One of the trends of oxidative protection in in vitro fertilization programs

Here we review published data from experimental and clinical international studies examining pathogenetic effects of melatonin upon using programs of In Vitro Fertilization (IVF); highlighting various viewpoints on its biological action as a regulator of circadian rhythms: on the one hand, the inhibitory effect of melatonin on pulsating secretion of gonadotropin-releasing hormone was considered, thereby achieving a contraceptive effect; on the other hand, its ability to induce the secretion of human chorionic gonadotropin ensuring ovulation process, was discussed. We also review the data on melatonin acting as a highly active antioxidant. While using melatonin as a metabolic supplement in IVF programs, its positive effect on oocyte morphology and quality of fertilization, embryo division was observed. Moreover, we also highlight the results of studies examining melatonin-related effects on quality of fertilization and embryo division after adding it to culture medium. Such effects demonstrated dose-depended pattern. Taking into account the data of the analyzed publications, adding exogenous melatonin to culture medium may represent a new strategy for personalized approach to improve outcome of IVF programs. Its effectiveness should be further investigated and considered for introduction within the framework of pregravid preparation.

1. Reiter R. J., Korkmaz A. Clinical aspects of melatonin. Saudi Med J. 2008;29(11):1537–47.

2. Lerner А., Case J., Takahashi Y. et al. Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc. 1958;80(10):2587–7.

3. Fernando S., Rombauts L. Melatonin: shedding light on infertility? A review of the recent literature. J Ovarian Res. 2014;7:98. https://doi.org/10.1186/s13048-014-0098-y.

4. Eryilmaz O. G., Devran A., Sarikaya E. et al. Melatonin improves the oocyte and the embryo in IVF patients with sleep disturbances, but does not improve the sleeping problems. J Assist Reprod Genet. 2011;28(9):815–20. https://doi.org/10.1007/s10815-011-9604-y.

5. Tordjman S., Chokron S., Delorme R. et al. Melatonin: pharmacology, functions and therapeutic benefits. Curr Neuropharmacol. 2017;15(3):434–43. https://doi.org/10.2174/1570159X14666161228122115.

6. Dragojevic Dikic S., Jovanovic A. M., Dikic S. et al. Melatonin: a “Higgs boson” in human reproduction. Gynecol Endocrinol. 2015;31(2):92–101. https://doi.org/10.3109/09513590.2014.978851.

7. Reiter R. J., Tan D. X., Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res. 2010;181:127–51. https://doi.org/10.1016/S0079-6123(08)81008-4.

8. Srinivasan V., Spence W. D., Pandi-Perumal S.R. et al. Melatonin and human reproduction: shedding light on the darkness hormone. Gynecol Endocrinol. 2009;25(12):779–85. https://doi.org/10.3109/09513590903159649.

9. Silman R. Melatonin and the human gonadotrophin-releasing hormone pulse generator. J Endocrinol. 1991;128(1):7–11. https://doi.org/10.1677/joe.0.1280007.

10. Minneman K. P., Wurtman R. J. The pharmacology of the pineal gland. Annu Rev Pharmacol Toxicol. 1976;16:33–51.

11. Tamura H., Takasaki A., Taketani T. et al. Melatonin and female reproduction. J Obstet Gynaecol Res. 2014;40(1):1–11. https://doi.org/10.1111/jog.12177.

12. Zhao D., Yu Y., Shen Y. et al. Melatonin synthesis and function: evolutionary history in animals and plants. Front Endocrinol (Lausanne). 2019;10:249. https://doi.org/10.3389/fendo.2019.00249.

13. Qi S., Yan L., Liu Z. et al. Melatonin inhibits 17β-estradiol-induced migration, invasion and epithelial-mesenchymal transition in normal and endometriotic endometrial epithelial cells. Reprod Biol Endocrinol. 2018;16(1):62. https://doi.org/10.1186/s12958-018-0375-5.

14. Tian X., Wang F., Zhang L. et al. Melatonin promotes the in vitro development of microinjected pronuclear mouse embryos via its antioxidative and anti-apoptotic effects. Int J Mol Sci. 2017;18(5). pii: E988. https://doi.org/10.3390/ijms18050988.

15. Zhao X., Wang D., Wu Z. et al. Female reproductive performance in the mouse: effect of oral melatonin. Molecules. 2018;23(8). pii: E1845. https://doi.org/10.3390/molecules23081845.

16. Dai X., Lu Y., Zhang M. et al. Melatonin improves the fertilization ability of post-ovulatory aged mouse oocytes by stabilizing ovastacin and Juno to promote sperm binding and fusion. Hum Reprod. 2017;32(3):598–606. https://doi.org/10.1093/humrep/dew362.

