Abstract
Melatonin, N-acetyl-5-methhoxytryptamine, is a molecule with diverse physiological function. It affects reproductive functions in a wide variety of species. This chapter describes the roles of melatonin on various reproductive parameters. Melatonin has an inhibitory influence on hypothalamic GnRH secretion. Melatonin acts as antioxidant and reduces oxidative stress-induced testicular dysfunctions and poor oocytes quality in many experimental animals. During fetal life, melatonin regulates circadian rhythm and has been suggested to play a role in the regulation of fetal REM and NREM sleep. In adults, melatonin regulates the time of parturition in both humans and nonhuman primates. Many studies have suggested that melatonin could be an effective treatment for preeclampsia, due to its antioxidant properties as well as its antihypertensive and anticonvulsive actions.
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Huebner O. Tumor des Glandula pinealis. Dtsch Med Wochenschr. 1898;24(pt 2):214–5.
Kitay JI, Altschule MD. The pineal gland. Cambridge: Harvard University Press; 1954.
Thieblot L, Le Bars H. Le Glande Pineale ou Epiphyse. Paris: Maloine; 1955.
Wurtman RJ, Axelrod J, Chu EW. Melatonin, a pineal substance: its effect on the rat ovary. Science. 1963;141:277–80.
Reiter RJ. The melatonin rhythm. Both a clock and calendar. Experientia. 1993;49:654–64.
Johnston JD, Messager S, Barrett P, Hazlerigg DG. Melatonin action in the pituitary: neuroendocrine synchronizer and developmental modulator? J Neuroendocrinol. 2003;15:405–8.
Rojansky N, Brzezinski A, Schenker JG. Seasonality in human reproduction: an update. Hum Reprod. 1992;7:735–45.
Kaupipila A, Kivela A, Pakarinen A, Vakkuri O. Inversed seasonal relationship between melatonin and ovarian activity in humans in a region with a strong seasonal contrast in luminosity. J Clin Endocrinol Metab. 1987;65:823–8.
Sanhal B. Seasonal birth pattern in Sweden in relation to birth order and maternal age. Acta Obstet Gynecol Scand. 1978;57:393–7.
Brzezinski A, Wurtman RJ. The pineal gland: it’s possible role in human reproduction. Obstet Gynecol Surv. 1988;43:197–207.
Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336:186–95.
Sizonenko PC. Physiology of puberty. J Endocrinol Invest. 1989;12:59–63.
Waldhauser F, Steger H. Changes in melatonin secretion with age and pubescence. J Neural Transm. 1986;21(Suppl):183–97.
Waldhauser F, Weiszenbacher G, Tatzer E, Gisinger B, Waldhauser M, Schemper M, Frisch H. Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metabol. 1988;66(3):648–52.
Iguchi H, Kato K, Ibayashi H. Age-dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinol Metabol. 1982;55:27–9.
Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM. Human melatonin production decreases with age. J Pineal Res. 1986;3:379–88.
Zhao ZY, Xie Y, Fu YR, Bogdan A, Touitou Y. Aging and the circadian rhythm of melatonin: a cross-sectional study of Chinese subjects 30–110 yr of age. Chronobiol Int. 2002;19:1171–82.
Carlomagno G, Nordio M, Chiu TT, Unfer V. Contribution of myo-inositol and melatonin to human reproduction. Eur J Obstet Gynecol Reprod Biol. 2011;159:267–72.
Buchanan KL, Yellon SM. Delayed puberty in the male Djungarian hamster: effect of short photoperiod or melatonin treatment on the Gn-RH neuronal system. Neuroendocrinology. 1991;54:96–102.
Silman RE. Melatonin and the human gonadotrophin-releasing hormone pulse generator. J Endocrinol. 1991;128:7–11.
Cavallo A. Melatonin and human puberty: current perspectives. J Pineal Res. 1993;15(3):115–21.
Crowley SJ, Acebo C, Carskadon MA. Human puberty: salivary melatonin profiles in constant conditions. Dev Psychobiol. 2012;54(4):468–73.
Cavallo A. Plasma melatonin rhythm in normal puberty: interactions of age and pubertal stages. Neuroendocrinology. 1992;55(4):372–9.
Waldhauser F, Boepple PA, Schemper M, Mansfield MJ, Crowley Jr WF. Serum melatonin in central precocious puberty is lower than in age-matched prepubertal children. J Clin Endocrinol Metabol. 1991;73(4):793–6.
