MELATONIN: THE MULTIFACETED HORMONE

Abstract

Melatonin is a hormone secreted by the pineal gland and its main biological function is to regulate the circadian rhythm. Melatonin synthesis varies according to light and dark conditions. While melatonin production is suppressed in the light environment, melatonin production increases in the dark environment. Melatonin acts through different mechanisms. One of these mechanisms is receptor-dependent signal transduction mechanism. Two types of receptors have been identified as melatonin receptor, melatonin receptor 1 and melatonin receptor 2. Through these mechanisms of action, in addition to circadian rhythm regulation, melatonin has various physiological and pathophysiological roles, including sleep cycle regulation, antioxidant and anti-inflammatory effects, immune system modulation, effects on cancer, cardiovascular system, central nervous system and neurodegenerative diseases. In this review, it is aimed to examine the roles of melatonin in physiological and pathophysiological processes.

Keywords

• cancer
• Circadian rhythm
• Hormone
• Melatonin

MELATONİN: ÇOK YÖNLÜ BİR HORMON

Abstract

Melatonin, epifiz bezi tarafından salgılanan bir hormondur ve temel biyolojik işlevi sirkadiyen ritmi düzenlemektir. Melatonin sentezi, aydınlık ve karanlık ortam koşullarına göre değişmektedir. Aydınlık ortamda, melatonin üretimi baskılanırken, karanlık ortamda melatonin üretimi artmaktadır. Melatonin farklı mekanizmalar aracılığıyla etki göstermektedir. Bu mekanizmalardan biri reseptöre bağımlı sinyal iletim mekanizmasıdır. Melatonin reseptörü olarak melatonin reseptörü 1 ve melatonin reseptörü 2 olmak üzere iki tip reseptör tanımlanmıştır. Bu etki mekanizmaları aracılığıyla sirkadiyen ritim düzenlenmesinin yanı sıra uyku döngüsünün düzenlenmesi, antioksidan ve anti-inflamatuar etkileri, immün sistem modülasyonu, kanser, kardiyovasküler sistem, santral sinir sistemi ve nörodejeneratif hastalıklar üzerine etkileri olmak üzere çeşitli fizyolojik ve patofizyolojik rolleri bulunmaktadır. Bu derlemede genel olarak melatoninin fizyolojik ve patofizyolojik süreçlerdeki rollerinin incelenmesi amaçlanmaktadır.

Keywords

• Kanser
• Sirkadiyen ritim
• Hormon
• Melatonin

References

1. Claustrat B, Leston J. Melatonin: physiological effects in humans. Neurochirurgie. 2015;61(2-3):77-84.
2. Merck KgaA [Internet]. Melatonin [cited 2025 May 02]. Available from: https://www.sigmaaldrich.com/TR/en/substance/melatonin2322873314
3. Talib WH, Alsayed AR, Abuawad A, Daoud S, Mahmod AI. Melatonin in cancer treatment: current knowledge and future opportunities. Molecules. 2021;26(9):2506.
4. Pandi‐Perumal SR, Srinivasan V, Maestroni GJM, Cardinali DP, Poeggeler B, Hardeland R. Melatonin: nature's most versatile biological signal?. The Febs Journal. 2006;273(13):2813-2838.
5. Cipolla-Neto J, Amaral FGD. Melatonin as a hormone: new physiological and clinical insights. Endocrine Reviews. 2018;39(6):990-1028.
6. Singh M, Jadhav HR. Melatonin: functions and ligands. Drug Discovery Today. 2014;19(9):1410-1418.
7. Günhan R.S. Melatonin ve önemi. Biological Diversity And Conservation. 2021;14(2):342-350.
8. Amaral FGD, Cipolla-Neto J. A Brief review about melatonin, a pineal hormone. Archives Of Endocrinology And Metabolism. 2018;62:472-479.

