Preview

Problems of Endocrinology

Advanced search

Meta-analysis of experimental studies of the effect of melatonin monotherapy on the levels of thyroid hormones and glucocorticoids in rats kept under standard condition

https://doi.org/10.14341/probl13396

Abstract

BACKGROUND: Melatonin is known to modulate circadian and seasonal rhythms in metabolism, reproduction, and behavior. However, the effect of exogenous melatonin supplementation on the functioning of the thyroid and adrenal glands in species without a clear seasonality in reproduction is still unclear.

AIM: Using a meta-analysis of publications, to investigate the effect of melatonin monotherapy on the concentrations of pituitary thyroid-stimulating hormone, thyroid hormones (TG), pituitary adrenocorticotropic hormone and corticosterone (CS) in rats kept under standard laboratory conditions.

MATERIALS AND METHODS: In our work, using the Review Manager 5.3 program, we conducted a meta-analysis of publications examining the effect of melatonin monotherapy on the functioning of the thyroid gland (22 papers) and adrenal glands (20 papers) in rats kept under standard conditions.

RESULTS: According to the results of our meta-analysis, the effects of melatonin on the levels of TG and CS depend on the dose and duration of therapy. A decrease in TG and CS was associated with therapy lasting no more than 4-5 weeks and with high doses of melatonin. An increase in CS and a trend toward increased TG levels were observed with longer therapy. However, a few studies have observed a decrease in TG with very long-term melatonin therapy (≥32 weeks). Among all TGs, total thyroxine (T4) showed maximum sensitivity to exogenous melatonin, which indicates the influence of melatonin on the secretory function of the thyroid gland. In addition, melatonin increased the relative weight of the adrenal glands. There was no convincing evidence that the effects of melatonin were influenced by the route and timing of administration, or the timing of blood sampling.

CONCLUSION: As a result, exogenous melatonin can modulate TG and CS levels, even in species without a clear seasonality in reproductive function.

About the Authors

N. V. Kuzmenko
Almazov National Medical Research Centre; First Pavlov State Medical University of St. Petersburg
Russian Federation

Nataliya V. Kuzmenko - PhD in biology.

St. Petersburg


Competing Interests:

none



V. A. Tsyrlin
Almazov National Medical Research Centre
Russian Federation

Vitaliy A. Tsyrlin - MD, PhD in medicine, DSc, professor.

St. Petersburg


Competing Interests:

none



M. G. Pliss
Almazov National Medical Research Centre
Russian Federation

Mikhail G. Pliss - PhD in medicine.

St. Petersburg


Competing Interests:

none



References

1. Emet M, Ozcan H, Ozel L, et al. A Review of Melatonin, Its Receptors and Drugs. Eurasian J Med. 2016;48(2):135-41. doi: https://doi.org/10.5152/eurasianjmed.2015.0267

2. Dardente H, Hazlerigg DG, Ebling FJ. Thyroid hormone and seasonal rhythmicity. Front Endocrinol (Lausanne). 2014;5(19). doi: https://doi.org/10.3389/fendo.2014.00019

3. Kinlein SA, Karatsoreos IN. The hypothalamic-pituitary-adrenal axis as a substrate for stress resilience: Interactions with the circadian clock. Front Neuroendocrinol. 2020;56:100819. doi: https://doi.org/10.1016/j.yfrne.2019.100819

4. Buijs RM, Wortel J, Van Heerikhuize JJ, et al. Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci. 1999;11(5):1535-44. doi: https://doi.org/10.1046/j.1460-9568.1999.00575.x

5. Romero LM. Seasonal changes in plasma glucocorticoid concentrations in free-living vertebrates. Gen Comp Endocrinol. 2002;128(1):1-24. doi: https://doi.org/10.1016/s0016-6480(02)00064-3

6. Lim CT, Khoo B. Normal Physiology of ACTH and GH Release in the Hypothalamus and Anterior Pituitary in Man.; 2000.

7. Ng KY, Leong MK, Liang H, Paxinos G. Melatonin receptors: distribution in mammalian brain and their respective putative functions. Brain Struct Funct. 2017;222(7):2921-2939. doi: https://doi.org/10.1007/s00429-017-1439-6