Young IM, Francis PL, Leone AM, Stovell P, Silman RE. Constant pineal output and increasing body mass account for declining melatonin levels during human growth and sexual maturation. J Pineal Res. 1988;5(1):71–85.
Cavallo A, Dolan LM. 6-Hydroxymelatonin sulfate excretion in human puberty. J Pineal Res. 1996;21(4):225–30.
Fideleff HL, Boquete H, Fideleff G, Albornoz L, Lloret SP, Suarez M, Cardinali DP. Gender-related differences in urinary 6-sulfatoxymelatonin levels in obese pubertal individuals. J Pineal Res. 2006;40(3):214–8.
Salti R, Galluzzi F, Bindi G, Perfetto F, Tarquini R, Halberg F, Cornelissen G. Nocturnal melatonin patterns in children. J Clin Endocrinol Metabol. 2000;85:2137–44.
Cain SW, Dennison CF, Zeitzer JM, Guzik AM, Khalsa SB, Santhi N, Duffy JF. Sex differences in phase angle of entrainment and melatonin amplitude in humans. J Biol Rhythms. 2010;25(4):288–96.
Wetterberg L, Bratlid T, von Knorring L, Eberhard G, Yuwiler A. A multinational study of the relationships between nighttime urinary melatonin production, age, gender, body size, and latitude. Eur Arch Psychiatry Clin Neurosci. 1999;249:256–62.
Burgess HJ, Fogg LF. Individual differences in the amount and timing of salivary melatonin secretion. PLoS One. 2008;3(8):e3055.
Griefahn B, Brode P, Blaszkewicz M, Remer T. Melatonin production during childhood and adolescence: a longitudinal study on the excretion of urinary 6-hydroxymelatonin sulfate. J Pineal Res. 2003;34(1):26–31.
Penny R. Melatonin excretion in normal males and females: increase during puberty. Metabolism. 1982;31:816–23.
Waldhauser F, Weiszenbacher G, Frisch H, Zeitlhuber U, Waldhauser M, Wurtman RJ. Fall in nocturnal serum melatonin during prepuberty and pubescence. Lancet. 1984;1(8373):362–5.
Tsutsui K. A new key neurohormone controlling reproduction, gonadotropin-inhibitory hormone (GnIH): biosynthesis, mode of action and functional significance. Prog Neurobiol. 2009;88(1):76–88.
Ubuka T, Bentley GE, Ukena K, Wingfield JC, Tsutsui K. Melatonin induces the expression of gonadotropin-inhibitory hormone in the avian brain. Proc Natl Acad Sci U S A. 2005;102(8):3052–7.
Cohen HN, Hay ID, Anneswley TM, Beastall GH, Wallace AM, Spooner R, Thomson JA, Eastwold P, Klee GG. Serum immunoreactive melatonin in boys with delayed puberty. Clin Endocrinol. 1982;17:291–7.
Commentz JC, Helmke K. Precocious puberty and decreased melatonin secretion due to a hypothalamic hamartoma. Horm Res. 1995;44(6):271–5.
Cavallo A. Plasma melatonin rhythm in disorders of puberty: interactions of age and pubertal stages. Horm Res. 1991;36(1–2):16–21.
Ehrenkranz JR, Tamarkin L, Comite F, Johnsonbaugh RE, Bybee DE, Loriaux DL, Cutler Jr GB. Daily rhythm of plasma melatonin in normal and precocious puberty. J Clin Endocrinol Metabol. 1982;55(2):307–10.
Berga SL, Jones KL, Kaufmann S, Yen SS. Nocturnal melatonin levels are unaltered by ovarian suppression in girls with central precocious puberty. Fertil Steril. 1989;52(6):936–41.
Silman RE, Leone RM, Hooper RJ, Preece MA. Melatonin, the pineal gland and human puberty. Nature. 1979;282(5736):301–3.
Arendt J. Melatonin and the mammalian pineal gland. 1st ed. London: Chapman & Hall; 1995. p. 17.
Brzezinski A. Melatonin and human reproduction: why the effect is so elusive? In: Pandi-Perumal SR, Cardinali Melatonin DP, editors. From molecules to therapy. New York: Nova; 2007. p. 219–25.
Brzezinski A, Lynch HJ, Wurtman RJ, Seibel MM. Possible contribution of melatonin to the timing of the luteinizing hormone surge. N Engl J Med. 1987;316:1550–1.
Laughin GA, Loucks AB, Yen SCC. Marked augmentation of nocturnal melatonin secretion in amenorrheic athletes but not in cycling atheletes. Unaltered by opiodergic or dopaminergic blockade. J Clin Endocrinol Metab. 1991;73:1321–6.
