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Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2011

Open Access 01-12-2011 | Research

Melatonin reduces LH, 17 beta-estradiol and induces differential regulation of sex steroid receptors in reproductive tissues during rat ovulation

Authors: Luiz Gustavo A Chuffa, Fábio RF Seiva, Wagner José Fávaro, Giovana R Teixeira, João PA Amorim, Leonardo O Mendes, Beatriz A Fioruci, Patrícia Fernanda F Pinheiro, Ana Angélica H Fernandes, Janete AA Franci, Flávia K Delella, Marcelo Martinez, Francisco E Martinez

Published in: Reproductive Biology and Endocrinology | Issue 1/2011

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Abstract

Background

Melatonin is associated with direct or indirect actions upon female reproductive function. However, its effects on sex hormones and steroid receptors during ovulation are not clearly defined. This study aimed to verify whether exposure to long-term melatonin is able to cause reproductive hormonal disturbances as well as their role on sex steroid receptors in the rat ovary, oviduct and uterus during ovulation.

Methods

Twenty-four adult Wistar rats, 60 days old (+/- 250 g) were randomly divided into two groups. Control group (Co): received 0.9% NaCl 0.3 mL + 95% ethanol 0.04 mL as vehicle; Melatonin-treated group (MEL): received vehicle + melatonin [100 μg/100 g BW/day] both intraperitoneally during 60 days. All animals were euthanized by decapitation during the morning estrus at 4 a.m.

Results

Melatonin significantly reduced the plasma levels of LH and 17 beta-estradiol, while urinary 6-sulfatoximelatonin (STM) was increased at the morning estrus. In addition, melatonin promoted differential regulation of the estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and melatonin receptor (MTR) along the reproductive tissues. In ovary, melatonin induced a down-regulation of ER-alpha and PRB levels. Conversely, it was observed that PRA and MT1R were up-regulated. In oviduct, AR and ER-alpha levels were down-regulated, in contrast to high expression of both PRA and PRB. Finally, the ER-beta and PRB levels were down-regulated in uterus tissue and only MT1R was up-regulated.

