement of reactive oxygen species in gastric ulceration: protection by melatonin. Indian J Exp Biol. 2002 Jun;40(6):693-705. [33] Jaworek J et al, Melatonin as an organoprotector in the stomach and the pancreas. J Pineal Res. 2005 Mar;38(2):73-83. [34] Bonilla E et al, Melatonin and viral infections. J Pineal Res. 2004 Mar;36(2):73-9.
REFERENCE: [1] Barrenetxe J et al, Physiological and metabolic functions of melatonin. J Physiol Biochem. 2004 Mar;60(1):61-72. [2] Zhou JN et al, Alterations in the circadian rhythm of salivary melatonin begin during middle-age. J Pineal Res. 2003 Jan;34(1):11-6. [3] Rohr UD and Herold J, Melatonin deficiencies in women. Maturitas. 2002 Apr 15;41 Suppl 1:S85-104. [4] Karasek M Melatonin, human aging, and age-related diseases. Exp Gerontol. 2004 Nov-Dec;39 (11-12):1723-9. [5] Macchi MM and Bruce JN Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol. 2004 Sep-Dec;25(3-4):177-95. [6] Maestroni GJ et al, Does melatonin play a disease-promoting role in rheumatoid arthritis? J Neuroimmunol. 2005 Jan;158(1-2):106-11. [7] Reiter RJ et al, Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol. 2002 Oct;54(10):1299-321. [8] Sulli A et al, Melatonin serum levels in rheumatoid arthritis. Ann N Y Acad Sci. 2002 Jun;966:276-83. [8] Reiter RJ et al, When melatonin gets on your nerves: its beneficial actions in experimental models of stroke. Exp Biol Med (Maywood). 2005 Feb;230(2):104-17. [9] Sewerynek E Melatonin and the cardiovascular system. Neuro Endocrinol Lett. 2002 Apr;23 Suppl 1:79-83. [10] Boguszewska A and Pasternak K Melatonin and its biological significance. Pol Merkuriusz Lek. 2004 Nov;17(101):523-7. [11] AHRQ Issues New Report on the Safety and Effectiveness of Melatonin Supplements. Press Release, December 8, 2004. Agency for Healthcare Research and Quality, Rockville, MD. [12] Sanchez-Barcelo EJ et al, Melatonin-estrogen interactions in breast cancer, J Pineal Res. 2005 May;38(4):217-22. [13] Blask DE et al, Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine. 2005 Jul;27(2):179-88. [14] Mills E et al, Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005 Nov;39(4):360-6. [15] Wojtowicz M and Jakiel G, from Kliniki Rozrodczosci i Andrologii Katedry Macierzynstwa i Prokreacji AM w Lublinie, Melatonin and its role in human reproduction Ginekol Pol. 2002 Dec;73(12):1231-7. [16] Mayo JC et al Melatonin and Parkinson's disease. Endocrine. 2005 Jul;27(2):169-78. [17] Srinivasan V et al, Role of melatonin in neurodegenerative diseases. Neurotox Res. 2005;7(4):293-318. [18] Olakowska E et al, The role of melatonin in the neurodegenerative diseases. Bratisl Lek Listy. 2005;106(4-5):171-4. [19] Cardinali DP et al, Melatonin effects on bone: experimental facts and clinical perspectives. J Pineal Res. 2003 Mar;34(2):81-7. [20] Peres MF Melatonin, the pineal gland and their implications for headache disorders. Cephalalgia. 2005 Jun;25(6):403-11. [21] Cuzzocrea S and Reiter RJ Pharmacological actions of melatonin in acute and chronic inflammation. Curr Top Med Chem. 2002 Feb;2(2):153-65. [22] Slominski A et al On the role of melatonin in skin physiology and pathology. Endocrine. 2005 Jul;27(2):137-48. [23] Nishida S. Metabolic effects of melatonin on oxidative stress and diabetes mellitus. Endocrine. 2005 Jul;27(2):131-6. [24] Macleod MR and co-workers, Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke. J Pineal Res. 2005 Jan;38(1):35-41. [25] Atkinson G et al The relevance of melatonin to sports medicine and science. Sports Med. 2003;33(11):809-31. [26] Boguszewska A and Pasternak K Melatonin and bio-elements Pol Merkuriusz Lek. 2004 Nov;17(101):528-9. [27] Cajochen C et al, Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol. 2003 Apr;15(4):432-7. [28] Claustrat B et al, The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005 Feb;9(1):11-24. [29] Arendt J et al, Melatonin as a chronobiotic. Sleep Med Rev. 2005 Feb;9(1):25-39. [30] Turek FW et al, Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med. 2004 Nov;5(6):523-32. [31] Turk J Melatonin supplementation for severe and intractable sleep disturbance in young people with genetically determined developmental disabilities: short review and commentary. J Med Genet. 2003 Nov;40(11):793-6. 32 Bandyopadhyay D et al, Involvement of reactive oxygen species in gastric ulceration: protection by melatonin. Indian J Exp Biol. 2002 Jun;40(6):693-705. [33] Jaworek J et al, Melatonin as an organoprotector in the stomach and the pancreas. J Pineal Res. 2005 Mar;38(2):73-83. [34] Bonilla E et al, Melatonin and viral infections. J Pineal Res. 2004 Mar;36(2):73-9.