Aleandri V, Spina V, Morini A. The pineal gland and reproduction. Hum Reprod Update. 1996;3:225–35.
Roy D, Belsham DD. Melatonin receptor activation regulates GnRH gene expression and secretion in GT1-7Gn-RH neurons. Signal transduction mechanisms. J Biol Chem. 2002;277:251–8.
Brzezinski A, Siebel MM, Lynch HJ, Deng MH, Wurtman RJ. Melatonin in human preovulatory follicular fluid. J Clin Endocrinol Metab. 1987;64:865–7.
Ronnberg L, Kauppila A, Leppaluoto J, Marikainen H, Vakkuuri O. Circadian and seasonal variation in human preovulatory follicular fluid melatonin concentration. J Clin Endocrinol Metab. 1990;71:492–6.
Ayre EA, Wang ZP, Brown GM, Pang SF. Localization and characterization of [125I] iodomelatonin binding sites in duck gonads. J Pineal Res. 1994;17:39–47.
Ayre EA, Pang SF. 2-[125I] Iodomelatonin binding sites in the testis and ovaries: putatitive melatonin receptors in the gonads. Biol Signals. 1994;3:71–84.
Cagnacci A, Volpe A. Influence of melatonin and photoperiod on animal and human reproduction. J Endocrinol Invest. 1996;19:382–411.
Yu ZH, Chow PH, Pang SF. Identification and characterization of 2[125I]-iodomelatonin binding sites in the rat epididymis. J Pineal Res. 1994;17:195–201.
Ng TB, Lo L. Inhibitory actions of pineal indoles on steroidogenesis in isolated rat Leydig cells. J Pineal Res. 1988;5:229–43.
Persengiev S, Kehajova J. Inhibitory actions of melatonin and structurally related compounds on testosterone production by mouse leydig cells in vitro. Cell Biochem Funct. 1991;9:281–6.
Shiu SYW, Yu ZH, Chow PH, Pang SF. Putative melatonin receptors in the male reproductive tissues. Front Horm Res. 1996;21:90–100.
Shiu SYW, Li L, Wong JTY, Pang SF. Biology of G-protein coupled melatonin receptors in the epididymis and prostate of mammals. Chin Med J. 1997;110:648–55.
Laudon M, Gilad E, Matzkin H, Braf Z, Zisapel N. Putatitive melatonin receptors in benign prostate tissue. J Clin Endocrinol Metab. 1996;81:1336–42.
Gilad E, Laudon M, Matzkin H, Pick E, Sofer M, Braf Z, Zisapel N. Functional melatonin receptors in the human prostate epithelial cells. Endocrinology. 1996;137:1412–7.
Awad H, Halawa F, Mostafa T, Atta H. Melatonin hormone profile in infertile males. Int J Androl. 2006;29:409–13.
Semercioz A, Onur R, Ogras S, Orhan I. Effects of melatonin on testicular tissue nitric oxide level and antioxidant enzyme activities in experimentally induced left varicocele. Neuro Endocrinol Lett. 2003;24:86–90.
Guneli E, Tugyan K, Ozturk H, Gumustekin M, Cilaker S, Uysal N. Effect of melatonin on testicular damage in streptozotocin-induced diabetes rats. Eur Surg Res. 2008;40:354–60.
Zhang K, Lv Z, Jia X, Huang D. Melatonin prevents testicular damage in hyperlipidaemic mice. Andrologia. 2012;44:230–6.
Koksal M, Oğuz E, Baba F, Ali Eren M, Ciftci H, Demir ME, Kurcer Z, Take G, Aral F, Ocak AR, Aksoy N, Ulas T. Effects of melatonin on testis histology, oxidative stress and spermatogenesis after experimental testis ischemia-reperfusion in rats. Eur Rev Med Pharmacol Sci. 2012;16:582–8.
Rao MV, Bhatt RN. Protective effect of melatonin on fluoride-induced oxidative stress and testicular dysfunction in rats. Res Rep Fluoride. 2012;45(2):116–24.
du Plessis SS, Hagenaar K, Lampiao F. The in vitro effects of melatonin on human sperm function and its scavenging activities on NO and ROS. Andrologia. 2010;42:112–6.
Bornman MS, Oosthuizen JM, Barnard HC, Schulenburg GW, Boomker D, Reif S. Melatonin and sperm motility. Andrologia. 1989;21:483–5.
van Vuuren RJ, Pitout MJ, van Aswegen CH, Theron JJ. Putative melatonin receptor in human spermatozoa. Clin Biochem. 1992;25:125–7.