17. Xiang S., Mao L., Yuan L. et al. Impaired mouse mammary gland growth and development is mediated by melatonin and its MT1G protein-coupled receptor via repression of ERα, Akt1, and Stat5. J Pineal Res. 2012;53(3):307–18. https://doi.org/10.1111/j.1600-079X.2012.01000.x.

18. Zhang H. M., Zhang Y. Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res. 2014;57(2):131–46. https://doi.org/10.1111/jpi.12162.

19. Kim M. K., Park E. A., Kim H. J. et al. Does supplementation of in-vitro culture medium with melatonin improve IVF outcome in PCOS? Reprod Biomed Online. 2013;26(1):22–9. https://doi.org/10.1016/j.rbmo.2012.10.007.

20. Brzezinski A., Seibel M. M., Lynch H. J. et al. Melatonin in human preovulatory follicular fluid. J Clin Endocrinol Metab. 1987;64(4):865–7. https://doi.org/10.1210/jcem-64-4-865.

21. Yang M., Tao J., Chai M. et al. Melatonin improves the quality of inferior bovine oocytes and promoted their subsequent IVF embryo development: mechanisms and results. Molecules. 2017;22(12). pii: E2059. https://doi.org/10.3390/molecules22122059.

22. Reiter R. J., Tamura H., Tan D. X., Xu X. Y. Melatonin and the circadian system: contributions to successful female reproduction. Fertil Steril. 2014;102(2):321–8. https://doi.org/10.1016/j.fertnstert.2014.06.014.

23. Reiter R. J., Tan D. X., Korkmaz A., Rosales-Corral S. A. Melatonin and stable circadian rhythms optimize maternal, placental and fetal physiology. Hum Reprod Update. 2014;20(2):293–307. https://doi.org/10.1093/humupd/dmt054.

24. Xiao L., Hu J., Song L. et al. Profile of melatonin and its receptors and synthesizing enzymes in cumulus-oocyte complexes of the developing sheep antral follicle-a potential estradiol-mediated mechanism. Reprod Biol Endocrinol. 2019;17(1):1. https://doi.org/10.1186/s12958-018-0446-7.

25. Carlomagno G., Minini M., Tilotta M., Unfer V. From implantation to birth: insight into molecular melatonin functions. Int J Mol Sci. 2018;19(9). pii: E2802. https://doi.org/10.3390/ijms19092802.

26. Cipolla-Neto J., Amaral F. G.D. Melatonin as a hormone: new physiological and clinical insights. Endocr Rev. 2018;39(6):990–1028. https://doi.org/10.1210/er.2018-00084.

27. Acuña-Castroviejo D., Escames G., Venegas C. et al. Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci. 2014;71(16):2997–3025. https://doi.org/10.1007/s00018-014-1579-2.

28. de Almeida E. A., Di Mascio P., Harumi T. et al. Measurement of melatonin in body fluids: standards, protocols and procedures. Childs Nerv Syst. 2011;27(6):879–91. https://doi.org/10.1007/s00381-010-1278-8.

29. Bubenik G. A., Blask D. E., Brown G. M. et al. Prospects of the clinical utilization of melatonin. Biol Signals Recept. 1998;7(4):195–219. https://doi.org/10.1159/000014545.

30. Cavallo A. Melatonin and human puberty: current perspectives. J Pineal Res. 1993;15(3):115–21. https://doi.org/10.1111/j.1600-079x.1993.tb00517.x.

31. Słowińska-Klencka D., Lewiński A. Role of melatonin in human physiology and pathology. I. Circadian rhythm of melatonin secretion. Involvement of melatonin in reproductive physiology. Melatonin and hypothalamic-pituitary-adrenal cortex axis. Postepy Hig Med Dosw. 1993;47(3):209–20. (In Polish).

32. Tamura H., Takasaki A., Taketani T. et al. The role of melatonin as an antioxidant in the follicle. J Ovarian Res. 2012;5:5. https://doi.org/10.1186/1757-2215-5-5.

33. Korkmaz A., Reiter R. J., Topal T. et al. Melatonin: an established antioxidant worthy of use in clinical trials. Mol Med. 2009;15(1–2):43–50. https://doi.org/10.2119/molmed.2008.00117.

34. Wang T., Gao Y. Y., Chen L. et al. Melatonin prevents postovulatory oocyte aging and promotes subsequent embryonic development in the pig. Aging (Albany NY). 2017;9(6):1552–64. https://doi.org/10.18632/aging.101252.

