Melatonin
Serotonin and Melatonin

Author: GianPieroBandelli MonicaBarrera
Date: 18/03/2008

Description

Melatonin is a hormone secreted by the pineal gland in the brain that helps regulate other hormones and maintains the body's circadian rhythm.

The circadian rhythm is an internal 24-hour time-keeping system that plays a critical role in determining when we fall asleep and when we wake up. Darkness stimulates the production of melatonin while light suppresses its activity. Exposure to excessive light in the evening or too little light during the day can disrupt the body’s normal melatonin cycles. For example, jet lag, shift work, and poor vision can disrupt melatonin cycles. In addition, some experts claim that exposure to low-frequency electromagnetic fields (common in household appliances) may disrupt normal cycles and production of melatonin. Melatonin also helps control the timing and release of female reproductive hormones. It helps determine when menstruation begins, the frequency and duration of menstrual cycles, and when menstruation ends (menopause). Many researchers also believe that melatonin levels are related to the aging process. For example, young children have the highest levels of night time melatonin. Researchers believe these levels diminish as we age. In fact, the decline in melatonin may explain why many older adults have disrupted sleep patterns and tend to go to bed and wake up earlier than when they were younger. However, emerging research calls this theory into question. In addition to its hormonal actions, melatonin has strong antioxidant effects. Melatonin is not only a hormone but is also synthesized in numerous extrapineal sites, in which it sometimes attains much higher quantities than in the pineal and the circulation. It is also present in many taxonomically distant groups of organisms, including bacteria, fungi, and plants. Moreover, melatonin is a source of bioactive metabolites, such as 5-methoxytryptamine, N (1)-acetyl-N (2)-formyl-5-methoxykynuramine and N (1)-acetyl-5-methoxykynuramine.

STRUCTURE

SYNTHESIS AND METABOLISM

Melatonin is synthesized within the pinealocytes- from tryptophan. Most synthetic activity occurs during the dark phase, with a major increase (7-150 fold) in the activity of serotonin-N-acetyltransferase (arylalkylamine N-acetyl transferase, AA-NAT). AA-NAT is usually rate limiting in melatonin production, but serotonin availability may also play a role. The rhythm of production is endogenous, being generated by interacting networks of clock genes in the suprachiasmatic nuclei (SCN), the major central rhythm-generating system or "clock" in mammals (the pineal itself is a self sustaining "clock" in some if not all lower vertebrates). The main feedback loop involving transcription of a number of genes (Per1, Per2, Per3, Cry1, Cry2, and Reverbα) is activated by heteromeric complexes of CLOCK and BMAL1. This transcription continues into the night until nuclear levels of PER and CRY proteins become sufficiently high to repress CLOCK/BMAL1 activation. Declining levels of PER/CRY in the early morning then allows transcription of the genes again and the cycle continues (most, if not all peripheral tissues also express this sequence. The SCN rhythm is synchronized to 24 hours primarily by the light-dark cycle acting via the retina and the retinohypothalamic projection to the SCN. The cDNAs encoding both AA-NAT and the O-methylating enzyme HIOMT have both been cloned. There are substantial species differences in regulation of AA-NAT. It is likely that in humans and ovines the enzyme is regulated primarily at a post transcriptional level, whereas in rodents the key event appears to be cyclic AMP-dependent phosporylation of a transcription factor that binds to the AA-NAT promoter. Rapid decline in activity with light treatment at night appears to depend on proteasomal proteolysis. According to distribution studies of AA-NAT mRNA this enzyme is expressed in the pineal, retina and, to a much lesser extent, some other brain areas, the pituitary and the testis, but apart from the pineal these structures contribute little to circulating concentrations in mammals. There is also evidence that melatonin may be synthesised in the gastro-intestinal tract and may contribute to gut function. Within the rodent retina a self sustaining 'clock' maintains rhythmic production of melatonin in vitro as it does in many lower vertebrates. Whether or not this is true of humans remains to be seen. In humans and rodents melatonin is metabolized to 6-sulphatoxymelatonin (aMT6s), primarily within the liver, by 6-hydroxylation, followed by sulfate conjugation. A number of minor metabolites are also formed, including the glucuronide conjugate. Exogenous oral or intravenous melatonin has a short metabolic half-life (20 to 60 minutes, depending on author and species), with a large hepatic first-pass effect and a biphasic elimination pattern. In ruminants longer half-lives are seen after oral administration. Most effects of pinealectomy can be reversed by melatonin, administered appropriately in physiological concentrations

