Prospects of using melatonin in the reproductive medicine

Т. Н. Тутченко

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.


Keywords


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

References


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GOST Style Citations


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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.

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DOI: http://dx.doi.org/10.18370/2309-4117.2016.31.34-39

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