The role of melatonin as an antioxidant in the follicle

Hiroshi Tamura, Akihisa Takasaki, Toshiaki Taketani, Manabu Tanabe, Fumie Kizuka, Lifa Lee, Isao Tamura, Ryo Maekawa, Hiromi Aasada, Yoshiaki Yamagata, Norihiro Sugino, Hiroshi Tamura, Akihisa Takasaki, Toshiaki Taketani, Manabu Tanabe, Fumie Kizuka, Lifa Lee, Isao Tamura, Ryo Maekawa, Hiromi Aasada, Yoshiaki Yamagata, Norihiro Sugino

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is secreted during the dark hours at night by pineal gland, and it regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It has been believed that melatonin regulates ovarian function by the regulation of gonadotropin release in the hypothalamus-pituitary gland axis via its specific receptors. In addition to the receptor mediated action, the discovery of melatonin as a direct free radical scavenger has greatly broadened the understanding of melatonin's mechanisms which benefit reproductive physiology. Higher concentrations of melatonin have been found in human preovulatory follicular fluid compared to serum, and there is growing evidence of the direct effects of melatonin on ovarian function especially oocyte maturation and embryo development. Many scientists have focused on the direct role of melatonin on oocyte maturation and embryo development as an anti-oxidant to reduce oxidative stress induced by reactive oxygen species, which are produced during ovulation process. The beneficial effects of melatonin administration on oocyte maturation and embryo development have been confirmed by in vitro and in vivo experiments in animals. This review also discusses the first application of melatonin to the clinical treatment of infertile women and confirms that melatonin administration reduces intrafollicular oxidative damage and increase fertilization rates. This review summarizes our recent works and new findings related to the reported beneficial effects of melatonin on reproductive physiology in its role as a reducer of oxidative stress, especially on oocyte maturation and embryo development.

Figures

Figure 1
Figure 1
Changes in intrafollicular concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct (HEL) during ovulation process. Immature (3 wks) rats received a subcutaneous injection of 20 units of pregnant mare serum gonadotropin (PMSG) to stimulate the multiple follicles. 48 hrs after PMSG injection, human chorionic gonadotropin (HCG) injection was performed to induce ovulation. The ovaries were quickly removed 0, 3, 6 and 9 hr after HCG injection and were transferred to the 500 μl of 0.01 M PBS buffer. Follicular fluids were collected by puncturing ovarian follicles with a 26-gauge needle under dissecting microscope and centrifuged at 300 g for 10 min, and the supernatants were collected and stored at -80C until assay. 8-OHdG and HEL concentrations were measured using ELISA kit. Data are shown as the mean ± SEM for 4 rats. *: p < 0.05 versus 0 h, 3 h.
Figure 2
Figure 2
The effect of melatonin on intracellular ROS production. Immature (3 wks) ICR mice were given an injection of 20 units of pregnant mare serum gonadotropin (PMSG) to stimulate the development of multiple follicles. Oocytes were collected by puncturing ovarian follicles after 48 hrs PMSG injection, and then the surrounding cumulus cells were removed. Oocytes were incubated with 1 mM H2O2 for 10 min in the presence of melatonin (0, 1 μg/ml, 100 μg/ml). Intracellular ROS were detected using an intracellular dye (dichlorofuorescin:DCF-DA). The nonfluorescent DCF-DA is oxidized by intracellular ROS to form the highly fluorescent DCF, intracellular ROS formation was visualized by fluorescence image and fluorescence intensity was analyzed using MetaMorph software. (A) H2O2 (1 mM); (B) H2O2 (1 mM)+ melatonin (1 μg/ml); (C) H2O2 (1 mM)+ melatonin (100 μg/ml); (D) Fluorescence intensity in the oocytes. Data are shown as the mean ± SEM for (6-9 oocytes). *: p < 0.05 versus H2O2 (1 mM).
Figure 3
Figure 3
Effect of melatonin treatment on embryo development in patients who underwent IVF-ET program. Nine patients undergoing IVF-ET who failed to become pregnant in the prior IVF-ET cycle were given a 3 mg tablet of melatonin (KAL, Park City, UT, USA) orally at 22:00 hr from the fifth day of the previous menstrual cycle until the day of oocyte retrieval. Embryo quality was assessed according to Veeck criteria at 2 days after insemination, and Veeck I or II embryo was defined as a good embryo. Rate of good embryos was calculated; divide the number of good embryos (VeeckI or II) by the number of oocytes retrieved. Data are shown as the mean ± SEM. *: p < 0.05 versus control cycle.