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CELLULAR FUNCTION

In its role as a pineal hormone, melatonin is a pleiotropic, nocturnally peaking and systemically acting chronobiotic. These effects are largely explained by actions via G protein-coupled membrane receptors found in the suprachiasmatic nucleus, but also in numerous other sites. Nuclear (ROR/RZR), cytoplasmic (quinone reductase-2, calmodulin, calreticulin) and mitochondrial binding sites and radical-scavenging properties contribute to the actions of melatonin.

REGULATION

Sympathetic denervation of the pineal in mammals abolishes the rhythmic synthesis of melatonin and the light-dark control of its production. Norepinephrine is clearly the major transmitter, acting via beta-1-adrenoceptors with potentiation by alpha-1 stimulation, but the role of neural serotonin is probably not negligible. There is a day-night variation in pineal norepinephrine, with highest values at night, approximately 180 degrees out of phase with the pineal serotonin rhythm. cAMP acts as a second messenger and stimulates AA-NAT activity. Beta-adrenergic receptor binding sites in the rat pineal vary over a 24-hour period, the lowest number being found toward the end of the dark phase, increasing shortly after lights on. There is evidence for modulation of melatonin synthesis in vitro by other factors, notably neuropeptides, but their physiological importance remains obscure.Regulation of pineal melatonin biosynthesis is largely explained by control mechanisms acting on arylalkylamine N-acetyltransferase, at the levels of gene expression and/or enzyme stability influenced by phosphorylation and interaction with 14-3-3 proteins.

USES

  • Insomnia

Although results are still controversial, studies suggest that melatonin supplements help induce sleep in people with disrupted circadian rhythms (such as those suffering from jet lag or poor vision or those who work the night shift) and those with low melatonin levels (such as some elderly and individuals with schizophrenia). In fact, a recent review of scientific studies found that melatonin supplements help prevent jet lag, particularly in people who cross five or more time zones. A few studies suggest that when taken for short periods of time (days to weeks) melatonin is significantly more effective than a placebo, or “dummy pill,” in decreasing the amount of time required to fall asleep, increasing the number of sleeping hours, and boosting daytime alertness. In addition, at least one study suggests that melatonin may improve the quality of life in people who suffer from insomnia and some experts suggest that melatonin may be helpful for children with learning disabilities who suffer from insomnia. Although research suggests that melatonin may be modestly effective for treating certain types of insomnia, few studies have investigated whether melatonin supplements are safe and effective for long term use.

Herxheimer A, Petrie KJ. Melatonin for preventing and treating jet lag. Cocharane Database Syst Rev . 2001;(1):CD001520

Arendt J. Melatonin, circadian rhythms and sleep. New Engl J Med ; 2000;343(15):1114-1116

Attele AS, Xie JT, Yuan CS. Treatment of insomnia: an alternative approach. Altern Med Rev . 2000;5(3):249-259

Chase JE, Gidal BE. Melatonin: Therapeutic use in sleep disorders. Ann Pharmacother . 1997;31:1218-1225

Jan JE, Espezel H, Appleton RE. The treatment of sleep disorders with melatonin. Dev Med Child Neurol . 1994;36(2):97-107

Jan JE, Espezel H, Freeman RD, Fast DK. Melatonin treatment of chronic sleep disorders. J Child Neurol. 1998; 13(2):98

  • Osteoporosis

Melatonin has been shown to stimulate cells called osteoblasts that promote bone growth. Since melatonin levels may be lower in some older individuals such as postmenopausal women, current studies are investigating whether decreased melatonin levels contribute to the development of osteoporosis, and whether treatment with melatonin can help prevent this condition.

