Abstract
Aims
To determine the effects of different doses of melatonin treatment on endometrial implants, the activity of antioxidant enzyme superoxide dismutase (SOD), the angiogenesis factor, the vascular endothelial growth factor (VEGF) and the waste metabolite product of lipid peroxidation malondialdehyde (MDA) in an oophorectomized rat endometriosis model.
Methods
Thirty-two, female, non-pregnant, nulligravid Sprague–Dawley, albino rats were used in this prospective, randomized, controlled and experimental study. Endometriosis was surgically induced in oophorectomized rats, and estradiol treatment was started after the first operation and continued till the end of the study. Second look, third look and necropsy operations were performed in the 2nd, 4th and 6th weeks. Mean volumes, histological scores and biochemical parameters were evaluated throughout the study.
Results
The mean volumes of endometriotic foci were 98.8 mm3 ± 17.2 vs. 108.2 mm3 ± 17.5, 54.1 mm3 ± 15.6 vs. 25.8 mm3 ± 3.6, 42.8 mm3 ± 10.5 vs. 32.7 mm3 ± 6.0 and histopathological scores were 2.2 ± 0.2 vs. 1.7 ± 0.1, 2.6 ± 0.2 vs. 2.2 ± 0.2, 2.6 ± 0.1 vs. 2.7 ± 0.2 in the 10 vs. 20-mg/kg/day melatonin group at the end of the second, fourth and sixth weeks, respectively. When the groups were compared, no significant differences were seen in the histopathologic scores, SOD and VEGF levels between the groups. However, the endometriotic foci volumes were significantly decreased in both melatonin treatment groups with respect to the control group at the end of the fourth and sixth weeks. Moreover, the mean MDA levels were significantly lower in the control group than in the 10-mg/kg/day melatonin group at the end of the fourth and sixth weeks.
Conclusion
Melatonin treatment resulted in the regression of endometriotic lesions in oophorectomized rats. Higher doses of melatonin treatment might be more effective in the regression of implants and improvement of histologic scores as well as in the precise evaluation of SOD, MDA and VEGF distributions in the rat experimental models.
Similar content being viewed by others
References
Bernardi Lia A, Pavone ME (2013) Endometriosis: an update on management. Women’s Health 9(3):233–250
Taylor HS, Osteen KG, Bruner-Tran KL, Lockwood CJ, Krikun G, Sokalska A, Duleba AJ (2011) Novel therapies targeting endometriosis. Reprod Sci 18(9):814–823
Nap AW, Groothuis PG et al (2004) Pathogenesis of endometriosis. Best Pract Res Clin Obstet Gynaecol 18(2):233–244
Seli E, Arici A (2003) Endometriosis: interaction of immune and endocrine systems. Semin Reprod Med 21(2):135–144
Attar R, Agachan B, Kucukhuseyin O, Toptas B, Attar E, Isbir T (2010) Association of interleukin 1beta gene (+3953) polymorphism and severity of endometriosis in Turkish women. Mol Biol Rep 37(1):369–374
Zhang X, Hei P, Deng L, Lin J (2007) Interleukin-10 gene promoter polymorphisms and their protein production in peritoneal fluid in patients with endometriosis. Mol Hum Reprod 13(2):135–140
Iwabe T, Harada T, Terakawa N (2002) Role of cytokines in endometriosis-associated infertility. Gynecol Obstet Invest 53:19–25
Wu MY, Ho HN (2003) The role of cytokines in endometriosis. Am J Reprod Immunol 49:285–296
Gupta S, Agarwal A, Krajcir N, Alvarez JG (2006) Role of oxidative stress in endometriosis. Reprod Biomed Online 13:126–134
Carvalho LF, Abrão MS, Biscotti C, Sharma R, Nutter B, Falcone T (2013) Oxidative cell injury as a predictor of endometriosis progression. Reprod Sci. 20(6):688–698
Szczepanska M, Kozlik J, Skrzypczak J, Mikolajczyk M (2003) Oxidative stress may be a piece in the endometriosis puzzle. Fertil Steril 79:1288–1293
Polak G, Koziol-Montewka M, Gogacz M, Tarkowski R, Kotarski J (2001) Total antioxidant status of peritoneal fluid in infertile women. Europ J Obstet Gynecol Reprod Biol 94:261–263
Arendt J (1995) Melatonin and the mammalian pineal gland. Chapman & Hall, London
Pevet P, Bothorel B, Slotten H, Saboureau M (2002) The chronobiotic properties of melatonin. Cell Tissue Res 309:183–191
Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, Vesnushkin GM, Vinogradova IA (2006) Melatonin as antioxidant, geroprotector and anticarcinogen. Biochim Biophys Acta 1757(5–6):573–589
Karbownik M, Garcia JJ, Lewinski A, Reiter RJ (2001) Carcinogeninduced, free radical-mediated reduction in microsomal membrane fluidity: reversal by indole-3-propionic acid. J Bioenerg Biomembr 33:73–78