Figure 4
Figure 4
Schematic representation of the presumed roles of melatonin in ovarian antral follicle. Melatonin, secreted by pineal gland, is taken up into the follicular fluid from the blood. ROS produced within the follicles, especially ovulation process, were scavenged by melatonin, and reduced oxidative stress may be involved in oocyte maturation and embryo development.

References

    1. Brigelius-Flohe R, Banning A, Kny M, Bol GF. Redox events in interleukin-1 signaling. Arch Biochem Biophys. 2004;423(1):66–73. doi: 10.1016/j.abb.2003.12.008.
    1. Forman HJ, Torres M. Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. Am J Respir Crit Care Med. 2002;166(12 Pt 2):S4–8.
    1. Li Q, Sanlioglu S, Li S, Ritchie T, Oberley L, Engelhardt JF. GPx-1 gene delivery modulates NFkappaB activation following diverse environmental injuries through a specific subunit of the IKK complex. Antioxid Redox Signal. 2001;3(3):415–432. doi: 10.1089/15230860152409068.
    1. Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2005;3:28. doi: 10.1186/1477-7827-3-28.
    1. Goud AP, Goud PT, Diamond MP, Gonik B, Abu-Soud HM. Reactive oxygen species and oocyte aging: role of superoxide, hydrogen peroxide, and hypochlorous acid. Free Radic Biol Med. 2008;44(7):1295–1304. doi: 10.1016/j.freeradbiomed.2007.11.014.
    1. Yang HW, Hwang KJ, Kwon HC, Kim HS, Choi KW, Oh KS. Detection of reactive oxygen species (ROS) and apoptosis in human fragmented embryos. Hum Reprod. 1998;13(4):998–1002. doi: 10.1093/humrep/13.4.998.
    1. Gillette MU, Tischkau SA. Suprachiasmatic nucleus: the brain's circadian clock. Recent Prog Horm Res. 1999;54:33–58; discussion 58-39.
    1. Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev. 1991;12(2):151–180. doi: 10.1210/edrv-12-2-151.
    1. Cardinali DP, Pevet P. Basic aspects of melatonin action. Sleep Med Rev. 1998;2(3):175–190. doi: 10.1016/S1087-0792(98)90020-X.
    1. Reiter RJ, Tan DX, Korkmaz A. The circadian melatonin rhythm and its modulation: possible impact on hypertension. J Hypertens Suppl. 2009;27(6):S17–20. doi: 10.1097/.
    1. Srinivasan V, Maestroni GJ, Cardinali DP, Esquifino AI, Perumal SR, Miller SC. Melatonin, immune function and aging. Immun Ageing. 2005;2:17. doi: 10.1186/1742-4933-2-17.
    1. Korkmaz A, Tamura H, Manchester LC, Ogden GB, Tan DX, Reiter RJ. Combination of melatonin and a peroxisome proliferator-activated receptor-gamma agonist induces apoptosis in a breast cancer cell line. J Pineal Res. 2009;46(1):115–116. doi: 10.1111/j.1600-079X.2008.00635.x.
    1. Tamura H, Nakamura Y, Narimatsu A, Yamagata Y, Takasaki A, Reiter RJ, Sugino N. Melatonin treatment in peri- and postmenopausal women elevates serum high-density lipoprotein cholesterol levels without influencing total cholesterol levels. J Pineal Res. 2008;45(1):101–105. doi: 10.1111/j.1600-079X.2008.00561.x.
    1. Takayama H, Nakamura Y, Tamura H, Yamagata Y, Harada A, Nakata M, Sugino N, Kato H. Pineal gland (melatonin) affects the parturition time, but not luteal function and fetal growth, in pregnant rats. Endocr J. 2003;50(1):37–43. doi: 10.1507/endocrj.50.37.
    1. Tamura H, Nakamura Y, Terron MP, Flores LJ, Manchester LC, Tan DX, Sugino N, Reiter RJ. Melatonin and pregnancy in the human. Reprod Toxicol. 2008;25(3):291–303. doi: 10.1016/j.reprotox.2008.03.005.
    1. Tamura H, Takayama H, Nakamura Y, Reiter RJ, Sugino N. Fetal/placental regulation of maternal melatonin in rats. J Pineal Res. 2008;44(3):335–340. doi: 10.1111/j.1600-079X.2007.00537.x.