35. Arnao M. B., Hernández-Ruiz J. The potential of phytomelatonin as a nutraceutical. Molecules. 2018;23(1). pii: E238. https://doi.org/10.3390/molecules23010238.

36. Manchester L. C., Coto-Montes A., Boga J. A. et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015;59(4):403–19. https://doi.org/10.1111/jpi.12267.

37. Garcia-Marin R., Fernandez-Santos J.M., Morillo-Bernal J. et al. Melatonin in the thyroid gland: regulation by thyroid-stimulating hormone and role in thyroglobulin gene expression. J Physiol Pharmacol. 2015;66(5):643–52.

38. Arushanian E. B., Beyer E. V. Pineal hormone melatonin is an universal adaptogenic agent. [Gormon mozgovoj zhelezy epifiza melatonin – universal’nyj estestvennyj adaptogen]. Uspekhi fiziologicheskih nauk. 2012;43(3):82–100. (In Russ.).

39. Cardinali D. P. Melatonin. Physiology and clinical applications. Vertex. 2007;18(74):288–93. (In Spanish).

40. Macchi M. M., Bruce J. N. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol. 2004;25(3–4):177–95. https://doi.org/10.1016/j.yfrne.2004.08.001.

41. Choi D. Potency of melatonin in living beings. Dev Reprod. 2013;17(3):149–77. https://doi.org/10.12717/DR.2013.17.3.149.

42. Cagnacci A. Melatonin in relation to physiology in adult humans. J Pineal Res. 1996;21(4):200–13. https://doi.org/10.1111/j.1600-079x.1996.tb00287.x.

43. Sarti P., Magnifico M. C., Altieri F. et al. New evidence for cross talk between melatonin and mitochondria mediated by a circadiancompatible interaction with nitric oxide. Int J Mol Sci. 2013;14(6):11259–76. https://doi.org/10.3390/ijms140611259.

44. Mishima K. Melatonin as a regulator of human sleep and circadian systems. Nihon Rinsho. 2012;70(7):1139–44. (In Japanese).

45. Meng X., Li Y., Li S. et al. Dietary sources and bioactivities of melatonin. Nutrients. 2017;9(4). pii: E367. https://doi.org/10.3390/nu9040367.

46. Honma A., Revell V. L., Gunn P. J. et al. Effect of acute total sleep deprivation on plasma melatonin, cortisol and metabolite rhythms in females. Eur J Neurosci. 2020;51(1):366–78. https://doi.org/10.1111/ejn.14411.

47. Hardeland R. Aging, melatonin, and the pro- and anti-inflammatory networks. Int J Mol Sci. 2019;20(5). pii: E1223. https://doi.org/10.3390/ijms20051223.

48. Bukowska A. Anticarcinogenic role of melatonin-potential mechanisms. Med Pr. 2011;62(4):425–34. (In Polish).

49. Mahmood D. Pleiotropic effects of melatonin. Drug Res (Stuttg). 2019;69(02):65–74. https://doi.org/10.1055/a-0656-6643.

50. Carpentieri A. R., Oliva C., Díez-Noguera A., Cambras T. Melatonin administration modifies circadian motor activit y under constant light depending on the lighting conditions during suckling. Chronobiol Int. 2015;32(7):994–1004. https://doi.org/10.3109/07420528.2015.1060243.

51. Voiculescu S. E., Zygouropoulos N., Zahiu C. D., Zagrean A. M. Role of melatonin in embryo fetal development. J Med Life. 2014;7(4):488–92.

52. Majidinia M., Reiter R. J., Shakouri S. K., Yousefi B. The role of melatonin, a multitasking molecule, in retarding the processes of ageing. Ageing Res Rev. 2018;47:198–213. https://doi.org/10.1016/j.arr.2018.07.010.

53. Fukushige H., Fukuda Y., Tanaka M. et al. Effects of tryptophan-rich breakfast and light exposure during the daytime on melatonin secretion at night. J Physiol Anthropol. 2014;33:33. https://doi.org/10.1186/1880-6805-33-33.

54. Tan D. X., Manchester L. C., Esteban-Zubero E. et al. Melatonin as a potent and inducible endogenous antioxidant: synthesis and metabolism. Molecules. 2015;20(10):18886–906. https://doi.org/10.3390/molecules201018886.

55. Weaver D. R., Stehle J. H., Stopa E. G., Reppert S. M. Melatonin receptors in human hypothalamus and pituitary: implications for circadian and reproductive responses to melatonin. J Clin Endocrinol Metab. 1993;76(2):295–301. https://doi.org/10.1210/jcem.76.2.8381796.

