Prospects of using melatonin in the reproductive medicine

Authors

DOI:

https://doi.org/10.18370/2309-4117.2016.31.34-39

Keywords:

melatonin, oocyte, ejaculate, infertility, reproductive technologies, review of the literature

Abstract

Studies in recent decades have greatly expanded understanding of the role of melatonin in the human organism, showing that its functions extend well beyond the regulation of the sleep-wake rhythms. The article describes the results of studies about role of the epiphyseal and non-epiphyseal melatonin in various processes occurring in the implementation of the human reproductive function, and analyzed of the prospects for the use of melatonin drugs in reproductive medicine and gynecology.

As numerous studies is showed, melatonin has an important integrating multifaceted role in regulation of the human reproduction. In particular, in addition to protective effects, melatonin has a direct impact on the growth and maturation of oocytes, as well as increases the level of fertilization. One of studies shows, what the application of melatonin (3 mg per day for 2 weeks) for women with low fertilization level in program of assisted reproductive technology (ART), was increased this level in the next cycle from 35.1 to 68.2%, and the number of high quality embryos was increased from 48 to 65.6%. The study authors conclude that the use of melatonin in ART cycles has a positive effect on cycles efficiency by reducing the damaging effects of oxidative stress on oocyte.

Furthermore, melatonin, which toxicity is extremely low, well penetrates through the hematotesticular barrier, which makes its use promising in the treatment of male infertility with ART. Studies by various authors convincingly demonstrate the protective effect of melatonin against the damaging effects of oxidative stress, which is accompanied by a manipulation with ejaculate as part of ART.

One of reviews in 2016 was analyzed all available literature data on safety of melatonin drugs. The results showed that short-term use of melatonin is safe even in extreme doses. None of the studies not reported about serious side effects. Among minor effects were observed dizziness, nausea, headache, drowsiness. The data indicate that the scope of clinical application of melatonin is not limited to the timing rhythms sleep-wake: its powerful antioxidant effects are universal and can be used in a treatment of variety of pathologies, including reproductive disorders in women and men.

Author Biography

Т. Н. Тутченко, State Institution “Institute of Pediatrics, Obstetrics and Gynecology of the NAMS of Ukraine”