Roth JA, Kim B-G, Lin W-L, Cho M-I. Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem . 1999;274:22041-22047

  • Menopause

Melatonin supplements may benefit menopausal women by promoting and sustaining sleep. Peri- or postmenopausal women who use melatonin supplements to regulate sleep patterns should do so only for a short period of time since long term effects are not known.

Brzezinski A. Melatonin replacement therapy for postmenopausal women: is it justified? Menopause . 1998;5:60-64

  • Depression

A recent study of postmenopausal women found that melatonin alleviated both depression and anxiety. Other studies show that people who suffer from major depression or panic disorder have low levels of melatonin. Healthy individuals with mild episodic depression and patients who have Seasonal Affective Disorder, (SAD -- a mild depression that correlates with fall and winter -- periods of light-phase shortening) also have lower than normal melatonin levels. Experimental studies show that melatonin causes a surge in the chemical serotonin, which helps alleviate symptoms of depressive illness, including major and mild depression and SAD. Melatonin should be used with caution in people with depression and should be appropriately timed with light therapy and sleep-phase changes. Disruption of normal circadian rhythm by poorly timed melatonin administration may worsen depression.

Carman JS, Post RM, Buswell R, Goodwin FK. Negative effects of melatonin on depression. Am J Psychiatry . 1976;133:1181-1186

Cauffield JS, Forbes HJ. Dietary supplements used in the treatment of depression, anxiety, and sleep disorders. Lippincotts Prim Care Pract . 1999; 3(3):290-304

Lewy AJ, Bauer VK, Cutler NL, Sack RL. Melatonin treatment of winter depression: a pilot study. Psych Res . 1998;77(1):57-61(97)00128-5/abstract

  • Eating Disorders

Melatonin levels may play a role in the symptoms of anorexia. For example, abnormally low melatonin levels may cause depressed mood in people with this condition. However, researchers do not know whether supplementation will change the course of the disease. Some researchers speculate that low melatonin levels in people with anorexia may indicate who is likely to benefit from antidepressant medications (a treatment often used for eating disorders).

Kennedy SH. Melatonin disturbances in anorexia nervosa and bulimia nervosa. Int J Eating Disord . 1994;16:257-265

  • Breast Cancer

Several studies indicate that melatonin levels may be linked with breast cancer risk. For example, women with breast cancer tend to have lower levels of melatonin than those without the disease. In addition, laboratory experiments have found that low levels of melatonin stimulate the growth of certain types of breast cancer cells, while adding melatonin to these cells inhibits their growth. Preliminary laboratory and clinical evidence also suggests that melatonin may enhance the effects of some chemotherapy drugs used to treat breast cancer. In a study that included a small number of women with breast cancer, melatonin (administered 7 days before beginning chemotherapy) prevented the lowering of platelets in the blood. This is a common complication of chemotherapy, known as thrombocytopenia that can lead to bleeding. In another study of a small group of women whose breast cancer was not improving with tamoxifen (a commonly used chemotherapy medication), adding melatonin caused tumors to modestly shrink in over 28% of the women. People with breast cancer who are considering taking melatonin supplements should consult their doctors before beginning supplementation.

Barcelo E. Melatonin – estrogen interactions in breast cancer. J of Pineal Res . 2005;38:217-222

Barcelo E. Melatonin and mammary cancer: a short review. Endocrine-Related Cancer . 2003;10:153-159

Cos S, Sanchez-Barcelo EJ. Melatonin, experimental basis for a possible application in breast cancer prevention and treatment. Histo Histopath . 2000;15:637-647

  • Prostate Cancer

Like breast cancer, studies show that people with prostate cancer have lower melatonin levels than men without the disease. Melatonin blocks the growth of prostate cancer cells in test tube studies. In one small-scale study, melatonin (when used in combination with conventional medical treatment) improved survival rates in 9 out of 14 patients with metastatic prostate cancer. Interestingly, since meditation may cause melatonin levels to rise it appears to be a valuable addition to the treatment of prostate cancer. More research is needed before doctors can make recommendations in this area.