Fujinoki M. Melatonin-enhanced hyperactivation of hamster sperm. Reproduction. 2008;136:533–41.
Puolakka J, Jarvinen PA, Kauppila A. Changing pattern of childbirth in northern Finland over the past three decades. In: Fortune circumpolar health. Seattle and London: University of Washington Press; 1985. p. 181–5.
Kauppilla A, Kivela A, Pakarinen A, Vakkuri O. Inverse seasonal relationship between melatonin and ovarian activity in humans in a region with a strong seasonal contrast in luminosity. J Clin Endocrinol Metab. 1987;65:823–8.
Kivela A, Kauppila A, Ylostalo P, Vakkuri O. Seasonal, menstrual and circadian secretion of melatonin gonadotrophins and prolactin in women. Acta Physiol Scand. 1988;132:321–7.
Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res. 2010;181:127–51.
Tamura H, Takasaki A, Miwa I, et al. Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res. 2008;44:280–7.
Nakamura Y, Tamura H, Kashida S, Takayama H, Yagamata Y, Karube A, Sugino N, Kato H. Changes of serum melatonin level and its relationship to feto-placental unit during pregnancy. J Pineal Res. 2001;30:29–33.
Kivela A. Serum melatonin during human pregnancy. Acta Endocrinol (Copenh). 1991;124:233–7.
Yellon SM, Longo LD. Effect of maternal pinealectomy and reverse photoperiod n the circadian melatonin in the sheep and fetus during the last trimester of pregnancy. Biol Reprod. 1988;39:1093–9.
Munoz-Hoyos A, Jaldo-Alba F, Molina-Carballo A, Rodriguez-Cabezas T, Molina-Font JA, Acuna-Castroviejo D. Absence of plasma melatonin circadian rhythm during the first 72 h of life in human infants. J Clin Endocrinol Metab. 1993;77:699–703.
Reppert SM, Weaver DR, Rivkees SA, Stopa EC. Putative melatonin receptor in a human biological clock. Science. 1998;242:78–81.
Thomas I, Pervis CC, Drew JE, Abramovich DR, Williams LM. Melatonin receptors in human fetal brain: 2-[125I] iodomelatonin binding site and MT1 gene expression. J Pineal Res. 2002;33:218–24.
Hawkins GA, Meyers DA, Bleeker ER, Pack AI. Identification of coding polymorphisms in human circadian rhythm genes Per 1, Per2, Per3, clock, AmtI, Cry1, Cry2, and timeless in multiethnic screening panel. DNA Seq. 2007;10:1.
Okatani Y, Okamura K, Hayashi K, Wakatsuki A, Tamura S, Sagara Y. Maternal-fetal transfer of melatonin in pregnant women near term. J Pineal Res. 1998;25:129–34.
Mirmiran M, Maas YG, Ariagno RL. Development of fetal and neonatal sleep and circadian rhythms. Sleep Med Rev. 2003;7:321–34.
Fait V, Sela S, Ophir E, Khoury S, Nissimov J, Tkach M, Hirsch Y, Khotaba S, Tarasowa L, Oettinger M. Hyperemesis gravidarum is associated with oxidative stress. Am J Perinatol. 2002;19:93–8.
Myatt L, Cui X. Oxidative stress in placenta. Histochem Cell Biol. 2004;122:369–82.
Reiter RJ. Interaction of the pineal hormone melatonin with oxygen centered free radicals: a brief review. Braz J Med Biol Res. 2003;26:1141–55.
Srinivasan V. Melatonin, oxidative stress and neurodegenerative diseases. Indian J Expt Biol. 2002;40:668–79.
Srinivasan V, Pandi-Perumal SR, Maestroni GJ, Esquifino AJ, Hardeland R, Cardinali DP. Role of melatonin in neurodegenerative diseases. Neurotox Res. 2005;7:293–318.
Tamura H, Nakamura Y, Terron MP, Flores LJ, Manchester LC, Tan DX, Sugino N, Reiter RJ. Melatonin and pregnancy in the human. Reprod Toxicol. 2008;25:291–303.
Wakatsuki A, Okatani Y, Ikenouse N, Shinohara K, Watanabe K, Fukaya T. Melatonin protects against oxidized low density lipoprotein induced inhibition of nitric oxide production in human umbilical artery. J Pineal Res. 2001;31:281–8.
Milczarek R, Klimek J, Zelewski L. Melatonin inhibits NADPH-dependent lipid peroxidation in human placental mitochondria. Horm Metab Res. 2000;32:84–5.