8. Richter HG, Torres-Farfan C, Garcia-Sesnich J, et al. Rhythmic expression of functional MT1 melatonin receptors in the rat adrenal gland. Endocrinology. 2008;149(3):995-1003. doi: https://doi.org/10.1210/en.2007-1009

9. Torres-Farfan C, Richter HG, Rojas-García P, et al. Mt1 melatonin receptor in the primate adrenal gland: Inhibition of adrenocorticotropin-stimulated cortisol production by melatonin. J Clin Endocrinol Metab. 2003. doi: https://doi.org/10.1210/jc.2002-021048

10. Ghosh H, Rai S, Manzar MD, et al. Differential expression and interaction of melatonin and thyroid hormone receptors with estrogen receptor α improve ovarian functions in letrozole-induced rat polycystic ovary syndrome. Life Sci. 2022;295:120086. doi: https://doi.org/10.1016/j.lfs.2021.120086

11. Baltaci AK, Mogulkoc R, Bediz CS, et al. Pinealectomy and zinc deficiency have opposite effects on thyroid hormones in rats. Endocr Res. 2003;29(4):473-81. doi: https://doi.org/10.1081/erc-120026953

12. Ostrowska Z, Kos-Kudla B, Nowak M, et al. The relationship between bone metabolism, melatonin and other hormones in sham-operated and pinealectomized rats. Endocr Regul. 2003;37(4):211-24. https://www.sav.sk/journals/endo/full/2003/2003_04c.pdf

13. Mustonen AM, Nieminen P, Hyvärinen H. Effects of continuous light and melatonin treatment on energy metabolism of the rat. J Endocrinol Invest. 2002;25(8):716-23. doi: https://doi.org/10.1007/BF03345106

14. Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D. Influence of lighting conditions on daily rhythm of bone metabolism in rats and possible involvement of melatonin and other hormones in this process. Endocr Regul. 2003;37(3):163-74. https://www.sav.sk/journals/endo/full/2003/2003_03d.pdf

15. Claustrat B, Valatx JL, Harthé C, Brun J. Effect of constant light on prolactin and corticosterone rhythms evaluated using a noninvasive urine sampling protocol in the rat. Horm Metab Res. 2008;40(6):398-403. doi: https://doi.org/10.1055/s-2008-1065330

16. Tchekalarova J, Atanasova M, Ivanova N, et al. Endurance training exerts time-dependent modulation on depressive responses and circadian rhythms of corticosterone and BDNF in the rats with pinealectomy. Brain Res Bull. 2020;162:40-48. doi: https://doi.org/10.1016/j.brainresbull.2020.05.012

17. Acuña D, Garcia del Rio C, Garcia-Torres L, et al. Role of pineal gland in kidney-adrenal homeostasis. Horm Metab Res. 1984;16(11):589-92. doi: https://doi.org/10.1055/s-2007-1014858

18. la Fleur SE, Kalsbeek A, Wortel J, et al. Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations. J Neuroendocrinol. 2001;13(12):1025-32. doi: https://doi.org/10.1046/j.1365-2826.2001.00717.x

19. Fraschini F, Mess B, Martini L. Pineal gland, melatonin and the control of luteinizing hormone secretion. Endocrinology. 1968;82(5):919-24. doi: https://doi.org/10.1210/endo-82-5-919

20. DeFronzo RA, Roth WD. Evidence for the existence of a pineal-adrenal and a pineal-thyroid axis. Acta Endocrinol (Copenh). 1972;70(1):35-42. doi: https://doi.org/10.1530/acta.0.0700035

21. Ekins R. Immunoassay standardization. Scand J Clin Lab Invest. 1991. doi: https://doi.org/10.3109/00365519109104600

22. Berson SA, Yalow RS. Radioimmunoassay of ACTH in plasma. J Clin Invest. 1968;47(12):2725-51. doi: https://doi.org/10.1172/JCI105955

23. Borenstein M, Hedges L V, Higgins JPT, Rothstein HR. Introduction to Meta-Analysis. 2009. doi: https://doi.org/10.1002/9780470743386

24. Arushanian EB, El’bek’ian KS. Different shifts in the plasma corticosterone content depending on the dose and administration route of melatonin. Eksp Klin Farmakol. 1994;57(5):34-5. (In Russian).