9. Salt A, Çenesiz M, Çenesiz S. Melatonin, etkileri ve kullanım alanları. Etlik Veteriner Mikrobiyoloji Dergisi. 2017;28(1):7-12.
10. Albreiki M. Characteristic, synthesis, and non-photic regulation of endogenous melatonin. In Melatonin-Recent Updates. 2022;Intechopen.
11. Şener G. Karanlığın hormonu: melatonin. Marmara Pharmaceutical Journal. 2010;14(3):112-120.
12. Ferlazzo N, Andolina G, Cannata A, Costanzo MG, Rizzo V, Currò M, et al. Is melatonin the cornucopia of the 21st century?. Antioxidants. 2020;9(11):1088.
13. Atasoy ÖB, Erbaş O. Melatonin hormonunun fizyolojik etkileri. İstanbul Bilim Üniversitesi Florence Nightingale Tıp Dergisi. 2017;3(1):52-62.
14. Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Medicine Reviews. 2005;9(1):11-24.
15. Hassell KJ, Reiter RJ, Robertson NJ. Melatonin and ıts role in neurodevelopment during the perinatal period: a review. Fetal And Maternal Medicine Review. 2013;24(2):76-107.
16. Talib WH. Melatonin and cancer hallmarks. Molecules. 2018;23(3):518.
17. Morvaridzadeh M, Sadeghi E, Agah S, Nachvak SM, Fazelian S, Moradi F, et al. Effect of melatonin supplementation on oxidative stress parameters: a systematic review and meta-analysis. Pharmacological Research. 2020;161:105210.
18. Jomova K, Valko M. Advances ın metal-induced oxidative stress and human disease. Toxicology. 2011;283(2-3):65-87.
19. Ertuğrul H, Yalçın B, Güneş M, Kaya B. Ameliorative effects of melatonin against nano and ıonic cobalt ınduced genotoxicity ın two in vivo drosophila assays. Drug And Chemical Toxicology. 2020;43(3):279-286.
20. Aydın S. Melatonın as an antıoxıdant and ıts protectıve effects on neurodegeneratıve dıseases. Health And Lıfe Wıth Dıfferent Aspects. Ankara; 2023. p. 89-124.
21. Atasoy N. Melatonin ve antioksidan etkileri. Düzce Üniversitesi Sağlık Bilimleri Enstitüsü Dergisi. 2019;9(3):196-201.
22. Topal T, Öter S, Korkmaz A. Melatonin ve kanserle ilişkisi. Journal Of General Medicine. 2009;19(3):137-143.
23. Verma AK, Khan MI, Ashfaq F, Rizvi SI. Crosstalk between aging, circadian rhythm, and melatonin. Rejuvenation Research. 2023;26(6):229-241.
24. Albreiki M. Characteristic, synthesis, and non-photic regulation of endogenous melatonin. In Melatonin-Recent Updates. 2022;Intechopen.
25. Zisapel N. New perspectives on the role of melatonin ın human sleep, circadian rhythms and their regulation. British Journal Of Pharmacology. 2018;175(16):3190-3199.
26. Megha KB, Arathi A, Shikha S, Alka R, Ramya P, Mohanan PV. Significance of melatonin ın the regulation of circadian rhythms and disease management. Molecular Neurobiology. 2024;61(8):5541-5571.
27. Deniz EB. Kanser epidemiyolojisi. Turkey Health Literacy Journal. 2022;3(2):102-111.
28. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
29. Nenclares P, Harrington KJ. The biology of cancer. Medicine. 2020;48(2):67-72.
30. Çimen A, Akbaş Y, Erbaş O. Uyku, melatonin ve kanser ilişkisi. İstanbul Bilim Üniversitesi Florence Nightingale Transplantasyon Dergisi. 2019;3(1-2):38-41.
31. Moloudizargari M, Moradkhani F, Hekmatirad S, Fallah M, Asghari MH, Reiter RJ. Therapeutic targets of cancer drugs: modulation by melatonin. Life Sciences. 2021;267:118934.
32. Putta CL, Eswar K, Rengan AK. Melatonin: avenues ın cancer therapy and ıts nanotechnological advancements. Medcomm–Biomaterials And Applications. 2023;2(3): E58.
33. Wang L, Wang C, Choi WS. Use of melatonin ın cancer treatment: where are we?. International Journal Of Molecular Sciences. 2022;23(7):3779.
34. Wang L, Su Y, Choi WS. Melatonin suppresses oral squamous cell carcinomas migration and ınvasion through blocking FGF19/FGFR 4 signaling pathway. International Journal Of Molecular Sciences. 2021;22(18):9907.
35. Maleki M, Khelghati N, Alemi F, Younesi S, Asemi Z, Abolhasan R, et al. Multiple ınteractions between melatonin and non‐coding rnas in cancer biology. Chemical Biology and Drug Design. 2021;98(3):323-340.