Conclusions

We suggest that melatonin partially suppress the hypothalamus-pituitary-ovarian axis, in addition, it induces differential regulation of sex steroid receptors in the ovary, oviduct and uterus during ovulation.
Appendix
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Literature
1.
Masana MI, Dubocovich ML: Melatonin receptor signaling: finding the path through the dark. Sci STKE. 2001, 107: pe39-
2.
Malpaux B, Migaud M, Tricoire H, Chemineau P: Biology of mammalian photoperiodism and the critical role of the pineal gland and melatonin. J Biol Rhythms. 2001, 16: 336-347. 10.1177/074873001129002051.CrossRefPubMed
3.
Glass JD, Knotts LK: A brain site for the antigonadal action of melatonin in the white-footed mouse (Peromyscus leucopus): involvement of the immunoreactive GnRH neuronal system. Neuroendocrinology. 1987, 46: 48-55. 10.1159/000124795.CrossRefPubMed
4.
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: 492-496.PubMed
5.
Tamura H, Nakamura Y, Korkmaz A, Manchester LC, Tan DX, Sugino N, Reiter RJ: Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2009, 92: 328-343. 10.1016/j.fertnstert.2008.05.016.CrossRefPubMed
6.
Dardes RC, Baracat EC, Simões MJ: Modulation of estrous cycle and LH, FSH and melatonin levels by pinealectomy and sham-pinealectomy in female rats. Prog Neuropsychopharmacol Biol Psychiatry. 2000, 24: 441-453. 10.1016/S0278-5846(99)00110-4.CrossRefPubMed
7.
Soares JM, Simões MJ, Oshima CT, Mora OA, De Lima GR, Baracat EC: Pinealectomy changes rat ovarian interstitial cell morphology and decreases progesterone receptor expression. Gynecol Endocrinol. 2003, 17: 115-123.CrossRefPubMed
8.
Okatani Y, Morioka N, Hayashi K: Changes in nocturnal pineal melatonin synthesis during the premenopausal period: relation to estrogen levels in female rats. J Pineal Res. 1999, 27: 65-72. 10.1111/j.1600-079X.1999.tb00598.x.CrossRefPubMed
9.
Chuffa LG, Amorim JP, Teixeira GR, Mendes LO, Fioruci BA, Pinheiro PF, Seiva FR, Novelli EL, Mello Júnior W, Martinez M, Martinez FE: Long-term melatonin treatment reduces ovarian mass and enhances tissue antioxidant defenses during ovulation in the rat. Braz J Med Biol Res. 2011, 44: 217-223. 10.1590/S0100-879X2011007500018.CrossRefPubMed
10.
Kachi T, Tanaka D, Watanabe S, Suzuki R, Tonosaki Y, Fujieda H: Physiological pineal effects on female reproductive function of laboratory rats: prenatal development of pups, litter size and estrous cycle in middle age. Chronobiol Int. 2006, 23: 289-300. 10.1080/07420520600588713.CrossRefPubMed
11.
Diaz E, Pazo D, Esquifino AI, Diaz B: Effects of ageing and exogenous melatonin on pituitary responsiveness to GnRH in rats. J Reprod Fertil. 2000, 119: 151-156.CrossRefPubMed
12.
Díaz E, Fernández C, Castrillón PO, Esquifino AI, Marín B, Díaz López B: Effect of exogenous melatonin on neuroendocrine-reproductive function of middle-aged female rats. J Reprod Fertil. 1999, 117: 331-337. 10.1530/jrf.0.1170331.CrossRefPubMed
13.
Abd-Allah AR, El-Sayed EM, Abdel-Wahab MH, Hamada FM: Effect of melatonin on estrogen and progesterone receptors in relation to uterine contraction in rats. Pharmacol Res. 2003, 47: 349-354. 10.1016/S1043-6618(03)00014-8.CrossRefPubMed
14.
Rato AG, Pedrero JG, Martinez MA, Del Rio B, Lazo PS, Ramos S: Melatonin blocks the activation of estrogen receptor for DNA binding. FASEB J. 1999, 13: 857-868.PubMed
15.
Romeu LRG, Motta ELA, Maganhin CC, Oshima CTF, Fonseca MC, Barrueco KF, Simões RS, Pellegrino R, Baracat EC, Soares-Junior JM: Effects of melatonin on histomorphology and on the expression of steroid receptors, VEGF, and PCNA in ovaries of pinealectomized female rats. Fertil Steril. 2011, 95: 1379-1384. 10.1016/j.fertnstert.2010.04.042.CrossRefPubMed
16.
Horne AW, King AE, Shaw E, McDonald SE, Williams AR, Saunders PT, Critchley HO: Attenuated sex steroid receptor expression in fallopian tube of women with ectopic pregnancy. J Clin Endocrinol Metab. 2009, 94: 5146-5154. 10.1210/jc.2009-1476.PubMedCentralCrossRefPubMed
17.
Mulac-Jericevic B, Lydon JP, DeMayo FJ, Conneely OM: Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci. 2003, 100: 9744-9749. 10.1073/pnas.1732707100.PubMedCentralCrossRefPubMed