25. Barchas J, Conner R, Levine S, Vernikos-Danellis J. Effects of chronic melatonin and saline injections on pituitary adrenal secretion. Experientia. 1969;25(4):413-4. doi: https://doi.org/10.1007/BF01899954

26. Gromova EA, Kraus M, Krecek J. Effect of melatonin and 5-hydroxytryptamine on aldosterone and corticosterone production by adrenal glands of normal and hypophysectomized rats. J Endocrinol. 1967;39(3):345-50. doi: https://doi.org/10.1677/joe.0.0390345.

27. Maslova LN, Evtiugina EM, Onischenko LS. Effect of melatonin on the hypothalamo-hypophyseo-adrenal system of rats. Probl Endokrinol (Mosk). 1973;19(5):55-9. (In Russian).

28. Mattila J, Männistö PT. Studies on the role of the pineal gland in the regulation of TSH secretion in postpuberal male rats. Horm Res. 1981;14(1):24-35. doi: https://doi.org/10.1159/000179354

29. Mitsuma T, Nogimori T. Effects of various drugs on thyrotropin secretion in rats. Horm Metab Res. 1985;17(7):337-41. doi: https://doi.org/10.1055/s-2007-1013537

30. Niles LP, Brown GM. Arginine vasotocin stimulates glucocorticoid secretion in male rats. Prog Neuropsychopharmacol Biol Psychiatry. 1983;7(4-6):841-4. doi: https://doi.org/10.1016/0278-5846(83)90079-9

31. Abd Allah ESH, Mahmoud AM. Melatonin attenuates chronic immobilization stress-induced muscle atrophy in rats: Influence on lactate-to-pyruvate ratios and Na+/K+ ATPase activity. Pathophysiology. 2018;25(4):353-357. doi: https://doi.org/10.1016/j.pathophys.2018.06.002

32. Ahmed HH, Mannaa F, Elmegeed GA, Doss SH. Cardioprotective activity of melatonin and its novel synthesized derivatives on doxorubicin-induced cardiotoxicity. Bioorg Med Chem. 2005;13(5):1847-57. doi: https://doi.org/10.1016/j.bmc.2004.10.066

33. Aoyama H, Mori N, Mori W. Anti-glucocorticoid effects of melatonin on adult rats. Acta Pathol Jpn. 1987; 37(7):1143-8. doi: https://doi.org/10.1111/j.1440-1827.1987.tb00431.x

34. Baltaci AK, Mogulkoc R, Kul A, Bediz CS, Ugur A. Opposite effects of zinc and melatonin on thyroid hormones in rats. Toxicology. 2004;195(1):69-75. doi: https://doi.org/10.1016/j.tox.2003.09.001

35. Benova T, Viczenczova C, Radosinska J, et al. Melatonin attenuates hypertension-related proarrhythmic myocardial maladaptation of connexin-43 and propensity of the heart to lethal arrhythmias. Can J Physiol Pharmacol. 2013;91(8):633-9. doi: https://doi.org/10.1139/cjpp-2012-0393

36. Bojková B, Marková M, Ahlersová E, et al. Metabolic effects of prolonged melatonin administration and short-term fasting in laboratory rats. Acta Vet Brno. 2006. doi: https://doi.org/10.2754/avb200675010021

37. Bojková B, Orendás P, Friedmanová L, et al. Prolonged melatonin administration in 6-month-old Sprague-Dawley rats: metabolic alterations. Acta Physiol Hung. 2008;95(1):65-76. doi: https://doi.org/10.1556/APhysiol.95.2008.4

38. Bondarenko LA, Gevorkyan AR. The influence of a course injection of melatonin on the hormonal activity of the hypophyseal-thyroid system in old rats with age-related hypophyroidism. Buk. Med. Herald. 2009;13(4):38-40.(In Ukraine).

