Three centuries ago, the French philosopher René Descartesdescribed the pineal gland as "the seat of the soul," but itwas not until the late 1950s that melatonin, the principal substancesecreted by the pineal gland, was identified.1 There is nowevidence that melatonin may have a role in the biologic regulationof circadian rhythms, sleep, mood, and perhaps reproduction,tumor growth, and aging (Table 1). However, uncertainties anddoubts still surround the role of melatonin in human physiologyand pathophysiology. This review summarizes current knowledgeabout melatonin in humans and its clinical implications.
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From the Department of Obstetrics and Gynecology, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel, where reprint requests should be addressed to Dr. Brzezinski.
References
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[Abstract][Full Text]
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(2007). Rapid Eye Movement Sleep Behavior Disorder. The Annals of Pharmacotherapy
41: 1833-1841
[Abstract][Full Text]
Inzelberg, R., Jankovic, J.
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69: 1542-1550
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Lee Barron, M.
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9: 49-69
[Abstract]
Bossola, M., Pacelli, F., Tortorelli, A., Doglietto, G. B.
(2007). Cancer Cachexia: It's Time for More Clinical Trials. Ann. Surg. Oncol.
14: 276-285
[Abstract][Full Text]
Suh, K. T., Lee, S. S., Kim, S. J., Kim, Y. K., Lee, J. S.
(2007). Pineal gland metabolism in patients with adolescent idiopathic scoliosis. J Bone Joint Surg Br
89-B: 66-71
[Abstract][Full Text]
Naguib, M., Samarkandi, A. H., Moniem, M. A., Mansour, E. E.-D., Alshaer, A. A., Al-Ayyaf, H. A., Fadin, A., Alharby, S. W.
(2006). The Effects of Melatonin Premedication on Propofol and Thiopental Induction Dose-Response Curves: A Prospective, Randomized, Double-Blind Study. Anesth. Analg.
103: 1448-1452
[Abstract][Full Text]
Geron, R., Shurtz-Swirski, R., Sela, S., Gurevitch, Y., Tanasijtchouk, T., Orr, Z. S., Shkolnik, G., Tanhilevski, O., Kristal, B.
(2006). Polymorphonuclear leucocyte priming in long intermittent nocturnal haemodialysis patients--is melatonin a player?. Nephrol Dial Transplant
21: 3196-3201
[Abstract][Full Text]
Johnson, M. W., Suess, P. E., Griffiths, R. R.
(2006). Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects.. Arch Gen Psychiatry
63: 1149-1157
[Abstract][Full Text]
Kubo, T., Ozasa, K., Mikami, K., Wakai, K., Fujino, Y., Watanabe, Y., Miki, T., Nakao, M., Hayashi, K., Suzuki, K., Mori, M., Washio, M., Sakauchi, F., Ito, Y., Yoshimura, T., Tamakoshi, A.
(2006). Prospective Cohort Study of the Risk of Prostate Cancer among Rotating-Shift Workers: Findings from the Japan Collaborative Cohort Study. Am J Epidemiol
164: 549-555
[Abstract][Full Text]
Wu, Y.-H., Fischer, D. F., Kalsbeek, A., Garidou-Boof, M.-L., van der Vliet, J., van Heijningen, C., Liu, R.-Y., Zhou, J.-N., Swaab, D. F.
(2006). Pineal clock gene oscillation is disturbed in Alzheimer's disease, due to functional disconnection from the "master clock". FASEB J.
20: 1874-1876
[Abstract][Full Text]
Aoki, K., Stephens, D. P., Zhao, K., Kosiba, W. A., Johnson, J. M.
(2006). Modification of cutaneous vasodilator response to heat stress by daytime exogenous melatonin administration. Am. J. Physiol. Regul. Integr. Comp. Physiol.
291: R619-R624
[Abstract][Full Text]
O'Leary, E. S., Schoenfeld, E. R., Stevens, R. G., Kabat, G. C., Henderson, K., Grimson, R., Gammon, M. D., Leske, M. C., for the Electromagnetic Fields and Breast Cancer o,
(2006). Shift Work, Light at Night, and Breast Cancer on Long Island, New York. Am J Epidemiol
164: 358-366
[Abstract][Full Text]
Capuzzo, M., Zanardi, B., Schiffino, E., Buccoliero, C., Gragnaniello, D., Bianchi, S., Alvisi, R.
(2006). Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery.. Anesth. Analg.
103: 121-123
[Abstract][Full Text]
Pinheiro, S. P., Schernhammer, E. S., Tworoger, S. S., Michels, K. B.
