Melatonin status in obese patients with ovarian dysfunction at reproductive age

BACKGROUND: Melatonin is the main hormone of the pineal gland. By regulating circadian rhythms and being an immune regulator and antioxidant, this hormone takes part in the work of the ovaries: its high concentrations block apoptosis and neutralize reactive oxygen species involved in folliculogenesis, ovulation, egg maturation and corpus luteum formation.

AIM: To study melatonin status and its relationship with menstrual dysfunction and sleep disorders in obese women of reproductive age.

MATERIALS AND METHODS. In a one-stage comparative study, women 18-35 years old took part: 30 patients with obesity and menstrual disorders of an inorganic nature and 30 healthy women in the comparison group with normal weight and regular menstrual cycle. All participants underwent a questionnaire to identify somnological disorders, and the level of melatonin in saliva and 6-sulfatoxymelatonin in urine was also investigated.

RESULTS: In the group of patients with obesity (n=30), various sleep disorders were encountered in 47% of cases (p=0.003), including more often obstructive sleep apnea syndrome was recorded (30% of cases), and a correlation was found between the indicators of the questionnaire survey of subjective sleep characteristics and body mass index of patients (r=0.450, p=0.030) compared with a group of healthy women with normal weight (n=30). In the main group, the level of melatonin in saliva was statistically significantly lower than in the control: median 12.6 pg / ml and 25.5 pg / ml, respectively (p=0.008), the same pattern was recorded for 6-sulfatoxymelatonin: 14, 72 pg / ml and 31.12 pg / ml, respectively.

CONCLUSION: Patients with obesity and menstrual dysfunction are more likely to suffer from various sleep disorders and have lower levels of melatonin in saliva and 6-sulfatoxymelatonin in urine.

1. Xu Z, You W, Liu J, et al. Elucidating the Regulatory Role of Melatonin in Brown, White, and Beige Adipocytes. Adv Nutr. 2019;46(5):847-852. https://doi.org/10.1093/advances/nmz070

2. Luchetti F, Canonico B, Bartolini D, et al. Melatonin regulates mesenchymal stem cell differentiation: a review. J Pineal Res. 2014;56(4):382-97. https://doi.org/10.1111/jpi.12133

3. Pandi-Perumal SR, BaHammam AS, Ojike NI, et al. Melatonin and Human Cardiovascular Disease. J Cardiovasc Pharmacol Ther. 2017;22(2):122-132. https://doi.org/10.1177/1074248416660622

4. Szewczyk-Golec K, Woźniak A, Reiter RJ. Inter-relationships of the chronobiotic, melatonin, with leptin and adiponectin: implications for obesity. J Pineal Res. 2015;59(3):277-91. https://doi.org/10.1111/jpi.12257

5. Rhee YH, Ahn JC. Melatonin attenuated adipogenesis through reduction of the CCAAT/enhancer binding protein beta by regulating the glycogen synthase 3 beta in human mesenchymal stem cells. J Physiol Biochem. 2016;72(2):145-55. https://doi.org/10.1007/s13105-015-0463-3

6. Jimenéz-Aranda A, Fernández-Vázquez G, Mohammad A-Serrano M, et al. Melatonin improves mitochondrial function in inguinal white adipose tissue of Zücker diabetic fatty rats. J Pineal Res. 2014;57(1):103-9. https://doi.org/10.1111/jpi.12147

7. Fernández Vázquez G, Reiter RJ, Agil A. Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats: implications for obesity control. J Pineal Res. 2018;64(4):e12472. https://doi.org/10.1111/jpi.12472.

8. Xu P, Wang J, Hong F, et al. Melatonin prevents obesity through modulation of gut microbiota in mice. J Pineal Res. 2017;62(4). https://doi.org/10.1111/jpi.12399.

9. Ireland KE, Maloyan A, Myatt L. Melatonin Improves Mitochondrial Respiration in Syncytiotrophoblasts From Placentas of Obese Women. Reprod Sci. 2018;25(1):120-130. https://doi.org/10.1177/1933719117704908

10. Peschke E, Bähr I, Mühlbauer E. Melatonin and pancreatic islets: interrelationships between melatonin, insulin and glucagon. Int J Mol Sci. 2013;14(4):6981-7015. https://doi.org/10.3390/ijms14046981

11. Qian J, Dalla Man C, Morris CJ, et al. Differential effects of the circadian system and circadian misalignment on insulin sensitivity and insulin secretion in humans. Diabetes Obes Metab. 2018;20(10):2481-2485. https://doi.org/10.1111/dom.13391

12. Reiter RJ, Mayo JC, Tan DX, et al. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016;61(3):253-78. https://doi.org/10.1111/jpi.12360

13. Markwald RR, Melanson EL, Smith MR, et al. Impact of insufficient sleep on total daily energy expenditure, food intake, and weight gain. Proc Natl Acad Sci U S A. 2013;110(14):5695-700. https://doi.org/10.1073/pnas.1216951110

14. Reiter RJ, Rosales-Corral S, Tan DX, et al. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell Mol Life Sci. 2017;74(21):3863-3881. https://doi.org/10.1007/s00018-017-2609-7

15. Genario R, Morello E, Bueno AA, Santos HO. The usefulness of melatonin in the field of obstetrics and gynecology. Pharmacol Res. 2019;147:104337. https://doi.org/10.1016/j.phrs.2019.104337

16. Fernandez B, Malde JL, Montero A, Acuña D. Relationship between adenohypophyseal and steroid hormones and variations in serum and urinary melatonin levels during the ovarian cycle, perimenopause and menopause in healthy women. J Steroid Biochem. 1990;35(2):257-62. https://doi.org/10.1016/0022-4731(90)90282-w

17. Ma M, Chen XY, Li B, Li XT. Melatonin protects premature ovarian insufficiency induced by tripterygium glycosides: role of SIRT1. Am J Transl Res. 2017;9(4):1580-1602.