    1. Tamura H, Nakamura Y, Takiguchi S, Kashida S, Yamagata Y, Sugino N, Kato H. Pinealectomy of melatonin implantation does not affect prolactin surge or luteal function in pseudopregnant rats. Endocr J. 1998;45(3):377–383. doi: 10.1507/endocrj.45.377.
    1. Brzezinski A, Seibel MM, Lynch HJ, Deng MH, Wurtman RJ. Melatonin in human preovulatory follicular fluid. J Clin Endocrinol Metab. 1987;64(4):865–867. doi: 10.1210/jcem-64-4-865.
    1. Ronnberg L, Kauppila A, Leppaluoto J, Martikainen H, Vakkuri O. Circadian and seasonal variation in human preovulatory follicular fluid melatonin concentration. J Clin Endocrinol Metab. 1990;71(2):492–496.
    1. 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):1012–1016. doi: 10.1016/S0015-0282(03)01008-2.
    1. Brannstrom M, Norman RJ. Involvement of leukocytes and cytokines in the ovulatory process and corpus luteum function. Hum Reprod. 1993;8(10):1762–1775.
    1. Nakamura Y, Smith M, Krishna A, Terranova PF. Increased number of mast cells in the dominant follicle of the cow: relationships among luteal, stromal, and hilar regions. Biol Reprod. 1987;37(3):546–549. doi: 10.1095/biolreprod37.3.546.
    1. Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82(1):47–95.
    1. Hensley K, Robinson KA, Gabbita SP, Salsman S, Floyd RA. Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med. 2000;28(10):1456–1462. doi: 10.1016/S0891-5849(00)00252-5.
    1. Fatehi AN, Roelen BA, Colenbrander B, Schoevers EJ, Gadella BM, Beverst MM, van den Hurk R. Presence of cumulus cells during in vitro fertilization protects the bovine oocyte against oxidative stress and improves first cleavage but does not affect further development. Zygote. 2005;13(2):177–185. doi: 10.1017/S0967199405003126.
    1. Tatemoto H, Muto N, Sunagawa I, Shinjo A, Nakada T. Protection of porcine oocytes against cell damage caused by oxidative stress during in vitro maturation: role of superoxide dismutase activity in porcine follicular fluid. Biol Reprod. 2004;71(4):1150–1157. doi: 10.1095/biolreprod.104.029264.
    1. Zuelke KA, Jones DP, Perreault SD. Glutathione oxidation is associated with altered microtubule function and disrupted fertilization in mature hamster oocytes. Biol Reprod. 1997;57(6):1413–1419. doi: 10.1095/biolreprod57.6.1413.
    1. Guerin P, El Mouatassim S, Menezo Y. Oxidative stress and protection against reactive oxygen species in the pre-implantation embryo and its surroundings. Hum Reprod Update. 2001;7(2):175–189. doi: 10.1093/humupd/7.2.175.
    1. Kowaltowski AJ, Vercesi AE. Mitochondrial damage induced by conditions of oxidative stress. Free Radic Biol Med. 1999;26(3-4):463–471. doi: 10.1016/S0891-5849(98)00216-0.
    1. Noda Y, Matsumoto H, Umaoka Y, Tatsumi K, Kishi J, Mori T. Involvement of superoxide radicals in the mouse two-cell block. Mol Reprod Dev. 1991;28(4):356–360. doi: 10.1002/mrd.1080280408.
    1. Chao HT, Lee SY, Lee HM, Liao TL, Wei YH, Kao SH. Repeated ovarian stimulations induce oxidative damage and mitochondrial DNA mutations in mouse ovaries. Ann N Y Acad Sci. 2005;1042:148–156. doi: 10.1196/annals.1338.016.
    1. Al-Gubory KH, Bolifraud P, Germain G, Nicole A, Ceballos-Picot I. Antioxidant enzymatic defence systems in sheep corpus luteum throughout pregnancy. Reproduction. 2004;128(6):767–774. doi: 10.1530/rep.1.00389.
    1. Paszkowski T, Traub AI, Robinson SY, McMaster D. Selenium dependent glutathione peroxidase activity in human follicular fluid. Clin Chim Acta. 1995;236(2):173–180. doi: 10.1016/0009-8981(95)98130-9.
    1. Tarin JJ, Perez-Albala S, Cano A. Oral antioxidants counteract the negative effects of female aging on oocyte quantity and quality in the mouse. Mol Reprod Dev. 2002;61(3):385–397. doi: 10.1002/mrd.10041.