56. Pevet P. Present and future of melatonin in human and animal reproduction functions. Contracept Fertil Sex. 1993;21(10):727–32. (In French).

57. Li Y., Fang L., Yu Y. et al. Higher melatonin in the follicle fluid and MT2 expression in the granulosa cells contribute to the OHSS occurrence. Reprod Biol Endocrinol. 2019;17(1):37. https://doi.org/10.1186/s12958-019-0479-6.

58. Amaral F. G.D., Andrade-Silva J., Kuwabara W. M.T., Cipolla-Neto J. New insights into the function of melatonin and its role in metabolic disturbances. Expert Rev Endocrinol Metab. 2019;14(4):293–300. https://doi.org/10.1080/17446651.2019.1631158.

59. Agathokleous E., Kitao M., Calabrese E. J. New insights into the role of melatonin in plants and animals. Chem Biol Interact. 2019;299:163–7. https://doi.org/10.1016/j.cbi.2018.12.008.

60. Zlotos D. P., Jockers R., Cecon E. et al. MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential. J Med Chem. 2014;57(8):3161–85. https://doi.org/10.1021/jm401343c.

61. Trivedi A. K., Kumar V. Melatonin: an internal signal for daily and seasonal timing. Indian J Exp Biol. 2014;52(5):425–37.

62. Zawilska J. B., Skene D. J., Arendt J. Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacol Rep. 2009;61(3):383–410. https://doi.org/10.1016/s1734-1140(09)70081-7.

63. Gitto E., Aversa S., Reiter R. J. et al. Update on the use of melatonin in pediatrics. J Pineal Res. 2011;50(1):21–8. https://doi.org/10.1111/j.1600-079X.2010.00814.x.

64. Li R., Luo X., Li L. et al. The protective effects of melatonin against oxidative stress and inflammation induced by acute cadmium exposure in mice testis. Biol Trace Elem Res. 2016;170(1):152–64. https://doi.org/10.1007/s12011-015-0449-6.

65. Reiter R. J., Rosales-Corral S., Tan D. X. et al. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell Mol Life Sci. 2017;74(21):3863–81. https://doi.org/10.1007/s00018-017-2609-7.

66. Galano A., Tan D. X., Reiter R. J. Melatonin: a versatile protector against oxidative DNA damage. Molecules. 2018;23(3). pii: E530. https://doi.org/10.3390/molecules23030530.

67. Miao Y., Zhou C., Bai Q. et al. The protective role of melatonin in porcine oocyte meiotic failure caused by the exposure to benzo(a)pyrene. Hum Reprod. 2018;33(1):116–27. https://doi.org/10.1093/humrep/dex331.

68. Tan D. X., Manchester L. C., Qin L., Reiter R. J. Melatonin: a mitochondrial targeting molecule involving mitochondrial protection and dynamics. Int J Mol Sci. 2016;17(12). pii: E2124. https://doi.org/10.3390/ijms17122124.

69. Yanar K., Simsek B., Çakatay U. Integration of melatonin related redox homeostasis, aging, and circadian rhythm. Rejuvenation Res. 2019;22(5):409–19. https://doi.org/10.1089/rej.2018.2159.

70. Venegas C., García J. A., Escames G. et al. Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res. 2012;52(2):217–27. https://doi.org/10.1111/j.1600-079X.2011.00931.x.

71. McCully K. S. Communication: melatonin, hyperhomocysteinemia, thioretinacoozonide, adenosylmethionine and mitochondrial dysfunction in aging and dementia. Ann Clin Lab Sci. 2018;48(1):126–31.

72. Loren P., Sánchez R., Arias M. E. et al. Melatonin scavenger properties against oxidative and nitrosative stress: impact on gamete handling and in vitro embryo production in humans and other mammals. Int J Mol Sci. 2017;18(6). pii: E1119. https://doi.org/10.3390/ijms18061119.

73. Behrman H. R., Kodaman P. H., Preston S. L., Gao S. Oxidative stress and the ovary. J Soc Gynecol Investig. 2001;8(1 Suppl Proceedings):S40–2. https://doi.org/10.1016/s1071-5576(00)00106-4.

74. Tong J., Sheng S., Sun Y. et al. Melatonin levels in follicular fluid as markers for IVF outcomes and predicting ovarian reserve. Reproduction. 2017;153(4):443–51. https://doi.org/10.1530/REP-16-0641.

75. Khan S. N., Shaeib F., Najafi T. et al. Diffused intra-oocyte hydrogen peroxide activates myeloperoxidase and deteriorates oocyte quality. PLoS One. 2015;10(7):e0132388. https://doi.org/10.1371/journal.pone.0132388.