39. Brazão V, Santello FH, Colato RP, et al. Melatonin down-regulates steroidal hormones, thymocyte apoptosis and inflammatory cytokines in middle-aged T. cruzi infected rats. Biochim Biophys Acta Mol Basis Dis. 2020;1866(11):165914. doi: https://doi.org/10.1016/j.bbadis.2020.165914

40. Esquifino A, Agrasal C, Velázquez E, et al. Effect of melatonin on serum cholesterol and phospholipid levels, and on prolactin, thyroid-stimulating hormone and thyroid hormone levels, in hyperprolactinemic rats. Life Sci. 1997;61(11):1051-8. doi: https://doi.org/10.1016/s0024-3205(97)00613-9

41. Gevorkyan A.R. Chronobiological features of the effect of exogenous melatonin on hormone thyroid activity in young rats. Journal of Education, Health and Sport. 2016;6 (10):547-556. doi: https://doi.org/10.5281/zenodo.167878

42. Gomaa AM, Galal HM, Abou-Elgait AT. Neuroprotective effects of melatonin administration against chronic immobilization stress in rats. Int J Physiol Pathophysiol Pharmacol. 2017;9(2):16-27. doi: https://e-century.us/files/ijppp/9/2/ijppp0050029.pdf

43. Jiménez-Ortega V, Cano Barquilla P, Fernández-Mateos P, et al. Cadmium as an endocrine disruptor: correlation with anterior pituitary redox and circadian clock mechanisms and prevention by melatonin. Free Radic Biol Med. 2012;53(12):2287-97. doi: https://doi.org/10.1016/j.freeradbiomed.2012.10.533

44. Kinson GA, MacDonald NE, Liu CC. The effects of melatonin and serotonin on blood flow fraction and testosterone metabolism in selected organs of the male rat. Can J Physiol Pharmacol. 1973;51(5):313-8. doi: https://doi.org/10.1139/y73-047

45. Konakchieva R, Mitev Y, Almeida OF, Patchev VK. Chronic melatonin treatment counteracts glucocorticoid-induced dysregulation of the hypothalamic-pituitary-adrenal axis in the rat. Neuroendocrinology. 1998;67(3):171-80. doi: https://doi.org/10.1159/000054312

46. Mercau ME, Calanni JS, Aranda ML, et al. Melatonin prevents early pituitary dysfunction induced by sucrose-rich diets. J Pineal Res. 2019;66(2):e12545. doi: https://doi.org/10.1111/jpi.12545

47. Mirunalini S, Subramanian P. Temporal oscillations of thyroid hormones in long term melatonin treated rats. Pharmazie. 2005;60(1):52-6. doi: https://www.ingentaconnect.com/content/govi/pharmaz/2005/00000060/00000001/art00010?crawler=true

48. Nasiraei-Moghadam SN, Parivar K, Ahmadiani A, et al. Protective Effect of Melatonin against Inequality-Induced Da mages on Testicular Tissue and Sper m Para meters. Int J Fertil Steril. 2014;7(4):313-22. doi: https://www.ijfs.ir/article_45208.html

49. Nir I, Hirschmann N, Puder M, Petrank J. Changes in rodent thyroid hormones and cyclic-AMP following treatment with pineal indolic compounds. Arch Int Physiol Biochim. 1978;86(2):353-62. doi: https://doi.org/10.3109/13813457809069910

50. Nordio M, Vaughan MK, Sabry I, Reiter RJ. Undernutrition potentiates melatonin effects in maturing female rats. J Endocrinol Invest. 1989;12(2):103-10. doi: https://doi.org/10.1007/BF03349933

51. Olukole SG, Lanipekun DO, Ola-Davies EO, Oke BO. Melatonin attenuates bisphenol A-induced toxicity of the adrenal gland of Wistar rats. Environ Sci Pollut Res Int. 2019;26(6):5971-5982. doi: https://doi.org/10.1007/s11356-018-4024-5

52. Ozturk G, Coşkun S, Erbaş D, Hasanoglu E. The effect of melatonin on liver superoxide dismutase activity, serum nitrate and thyroid hormone levels. Jpn J Physiol. 2000;50(1):149-53. doi: https://doi.org/10.2170/jjphysiol.50

53. Poliandri AH, Esquifino AI, Cano P, et al. In vivo protective effect of melatonin on cadmium-induced changes in redox balance and gene expression in rat hypothalamus and anterior pituitary. J Pineal Res. 2006;41(3):238-46. doi: https://doi.org/10.1111/j.1600-079X.2006.00360.x

