Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures that have been studied from algae to humans, at levels that vary in a diurnal cycle. In higher animals melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina and GI tract. It is naturally synthesized from the amino acid tryptophan (derived from serotonin) by the enzyme 5-hydroxyindole-O-methyltransferase. Many biological effects of melatonin are produced by its binding to and action on melatonin receptors, others are due to its role as a pervasive and extremely powerful antioxidant with a particular role in the protection of nuclear and mitochondrial DNA . Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.
It is referred to by some biochemists and human physiologists as the master hormone, because it regulates the production of most human hormones, both paracrine and endocrine. Melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the blood, whereas melatonin produced by the retina and the GI tract acts as a paracrine hormone.
Nobel Prize laureate Julius Axelrod performed many of the seminal experiments that elucidated the role of melatonin and the pineal gland in regulating sleep-wake cycles (circadian rhythms). Normally, production of melatonin by the pineal gland is inhibited by light and permitted by darkness. Until recent history, humans in temperate climates were exposed to up to eighteen hours of darkness in the winter. In the modern world, artificial lighting typically reduces this to eight hours or less per day all year round. Even low light levels inhibit melatonin production to some extent. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers .
Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long, such as sheep.
Certain studies have noted that wearing garments such as bras are linked to a decrease in melatonin production. Beta blockers also decrease nocturnal melatonin release.
Medical uses of melatonin
In recent times, melatonin has become available as a medication and a dietary supplement. Because it does not have to be prescribed and is in the public domain, there have been few clinical trials conducted to determine its effectiveness in treating diseases.
Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier. Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant. In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.
The antioxidant activity of melatonin may reduce damage caused by some types of Parkinson's disease, and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.
In addition, when taken alone, it is an immunoregulator that enhances T cell production somewhat. When taken in conjunction with calcium, it is a very potent immunostimulator of the T cell response. Due to these immunoregulatory effects, it is used as an adjuvant in many clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders.
Melatonin appears to have some use against insomnia, jet lag, and other types of misalignments in circadian rhythms. It has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), and sexual dysfunction; the results of most of these studies remain inconclusive. A study by Alfred J. Lewy and other researchers at OHSU found that it may ameliorate SAD and circadian misalignment, but as of 2006 it is known to affect the timing of endogenous melatonin production, raising the risk that it can exacerbate both clinical depression and SAD. As well, exogenous melatonin supplements are assumed to reduce normal melatonin production, according to the principle of homeostasis.
Melatonin receptors appear to be important in mechanisms of learning and memory, and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). Melatonin has been shown to prevent the hyperphosphorylation of the tau protein. Hyperphosphorylation of tau protein can result in the formation of neurofibrillary tangles, a pathological feature seen in Alzheimer's disease). Thus, melatonin may be effective for treating Alzheimer's disease.
There may be other, far-reaching therapeutic uses for melatonin, such as in the treatment of various forms of cancer, HIV, and other viral diseases. For instance, it has been shown that melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).
Melatonin is practically nontoxic and exhibits almost no toxic side effects, except for the occurrence of somnolence in most of the population at higher doses. Exogenous melatonin normally does not affect the endogenous melatonin profile in the short or medium-term. However, melatonin taken in combination with monoamine oxidase inhibitors (MAOIs) can lead to overdose because MAOIs inhibit the breakdown of melatonin by the body.
Individuals who experience orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonins supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate the symptoms by reducing nerve activity in those who experience the condition, the study found.
Melatonin has been associated with a worsening of autoimmune disorders, and its use by those suffering multiple sclerosis is controversial, according to a University of Maryland Medical Center advisory reviewed by ADAM, an American Accreditation HealthCare Commission accredited publication editied by Harvey Simon, MD, an Associate Professor of Medicine at Harvard Medical School who practices at Massachusetts General Hospital.
An Andrews University Nutrition Department report classifies melatonin among nutritional suppliments sometimes promoted beyond their proven efficacy, though information from a company that sells melatonin says theoretical studies suggest may help those suffering multiple sclerosis.
Andrews University Nutrition Department report states that over-the-counter doses of Melatonin can cause severe headaches, mental impairment, and mood changes. Victor Herbert, M.D., J.D. Mt. Sinai School of Medicine cites studies from Massechussets Institute of Technology that say melatonin pills sold as supplements contain three to 10 times amount needed to produce the desirable physiologic nocturnal blood melatonin level for enhancement of nighttime rest. It is at those elevated levels produced by typical over-the-counter dosage units that studies have found mental impairment and headaches result, Herbert wrote in Nutrition Today article subtitled "Harms from a pseudo-cure-all.. These opinions contrast with several clinical studies that indicate that supplementation with melatonin is an effective preventative treatment for migraine sufferers
Melatonin also has antithyroidal properties that can be either helpful or harmful depending on the condition and needs of an individual, Herbert wrote, although this appears to be contradicted by research that concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause .
Many animals use the variation in duration and quantity of melatonin production in each day as a seasonal clock . In seasonal breeders which do not have long gestation periods, and which mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds and hamsters . Melatonin is also related to the mechanism by which some amphibians and reptiles change the color of their skin.
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