PhD, researcher of the Endocrine Gynecology Department

References

  1. Melatonin: prospects of clinical application. Ed. by prof. S.I. Rapoport. Moscow. IMA-PRESS (2012): 176 p.
  2. Dragojevic Dikic, S., et al. “Melatonin: a ‘Higgs boson’ in human reproduction.” Gynecological Endocrinology 31.2 (2015): 92–101.
  3. Reiter, R.J., Richardson, B.A., Matthews, S.A., et al. “Rhythms of immunoreactive melatonin in the retina and Harderian glands of rats: Persistence after pinealectomy.” Life Sci 32 (1983): 1299–336.
  4. Huether, G., Poeggeler, B., Reimer, A., George, A. “Effects of tryptophan administration on circulating melatonin levels in chicks and rats: Evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract.” Life Sci 51 (1992): 946–53.
  5. Abe, M., Itoh, M.T., Miyata, M., et al. “Circadian rhythm of serotonin N-acetyltransferace activity in rat lens.” Exp Eye Res 70 (2000): 805–8.
  6. Manchester, L.C., Poeggeler, B., Alvares, F.L., et al. “Melatonin immunoreactivity in the photosynthetic prokaryote Rhodospirillum rubrum: Implications for an ancient antioxidant system.” Cell Mol Biol Res 41 (1996): 391–5.
  7. Poeggeler, B., Hardeland, R. “Detection and quantification of melatonin in a dinoflagellate, Gonyaulax polyedra: Solutions to the problem of methoxyindole destruction in non-vertebrate material.” J Pineal Res 17 (1994): 1–10.
  8. Dubbels, R., Reiter, R.J., Klenke, E., et al. “Melatonin in edible plants identified by radioimmunoassay and high performance liquid chromatography-mass spectrometry.” J Pineal Res 18 (1995): 28–31.
  9. Tan, D.X., Chen, L.D., Poeggeler, B., et al. “Melatonin: A potent, endogenous hydroxyl radical scavenger.” Endocr J 1 (1993): 57–60.
  10. Hardeland, R., Reiter, R.J., Poeggeler, B., Tan, D.X. “The significance of the metabolism of the neurohormone melatonin: Antioxidative protection and formation of bioactive substances.” Neurosci Biobehav Rev 17 (1993): 347–57.
  11. Tan, D.X., Manchester, L.C., Reiter, R.J., et al. “Ischemia/reperfusion-induced arrhythmias in the isolated rat heart: Prevention by melatonin. J Pineal Res 25 (1999): 184–91.
  12. Reiter, R.J., Paradies, S.D., Manchester, L.C., Tan, D.X. “Reducing oxidative/nitrosative stress: A newly-discovered gene for melatonin.” Crit Rev Biochem Mol Biol 44 (2009): 175–200.
  13. Sewerynek, E., Abe, M., Reiter, R.J., et al. “Melatonin administration prevents lipopolysaccharide-induced oxidative damage in phenobarbital-treated animals.” J Cell Biochem 58 (1995): 436–44.
  14. Melchiorri, D., Reiter, R.J., Sewerynek, E., et al. “Paraquat toxicity and oxidative damage: Reduction by melatonin.” Biochem Pharmacol 51 (1996): 1095–9.
  15. Reiter, R.J., Tan, D.X., Manchester, L.C., et al. “Medical implications of melatonin: Receptor-mediated and receptor-independent actions.” Adv Med Soc 52 (2007): 11–28.
  16. Lincoln, G.A., Short, R.V. “Seasonal breeding: Nature’s contraceptive.” Rec Progr Horm Res 36 (1980): 1–52.
  17. Hoffman, R.A., Reiter, R.J. “Pineal gland: Influence on gonads of male hamsters.” Science 148 (1995): 1609–11.
  18. Reiter, R.J. “The pineal and its hormones in the control of reproduction in mammals.” Endocr Rev 1 (1980): 109–31.
  19. Dubocovich, M.L., Markowska, M. “Functional MT1 and MT2 melatonin receptors in mammals.” Endocrine 27 (2005): 101–10.
  20. Vanecek, J. “Cellular mechanisms of melatonin action.” Physiol Rev 78 (1998): 687–21.
  21. Ishii, H., Tanaka, N., Kobayashi, M., et al. “Gene structures, biochemical characterization and distribution of rat melatonin receptors.” J Physiol Sci 59 (2009): 37–47.
  22. Hardeland, R., Cardinali, D.P., Srinivasan, V., et al. “Melatonin – A pleiotropic, orchestrating regulator molecule.” Prog Neurobiol 93 (2011): 350–84.
  23. Ekmekcioglu, C. “Melatonin receptors in humans: Biological role and clinical relevance.” Biomed Pharmacother 60 (2006): 97–108.
  24. Niles, L.P., Wang, J., Shen, L., et al. “Melatonin receptor mRNA expression in human granulosa cells.” Mol Cell Endocrinol 156 (1999): 107–10.
  25. Soares, J.M. Jr., Masana, M.I., Ersahin, D., Dubocovich, M.L. “Functional melatonin receptors in rat ovaries at various stages of the estrous cycle.” J Pharmacol Exp Ther 306 (2003): 694–702.