(2006). A prospective study on habitual duration of sleep and incidence of breast cancer in a large cohort of women.. Cancer Res.
66: 5521-5525
[Abstract][Full Text]
Huang, H., Lee, S.-C., Yang, X.-L.
(2005). Modulation by melatonin of glutamatergic synaptic transmission in the carp retina. J. Physiol.
569: 857-871
[Abstract][Full Text]
Pompeii, L. A., Savitz, D. A., Evenson, K. R., Rogers, B., McMahon, M.
(2005). Physical Exertion at Work and the Risk of Preterm Delivery and Small-for-Gestational- Age Birth. Obstet Gynecol
106: 1279-1288
[Abstract][Full Text]
Knight, J. A., Thompson, S., Raboud, J. M., Hoffman, B. R.
(2005). Light and Exercise and Melatonin Production in Women. Am J Epidemiol
162: 1114-1122
[Abstract][Full Text]
Ximenes, V. F., Silva, S. d. O., Rodrigues, M. R., Catalani, L. H., Maghzal, G. J., Kettle, A. J., Campa, A.
(2005). Superoxide-dependent Oxidation of Melatonin by Myeloperoxidase. J. Biol. Chem.
280: 38160-38169
[Abstract][Full Text]
Han, S., Kim, T.-D., Ha, D.-C., Kim, K.-T.
(2005). Rhythmic Expression of Adenylyl Cyclase VI Contributes to the Differential Regulation of Serotonin N-Acetyltransferase by Bradykinin in Rat Pineal Glands. J. Biol. Chem.
280: 38228-38234
[Abstract][Full Text]
Verkasalo, P. K., Lillberg, K., Stevens, R. G., Hublin, C., Partinen, M., Koskenvuo, M., Kaprio, J.
(2005). Sleep Duration and Breast Cancer: A Prospective Cohort Study. Cancer Res.
65: 9595-9600
[Abstract][Full Text]
Prada, C., Udin, S. B., Wiechmann, A. F., Zhdanova, I. V.
(2005). Stimulation of Melatonin Receptors Decreases Calcium Levels in Xenopus Tectal Cells by Activating GABAC Receptors. J. Neurophysiol.
94: 968-978
[Abstract][Full Text]
Schernhammer, E. S., Hankinson, S. E.
(2005). Urinary Melatonin Levels and Breast Cancer Risk. JNCI J Natl Cancer Inst
97: 1084-1087
[Abstract][Full Text]
Demirbag, S., Cetinkursun, S., Tasdemir, U., Ozturk, H., Pekcan, M., Yesildaglar, N.
(2005). Comparison of hyaluronate/carboxymethylcellulose membrane and melatonin for prevention of adhesion formation in a rat model. Hum Reprod
20: 2021-2024
[Abstract][Full Text]
Frisch, H., Waldhauser, F., Waldhor, T., Mullner-Eidenbock, A., Neupane, P., Schweitzer, K.
(2004). Increase in 6-Hydroxymelatonin Excretion in Humans during Ascent to High Altitudes. J. Clin. Endocrinol. Metab.
89: 4388-4390
[Abstract][Full Text]
Peck, J. S., LeGoff, D. B., Ahmed, I., Goebert, D.
(2004). Cognitive Effects of Exogenous Melatonin Administration in Elderly Persons: A Pilot Study. AJGP
12: 432-436
[Abstract][Full Text]
Schernhammer, E. S., Rosner, B., Willett, W. C., Laden, F., Colditz, G. A., Hankinson, S. E.
(2004). Epidemiology of Urinary Melatonin in Women and Its Relation to Other Hormones and Night Work. Cancer Epidemiol. Biomarkers Prev.
13: 936-943
[Abstract][Full Text]
Armour, D., Paton, C.
(2004). Melatonin in the treatment of insomnia in children and adolescents. Psychiatr. Bull.
28: 222-224
[Abstract][Full Text]
Kliukiene, J., Tynes, T., Andersen, A.
(2004). Residential and Occupational Exposures to 50-Hz Magnetic Fields and Breast Cancer in Women: A Population-based Study. Am J Epidemiol
159: 852-861
[Abstract][Full Text]
Lipsitz, L. A.
(2004). Physiological Complexity, Aging, and the Path to Frailty. Sci Aging Knowl Environ
2004: pe16-pe16
[Abstract][Full Text]
Gamst, A., Wolfson, T., Parry, B.