18.
Kuiper GGJM, Enmark E, Pelto Huikko M, Nilsson S, Gustafsson JA: Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci. 1996, 93: 5925-5930. 10.1073/pnas.93.12.5925.PubMedCentralCrossRefPubMed
19.
Okada A, Sato T, Ohta Y, Iguchi T: Sex steroid hormone receptors in the developing female reproductive tract of laboratory rodents. J Toxicol Sci. 2005, 30: 75-89. 10.2131/jts.30.75.CrossRefPubMed
20.
Bardin A, Hoffmann P, Boulle N, Katsaros D, Vignon F, Pujol P, Lazennec G: Involvement of estrogen receptor beta in ovarian carcinogenesis. Cancer Res. 2004, 64: 5861-5869. 10.1158/0008-5472.CAN-04-0552.CrossRefPubMed
21.
Kraus WL, Montano MM, Katzenellenbogen BS: Identification of multiple, widely spaced estrogen-responsive regions in the rat progesterone receptor gene. Mol Endocrinol. 1994, 8: 952-969. 10.1210/me.8.8.952.PubMed
22.
Schneider W, Ramachandran C, Satyaswaroop PG, Shyamala G: Murine progesterone receptor exists predominantly as the 83-kDa A form. J Steroid Biochem Mol Biol. 1991, 38: 285-291. 10.1016/0960-0760(91)90099-Q.CrossRefPubMed
23.
Syvala H, Vienonen A, Ylikomi T, Blauer M, Zhuang Y, Tuohimaa P: Expression of the chicken progesterone receptor forms A and B is differentially regulated by estrogen in vivo. Biochem Biophys Res Commun. 1997, 231: 573-576. 10.1006/bbrc.1997.6149.CrossRefPubMed
24.
Benitez-King G: Melatonin as a cytoskeletal modulator: implications for cell physiology and disease. J Pineal Res. 2006, 40: 1-9. 10.1111/j.1600-079X.2005.00282.x.CrossRefPubMed
25.
Olsen NJ, Kovacs WJ: Gonadal steroids and immunity. Endocr Rev. 1996, 17: 369-384.PubMed
26.
Molis TM, Spriggs LL, Hill SM: Modulation of estrogen receptor mRNA expression by melatonin in MCF-7 human breast cancer cells. Mol Endocrinol. 1994, 8: 1681-1690. 10.1210/me.8.12.1681.PubMed
27.
Revel FG, Ansel L, Klosen P, Saboureau M, Pevet P, Mikkelsen JD, Simonneaux V: Kisspeptin: a key link to seasonal breeding. Rev Endocr Metab Disord. 2007, 8: 57-65. 10.1007/s11154-007-9031-7.CrossRefPubMed
28.
Malpaux B, Thiéry JC, Chemineau P: Melatonin and the seasonal control of reproduction. Reprod Nutr Dev. 1999, 39: 355-366. 10.1051/rnd:19990308.CrossRefPubMed
29.
Revel FG, Saboureau M, Masson-Pevet M, Pevet P, Mikkelsen JD, Simonneaux V: Kisspeptin mediates the photoperiodic control of reproduction in hamsters. Curr Biol. 2006, 16: 1730-1735. 10.1016/j.cub.2006.07.025.CrossRefPubMed
30.
Chiba A, Akema T, Toyoda J: Effects of pinealectomy and melatonin on the timing of the proestrous luteinizing hormone surge in the rat. Neuroendocrinology. 1994, 59: 163-168. 10.1159/000126654.CrossRefPubMed
31.
Reiter RJ, Johnson LY, Vanghan MK, Richardson BA, Petterborg LJ: Variation in pineal melatonin content during the estrous cycle of the rat. Proc Soc Exp Biol Med. 1982, 169: 416-419.CrossRefPubMed
32.
Brzezinski A, Seibel MM, Lynch HJ, Deng MH, Wurtman RJ: Melatonin in human preovulatory follicular fluid. J Clin Endocrinol Metab. 1987, 64: 865-867. 10.1210/jcem-64-4-865.CrossRefPubMed
33.
Macchi MM, Bruce JN: Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol. 2004, 25: 177-195. 10.1016/j.yfrne.2004.08.001.CrossRefPubMed
34.
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: 135-141. 10.1111/j.1600-079X.1998.tb00551.x.CrossRefPubMed
35.
Martínez-Campa CM, González A, Mediavilla MD, Alonso-González C, Sánchez-Barceló EJ, Cos S: Melatonin enhances the inhibitory effect of aminoglutethimide on aromatase activity in MCF-7 human breast cancer cells. Breast Cancer Res Treat. 2005, 94: 249-254. 10.1007/s10549-005-9006-x.CrossRefPubMed
36.
Graham C, Cook MR, Kavet R, Sastre A, Smith DK: Prediction of nocturnal plasma melatonin from morning urinary measures. J Pineal Res. 1998, 24: 230-238. 10.1111/j.1600-079X.1998.tb00538.x.CrossRefPubMed
37.
Wurtman RJ, Axelrod J, Chu EW: Melatonin, a pineal substance: effect on the rat ovary. Science. 1963, 141: 277-278. 10.1126/science.141.3577.277.CrossRefPubMed
38.
Chuffa LG, Amorim JP, Teixeira GR, Mendes LO, Fioruci BA, Pinheiro PF, Seiva FR, Novelli EL, de Mello Júnior W, Martinez M, Almeida-Francia CC, Martinez FE: Long-term exogenous melatonin treatment modulates overall feed efficiency and protects ovarian tissue against injuries caused by ethanol-induced oxidative stress in adult UChB rats. Alcohol Clin Exp Res. 2011, 35: 1498-1508.PubMed