  26. Tamura, H., Takasaki, A., Taketani, T., et al. “Melatonin as a free radical scavenger in the ovarian follicle.” Endocr J 2013, in press.
  27. Brzezinski, A., Seibel, M.M., Lynch, H.J., et al. “Melatonin in human preovulatory follicular fluid.” J Clin Endocrinol Metab 64 (1987): 865–7.
  28. Ronnberg, L., Kauppila, A., Leppaluoto, J., et al. “Circadian and seasonal variation in human preovulatory fluid melatonin concentration.” J Clin Endocrinol Metab 71 (1990): 492–6.
  29. Nakamura, Y., Tamura, H., Takayama, H., Kato, H. “Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production.” Fertil Steril 80 (2003): 1012–6.
  30. Tan, D.X., Manchester, L.C., Terron, M.P., et al. “One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species?” J Pineal Res 42 (2007): 28–42.
  31. Hardeland, R., Tan, D.X., Reiter, R.J. “Kynuramines, metabolites of melatonin and other indoles: The resurrection of an almost forgotten class of biogenic amines.” J Pineal Res 47 (2009): 109–26.
  32. Espey, L.L. “Current status of the hypothesis that mammalian ovulation is comparable to an inflammatory reaction.” Biol Reprod 50 (1994): 233–8.
  33. Tamura, H., Nakamura, Y., Korkmaz, A., et al. “Melatonin and the ovary: Physiological and pathophysiological implication.” Fertil Steril 92 (2009): 328–43.
  34. Salhab, M., Dhorne-Pollets, S., Auclair, S., et al. “In vitro maturation of oocytes alters gene expression and signaling pathways in bovine cumulus cells.” Mol Reprod Dev 80 (2013): 166–82.
  35. Johnston, J.D., Bashforth, R., Diack, A., et al. “Rhythmic melatonin secretion does not correlate with the expression of arylalkylamine N-acetyltransferase, inducible cyclic AMP early repressor period 1 or cytochrome 1 mRNA in the sheep pineal.” Neuroscience 124 (2004): 789–95.
  36. Liu, T., Borjigin, J. “N-acetyltransferase is not the rate limiting enzyme of melatonin synthesis at night.” J Pineal Res 39 (2005): 91–6.
  37. Sugino, N. “Reactive oxygen species in ovarian physiology.” Reprod Med Biol 4 (2005): 31–44.
  38. Galano, A., Tan, D.X., Reiter, R.J. “Melatonin as a natural ally against oxidative stress: A physicochemical examination.” J Pineal Res 51 (2011): 1–16.
  39. Allegra, M., Reiter, R.J., Tan, D.X., et al. “The chemistry of melatonin’s interaction with reactive species.” J Pineal Res 34 (2003): 1–10.
  40. Antolin, I., Rodriguez, C., Sainz, R.M., et al. “Neurohormone melatonin prevents cell damage: Effect on gene expression for antioxidant enzymes.” FASEB J 10 (1996): 882–90.
  41. Rodriguez, C., Mayo, J.C., Sainz, R.M., et al. “Regulation of antioxidant enzymes: A significant role for melatonin.” J Pineal Res 36 (2004): 1–9.
  42. Tomas-Zapico, C., Coto-Montes, A. “A proposed mechanism to explain the stimulating effect of melatonin on antioxidative enzymes.” J Pineal Res 39 (2005): 99–104.
  43. Tamura, H., Nakamura, Y., Terron, M.P., et al. “Melatonin and pregnancy in the human.” Reprod Toxicol 25 (2008): 291–303.
  44. 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 44 (2008): 280–7.
  45. El-Raey, M., Geshi, M., Somfai, T., et al. “Evidence of melatonin synthesis in the cumulus oocyte complexes and its role in enhancing oocyte maturation in vitro in cattle.” Mol Reprod Dev 78 (2011): 250–62.
  46. Benitez-King, G., Soto-Vega, E., Dominguez-Rodriguez, G. “Melatonin modulates microfilament phenotypes in epithelial cells: Implications for adhesion and inhibition of cancer cell migration.” Histol Histopathol 24 (2009): 789–99.
  47. Acuna-Castroviejo, D., Escames, G., Rodriguez, M., Lopez, L.C. “Melatonin role in the mitochondrial function.” Front Biosci 12 (2007): 947–63.
  48. Rocha, R.M.P., Lima, L.F., Alves, A.M.C.V., et al. “Interaction between melatonin and follicle-stimulating hormone promotes in vitro development of caprine preantral follicles.” Dom Anim Endocrinol 44 (2013): 1–9.
  49. Dhalpuria, S., Vyas, S., Purohit, G.N., Patkak, K.M. “Songraphic monitoring of early follicle growth induced by melatonin implants in camels and the subsequent fertility.” J Ultrasound 15 (2012): 135–41.
  50. Wilson, P.R., Walker, I.H., Bond, D.B., et al. “Field evaluation of melatonin implants to advance the breeding season in 1-year-old formed red deer hinds.” N Z Vet J 39 (1991): 23–8.