    1. Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC. Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis. J Pineal Res. 1993;14(4):151–168. doi: 10.1111/j.1600-079X.1993.tb00498.x.
    1. Schindler AE, Christensen B, Henkel A, Oettel M, Moore C. High-dose pilot study with the novel progestogen dienogestin patients with endometriosis. Gynecol Endocrinol. 2006;22(1):9–17. doi: 10.1080/09513590500431482.
    1. Reiter RJ, Tan DX, Manchester LC, Qi W. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem Biophys. 2001;34(2):237–256. doi: 10.1385/CBB:34:2:237.
    1. Tan DX, Manchester LC, Reiter RJ, Plummer BF, Limson J, Weintraub ST, Qi W. Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation. Free Radic Biol Med. 2000;29(11):1177–1185. doi: 10.1016/S0891-5849(00)00435-4.
    1. Peyrot F, Ducrocq C. Potential role of tryptophan derivatives in stress responses characterized by the generation of reactive oxygen and nitrogen species. J Pineal Res. 2008;45(3):235–246. doi: 10.1111/j.1600-079X.2008.00580.x.
    1. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res. 2007;42(1):28–42. doi: 10.1111/j.1600-079X.2006.00407.x.
    1. Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine. 2005;27(2):119–130. doi: 10.1385/ENDO:27:2:119.
    1. Allegra M, Reiter RJ, Tan DX, Gentile C, Tesoriere L, Livrea MA. The chemistry of melatonin's interaction with reactive species. J Pineal Res. 2003;34(1):1–10. doi: 10.1034/j.1600-079X.2003.02112.x.
    1. Reiter RJ, Tan DX, Gitto E, Sainz RM, Mayo JC, Leon J, Manchester LC, Vijayalaxmi, Kilic E, Kilic U. Pharmacological utility of melatonin in reducing oxidative cellular and molecular damage. Pol J Pharmacol. 2004;56(2):159–170.
    1. Tan DX, Manchester LC, Sainz RM, Mayo JC, Leon J, Hardeland R, Poeggeler B, Reiter RJ. Interactions between melatonin and nicotinamide nucleotide: NADH preservation in cells and in cell-free systems by melatonin. J Pineal Res. 2005;39(2):185–194. doi: 10.1111/j.1600-079X.2005.00234.x.
    1. Silva SO, Rodrigues MR, Carvalho SR, Catalani LH, Campa A, Ximenes VF. Oxidation of melatonin and its catabolites, N1-acetyl-N2 -formyl-5-methoxykynuramine and N1-acetyl-5-methoxykynuramine, by activated leukocytes. J Pineal Res. 2004;37(3):171–175. doi: 10.1111/j.1600-079X.2004.00149.x.
    1. Manda K, Ueno M, Anzai K. AFMK, a melatonin metabolite, attenuates X-ray-induced oxidative damage to DNA, proteins and lipids in mice. J Pineal Res. 2007;42(4):386–393. doi: 10.1111/j.1600-079X.2007.00432.x.
    1. Rosen J, Than NN, Koch D, Poeggeler B, Laatsch H, Hardeland R. Interactions of melatonin and its metabolites with the ABTS cation radical: extension of the radical scavenger cascade and formation of a novel class of oxidation products, C2-substituted 3-indolinones. J Pineal Res. 2006;41(4):374–381. doi: 10.1111/j.1600-079X.2006.00379.x.
    1. Mayo JC, Sainz RM, Antoli I, Herrera F, Martin V, Rodriguez C. Melatonin regulation of antioxidant enzyme gene expression. Cell Mol Life Sci. 2002;59(10):1706–1713. doi: 10.1007/PL00012498.
    1. Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Reiter RJ. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res. 2004;36(1):1–9. doi: 10.1046/j.1600-079X.2003.00092.x.
    1. Chen LJ, Gao YQ, Li XJ, Shen DH, Sun FY. Melatonin protects against MPTP/MPP+ -induced mitochondrial DNA oxidative damage in vivo and in vitro. J Pineal Res. 2005;39(1):34–42. doi: 10.1111/j.1600-079X.2005.00209.x.
    1. Melchiorri D, Reiter RJ, Sewerynek E, Chen LD, Nistico G. Melatonin reduces kainate-induced lipid peroxidation in homogenates of different brain regions. FASEB J. 1995;9(12):1205–1210.
    1. Ortega-Gutierrez S, Fuentes-Broto L, Garcia JJ, Lopez-Vicente M, Martinez-Ballarin E, Miana-Mena FJ, Millan-Plano S, Reiter RJ. Melatonin reduces protein and lipid oxidative damage induced by homocysteine in rat brain homogenates. J Cell Biochem. 2007;102(3):729–735. doi: 10.1002/jcb.21327.
    1. Tan DX, Manchester LC, Reiter RJ, Cabrera J, Burkhardt S, Phillip T, Gitto E, Karbownik M, Li QD. Melatonin suppresses autoxidation and hydrogen peroxide-induced lipid peroxidation in monkey brain homogenate. Neuro Endocrinol Lett. 2000;21(5):361–365.
    1. Yamamoto HA, Mohanan PV. Melatonin attenuates brain mitochondria DNA damage induced by potassium cyanide in vivo and in vitro. Toxicology. 2002;179(1-2):29–36. doi: 10.1016/S0300-483X(02)00244-5.
    1. Wurtman RJ, Axelrod J, Potter LT. The uptake of h3-melatonin in endocrine and nervous tissues and the effects of constant light exposure. J Pharmacol Exp Ther. 1964;143:314–318.
    1. Tamura H, Nakamura Y, Takiguchi S, Kashida S, Yamagata Y, Sugino N, Kato H. Melatonin directly suppresses steroid production by preovulatory follicles in the cyclic hamster. J Pineal Res. 1998;25(3):135–141. doi: 10.1111/j.1600-079X.1998.tb00551.x.
    1. Tamura H, Takasaki A, Miwa I, Taniguchi K, Maekawa R, Asada H, Taketani T, Matsuoka A, Yamagata Y, Shimamura K. et al.Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res. 2008;44(3):280–287. doi: 10.1111/j.1600-079X.2007.00524.x.
    1. Jahnke G, Marr M, Myers C, Wilson R, Travlos G, Price C. Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicol Sci. 1999;50(2):271–279. doi: 10.1093/toxsci/50.2.271.
    1. Ishizuka B, Kuribayashi Y, Murai K, Amemiya A, Itoh MT. The effect of melatonin on in vitro fertilization and embryo development in mice. J Pineal Res. 2000;28(1):48–51. doi: 10.1034/j.1600-079x.2000.280107.x.
    1. Rodriguez-Osorio N, Kim IJ, Wang H, Kaya A, Memili E. Melatonin increases cleavage rate of porcine preimplantation embryos in vitro. J Pineal Res. 2007;43(3):283–288. doi: 10.1111/j.1600-079X.2007.00475.x.
    1. Shi JM, Tian XZ, Zhou GB, Wang L, Gao C, Zhu SE, Zeng SM, Tian JH, Liu GS. Melatonin exists in porcine follicular fluid and improves in vitro maturation and parthenogenetic development of porcine oocytes. J Pineal Res. 2009;47(4):318–323. doi: 10.1111/j.1600-079X.2009.00717.x.
    1. Papis K, Poleszczuk O, Wenta-Muchalska E, Modlinski JA. Melatonin effect on bovine embryo development in vitro in relation to oxygen concentration. J Pineal Res. 2007;43(4):321–326. doi: 10.1111/j.1600-079X.2007.00479.x.
    1. Reiter RJ, Tan DX, Manchester LC, Paredes SD, Mayo JC, Sainz RM. Melatonin and reproduction revisited. Biol Reprod. 2009;81(3):445–456. doi: 10.1095/biolreprod.108.075655.
    1. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ. 2006;332(7538):385–393. doi: 10.1136/bmj.38731.532766.F6.
    1. Carr R, Wasdell MB, Hamilton D, Weiss MD, Freeman RD, Tai J, Rietveld WJ, Jan JE. Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm sleep disorders. J Pineal Res. 2007;43(4):351–359. doi: 10.1111/j.1600-079X.2007.00485.x.
    1. Chan WY, Ng TB. Development of pre-implantation mouse embryos under the influence of pineal indoles. J Neural Transm Gen Sect. 1994;96(1):19–29. doi: 10.1007/BF01277925.
    1. McElhinny AS, Davis FC, Warner CM. The effect of melatonin on cleavage rate of C57BL/6 and CBA/Ca preimplantation embryos cultured in vitro. J Pineal Res. 1996;21(1):44–48. doi: 10.1111/j.1600-079X.1996.tb00269.x.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다