39.
Adriaens I, Jacquet P, Cortvrindt R, Janssen K, Smitz J: Melatonin has dose-dependent effects on folliculogenesis, oocyte maturation capacity and steroidogenesis. Toxicology. 2006, 228: 333-343. 10.1016/j.tox.2006.09.018.CrossRefPubMed
40.
Brzezinski A, Fibich T, Cohen M, Schenker JG, Laufer N: Effects of melatonin on progesterone production by human granulosa lutein cells in culture. Fertil Steril. 1992, 58: 526-529.PubMed
41.
Aronika SM, Kraus WL, Katzenellenbogen BS: Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci. 1994, 91: 8517-8521. 10.1073/pnas.91.18.8517.CrossRef
42.
Godson C, Reppert SM: The mel1a melatonin receptor is coupled to parallel signal transduction pathways. Endocrinology. 1997, 138: 397-404. 10.1210/en.138.1.397.PubMed
43.
Chalbos D, Galtier F: Differential effect of forms A and B of human progesterone receptor on estradiol-dependent transcription. J Biol Chem. 1994, 269: 23007-23012.PubMed
44.
Vegeto E, Shahbaz MM, Wen DX, Goldman ME, O'Malley BW, McDonnell DP: Human progesterone receptor A form is a celland promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol. 1993, 7: 1244-1255. 10.1210/me.7.10.1244.PubMed
45.
Okatani Y, Watanabe K, Morioka N, Hayashi K, Sagara Y: Nocturnal change in pineal melatonin synthesis during puberty: relation to estrogen and progesterone levels in female rats. J Pineal Res. 1997, 22: 33-41. 10.1111/j.1600-079X.1997.tb00300.x.CrossRefPubMed
46.
Moujir F, Bordon R, Santana C, Abreu P, Hernandez G, Alonso R: Ovarian steroids block the isoproterenol-induced elevation of pineal melatonin production in the female rat. Neurosci Lett. 1990, 119: 12-14. 10.1016/0304-3940(90)90743-S.CrossRefPubMed
47.
Giangrande PH, Pollio G, McDonnell DP: Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. J Biol Chem. 1997, 272: 32889-32900. 10.1074/jbc.272.52.32889.CrossRefPubMed
48.
Mulac-Jericevic B, Conneely OM: Reproductive tissue selective actions of progesterone receptors. Reproduction. 2004, 128: 139-146. 10.1530/rep.1.00189.CrossRefPubMed
49.
Cos S, González A, Martínez-Campa C, Mediavilla MD, Alonso-González C, Sánchez-Barceló EJ: Estrogen-signaling pathway: a link between breast cancer and melatonin oncostatic actions. Cancer Detect Prev. 2006, 30: 118-128. 10.1016/j.cdp.2006.03.002.CrossRefPubMed
50.
Li W, Boomsma RA, Verhage HG: Immunocytochemical analysis of estrogen and progestin receptors in uteri of steroid-treated and pregnant cats. Biol Reprod. 1992, 47: 1073-1081. 10.1095/biolreprod47.6.1073.CrossRefPubMed
51.
Zhao H, Pang SF, Poon AMS: Variations of mt1 melatonin receptor density in the rat uterus during decidualization, the estrous cycle and in response to exogenous steroid treatment. J Pineal Res. 2002, 33: 140-145. 10.1034/j.1600-079X.2002.02898.x.CrossRefPubMed
52.
Tibbetts TA, Mendoza-Meneses M, O'Malley BW, Conneely OM: Mutual and intercompartmental regulation of estrogen receptor and progesterone receptor expression in the mouse uterus. Biol Reprod. 1998, 59: 1143-1152. 10.1095/biolreprod59.5.1143.CrossRefPubMed
53.
Kuiper GJM, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA: Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology. 1997, 138: 863-870. 10.1210/en.138.3.863.PubMed
54.
Clemens JW, Jarzynka MJ, Witt-Enderby PA: Down-regulation of mt1 melatonin receptors in rat ovary following estrogen exposure. Life Sci. 2001, 69: 27-35. 10.1016/S0024-3205(01)01097-9.CrossRefPubMed
Metadata
Title
Melatonin reduces LH, 17 beta-estradiol and induces differential regulation of sex steroid receptors in reproductive tissues during rat ovulation
Authors
Luiz Gustavo A Chuffa
Fábio RF Seiva
Wagner José Fávaro
Giovana R Teixeira
João PA Amorim
Leonardo O Mendes
Beatriz A Fioruci
Patrícia Fernanda F Pinheiro
Ana Angélica H Fernandes
Janete AA Franci
Flávia K Delella
Marcelo Martinez
Francisco E Martinez
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2011
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/1477-7827-9-108

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