18. Tamura H, Takasaki A, Taketani T, et al. Melatonin as a free radical scavenger in the ovarian follicle. Endocr J. 2013;60(1):1-13. https://doi.org/10.1507/endocrj.ej12-0263

19. Tan DX, Manchester LC, 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

20. 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. 2003;80(4):1012-6. https://doi.org/10.1016/s0015-0282(03)01008-2

21. Teixeira AAC, Simöes MdJ, Teixeira VW, Soares Júnior JM. Evaluation of the implantation in pinealectomized and/or submitted to the constant illumination rats. Int. J. Morphol. 2004;22:189–194.

22. Song C, Peng W, Yin S, et al. Melatonin improves ageinduced fertility decline and attenuates ovarian mitochondrial oxidative stress in mice. Sci Rep. 2016;6:35165. https://doi.org/10.1038/srep35165

23. Tagliaferri V, Romualdi D, Scarinci E, et al. Melatonin Treatment May Be Able to Restore Menstrual Cyclicity in Women With PCOS: A Pilot Study. Reprod Sci. 2018;25(2):269-275. https://doi.org/10.1177/1933719117711262

24. Genario R, Cipolla-Neto J, Bueno AA, Santos HO. Melatonin supplementation in the management of obesity and obesityassociated disorders: A review of physiological mechanisms and clinical applications. Pharmacol Res. 2021;163:105254. https://doi.org/10.1016/j.phrs.2020.105254

25. Levin YaI, Eligulashvili TS, Posokhov SI, et al. Farmakoterapiya insomnii: rol’ Imovana. V kn. Rasstroistva sna. Рod red. Yu.A. Aleksandrovskogo i A.M. Veina. Sankt-Peterburg: Meditsinskoe informatsionnoe agenstvo, 1995. S. 56-61 (in Russian).

26. Summa KC, Turek FW. Chronobiology and obesity: Interactions between circadian rhythms and energy regulation. Adv Nutr. 2014;5(3):312S-9S. https://doi.org/10.3945/an.113.005132

27. Corbalán-Tutau D, Madrid JA, Nicolás F, Garaulet M. Daily profile in two circadian markers «melatonin and cortisol» and associations with metabolic syndrome components. Physiol Behav. 2014;123:231-5. https://doi.org/10.1016/j.physbeh.2012.06.005

28. Reiter RJ, Tan DX, Korkmaz A, Ma S. Obesity and metabolic syndrome: association with chronodisruption, sleep deprivation, and melatonin suppression. Ann Med. 2012;44(6):564-77. https://doi.org/10.3109/07853890.2011.586365

29. Taheri S, Lin L, Austin D, et al. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1(3):e62. https://doi.org/10.1371/journal.pmed.0010062

30. Willis SK, Hatch EE, Wise LA. Sleep and female reproduction. Curr Opin Obstet Gynecol. 2019;31(4):222-227. https://doi.org/10.1097/GCO.0000000000000554

31. Liu Y, Wheaton AG, Chapman DP, et al. Prevalence of Healthy Sleep Duration among Adults — United States, 2014. MMWR Morb Mortal Wkly Rep. 2016;65(6):137-41. https://doi.org/10.15585/mmwr.mm6506a1

32. Wang Y, Gu F, Deng M, et al. Rotating shift work and menstrual characteristics in a cohort of Chinese nurses. BMC Womens Health. 2016;16:24. https://doi.org/10.1186/s12905-016-0301-y

33. Kang W, Jang KH, Lim HM, et al. The menstrual cycle associated with insomnia in newly employed nurses performing shift work: a 12-month follow-up study. Int Arch Occup Environ Health. 2019;92(2):227-235. https://doi.org/10.1007/s00420-018-1371-y

34. Goldstein CA, Lanham MS, Smith YR, O’Brien LM. Sleep in women undergoing in vitro fertilization: a pilot study. Sleep Med. 2017;32:105-113. https://doi.org/10.1016/j.sleep.2016.12.007

35. Wang ID, Liu YL, Peng CK, et al. Non-Apnea Sleep Disorder Increases the Risk of Subsequent Female Infertility-A Nationwide Population-Based Cohort Study. Sleep. 2018;41(1). https://doi.org/10.1093/sleep/zsx186

36. Willis SK, Hatch EE, Wesselink AK, et al. Female sleep patterns, shift work, and fecundability in a North American preconception cohort study. Fertil Steril. 2019;111(6):1201-1210.e1. https://doi.org/10.1016/j.fertnstert.2019.01.037

37. Sturgeon SR, Doherty A, Reeves KW, et al. Urinary levels of melatonin and risk of postmenopausal breast cancer: women’s health initiative observational cohort. Cancer Epidemiol Biomarkers Prev. 2014;23(4):629-37. https://doi.org/10.1158/1055-9965.EPI-13-1028

38. Gómez-Acebo I, Dierssen-Sotos T, Papantoniou K, et al. Association between exposure to rotating night shift versus day shift using levels of 6-sulfatoxymelatonin and cortisol and other sex hormones in women. Chronobiol Int. 2015;32(1):128-35. https://doi.org/10.3109/07420528.2014.958494

39. Luboshitzky R, Qupti G, Ishay A, et al. Increased 6-sulfatoxymelatonin excretion in women with polycystic ovary syndrome. Fertil Steril. 2001;76(3):506-10. https://doi.org/10.1016/s0015-0282(01)01930-6