Coker KH. Meditation and prostate cancer: integrating a mind/body intervention with traditional therapies. Sem Urol Onc . 1999;17(2):111-118

  • Cancer-related Weight Loss

Weight loss and malnutrition are concerns for people with cancer. In one study of 100 people with advanced cancer, those who received melatonin supplements were less likely to lose weight than those who did not receive the supplements.

Lissoni P, Paolorossi F, Tancini G, Barni S, Ardizzoia A, Brivio F, Zubelewicz B, Chatikhine V. Is there a role for melatonin in the treatment of neoplastic cachexia? Eur J Cancer . 1996;32A(8):1340-1343

  • Sarcoidosis

Some physicians use melatonin to help treat sarcoidosis (a condition where fibrous tissue develops in the lungs and other tissues). Two case reports suggest that melatonin may be helpful for those who do not improve from conventional steroid treatment.

Cagnoni ML, Lombardi A, Cerinic MC, Dedola GL, Pignone A. Melatonin for treatment of chronic refractory sarcoidosis [letter]. Lancet . 1995;346(4):1299-1230

  • Rheumatoid Arthritis

Melatonin levels are lower in patients with rheumatoid arthritis than in healthy individuals without arthritis. However, when arthritis patients were treated with the anti-inflammatory medication indomethacin, melatonin levels returned to normal. The chemical structure of melatonin resembles indomethacin, so researchers suspect that melatonin supplements may work similarly to this medication for people with rheumatoid arthritis. However, this theory has not been tested.
Attention Deficit/Hyperactivity Disorder (ADHD)
Although melatonin supplementation does not appear to improve the key behavioral symptoms of ADHD, it may be effective in managing sleep disturbances in children with this condition.

West Sk, Oosthuizen JM. Melatonin levels are decreased in rheumatoid arthritis. J Basic Clin Physiol Pharmacol . 1992;3(1):33-40

  • Epilepsy

    Preliminary research suggests that melatonin reduces the number of seizures in certain animals and may reduce seizures in people with epilepsy. However, not all experts agree with these findings. In fact, some researchers are concerned that melatonin (1 to 5 mg per day) may actually induce seizures, particularly in children with neurologic disorders. Since this research is in the early stages, some experts suggest that doctors should administer melatonin only to a select group of people who suffer from seizures that cannot be controlled by any other type of therapy.

Bazil CW, Short D, Crispin D, Zheng W. Patients with intractable epilepsy have low melatonin, which increases following seizures. Neurology . 2000;55(11):1746-1748

Fauteck J, Schmidt H, Lerchl A, Kurlemann G, Wittkowski W. Melatonin in epilepsy: first results of replacement therapy and first clinical results. Biol Signals Recept . 1999;8(1-2):105-110.

  • Sunburn

A few small studies suggest that gels, lotions, or ointments containing melatonin may protect against redness (erythema) and other skin damage when used alone or in combination with topical vitamin E prior to exposure to UV radiation from the sun.

Dreher F, Denig N, Gabard B, Schwindt DA, Maibach HI. Effect of topical antioxidants on UV-induced erythema formation when administered after exposure. Dermatology . 1999;198(1):52-55

  • Viral Encephalitis

Although melatonin has not been scientifically evaluated for use in treating human encephalitis (inflammation of the brain), some studies suggest that this supplement may protect animals from serious complications associated with the condition and even increase their survival rates. In one study of mice infected with Venezuelan equine virus (a type of organism that causes viral encephalitis), melatonin supplements significantly lowered the presence of virus in the blood and reduced death rates by more than 80%. More studies are needed to determine whether similar treatment may offer the same protection to people with viral encephalitis.