(2004). Local Polynomial Regression Modeling of Human Plasma Melatonin Levels. J Biol Rhythms
19: 164-174
[Abstract]
Kunz, D., Mahlberg, R., Muller, C., Tilmann, A., Bes, F.
(2004). Melatonin in Patients with Reduced REM Sleep Duration: Two Randomized Controlled Trials. J. Clin. Endocrinol. Metab.
89: 128-134
[Abstract][Full Text]
Wu, Y.-H., Feenstra, M. G. P., Zhou, J.-N., Liu, R.-Y., Torano, J. S., Van Kan, H. J. M., Fischer, D. F., Ravid, R., Swaab, D. F.
(2003). Molecular Changes Underlying Reduced Pineal Melatonin Levels in Alzheimer Disease: Alterations in Preclinical and Clinical Stages. J. Clin. Endocrinol. Metab.
88: 5898-5906
[Abstract][Full Text]
Fischer, S., Smolnik, R., Herms, M., Born, J., Fehm, H. L.
(2003). Melatonin Acutely Improves the Neuroendocrine Architecture of Sleep in Blind Individuals. J. Clin. Endocrinol. Metab.
88: 5315-5320
[Abstract][Full Text]
Gindes, L., Yoeli, R., Orvieto, R., Shelef, M., Ben-Rafael, Z., Bar-Hava, I.
(2003). Pregnancy rate fluctuations during routine work in an assisted reproduction technology unit. Hum Reprod
18: 2485-2488
[Abstract][Full Text]
Steffens, F., Zhou, X.-B., Sausbier, U., Sailer, C., Motejlek, K., Ruth, P., Olcese, J., Korth, M., Wieland, T.
(2003). Melatonin Receptor Signaling in Pregnant and Nonpregnant Rat Uterine Myocytes as Probed by Large Conductance Ca2+-Activated K+ Channel Activity. Mol. Endocrinol.
17: 2103-2115
[Abstract][Full Text]
Travis, R. C., Allen, N. E., Peeters, P. H. M., van Noord, P. A. H., Key, T. J.
(2003). Reproducibility over 5 Years of Measurements of 6-Sulphatoxymelatonin in Urine Samples from Postmenopausal Women. Cancer Epidemiol. Biomarkers Prev.
12: 806-808
[Abstract][Full Text]
Ozcelik, B., Serin, I.S., Basbug, M., Uludag, S., Narin, F., Tayyar, M.
(2003). Effect of melatonin in the prevention of post-operative adhesion formation in a rat uterine horn adhesion model. Hum Reprod
18: 1703-1706
[Abstract][Full Text]
Gerdin, M. J., Masana, M. I., Ren, D., Miller, R. J., Dubocovich, M. L.
(2003). Short-Term Exposure to Melatonin Differentially Affects the Functional Sensitivity and Trafficking of the hMT1 and hMT2 Melatonin Receptors. J. Pharmacol. Exp. Ther.
304: 931-939
[Abstract][Full Text]
Torres-Farfan, C., Richter, H. G., Rojas-Garcia, P., Vergara, M., Forcelledo, M. L., Valladares, L. E., Torrealba, F., Valenzuela, G. J., Seron-Ferre, M.
(2003). mt1 Melatonin Receptor in the Primate Adrenal Gland: Inhibition of Adrenocorticotropin-Stimulated Cortisol Production by Melatonin. J. Clin. Endocrinol. Metab.
88: 450-458
[Abstract][Full Text]
De Leersnyder, H, Bresson, J L, de Blois, M-C, Souberbielle, J-C, Mogenet, A, Delhotal-Landes, B, Salefranque, F, Munnich, A
(2003). {beta}1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome. J. Med. Genet.
40: 74-78
[Full Text]
Sutherland, E. R., Martin, R. J., Ellison, M. C., Kraft, M.
(2002). Immunomodulatory Effects of Melatonin in Asthma. Am. J. Respir. Crit. Care Med.
166: 1055-1061
[Abstract][Full Text]
Muller, H. L., Handwerker, G., Wollny, B., Faldum, A., Sorensen, N.
(2002). Melatonin Secretion and Increased Daytime Sleepiness in Childhood Craniopharyngioma Patients. J. Clin. Endocrinol. Metab.
87: 3993-3996
[Abstract][Full Text]
Guo, X., Kuzumi, E., Charman, S. C., Vuylsteke, A.
(2002). Perioperative Melatonin Secretion in Patients Undergoing Coronary Artery Bypass Grafting. Anesth. Analg.
94: 1085-1091
[Abstract][Full Text]
Lipsitz, L. A.
