Associative administration of cimetidine and exogenous melatonin on the endometrial receptors of estrogen, collagen and hormone levels in adult rats

Autores

  • Sandra Maria Souza da Silva UFPE
  • Laíse de Souza Elias Federal Rural University of Pernambuco
  • Romildo Luciano da Silva UFPE
  • Paloma Lys de Medeiros UFPE
  • Jeymesson Raphael Cardoso Vieira UFPE
  • Álvaro Aguiar Coelho Teixeira Federal Rural University of Pernambuco
  • Valéria Wanderley-Teixeira Federal Rural University of Pernambuco

DOI:

https://doi.org/10.29215/pecen.v4i0.1597

Resumo

Cloridrato de cimetidina, um bloqueador de receptores H2 das células parietais gástricas, que age reduzindo a secreção de ácido no estômago e tem sido estudado como substância xenoestrogênica. O uso crônico da cimetidina produz distúrbios homonais e toxidade no aparelho reprodutor masculino, além de reduzir o estradiol 2-hidroxilado e aumentar níveis séricos de estradiol e prolactina em mulheres, levando a hiperprolactinemia, que pode ser fator de risco para o câncer. A melatonina, neurohormônio sintetizado pela glândula pineal tem importante papel na função reprodutiva, regulando a produção de estrógeno, progesterrona e prolactina. O estudo testou a hipótese de que a melatonina pode bloquear ou reduzir os efeitos estrogênicos da cimetidina no estroma uterino, interferindo nos receptores de estrógeno, no teor de fibras colágenas e nos níveis hormonais em ratas adultas. Quarenta e cinco (45) ratas albinas divididas em três grupos: I – tratadas com placebo (controle); II – tratado com cimetidina (50 mg/kg) e III – tratado com cimetidina (50 mg/kg) associada à melatonina (200 μg/100 g). Os experimentos foram conduzidos por 7, 14 e 19 dias. Nos grupos tratados apenas com cimetidina, observou-se marcações mais intensas dos receptores REα, maior distribuição das fibras colágenas no endométrio, elevação dos níveis séricos de estrogênio, prolactina e redução da progesterona, nos animais tratados por 19 dias. Na associação cimetidina e melatonina, acredita-se que a melatonina bloqueou esses efeitos. A melatonina tem atividade citoprotetora para efeitos crônicos da cimetidina no estroma endometrial, por reduzir ou prevenir o aumento da síntese de fibras de colágeno pelos fibroblastos regulando a atividade do estrogênio sérico, bem como a expressão de seus receptores endometriais, além de manter os níveis normais de progesterona e prolactina.

Palavras chave: Melatonina, receptor de estrógeno, xenoestrógeno, morfometria, níveis hormonais.

Referências

Adriaens I., Jacquet P., Cortvrindt R., Janssen K. & Smitz J. (2006) Melatonin has dose-dependent effects on folliculogenesis, oocyte maturation capacity and steroidogenesis. Toxicology, 228: 333–343. I: http://dx.doi.org/10.1016/j.tox.2006.09.018

Akingbemi B.T., Sottas C.M., Koulova A.I., Klinefelter G.R. & Hardy M.P. (2004) The inhibition of testicular steroidogenesis by the xenoestrogen bisphenol A is associated with reduced pituitary luteinizing hormone secretion and decreased steroidogenic enzyme gene expression in rat Leydig cells. Endocrinology, 145(2): 592–603. http://dx.doi.org/10.1210/en.2003-1174

Bredfeldt T.G., Greathouse K.L., Safe S.H., Hung M.C., Bedford M.T. & Walker C.L. (2010) Xenoestrogen-induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Molecular Endocrinology, 24(5): 993–1006. https://doi.org/10.1210/me.2009-0438

Bromer J.G., Zhou Y., Taylor M.B., Doherty L. & Taylor H.S. (2010) Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. Federation of American Societies for Experimental Biology, 24: 2273–2280. https://doi.org/10.1096/fj.09-140533

Christin-Maître S., Delemer B., Touraine P. & Young J. (2007) Prolactinoma and estrogens: pregnancy, contraception and hormonal replacement therapy. Annales d'Endocrinologie, 68: 106–112. https://doi.org/10.1016/j.ando.2007.03.008

Close F.T. & Freeman M.E. (1997) Effects of ovarian steroid hormones on dopamine-controlled prolactin secretory responses in vitro. Neuroendocrinology, 65: 430–435. https://doi.org/10.1159/000127206

Cotton R.B., Shah L.P., Stanley D.P., Ehinger N.J., Brown N., Shelton E.L., Slaughter J.C., Baldwin H.S., Paria B.C. & Reese J. (2013) Cimetidine–associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonism. Journal of Molecular and Cellular Cardiology, 59: 86–94. https://doi.org/10.1016/j.yjmcc.2013.02.010

Dair E.L., Simões R.S., Simões M.J., Romeu L.R.G., Oliveira-Filho R.M. & Haidar M.A. (2008) Effects of melatonin on the endometrial morphology and embryo implantation in rats. Fertility and Sterility, 89(5): 1299–1305. https://doi.org/10.1016/j.fertnstert.2007.03.050

Deroo B.J. & Korach K.S. (2006) Estrogen receptors and human disease. The Journal of Clinical Investigation, 116(3): 561–570. https://doi.org/10.1172/JCI27987

Fluttert M., Dalm S. & Oitzl M.S. (2000) A refined method for sequencial blood sampling by tail incision in rats. Laboratory Animals, 34(4): 372–378. https://doi.org/10.1258/002367700780387714

França L.R., Leal M.C., Sasso-Cerri E., Vasconcelos A., Debeljuk L. & Russell L.D. (2000) Cimetidine (Tagamet®) is a reproductive toxicant in male rats affecting peritubular cells. Biology of Reproduction, 63: 1403–1412. https://doi.org/10.1095/biolreprod63.5.1403

Freeman M.E., Kanyicska B., Lerant A. & Nagy G. (2000) Prolactin: structure, function, and regulation of secretion. Physiological Reviews, 80(4): 1523–1631. https://doi.org/10.1152/physrev.2000.80.4.1523

Hankinson S.E., Willett W.C., Michaud D.S., Manson J.E., Colditz G.A. & Longcope C. (1999) Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women. Journal of the National Cancer Institute, 91(7): 629–634. https://doi.org/10.1093/jnci/91.7.629

Jesus T.B. & Carvalho C.E.V. (2008) Using biomarkers in fish to detect environmental contamination by mercury. Oecologia Australis, 12: 680–693.

Karadayian A.G., Mac Laughlin M.A. & Cutera R.A. (2012) Estrogen blocks the protective action of melatonin in a behavioral model of ethanol-induced hangover in mice. Physiology & Behavior, 107(2): 181–186. https://doi.org/10.1016/j.physbeh.2012.07.003

Katayama S. & Fishman J. (1982) 2-Hydroxyestrone suppresses and 2-methoxyestrone augments the preovulatory prolactin surge in the cycling rat. Endocrinology, 110(4): 1448–1450. https://doi.org/10.1210/endo-110-4-1448

Koshimizu J.Y., Beltrame F.L., Pizzol J.P., Paulo S.C., Caneguim B.H. & Sasso-Cerri E. (2013) NF-kB overexpression and decreased immunoexpression of AR in the muscular layer is related to structural damages and apoptosis in cimetidine-treated rat vas deferens. Reproductive Biology and Endocrinology, 11: 29. http://dx.doi.org/10.1186/1477-7827-11-29

Kuiper G.G., Enmark E., Pelto-Huikko M., Nilsson S. & Gustafsson J.A. (1996) