• The role of melatonin in the reproductive realization of women with infertility

The role of melatonin in the reproductive realization of women with infertility

HEALTH OF WOMAN. 2017.8(124):99–104; doi 10.15574/HW.2017.124.99  

Orlova V. V., Suslikova L. V.
National Medical Academy of Postgraduate Education P. L. Shupyk, Kiev

The prevalence of infertility, including tubal-peritoneal genesis, led to the development of assisted reproductive technology (ART) as the most effective treatment and achievement of the expected pregnancy. But the success of ART is about 40% and depends on many factors: genetic, immunological, hormonal, age, control ovarial stimulation, sperm quality, quantity and quality received oocytes and embryos and implantation ability of endometrium. Therefore, it is important to consider the mechanisms and factors behind the successful implantation. Particular attention is given to the study of disturbances of oxidative stress and apoptosis in the reproductive tract of infertile women.
Under the influence of adverse factors and in pathology, as a result of reducing the cell’s ability to neutralize free radicals and active forms of oxygen, antioxidant protection is disturbed, and oxidative stress develops, which promotes the onset of apoptosis. The programmed cell death occurs in the physiological functioning of the reproductive system: follicular atresia and regression of the functional layer of the endometrium when pregnancy is not occur. However, today the negative influence of oxidative stress and violation of the regulation of apoptosis on the reproductive function, namely the success of in vitro fertilization, has been confirmed. Also, the use of ART has some of the negative effects on gametes and embryos, which is accompanied by the emergence of oxidative stress and reduces the probability of pregnancy.
Melatonin is a universal hormone that plays a key role in the functioning of sex hormones and has powerful antioxidant properties. As a key antioxidant regulator As a key antioxidant regulator at the biochemical and hormonal levels, melatonin positively influences the maturation of oocytes and the preparation of the endometrium before implantation. Therefore, there is a reasonable justification for the use of melatonin during treatment with ART. Many studies are devoted to the study of the effectiveness of the use of exogenous melatonin in the treatment of infertility, but to date, the level of evidence is insufficient for use in it ART.

Key words: melatonin, infertility, oxidative stress, apoptosis, ART.


1. Ayryan EK. 2012. Frequency of tubal-peritoneal infertility in women who have had peritonitis in childhood. Sat. theses of the medical internet conference 2;2:148.

2. Boris EN, Suslikova LV, Kaminsky VV, Onishchik LN, Serbenyuk AV. 2015. Optimization of preparation of morphofunctional structure of endometrium in programs of auxiliary reproductive technologies. Reproductive Endocrinology 1(21):60-63.

3. Voronova OV, Feoktistov TE, Vetoshkina IA, Savicheva NV, Barseghyan AKh. 2011. Pathomorphological endometrial changes in underdeveloped pregnancy.  Mother and child: materials of V regional forum (Gelendzhik, June 28-30, 2011) red. Sukhykh GT. M, MEDIEXPO: 41-42.

4. Kulakov VI, Manukhin IB, Savelyeva GM. 2009. Gynecology: national leadership. M, GEOTAR-MEDIA:1088.

5. Menshchikova EB, Lankin VZ, Zenkov NK, Cooper IA. 2006. Oxidative stress. Prooxidants and antioxidants. M: 556.

6.Mironova SP,  Kotelnikov GP. 2013. National leadership. 2nd ed., Pererab. and add. M, GEOTAR-Media: 944.

7. Onul NM. 2014. The problem of male and female infertility in conditions of technogenic pollution of the environment. Bulletin of the problems of biology and medicine. 3;3(112):51-54.

8. Orlova VV, Simrok VV, Korobkova OA, Romanenko IYu, Lysenko OA. 2014. Age aspects of diagnostic value of melatonin in women. Southern Ukrainian Medical Journal 8(08):98-102.

9. Pavlovskaya MA. 2015. Endometrial hyperplasia in women of fertile age: clinic, diagnosis, pathogenesis and therapeutic options. Journal of the Grodno State Medical University 2:123-127.

10.Radzinsky VE, Ermolenko KS, Rapoport SI. 2014. On the role of melatonin in optimizing the outcomes of auxiliary reproductive technologies. Gynecological Endocrinology 8 (96);1: 35-38.

11. Fedorovich OK. Influence of the level of secretion of melatonin and estradiol on the development of abnormalities of labor. Mother and child: materials of the XI All-Russian scientific forum. Moscow. 2010: 251-252.

12.Yamanova MV, Salmin. Endocrine infertility: cell and molecular pathology of implantation. Medica. 2009.

13. Agarwal A, Said TM, Bedaiwy MA, Banerjee J, Alvarez JG. 2006. Oxidative stress in an assisted reproductive techniques setting. Fertil Steril. 86:503–12. https://doi.org/10.1016/j.fertnstert.2006.02.088; PMid:16860798

14. Al-Gubory KH, Fowler PA, Garrel C. 2010. The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes. Int J Biochem Cell Biol. 42:1634–50. https://doi.org/10.1016/j.biocel.2010.06.001; PMid:20601089

15. Antsiferova Y, Sotnikova N, Bogatova I, Boitsova A. 2014. Changes of apoptosis regulation in the endometrium of infertile women with tubal factor and endometriosis undergoing in vitro fertilization treatment. JBRA Assisted Reproduction 18(1):2-6. https://doi.org/10.5935/1518-0557.20140084

16. Bahadori MH, Ghasemian F, Ramezani M, Asgari Z. 2013. Melatonin effect during different maturation stages of oocyte and subsequent embryo development in mice. Iran J Reprod Med 11:11–18. PMid:24639687 PMCid:PMC3941378

17. Batıoğlu A, Şahin U, Gürlek B, Öztürk N, Ünsal E. 2012. The efficacy of melatonin administration on oocyte quality. Gynecol Endocrinol 28:91–93. https://doi.org/10.3109/09513590.2011.589925; PMid:21770829

18. Bedaiwy M, Elnashar S, Goldberg J, Sharma R, Mascha E, Arrigain S, Agarwal A, Falcone T. 2012. Effect of follicular fluid oxidative stress parameters on intracytoplasmic sperm injection outcome. Gynecol Endocrinol 28:51–55. https://doi.org/10.3109/09513590.2011.579652; PMid:21714695

19. Chakravarty S, Rizvi SI. 2008. Physiological effects of melatonin: implications on human health. Biomedicine 28:252–255.

20. Chow JF, Yeung WS, Lau EY, Lee VC, Ng EH, Ho PC. 2014. Array comparative genomic hybridization analyses of all blastomeres of a cohort of embryos from young IVF patients revealed significant contribution of mitotic errors to embryo mosaicism at the cleavage stage. Reprod Biol Endocrinol 12:105–115. https://doi.org/10.1186/1477-7827-12-105; PMid:25420429 PMCid:PMC4256731

21. Combelles C, Gupta S, Agarwal A. 2009. Could oxidative stress influence the invitro maturation of oocytes? Reprod Biomed Online 18:864–880.; Bedaiwy M, Elnashar S, Goldberg J, Sharma R, Mascha E, Arrigain S, Agarwal A, Falcone T. 2012. Effect of follicular fluid oxidative stress parameters on intracytoplasmic sperm injection outcome. Gynecol Endocrinol 28:51–55.

22. Dair EL, Simoes RS, Simoes MJ et al. 2008. Effects of melatonin on the endometrial morphology and embryo implantation in rats. Fertility and sterility 89(5 Suppl):1299-1305. https://doi.org/10.1016/j.fertnstert.2007.03.050; PMid:17561006

23. de Almeida E, DiMascio P, Harumi T, Spence D, Moscovitch A, Hardeland R, Cardinali D, Brown G, Pandi-Perumal S. 2011. Measurement of melatonin in body fluids: standards, protocols and procedures. Childs Nerv Syst 27:879–891. https://doi.org/10.1007/s00381-010-1278-8; PMid:21104186 PMCid:PMC3128751

24. El-Raey M, Geshi M, Somfai T, Kaneda M, Hirako M, Abdel-Ghaffar A, Sosa G, El-Roos M, Nagai T. 2011. Evidence of melatonin synthesis in the cumulus oocyte complexes and its role in enhancing oocyte maturation in-vitro in cattle. Mol Reprod Dev 78:250–262. https://doi.org/10.1002/mrd.21295; PMid:21381146

25. Eryilmaz O, Devran A, Sarikaya E, Aksakal F, Mollamahmutoğlu L, Cicek N. 2011. Melatonin improves the oocyte and the embryo in IVF patients with sleep disturbances, but does not improve the sleeping problems. J Assist Reprod Genet 28:815-820. https://doi.org/10.1007/s10815-011-9604-y; PMid:21748445 PMCid:PMC3169684

26. Feldmann G, Benifla JL, Madelenat P. 2006. Apoptosis of granulose cells as a predictive marker of in vitro fertilization success. Gynecol Obstet Fertil 34(7–8):547–582.

27. Gellersen B, Brosens JJ. 2014. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev 35:851–905. https://doi.org/10.1210/er.2014-1045; PMid:25141152

28. Haouzi D, Hamamah S. 2009. Pertinence of apoptosis markers for the improvement of in vitro fertilization (IVF). Current Med. Chemistry 16:1905–1916. https://doi.org/10.2174/092986709788186075

29. Imai M, Qin J, Tamakawa N, Miyado K, Umezawa AY, Pereira LV. 2012. Molecular alterations during female reproductive aging: Can aged oocytes remind youth? editor. Embryology. Updates and Highlights on Classic Topics: InTech.: 3–22.

30. Jauniaux E, Rizk B. 2012. Pregnancy after reproductive technology. Cambridge University Press, Cambridge. https://doi.org/10.1017/CBO9780511902604

31. Kajihara T, Uchino S, Itakura A. 2011. Human chorionic gonadotropin confers resistance to oxidative stress-induced apoptosis in decidualizing human endometrial stromal cells. Fertil Steril 95(4):1302–1307. https://doi.org/10.1016/j.fertnstert.2010.05.048; PMid:20615501

32. Kang J, Koo O, Kwon D, Park H, Jang G, Kang S, Lee B. 2009. Effects of melatonin on in-vitro maturation of porcine oocyte and expression of melatonin receptor RNA in cumulus and granulosa cells. J Pineal Res 46:22–28. https://doi.org/10.1111/j.1600-079X.2008.00602.x; PMid:18494781

33. Karaaslan C, Suzen S. 2015. Antioxidant properties of melatonin and its potential action in diseases. Curr Top Med Chem. 15(9):894-903. https://doi.org/10.2174/1568026615666150220120946; PMid:25697560

34. Karuputhula NB, Chattopadhyay R, Chakravarty B, Chaudhury K. 2013. Oxidative status in granulosa cells of infertile women undergoing IVF. Journal Systems Biology in Reproductive Medicine. Issue: 91-98.

35. Kim M, Park E, Kim H, Choi W, Cho J, Lee W, Cha K, Kim Y, Lee D, Yoon T. 2013. Does supplementation of in-vitro culture medium with melatonin improve IVF outcome in PCOS? Reprod Biomed Online 26:22–29. https://doi.org/10.1016/j.rbmo.2012.10.007; PMid:23177415

36. Liu J, Li Y. 2010, Sep. Effect of oxidative stress and apoptosis in granulosa cells on the outcome of IVF-ET. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 35(9):990-4. Chinese. PMid:20871166

37. Lopes AS, Lane M, Thompson JG. 2010. Oxygen consumption and ROS production are increased at the time of fertilization and cell cleavage in bovine zygotes. Hum Reprod. 25:2762–73. https://doi.org/10.1093/humrep/deq221; PMid:20823113

38. Lord T. 2013. Melatonin prevents postovulatory oocyte aging in the mouse and extends the window for optimal fertilisation in-vitro. Biol Reprod 88:67. https://doi.org/10.1095/biolreprod.112.106450; PMid:23365415

39. Lowes D, Webster N, Murphy M, Galley H. 2013. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve Fernando and Rombauts Journal of Ovarian Research 2014, 7:98 Page 12 of 14 mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br J Anaesth 110:472–480. https://doi.org/10.1093/bja/aes577; PMid:23381720 PMCid:PMC3570068

40. Nayki C, Nayki U, Gunay M, Kulhan M, Çankaya M, Humeyra Taskın Kafa A, Balci G. 2017, Mar. Oxidative and antioxidative status in the endometrium of patients with benign gynecological disorders. J Gynecol Obstet Hum Reprod. 46(3):243-247. https://doi.org/10.1016/j.jogoh.2017.02.002. Epub 2017 Feb 3.

41. Nikseresht M, Toori MA, Rahimi HR, Fallahzadeh AR, Kahshani IR, Hashemi SF, Bahrami S, and Mahmoudi R. 2017, Feb. Effect of Antioxidants (β-mercaptoethanol and Cysteamine) on Assisted Reproductive Technology In vitro. J Clin Diagn Res. 11(2):BC10–BC14. https://doi.org/10.7860/JCDR/2017/21778.9298

42. Nishihara T, Hashimoto S, Ito K, Nakaoka Y, Matsumoto K, Hosoi Y, Morimoto Y. 2014. Oral melatonin supplementation improves oocyte and embryo quality in women undergoing in-vitro fertilisation-embryo transfer. Gynecol Endocrinol 30:359–362. https://doi.org/10.3109/09513590.2013.879856; PMid:24628045

43. Ozturk S, Demir R. 2010. Particular functions of estrogen and progesterone in establishment of uterine receptivity and embryo implantation. Histol Histopathol 25:1215–1228. PMid:20607663

44. Rahiminejad, Mohammad Ehsan et al. 2016, August. Oxidative stress biomarkers in endometrial secretions: A comparison between successful and unsuccessful in vitro fertilization cycles. Journal of Reproductive Immunology 116:70–75. https://doi.org/10.1016/j.jri.2016.05.003; PMid:27232354

45.Rizk B, Sallam HN (2012) The uterine factor in infertility. In: Rizk B, Sallam HN (eds) Clinical infertility and in vitro fertilization. Jaypee Brothers Medical Publishers. St. Louis: 84–96. https://doi.org/10.5005/jp/books/11630

46. Rocha CS, Rato L, Martins AD, Alves MG, Oliveira PF. 2015. Melatonin and male reproductive health: relevance of darkness and antioxidant properties. Curr Mol Med. 15(4):299-311. Review. https://doi.org/10.2174/1566524015666150505155530; PMid:25941822

47. Rombauts L. 2007. Is there a recommended maximum starting dose of FSH in IVF? J Assist Reprod Genet 24:343–349. https://doi.org/10.1007/s10815-007-9134-9; PMid:17574524 PMCid:PMC3454944

48. Salhab M, Dhorne-Pollet S, Auclair S, Guyader-Joly C, Brisard D, Dalbies-Tran R, Dupont J, Ponsart C, Mermillod P, Uzbekova S. 2013. In-vitro maturation of oocytes alters gene expression and signaling pathways in bovine cumulus cells. Mol Reprod Dev 80:166–182. https://doi.org/10.1002/mrd.22148; PMid:23280668

49. Salimi M, Salehi M, Masteri Farahani R, Dehghani M, Abadi M, Novin M, Nourozian M, Hosseini A. 2014. The effect of melatonin on maturation, glutathione level and expression of HMGB1 gene in Brilliant Cresyl Blue (BCB) stained immature oocyte. Cell J 15:294–301. PMid:24381853

50. Seko L, Moroni R, Leitao V, Teixeira D, Nastri C, Martins W. 2014. Melatonin supplementation during controlled ovarian stimulation for women undergoing assisted reproductive technology: systematic review and metaanalysis of randomise controlled trials. Fertil Steril 101:154–161. https://doi.org/10.1016/j.fertnstert.2013.09.036; PMid:24182414

51. Sharkey JT, Puttaramu R, Word RA, Olcese J. 2009. Melatonin synergizes with oxytocin to enhance contractility of human myometrial smooth muscle cells j clin endocrinol metab. 94;2:421-427.

52. Shee-Uan Chen, Chia-Hung Chou, Mei-Jou Chen, Tzu-Hsin Chen, Yu-Shih Yang, Jehn-Hsiahn Yang. 2014, June 1. Аpoptotic effects of high estradiol concentrations on endometrial glandular cells, The Journal of Clinical Endocrinology & Metabolism. 99; 6:E971–E980.

53. Shkolnik K, Tadmor A, Ben-Dor S, Nevo N, Galiani D, Dekel N. 2011. Reactive oxygen species are indispensable in ovulation. Proc Natl Acad Sci U S A. 108:1462–7. https://doi.org/10.1073/pnas.1017213108; PMid:21220312 PMCid:PMC3029775

54. Showell M, Brown J, Clarke J, Hart R. 2013. Antioxidants for female subfertility. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD007807.pub2; PMid:23913583

55. Showell MG, Mackenzie-Proctor R, Jordan V, Hart RJ. 2017, Jul. Antioxidants for female subfertility. Cochrane Gynaecology and Fertility Group, Cochrane Database Syst Rev. 28;7.

56. Singh AK, Chattopadhyay R, Chakravarty B, Chaudhury K. 2013, Dec. Markers of oxidative stress in follicular fluid of women with endometriosis and tubal infertility undergoing IVF. Reprod Toxicol. 42:116-24. https://doi.org/10.1016/j.reprotox.2013.08.005; PMid:23994512

57. Srinivasan V, Spence W, Pandi-Perumal SR, Zakharia R, Bhatnagar K, Brzezinski A. 2009. Melatonin and human reproduction: shedding light on the darkness hormone. Gynecol Endocrinol 25:779–785. https://doi.org/10.3109/09513590903159649; PMid:19905996

58. Szmidt M, Sysa P, Niemiec T, Urbańska K, Bartyzel B. 2010. Regulation of Apoptosis in Endometrium Preparation for Menstruation or Embryo Implantation. Ginekol Pol 81(11):856-859. PMid:21365903

59.Takasaki A, Tamura H, Taniguchi K, Asada H, Taketani T, Matsuoka A, Yamagata Y, Shimamura K, Morioka H, Sugino N. 2009. Luteal blood flow and luteal function. J Ovarian Res 2. https://doi.org/10.1186/1757-2215-2-1

60. Taketani T, Tamura H, Takasaki A, Lee L, Kizuka F, Tamura I, Taniguchi K, Maekawa R, Asada H, Shimamura K, Reiter RJ, Sugino N. 2011. Protective role of melatonin in progesterone production by human luteal cells. J Pineal Res 51(2):207–13. https://doi.org/10.1111/j.1600-079X.2011.00878.x; PMid:21585519

61. Tamura H, Nakamura Y, Korkmaz A, Manchester L, Tan D, Sugino N, Reiter R. 2009. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril 92:328–343. https://doi.org/10.1016/j.fertnstert.2008.05.016; PMid:18804205

62.Tamura H, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee L, Tamura I, Maekawa R, Aasada H, Yamagata Y, Sugino N. 2012. The role of melatonin as an antioxidant in the follicle. J Ovarian Res 5. https://doi.org/10.1186/1757-2215-5-5; PMid:22277103 PMCid:PMC3296634

63. Wojsiat J, Korczyński J, Borowiecka M, Żbikowska HM. 2017, May 9. The role of oxidative stress in female infertility and in vitro fertilization. Postepy Hig Med Dosw (Online). 71(0):359-366. https://doi.org/10.5604/01.3001.0010.3820

64. Yao H, Guo L, Jiang BH, Luo J, Shi X. 2008. Oxidative stress and chromium (VI) carcinogenesis. J. Environ. Pathol. Toxicol. Oncol. 27:77-88. https://doi.org/10.1615/JEnvironPatholToxicolOncol.v27.i2.10; PMid:18540844

65. Young SL, Lessey BA. 2010. Progesterone function in human endometrium: clinical perspectives. Semin Reprod Med 28:5-16. https://doi.org/10.1055/s-0029-1242988; PMid:20104424

66. Young SL. 2013. Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity. Reprod Biomed Online 27:497–505. https://doi.org/10.1016/j.rbmo.2013.06.010; PMid:23933037 PMCid:PMC3818404

67. Zavareh S, Talebi A, Hasanzadeh H. 2015. Amending invitro culture condition to overcome oxidative stress in assisted reproduction techniques (ART) J. Paramed Sci. 6:135–48.

68. Zhang HM, Zhang Y. 2014, Sep. Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res. 57(2):131-46. https://doi.org/10.1111/jpi.12162; PMid:25060102