  51. Chemineau, P., Berthelot, X., Daneau, A., et al. “Can melatonin be used in out-of-season reproduction in domestic mammals?” Contracept Fertil Sex 21 (1993): 733–8, article in French.
  52. De Nicolo, G., Morris, S.T., Kenyon, P.R., et al. “Melatonin-improved reproductive performance in sheep bred out of season.” Anim Reprod Sci 109 (2008): 124–33.
  53. Scott, P.R., Sargison, N.D., Macrae, A.L., Gaugh, M.R. “Melatonin treatment prior to the normal breeding season increases fetal number in United Kingdom sheep flocks.” Vet J 182 (2009): 198–202.
  54. Nishihara, Takuji, et al. “Oral melatonin supplementation improves oocyte and embryo quality in women undergoing in vitro fertilization-embryo transfer.” Gynecological Endocrinology 30.5 (2014): 359-362.
  55. Sirotkin, A.V., Schaeffer, H.J. “Direct regulation of mammalian reproductive organs by serotonin and melatonin.” J Endocrinol 154 (1997): 1–5.
  56. Murayama, T., Kawashima, M., Takahashi, T., et al. “Direct action of melatonin on hen ovarian granulosa cells to lower responsiveness to luteinizing hormone.” Proc Soc Exp Biol 215 (1997): 386–92.
  57. Tamura, H., Nakamura, Y., Takiguchi, S., et al. “Melatonin directly suppresses steroid production by preovulatory follicles in the cyclic hamster.” J Pineal Res 35 (1998): 135–41.
  58. Woo, M.M.M., Tai, C.J., Kang, S.K., et al. “Direct action of melatonin in human granulosa-luteal cells.” J Clin Endocrinol Metab 86 (2001): 4789–97.
  59. Fiske, V.M., Parker, K.L., Ulmer, R.A., et al. “Effect of melatonin alone or in combination with human chorionic gonadotropin or ovine luteinizing hormone on the in vitro secretion of estrogens or progesterone by granulosa cells of rats.” Endocrinology 114 (1984): 407–10.
  60. Baratta, M., Tamanini, C. “Effect of melatonin on the in vitro secretion of progesterone and estradiol-17β by ovine granulosa cells.” Acta Endocrinol 127 (1992): 366–70.
  61. Tanavde, V.S., Maitra, A. “In vitro modulation of steroidogenesis and gene expression by melatonin: A study with porcine antral follicles.” Endocrinol Res 29 (2003): 399–410.
  62. Webley, G.E., Luck, M.R. “Melatonin directly stimulates the secretion of progesterone by human bovine granulosa cells luteinized in vitro.” J Reprod Fertil 78 (1986): 711–17.
  63. Adriaens, I., Jacquet, P., Cortvrindt, R., et al. “Melatonin has dose-dependent effects on folliculogenesis, oocyte maturation capacity and steroidogenesis.” Toxicology 228 (2006): 333–43.
  64. Hemadi, M.M., Abolhassani, F., Akbari, M.,et al. “Melatonin promotes the cumulus-oocyte complexes quality of vitrified-thawed murine ovaries with increases mean number of follicles survival and ovary size following heterotopic transplantation.” Eur J Pharmacol 618 (2009): 84–90.
  65. Mazoochi, T., Salehnia, M., Valojerdi, M.R., Mowla, S.J. “Morphologic, ultrastructural, and biochemical identification of apoptosis in vitrified-warmed mouse ovarian tissue.” Fertil Steril 90 (2008): 1480–6.
  66. Kwon, S.Y., McIntyre, P.B., Flecker, A.S., Campbell, L.M. “Mercury biomagnification in the food web of a neotropical stream.” Sci Total Environ 417–418 (2012): 92–7.
  67. Kirk, J.L., Lehnherr, I., Andersson, M., et al. “Mercury in Arctic marine ecosystems: Sources, pathways and exposure.” Environ Res 119 (2012): 64–87.
  68. Koedrith, P., Seo, Y.R. “Advances in carcinogenic metal toxicity and potential molecular markers.” Int J Mol Sci 12 (2011): 9576–95.
  69. Pal, P.B., Pal, S., Das, J., Sil, P.C. “Modulation of mercury-induced mitochondrial-dependent apoptosis by glycine in hepatocytes.” Amino Acids 42 (2012): 1669–83.
  70. Rao, M.V., Gangadharan, B. “Antioxidant potential of melatonin against mercury induced intoxication in spermatozoa in vitro.” Toxicol In Vitro 22 (2008): 935–42.
  71. Sarabia, L., Maurer, I., Bustos-Obregon, E. “Melatonin prevents damage elicited by organophosphorous pesticide diazinon on mouse sperm DNA.” Ecotoxicol Environ Saf 72 (2009): 663–8.
  72. Peiris-John, R.J., Wickremasinghe, R. “Impact of low-level exposure to organophosphates on human reproduction and survival.” Trans R Soc Trop Med Hyg 102 (2008): 239–45.
  73. Jurewicz, J., Hanke, W., Radwan, M., Bonde, J.P. “Environmental factors and semen quality.” Int J Occup Med Environ Health 22 (2009): 305–29.