54. Rasmussen DD, Boldt BM, Wilkinson CW, et al. Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology. 1999;140(2):1009-12. doi: https://doi.org/10.1210/endo.140.2.6674

55. Rom-Bugoslavskaia ES, Shcherbakova VS. Seasonal characteristics of the effect of melatonin on thyroid function. Biull Eksp Biol Med. 1986;101(3):268-9 (In Russian). doi: https://link.springer.com/article/10.1007/BF00835913

56. Sewerynek E, Wiktorska J, Lewinski A. Effects of melatonin on the oxidative stress induced by thyrotoxicosis in rats. Neuro Endocrinol Lett. 1999;20(3-4):157-161. https://www.nel.edu/userfiles/articlesnew/NEL203499A01.pdf

57. Vaughan MK, Oaknin S, Cozzi B, et al. Influence of melatonin on the testicular regression induced by subcutaneous testosterone pellets in male rats kept in long or short photoperiod. J Reprod Fertil. 1988;82(1):277-84. doi: https://doi.org/10.1530/jrf.0.0820277

58. Vinogradova IA.[Effect of preparations melatonin and epitalon on the age-related dynamics of thyrotrophic activity of the hypophysis and thyroid gland function in different light regimes. Adv Gerontol. 2009;22(4):631-8 (In Russian).

59. Wang L, McFadden JW, Yang G, et al. Effect of melatonin on visceral fat deposition, lipid metabolism and hepatic lipo-metabolic gene expression in male rats. J Anim Physiol Anim Nutr (Berl). 2021;105(4):787-796. doi: https://doi.org/10.1111/jpn.13497

60. Wolden-Hanson T, Mitton DR, McCants RL, et al. Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat. Endocrinology. 2000;141(2):487-97. doi: https://doi.org/10.1210/endo.141.2.7311

61. Segal J, Troen BR, Ingbar SH. Influence of age and sex on the concentrations of thyroid hormone in serum in the rat. J Endocrinol. 1982;93(2):177-81. doi: https://doi.org/10.1677/joe.0.0930177

62. Silvestri E, Lombardi A, de Lange P, et al. Age-related changes in renal and hepatic cellular mechanisms associated with variations in rat serum thyroid hormone levels. Am J Physiol Endocrinol Metab. 2008;294(6):E1160-8. doi: https://doi.org/10.1152/ajpendo.00044.2008

63. Stevenson TJ, Prendergast BJ. Reversible DNA methylation regulates seasonal photoperiodic time measurement. Proc Natl Acad Sci U S A. 2013;110(41):16651-6. doi: https://doi.org/10.1073/pnas.1310643110

64. Lewiński A, Sewerynek E, Zerek-Mełeń G, et al. Influence of melatonin and N-acetylserotonin on the cyclic AMP concentration in the rat thyroid lobes incubated in vitro. J Pineal Res. 1989;7(1):55-61. doi: https://doi.org/10.1111/j.1600-079x.1989.tb00442.x

65. Lewiński A, Sewerynek E. Melatonin inhibits the basal and TSH-stimulated mitotic activity of thyroid follicular cells in vivo and in organ culture. J Pineal Res. 1986;3(3):291-9. doi: https://doi.org/10.1111/j.1600-079x.1986.tb00752.x

66. Wajs E, Lewiński A. Inhibitory influence of late afternoon melatonin injections and the counter-inhibitory action of melatonin-containing pellets on thyroid growth process in male Wistar rats: comparison with effects of other indole substances. J Pineal Res. 1992;13(4):158-66. doi: https://doi.org/10.1111/j.1600-079x.1992.tb00071.x

67. Yanko RV. The morphological structure of thyroid gland in young rats obtained melatonin. Endocrinology. 2014; 19(3): 195-199. (In Ukraine). https://endokrynologia.com.ua/index.php/journal/article/download/268/239/

68. De Prospo ND, Hurley J. A comparison of intracerebral and intraperitoneal injections of melatonin and its precursors on 131 I uptake by the thyroid glands of rats. Agents Actions. 1971;2(1):14-7. doi: https://doi.org/10.1007/BF01965374