(2002). Dynamics of Stability: The Physiologic Basis of Functional Health and Frailty. J. Gerontol. A Biol. Sci. Med. Sci.
57: B115-125
[Abstract][Full Text]
Peres, M F P, del Rio, M S., Seabra, M L V, Tufik, S, Abucham, J, Cipolla-Neto, J, Silberstein, S D, Zukerman, E
(2001). Hypothalamic involvement in chronic migraine. J. Neurol. Neurosurg. Psychiatry
71: 747-751
[Abstract][Full Text]
Erren, T. C., Bjerregaard, P., Cocco, P., Lerchl, A., Verkasalo, P., Savitz, D. A.
(2001). RE: "INVITED COMMENTARY: ELECTROMAGNETIC FIELDS AND CANCER IN RAILWAY WORKERS". Am J Epidemiol
154: 977-979
[Full Text]
Masana, M. I., Dubocovich, M. L.
(2001). Melatonin Receptor Signaling: Finding the Path Through the Dark. Sci Signal
2001: pe39-pe39
[Abstract][Full Text]
Hansen, J.
(2001). Light at Night, Shiftwork, and Breast Cancer Risk. JNCI J Natl Cancer Inst
93: 1513-1515
[Full Text]
Schernhammer, E. S., Laden, F., Speizer, F. E., Willett, W. C., Hunter, D. J., Kawachi, I., Colditz, G. A.
(2001). Rotating Night Shifts and Risk of Breast Cancer in Women Participating in the Nurses' Health Study. JNCI J Natl Cancer Inst
93: 1563-1568
[Abstract][Full Text]
Levallois, P., Dumont, M., Touitou, Y., Gingras, S., Masse, B., Gauvin, D., Kroger, E., Bourdages, M., Douville, P.
(2001). Effects of Electric and Magnetic Fields from High-power Lines on Female Urinary Excretion of 6-Sulfatoxymelatonin. Am J Epidemiol
154: 601-609
[Abstract][Full Text]
De Leersnyder, H., de Blois, M.-C., Vekemans, M., Sidi, D., Villain, E., Kindermans, C., Munnich, A.
(2001). {beta}1-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, Smith-Magenis syndrome. J. Med. Genet.
38: 586-590
[Abstract][Full Text]
Roth, G. S., Lesnikov, V., Lesnikov, M., Ingram, D. K., Lane, M. A.
(2001). Dietary Caloric Restriction Prevents the Age-Related Decline in Plasma Melatonin Levels of Rhesus Monkeys. J. Clin. Endocrinol. Metab.
86: 3292-3295
[Abstract][Full Text]
Stevens, R. G., Hilakivi-Clarke, L.
(2001). Alcohol exposure in utero and breast cancer risk later in life. Alcohol Alcohol
36: 276-277
[Full Text]
Yang, Q., Scalbert, E., Delagrange, P., Vanhoutte, P. M., O'Rourke, S. T.
(2001). Melatonin potentiates contractile responses to serotonin in isolated porcine coronary arteries. Am. J. Physiol. Heart Circ. Physiol.
280: H76-H82
[Abstract][Full Text]
Bazil, C. W., Short, D., Crispin, D., Zheng, W.
(2000). Patients with intractable epilepsy have low melatonin, which increases following seizures. Neurology
55: 1746-1748
[Abstract][Full Text]
EDERY, I.
(2000). Circadian rhythms in a nutshell. Physiol. Genomics
3: 59-74
[Abstract][Full Text]
Potocki, L., Glaze, D., Tan, D.-X., Park, S.-S., Kashork, C. D, Shaffer, L. G, Reiter, R. J, Lupski, J. R
(2000). Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. J. Med. Genet.
37: 428-433
[Abstract][Full Text]
Bazil, C. W., Castro, L. H. M., Walczak, T. S.
(2000). Reduction of Rapid Eye Movement Sleep by Diurnal and Nocturnal Seizures in Temporal Lobe Epilepsy. Arch Neurol
57: 363-368
[Abstract][Full Text]
Kovács, J., Brodner, W., Kirchlechner, V., Arif, T., Waldhauser, F.
(2000). Measurement of Urinary Melatonin: A Useful Tool for Monitoring Serum Melatonin after Its Oral Administration. J. Clin. Endocrinol. Metab.
85: 666-670
[Abstract][Full Text]
Holbrook, A. M., Crowther, R., Lotter, A., Cheng, C., King, D.