Simko F, Paulis L. Melatonin as a potential antihypertensive treatment. J Pineal Res. 2007;42:319–22.
Pagni CA, Zenga F. Posttraumatic epilepsy with special emphasis on prophylaxis and prevention. Acta Neurochir Suppl. 2005;93:27–34.
Plaut SM, Grota LJ, Ader R, Graham CW. Effects of handling and the light–dark cycle on time of parturition in the rat. Lab Anim Care. 1970;20:447–53.
Boer K, Lincoln DW, Swaab DF. Effects of electrical stimulation of the neurohypophysis on labour in the rat. J Endocrinol. 1975;65:163–76.
Lincoln DW, Porter DG. Timing of the photoperiod and the hour of birth in rats. Nature. 1976;260:780–1.
Takayama H, Nakamura Y, Tamura H, Yamaagata Y, Harada A, Nakata M, Sugino N, Kato H. Pineal gland (melatonin) affects the parturition time, but not luteal function and fetal growth, in pregnant rats. Endocr J. 2003;50:37–43.
Glattre E, Bjerkedal T. The 24-hour rhythmicity of birth: a population study. Acta Obstet Gynecol Scand. 1983;62:31–6.
Cooperstock M, England JE, Wolfe RA. Circadian incidence of labor onset hour in preterm birth and chorioamnionitis. Obstet Gynecol. 1987;70:852–5.
Lindow SW, Jha RR, Thompson JW. 24-hour rhythm to the onset of preterm labour. BJOG. 2000;107:1145–8.
Vatish M, Steer PJ, Blanks AM, Hon M, Thornton S. Diurnal variation is lost in preterm deliveries before 28 weeks of gestation. BJOG. 2010;117:765–7.
Longo LD, Yellon SM. Biological time keeping during pregnancy and the role of circadian rhythms during parturition. In: Kunzel W, Jensen A, editors. The endocrine control of the fetus. Berlin: Springer; 1988. p. 173–92.
Schlabritz-Loutsevitch N, Hellner N, Middendorf R, Muller D, Olcese J. The human myometrium as a target for melatonin. J Clin Endocrinol Metab. 2003;88:908–13.
Martensson LG, Andersson RG, Berg G. Melatonin together with noradrenaline augments contractions of human myometrium. Eur J Pharmacol. 1996;316:273–5.
Salomonis N, Cotte N, Zambon AC, Pollard KS, Vranizan K, Doniger SW, Dolganov G, Conklin BR. Identifying genetic networks underlying myometrial transition to labor. Genome Biol. 2005;6:R12.1–R16.
Olecese J. Melatonin effects on uterine physiology. In: Pandi-Perumal SR, Cardinali DP, editors. Melatonin: from molecules to therapy. New York: Nova; 2007. p. 205–25.
Ducsay CA, Yellon SM. Photoperiod regulation of uterine activity and melatonin rhythms in the pregnant rhesus macaque. Biol Reprod. 1991;44:967–74.
Zahn V, Hattensperger W. Circadian rhythm of pregnancy contractions. Z Geburtshilfe Perinatol. 1993;197:1–10.
Farber DM, Giussani DA, Jenkins SL, Mecenas CA, Winter JA, Wentworth RA, Nathanielsz PW. Timing of the switch from myometrial contractures to contractions in late-gestation pregnant rhesus monkeys as recorded by myometrial electromyogram during spontaneous term and androstenedione-induced labor. Biol Reprod. 1997;56:557–62.
Olcese J. Circadian aspects of mammalian parturition: a review. Mol Cell Endocrinol. 2012;349:62–7.
Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature. 2002;418:935–41.
Sharkey JT, Puttaramu R, Word RA, Olcese J. Melatonin synergizes with oxytocin to enhance contractility of human myometrial smooth muscle cells. J Clin Endocrinol Metab. 2009;94:421–7.
Lerner AB, Case JD, Takahashi Y, Lee Y, Mori W. Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc. 1958;80:2587.
Stevens RG. Circadian disruption and breast cancer: from melatonin to clock genes. Epidemiology. 2005;16:254–8.
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Zakaria, R., Brzezinski, A., Srinivasan, V. (2014). Melatonin’s Role in Human Reproduction: Recent Studies. In: Srinivasan, V., Brzezinski, A., Oter, S., Shillcutt, S. (eds) Melatonin and Melatonergic Drugs in Clinical Practice. Springer, New Delhi. https://doi.org/10.1007/978-81-322-0825-9_13
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