69. Juszczak M, Roszczyk M, Kowalczyk E, Stempniak B. The influence of melatonin receptors antagonists, luzindole and 4-phenyl-2-propionamidotetralin (4-P-PDOT), on melatonin-dependent vasopressin and adrenocorticotropic hormone (ACTH) release from the rat hypothalamo-hypophysial system. In vitro and in vivo studies. J Physiol Pharmacol. 2014;65(6):777-84. https://www.jpp.krakow.pl/journal/archive/12_14/pdf/777_12_14_article.pdf

70. Lesniewska B, Nowak M, Nussdorfer GG, Malendowicz LK. Sex-dependent effect of melatonin on the secretory activity of rat and hamster adrenal gland in vitro. Life Sci. 1990;47(3):241-5. doi: https://doi.org/10.1016/0024-3205(90)90326-m

71. Niijima A, Chun SJ, Shima T, et al. Effect of intravenous administration of melatonin on the efferent activity of the adrenal nerve. J Auton Nerv Syst. 1998;71(2-3):134-8. doi: https://doi.org/10.1016/s0165-1838(98)00067-8

72. Scaccianoce S, Di Sciullo A, Angelucci L. Age-related changes in hypothalamo-pituitary-adrenocortical axis activity in the rat. In vitro studies. Neuroendocrinology. 1990;52(2):150-5. doi: https://doi.org/10.1159/000125566

73. Marinova C, Persengiev S, Konakchieva R, et al. Melatonin effects on glucocorticoid receptors in rat brain and pituitary: significance in adrenocortical regulation. Int J Biochem. 1991;23(4):479-81. doi: https://doi.org/10.1016/0020-711x(91)90177-o

74. De Prospo N, Hurley J. Effects of injecting melatonin and its precursors into the lateral cerebral ventricles on selected organs in rats. J Endocrinol. 1971;49(3):545-6. doi: https://doi.org/10.1677/joe.0.0490545

75. Kuzmenko NV, Tsyrlin VA, Pliss MG. Meta-analysis of experimental studies of diet-dependent effects of melatonin monotherapy on circulatory levels of triglycerides, cholesterol, glucose and insulin in rats. Journal of Evolutionary Biochemistry and Physiology. 2023;59(1):213–231. (In Russ.). doi: https://doi.org/10.1134/S0022093023010180


Supplementary files

1. Figure 1. Effect of a single intravenous administration of melatonin on the level of TSH and thyroid hormones.
Subject
Type Research Instrument
Download (60KB)    
Indexing metadata ▾
2. Figure 2. Effect of long-term melatonin therapy on the level of circulating TSH and thyroid hormones. Without additional standardization for dose and route of administration.
Subject
Type Research Instrument
Download (323KB)    
Indexing metadata ▾
3. Figure 3. Effect of long-term melatonin therapy on changes in daytime and nighttime values of TSH and thyroid hormones. Without additional standardization for dose and route of administration.
Subject
Type Research Instrument
Download (40KB)    
Indexing metadata ▾
4. Figure 4. Effect of a single administration of melatonin on the level of corticosterone and ACTH.
Subject
Type Research Instrument
Download (28KB)    
Indexing metadata ▾
5. Figure 5. Effect of long-term melatonin therapy on the level of circulating ACTH, corticosterone and adrenal mass. Without additional standardization for dose and route of administration.
Subject
Type Research Instrument
Download (66KB)    
Indexing metadata ▾
6. Figure 6. Effect of long-term melatonin therapy on changes in daytime and nighttime corticosterone levels. Without additional standardization for dose and route of administration.
Subject
Type Research Instrument
Download (42KB)    
Indexing metadata ▾

Review

For citations:


Kuzmenko N.V., Tsyrlin V.A., Pliss M.G. Meta-analysis of experimental studies of the effect of melatonin monotherapy on the levels of thyroid hormones and glucocorticoids in rats kept under standard condition. Problems of Endocrinology. 2024;70(5):91-105. (In Russ.) https://doi.org/10.14341/probl13396

Views: 1519


ISSN 0375-9660 (Print)
ISSN 2308-1430 (Online)