Reiter RJ, Tan DX, Manchester LC, Qi W (2001) Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem Biophys 34:237–256
Qi W, Reiter RJ, Tan DX, Manchester LC, Siu AW, Garcia JJ (2001) Increased level of oxidatively damaged DNA induced by chromium (III) and H2O2: protection by melatonin and related molecules. J Pineal Res 29:54–61
Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R (2002) Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2:181–197
Guerrero JM, Reiter RJ (2002) Melatonin–immune system relationships. Curr Top Med Chem 2:167–179
Esquifino AI, Pandi-Perumal SR, Cardinali DP (2004) Circadian organization of the immune response: a role for melatonin. Clin Appl Immunol Rev 4:423–433
Maestroni GJM, Conti A, Pierpaoli W (1986) Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone. J Neuroimmunol 13:19–30
Maestroni GJM (1998) Is hematopoiesis under the influence of neural and neuroendocrine mechanisms? Histol Histopathol 13:271–274
Tamura H, Nakamura Y, Korkmaz A et al (2009) Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril 92(1):328–343
García-Pergañeda A, Pozo D, Guerrero JM, Calvo JR (1997) Signal transduction for melatonin in human lymphocytes: Involvement of a pertussistoxin sensitive G protein. J Immunol 159:3774–3781
Barjavel MJ, Mamdouh Z, Raghbate N, Bakouche O (1998) Differential expression of the melatonin receptor in human monocytes. J Immunol 160:1191–1197
Srinivasan V, Maestroni GJ, Cardinali DP, Esquifino AI, Perumal SR, Miller SC (2005) Melatonin, immune function and aging. Immun Ageing 2:17
Petrovsky N, Harrison L (1998) The chronobiology of human cytokine production. Int Rev Immunol 16:635–649
Raghavendra V, Singh V, Kulkarni SK, Agrewala JN (2001) Melatonin enhances Th2 cell mediated immune responses: lack of sensitivity to reversal by naltrexone or benzodiazepine receptor antagonists. Mol Cell Biochem 221:57–62
Kang JC, Ahn M, Kim YS, Moon C, Lee Y, Wie MB et al (2001) Melatonin ameliorates autoimmune encephalomyelitis through suppression of intercellular adhesion molecule-1. J Vet Sci 2:85–89
Voznesenskaya T, Makogon N, Bryzgina T, Sukhina V, Grushka N, Alexeyeva I (2007) Melatonin protects against experimental immune ovarian failure in mice. Reprod Biol 7:207–220
Guney M, Oral B, Karahan N, Mungan T (2008) Regression of endometrial explants in a rat model of endometriosis treated with melatonin. Fertil Steril 89:934–942
Yildirim G, Attar R, Ozkan F, Kumbak B, Ficicioglu C, Yesildaglar N (2010) The effects of letrozole and melatonin on surgically induced endometriosis in a rat model: a preliminary study. Fertil Steril 93:1787–1792
Keenan JA, Williams-Boyce PK, Massey PJ, Chen TT, Caudleb MR, Bukovsky A (1999) Regression of endometrial explants in a rat model of endometriosis treated with the immune modulators loxoribine and levamisole. Fertil Steril 72:135–141
Kocadal NC, Attar R, Yıldırım G, Fıçıcıoğlu C, Özkan F, Yılmaz B, Yesildaglar N (2013) Melatonin treatment results in regression of endometriotic lesions in an ooferectomized rat endometriosis model. JTGGA 14(2):81–86
Streuli I, de Ziegler D, Santulli P, Marcellin L, Borghese B, Batteux F, Chapron C (2013) An update on the pharmacological management of endometriosis. Expert Opin Pharmacother 14(3):291–305 (Review)
Hughes E, Fedorkow D, Collins J, Vandekerckhove P (2003) Ovulation suppressionfor endometriosis. Cochrane Database Syst Rev 3:CD000155
Hardeland R, Pandi-Perumal SR, Cardinali DP (2006) Melatonin. Int J Biochem Cell Biol 38:313–316
Schwertner A, Conceicao Dos Santos CC, Costa GD, Deitos A, de Souza A, de Souza IC et al (2013) Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial. Pain 154(6):874–881
Paul S, Sharma AV, Mahapatra PD, Bhattacharya P, Swarnakar S (2008) Role of melatonin in regulating matrix metalloproteinase-9 via tissue inhibitors of metalloproteinase-1 during protection against endometriosis. J Pineal Res 44:439–449
Conflict of interest
We declare that we have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cetinkaya, N., Attar, R., Yildirim, G. et al. The effects of different doses of melatonin treatment on endometrial implants in an oophorectomized rat endometriosis model. Arch Gynecol Obstet 291, 591–598 (2015). https://doi.org/10.1007/s00404-014-3466-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00404-014-3466-3