Ben-Nathan D, Maestroni GJ, Lustig S, Conti A. Protective effects of melatonin in mice infected with encephalitis viruses. Arch Virol . 1995;140(2):223-230

  • Heart Disease

Low blood levels of melatonin are associated with heart disease, but it is not clear whether melatonin levels are low in response to having heart disease or if low levels of melatonin cause people to develop this condition. In addition, several animal studies suggest that melatonin may protect the heart from the damaging effects of ischemia (decreased blood flow and oxygen that often leads to a heart attack). However, researchers are unclear whether melatonin supplements may help prevent or treat heart disease in people. More studies are needed before scientists can draw any conclusions.

Sakotnik A, Liebmann PM, Stoschitzky K, Lercher P, Schauenstein K, Klein W, et al. Decreased melatonin synthesis in patients with coronary artery disease. Eur Heart J . 199;20(18):1314-1317

Kaneko S, Okumura K, Numaguchi Y, Matsui H, Murase K, Mokuno S, et al. Melatonin scavenges hydroxyl radical and protects isolated rat hearts from ischemic reperfusion injury. Life Sciences . 2000;67(2):101-112

Comments
2010-03-01T13:41:12 - Gianpiero Pescarmona

Melatonin and Cancer

Therapeutic actions of melatonin on gastrointestinal cancer development and progression, 2013

Melatonin exerts a multitude of physiological functions including the regulation of the sleep cycle and circadian rhythm. Although the synthesis of melatonin in the pineal gland is regulated by changes in the light/dark cycle, the release of melatonin in the gastrointestinal tract is related to food consumption. Melatonin regulates antioxidative processes and it improves T-helper cell response by stimulating the production of specific cytokines. Melatonin is directly involved in preventing tumor initiation, promotion, and progression in a variety of cancers of the gastrointestinal tract including colorectal cancer, cholangiocarcinoma, hepatocarcinoma, and pancreatic carcinoma. This paper is a review of the literature regarding melatonin in the gastrointestinal tract and as a potential therapy for gastrointestinal cancers.

Keywords: Gastrointestinal cancer; melatonin; T-helper cell; colorectal cancer; cholangiocarcinoma; hepatocarcinoma; pancreatic cancer

Submitted Jul 12, 2012. Accepted for publication Aug 15, 2012.

Transl Gastrointest Cancer 2013;2(1). DOI:10.3978/j.issn.2224-4778.2012.08.03

In vitro modulation of steroidogenesis and gene expression by melatonin: a study with porcine antral follicles. 2003

J Pineal Res. 2006 Mar;40(2):116-24.
Urinary 6-sulfatoxymelatonin levels and their correlations with lifestyle factors and steroid hormone levels.

Schernhammer ES, Kroenke CH, Dowsett M, Folkerd E, Hankinson SE.

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. eva.schemhammer@channing.harvard.edu

Exposure to light at night, as experienced by rotating night shift workers, has been related to lower circulating levels of melatonin, a hormone with recognized cancer protective properties. However, little is known about the relationship of other lifestyle factors or endogenous sex steroid hormones with melatonin levels. We examined cross-sectional associations of age, reproductive and menopausal factors, body mass index (BMI), alcohol consumption, smoking history, night shift work, as well as several other breast cancer risk factors, and circulating sex steroid hormone levels with creatinine-adjusted morning urinary melatonin (6-sulfatoxymelatonin, aMT6s) levels. Participants were 459 healthy, primarily premenopausal (age range 33-50 yr) women from the Nurses' Health Study II (NHS II). Using multiple linear regression, we computed least-square mean hormone levels across categories of lifestyle factors. Age was inversely related to aMT6s levels, particularly before menopause (premenopausal women, or=49 yr; aMT6s, 20.8 ng/mg versus 11.8 ng/mg creatinine; P for trend, 0.02). In multivariate analyses, BMI was significantly and inversely associated with aMT6s levels (P for trend, <0.01). Higher pack-years of smoking were associated with significantly lower aMT6s levels (never smoker versus 15+ pack-years, aMT6s = 17.4 ng/mg versus 12.3 ng/mg creatinine; P for trend, 0.04). We also observed a positive association between parity and aMT6s levels (P for trend, <0.01), but no other reproductive factors nor any of the sex hormones (estradiol, progesterone, estrone, estrone sulfate, dehydroepiandrostenedione, dehydroepiandrostenedione sulfate, testosterone, and androstenedione), as measured either in the luteal or the follicular phase of the menstrual cycle, were significantly associated with aMT6s. In conclusion, higher age, BMI, and heavy smoking were significantly related to lower levels of melatonin, whereas parity was significantly associated with higher aMT6s levels. Melatonin levels may be one mechanism through which these factors influence the development of cancer, but more studies are needed to elucidate these mechanisms definitively.