76. Galano A., Reiter R. J. Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection. J Pineal Res. 2018;65(1):e12514. https://doi.org/10.1111/jpi.12514.

77. Mayo J. C., Sainz R. M., González-Menéndez P. et al. Melatonin transport into mitochondria. Cell Mol Life Sci. 2017;74(21):3927–40. https://doi.org/10.1007/s00018-017-2616-8.

78. Tripodi L., Tripodi A., Mammì C. et al. Pharmacological effects of melatonin on reproductive activity: experimental bioimplants with sustained-release polymeric systems. Clin Exp Obstet Gynecol. 2004;31(2):117–9.

79. Aleandri V., Spina V., Morini A. The pineal gland and reproduction. Hum Reprod Update. 1996;2(3):225–35. https://doi.org/10.1093/humupd/2.3.225.

80. Delfs T. M., Baars S., Fock C. et al. Sex steroids do not alter melatonin secretion in the human. Hum Reprod. 1994;9(1):49–54. https://doi.org/10.1093/oxfordjournals.humrep.a138318.

81. Wójtowicz M., Jakiel G. Melatonin and its role in human reproduction. Ginekol Pol. 2002;73(12):1231–7. (In Polish).

82. Boczek-Leszczyk E., Juszczak M. The influence of melatonin on human reproduction. Pol Merkur Lekarski. 2007;23(134):128–30. (In Polish).

83. Shirlow R., Healey M., Volovsky M. et al. The effects of adjuvant therapies on embryo transfer success. J Reprod Infertil. 2017;18(4):368–78.

84. Díaz López B., Debeljuk L. Prenatal melatonin and its interaction with tachykinins in the hypothalamic-pituitary-gonadal axis. Reprod Fertil Dev. 2007;19(3):443–51.

85. Chuffa L. G., Seiva F. R., Fávaro W. J. et al. Melatonin reduces LH, 17 beta-estradiol and induces differential regulation of sex steroid receptors in reproductive tissues during rat ovulation. Reprod Biol Endocrinol. 2011;9(1):108. https://doi.org/10.1186/1477-7827-9-108.

86. Zheng M., Tong J., Li W. P. et al. Melatonin concentration in follicular fluid is correlated with antral follicle count (AFC) and in vitro fertilization (IVF) outcomes in women undergoing assisted reproductive technology (ART) procedures. Gynecol Endocrinol. 2018;34(5):446–50. https://doi.org/10.1080/09513590.2017.1409713.

87. Reiter R. J., Tan D. X., Manchester L. C. et al. Melatonin and reproduction revisited. Biol Reprod. 2009;81(3):445–56. https://doi.org/10.1095/biolreprod.108.075655.

88. Rönnberg L., Kauppila A., Leppäluoto J. et al. Circadian and seasonal variation in human preovulatory follicular fluid melatonin concentration. J Clin Endocrinol Metab. 1990;71(2):492–6. https://doi.org/10.1210/jcem-71-2-493.

89. Itoh M. T., Ishizuka B., Kuribayashi Y. Melatonin, its precursors, and synthesizing enzyme activities in the human ovary. Mol Hum Reprod. 1999;5(5):402–8. https://doi.org/10.1093/molehr/5.5.402.

90. Maganhin C. C., Fuchs L. F., Simões R. S. et al. Effects of melatonin on ovarian follicles. Eur J Obstet Gynecol Reprod Biol. 2013;166(2):178–84. https://doi.org/10.1016/j.ejogrb.2012.10.006.

91. 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(3):280–7. https://doi.org/10.1111/j.1600-079X.2007.00524.x.

92. Kang J. T., Koo O. J., Kwon D. K. et al. Effects of melatonin on in vitro maturation of porcine oocyte and expression of melatonin receptor RNA in cumulus and granulosa cells. J Pineal Res. 2009;46(1):22–8. https://doi.org/10.1111/j.1600-079X.2008.00602.x.

93. Carlomagno G., Nordio M., Chiu T. T., Unfer V. Contribution of myo-inositol and melatonin to human reproduction. Eur J Obstet Gynecol Reprod Biol. 2011;159(2):267–72. https://doi.org/10.1016/j.ejogrb.2011.07.038.

94. Baksheev V. I., Kolomoets N. M. Melatonin: its role in the system of neurohumoral regulation in man. Part 2. [Melatonin – mesto v sisteme nejrogumoral’noj regulyacii u cheloveka. Chast’ 2]. Klinicheskaya medicina. 2011;89(2):8–13. (In Russ.).