36. Mehrzadi S, Pourhanifeh MH, Mirzaei A, Moradian F, Hosseinzadeh A. An updated review of mechanistic potentials of melatonin against cancer: pivotal roles ın angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Cancer Cell İnternational. 2021;21:1-28.
37. Samanta S. Melatonin: an endogenous miraculous ındolamine, fights against cancer progression. Journal Of Cancer Research And Clinical Oncology. 2020;146:1893-1922.
38. Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, et al. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017;8(24):39896.
39. Verma AK, Singh S, Rizvi SI. Therapeutic potential of melatonin and ıts derivatives ın aging and neurodegenerative diseases. Biogerontology. 2023;24(2):183-206.
40. Chen D, Zhang T, Lee TH. Cellular mechanisms of melatonin: ınsight from neurodegenerative diseases. Biomolecules. 2020;10(8):1158.
41. Dailah HG. Potential of therapeutic small molecules ın apoptosis regulation ın the treatment of neurodegenerative diseases: an updated review. Molecules. 2022;27(21):7207.
42. Feybesse C, Chokron S, Tordjman S. Melatonin in neurodevelopmental disorders: a critical literature review. Antioxidants. 2023;12(11):2017.
43. Kopustinskiene DM, Bernatoniene J. Molecular mechanisms of melatonin-mediated cell protection and signaling in health and disease. Pharmaceutics. 2021;13(2):129.
44. Potes Y, Cachán-Vega C, Antuña E, García-González C, Menéndez-Coto N, Boga JA, et al. Benefits of the neurogenic potential of melatonin for treating neurological and neuropsychiatric disorders. International Journal Of Molecular Sciences. 2023;24(5): 4803.
45. Majidinia M, Sadeghpour A, Mehrzadi S, Reiter RJ, Khatami N, Yousefi B. Melatonin: a pleiotropic molecule that modulates dna damage response and repair pathways. Journal Of Pineal Research. 2017;63(1): E12416.
46. Pourhanifeh MH, Dehdashtian E, Hosseinzadeh A, Sezavar SH, Mehrzadi S. Clinical application of melatonin ın the treatment of cardiovascular diseases: current evidence and new insights ınto the cardioprotective and cardiotherapeutic properties. Cardiovascular Drugs And Therapy. 2022;36(1):131-155.
47. Tobeiha M, Jafari A, Fadaei S, Mirazimi SMA, Dashti F, Amiri A, et al. Evidence for the benefits of melatonin ın cardiovascular disease. Frontiers In Cardiovascular Medicine. 2022;9:888319.
48. Ozkalayci F, Kocabas U, Altun BU, Pandi-Perumal S, Altun A. Relationship between melatonin and cardiovascular disease. Cureus, 2021;13(1).
49. Mendes L, Queiroz M, Sena CM. Melatonin and vascular function. Antioxidants. 2024;13(6):747.
50. Abdulqader BK. Effect of endogenous melatonin hormone on cardiovascular system: a review of literature. Ann Coll Med Mosul. 2023;45(1):84-91.
51. Fourtillan JB, Brisson AM, Gobin P, Ingrand I, Decourt JP, Girault J. Bioavailability of melatonin in humans after day‐time administration of D7 melatonin. Biopharmaceutics and Drug Disposition. 2000;21(1):15-22.
52. DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino Jr JS. The absolute bioavailability of oral melatonin. The Journal of Clinical Pharmacology. 2000;40(7):781-784.
53. Zetner D, Andersen LPH, Rosenberg, J. Pharmacokinetics of alternative administration routes of melatonin: a systematic review. Drug Research. 2016;66(04):169-173.
54. Niu G, Yousefi B, Qujeq D, Marjani A, Asadi J, Wang Z, Mir SM. Melatonin and doxorubicin co-delivered via a functionalized graphene-dendrimeric system enhances apoptosis of osteosarcoma cells. Materials Science and Engineering:C. 2021;119:111554.
55. Gurunathan S, Qasim M, Kang MH, Kim JH. Role and therapeutic potential of melatonin in various type of cancers. OncoTargets and Therapy. 2021; 2019-2052.
56. Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. Complementary Therapies in Medicine. 2019;42:65-81.
57. Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, Mills E. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integrative Cancer Therapies. 2012;11(4):293-303.
58. Cao Y, Zhang H, Chen X, Li C, Chen J. Melatonin: a natural guardian in cancer treatment. Frontiers in Pharmacology. 2025;16:1617508.