J Hypertens. 2010 Mar;28(3):446-51.
Urinary melatonin and risk of incident hypertension among young women.

Forman JP, Curhan GC, Schernhammer ES.

Channing Laboratory, Department of Medicine, 181 Longwood Avenue, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. jforman@partners.org

OBJECTIVE: Administered in supraphysiologic doses, the hormone melatonin may reduce blood pressure, particularly nocturnal blood pressure. However, whether lower physiologic levels of melatonin are an independent risk factor for the development of hypertension has never been reported. METHODS: We examined the association between first morning urine melatonin levels and the risk of developing hypertension among 554 young women without baseline hypertension who were followed for 8 years. Cox proportional hazards models were adjusted for age, BMI, physical activity, alcohol intake, smoking status, urinary creatinine, and family history of hypertension. RESULTS: During 8 years of follow-up, a total of 125 women developed hypertension. The relative risk for incident hypertension among women in the highest quartile of urinary melatonin (>27.0 ng/mg creatinine) as compared with the lowest quartile (<10.1 ng/mg creatinine) was 0.49 (95% confidence interval 0.28-0.85, P < 0.001). CONCLUSION: First morning melatonin levels are independently and inversely associated with incident hypertension; low melatonin production may be a pathophysiologic factor in the development of hypertension.

J Pediatr Endocrinol Metab. 2009 Nov;22(11):1009-15.
Daily profiles of salivary and urinary melatonin and steroids in healthy prepubertal boys.

Touitou Y, Auzéby A, Camus F, Djeridane Y.

Faculté de Médecine Pierre et Marie Curie, Service de Biochimie Médicale et Biologie Moléculaire and INSERM UMRS 975, Paris, France. yvan.touitou@upmc.fr

The aim of this study was to assess the circadian hormonal profile of two circadian markers, melatonin and cortisol, as well as other steroids in prepubertal boys (Tanner stage I). Nine volunteer healthy prepubertal boys aged 10.8 +/- 0.11 years participated in this study. Concentrations of daily salivary and urinary hormones were quantified around 24-hours, every 3 hours, in daytime samples (collected between 07.00 h +/- 30 min and 21.00 h +/- 30 min) and night-time samples (collected between 21.00 h +/- 30 min and 07.00 h +/- 30 min). Significant differences (p < 0.01) were found between day- and nighttime secretion of salivary melatonin and urinary 6-sulphatoxymelatonin, whereas no significant differences were found between day- and nighttime secretion of salivary and urinary cortisol nor between day- and nighttime secretion of 17-hydroxycorticosteroids (17-OHCS). The circadian profiles of salivary melatonin and cortisol showed large amplitude with a peak occurring at night (approximately 03.00 h) for melatonin and in the early morning (between 06.00 and 09.00 h) for cortisol. The curve patterns of the urinary 6-sulphatoxymelatonin and steroids (free cortisol and 17-OHCS) were coherent with data on saliva. The pattern of salivary androstenedione and testosterone were undetectable due to the very low concentrations of these steroids in the saliva of the prepubertal children. A strong significant positive correlation was observed between the daily salivary melatonin levels and the daily urinary 6-sulphatoxymelatonin excretion (R = 0.968, p < 0.001), and between free urinary cortisol and urinary 17-OHCS (R = 0.733, p = 0.025). The salivary and urinary hormones studied were independent of body mass index. This study shows the relevance of salivary cortisol and melatonin, although lower than in plasma, in testing adrenal and pineal function as markers of circadian rhythms. The data are of interest for the diagnosis and treatment of chronobiological disorders in prepubertal children.

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