(2000). The diagnosis and management of insomnia in clinical practice: a practical evidence-based approach. CMAJ
162: 216-210
[Abstract][Full Text]
Luboshitzky, R., Levi, M., Shen-Orr, Z., Blumenfeld, Z., Herer, P., Lavie, P.
(2000). Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men. Hum Reprod
15: 60-65
[Abstract][Full Text]
Skinner, D. C., Malpaux, B.
(1999). High Melatonin Concentrations in Third Ventricular Cerebrospinal Fluid Are Not due to Galen Vein Blood Recirculating through the Choroid Plexus. Endocrinology
140: 4399-4405
[Abstract][Full Text]
Sakotnik, A., Liebmann, P.M., Stoschitzky, K., Lercher, P., Schauenstein, K., Klein, W., Eber, B.
(1999). Decreased melatonin synthesis in patients with coronary artery disease. Eur Heart J
20: 1314-1317
[Abstract]
Gurney, J. G., van Wijngaarden, E.
(1999). Extremely low frequency electromagnetic fields (EMF) and brain cancer in adults and children: Review and comment. Neuro Oncol
1: 212-220
[Abstract]
Paul, P., Lahaye, C., Delagrange, P., Nicolas, J.-P., Canet, E., Boutin, J. A.
(1999). Characterization of 2-[125I]Iodomelatonin Binding Sites in Syrian Hamster Peripheral Organs. J. Pharmacol. Exp. Ther.
290: 334-340
[Abstract][Full Text]
De Bleecker, J. L., Lamont, B. H., Verstraete, A. G., Schelfhout, V. J.
(1999). Melatonin and painful gynecomastia. Neurology
53: 435-435
[Full Text]
Itoh, M. T., Ishizuka, B., Kuribayashi, Y., Amemiya, A., Sumi, Y.
(1999). Melatonin, its precursors, and synthesizing enzyme activities in the human ovary. Mol Hum Reprod
5: 402-408
[Abstract][Full Text]
Wiid, I., Hoal-van Helden, E., Hon, D., Lombard, C., van Helden, P.
(1999). Potentiation of Isoniazid Activity against Mycobacterium tuberculosis by Melatonin. Antimicrob. Agents Chemother.
43: 975-977
[Abstract][Full Text]
Brenner, S., Chandra, V., Pandav, R., Ganguli, M., Johnston, J., Belle, S., DeKosky, S. T.
(1999). Prevalence of AD and other dementias in rural India. Neurology
52: 1517-1517
[Full Text]
Liu, R.-Y., Zhou, J.-N., van Heerikhuize, J., Hofman, M. A., Swaab, D. F.
(1999). Decreased Melatonin Levels in Postmortem Cerebrospinal Fluid in Relation to Aging, Alzheimer's Disease, and Apolipoprotein E-{epsilon}4/4 Genotype. J. Clin. Endocrinol. Metab.
84: 323-327
[Abstract][Full Text]
De Salvia, R., Fiore, M., Aglitti, T., Festa, F., Ricordy, R., Cozzi, R.
(1999). Inhibitory action of melatonin on H2O2- and cyclophosphamide-induced DNA damage. Mutagenesis
14: 107-112
[Abstract][Full Text]
Duell, P. B., Wheaton, D. L., Shultz, A., Nguyen, H.
(1998). Inhibition of LDL oxidation by melatonin requires supraphysiologic concentrations. Clin. Chem.
44: 1931-1936
[Abstract][Full Text]
Van Den Heuvel, C. J., Kennaway, D. J., Dawson, D.
(1998). Effects of daytime melatonin infusion in young adults. Am. J. Physiol. Endocrinol. Metab.
275: E19-E26
[Abstract][Full Text]
Pillar, G, Etzioni, A, Shahar, E, Lavie, P
(1998). Melatonin treatment in an institutionalised child with psychomotor retardation and an irregular sleep-wake pattern. Arch. Dis. Child.
79: 63-64
[Abstract][Full Text]
Di, W.-L., Kadva, A., Djahanbakhch, O., Silman, R.
(1998). Radioimmunoassay of bound and free melatonin in plasma. Clin. Chem.
44: 304-310
[Abstract][Full Text]
Dave, R. H., Hale, S. L., Kloner, R. A.
(1998). The Effect of Melatonin on Hemodynamics, Blood Flow, and Myocardial Infarct Size in a Rabbit Model of Ischemia-Reperfusion. J CARDIOVASC PHARMACOL THER
3: 153-159
[Abstract]
Weaver, D. R.
(1997). Reproductive Safety of Melatonin: A "Wonder Drug" to Wonder About. J Biol Rhythms
12: 682-689
[Abstract]