  74. Vargas, A., Bustos-Obregon, E., Hartley, R. “Effects of hypoxia on epididymal sperm parameters and protective role of ibuprofen and melatonin.” Biol Res 44 (2011): 161–7.
  75. Tamme, L.A., Still, D.L., Acromite, M.T. “Hypoxia and flight performance of military instructor pilots in a flight simulator.” Aviat Space Environ Med 81 (2010): 654–9.
  76. Li, L., Xu, J.N., Wong, Y.H., et al. “Molecular and cellular analyses of melatonin receptormediated cAMP signaling in rat corpus epididymis.” J Pineal Res 25 (1998): 219–28.
  77. Shiu, S.Y., Li, L., Siu, S.W., et al. “Biological basis and possible physiological implications of melatonin receptor-mediated signaling in the rat epididymis.” Biol Signals Recept 9 (2000): 172–87.
  78. Casao, A., Gallego, M., Abecia, J.A., et al. “Identification and immunolocalisation of melatonin MT(1) and MT(2) receptors in Rasa aragonesa ram spermatozoa.” Reprod Fertil Dev 24 (2012): 953–61.
  79. Kaya, A., Aksoy, M., Baspinar, N., et al. “Effect of melatonin implantation to sperm donor rams on post-thaw viability and acrosomal integrity of sperm cells in the breeding and non-breeding season.” Reprod Domest Anim 36 (2001): 211–15.
  80. Casao, A., Vega, S., Palacin, I., et al. “Effects of melatonin implants during non-breeding season on sperm motility and reproductive parameters in Rasa aragonesa rams.” Reprod Domest Anim 45 (2010): 425–32.
  81. Webster, J.R., Suttie, J.M., Veenoliet, B.A., et al. “Effect of melatonin implants in secretion of luteinizing hormone in intact and castrated rams.” J Reprod Fertil 92 (1991): 21–31.
  82. Lincoln, G.A., Clarke, I.J. “Refractoriness to a static melatonin signal develops in the pituitary gland for the control of prolactin secretion in the ram.” Biol Reprod 57 (1997): 460–7.
  83. Rosa, H.J., Juniper, D.T., Bryant, M.J. “Effects of recent sexual experience and melatonin treatment of rams on plasma testosterone concentrations, sexual behavior and ability to induce ovulation in seasonally anestrous ewes.” J Reprod Fertil 120 (2000): 169–76.
  84. Bornman, M.S., Oosthuizen, J.M.C., Barnard, H.C., et al. “Melatonin and sperm motility.” Andrologia 21 (1989): 483–5.
  85. Luboshitzky, R., Shen-Orr, Z., Nave, R., et al. “Melatonin administration alters semen quality in healthy men.” J Androl 23 (2002): 572–8.
  86. Shang, X., Huang, Y., Ye, Z., Yu, X., Gu, W. “Protection of melatonin against damage of sperm mitochondrial function induced by reactive oxygen species.” Zhonghaw Nan Ke Xue 10 (2004): 604–7, article in Chinese.
  87. Du Plessis, S.S., Hagenaar, K., Lampiao, F. “The in vitro effects of melatonin on human sperm function and its scavenging activities on NO and ROS.” Andrologia 42 (2010): 112–6.
  88. Espino, J., Bejarano, I., Ortiz, A., et al. “Melatonin as a potential tool against oxidative damage and apoptosis in ejaculated human spermatozoa.” Fertil Steril 94 (2010): 1915–7.
  89. Espino, J., Ortiz, A., Bejarano, I., et al. “Melatonin protects human spermatozoa from apoptosis via melatonin receptor- and extracellular signal-regulated kinasemediated pathways.” Fertil Steril 95 (2011): 2290–6.
  90. Ortiz, A., Espino, J., Bejarano, I., et al. “High endogenous melatonin concentrations enhance sperm quality and short-term in vitro exposure improves aspects of sperm motility.” J Pineal Res 50 (2011): 132–9.
  91. Oba, S., Nakamura, K., Sahashi, Y., et al. “Consumption of vegetables alters urinary 6-sulfatoxymelatonin concentrations.” J Pineal Res 45 (2008): 17–23.
  92. Andersen, Lars Peter Holst, et al. “The safety of melatonin in humans.” Clinical drug investigation 36.3 (2016): 169–175.

Downloads

Published

2016-10-21

How to Cite

Тутченко, Т. Н. (2016). Prospects of using melatonin in the reproductive medicine. REPRODUCTIVE ENDOCRINOLOGY, (31), 34–39. https://doi.org/10.18370/2309-4117.2016.31.34-39

Issue

No. 31 (2016)

Section

Reproductology

License

Copyright (c) 2016 Т. Н. Тутченко

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors who publish with this journal agree to the following terms:

    1. Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.

    1. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.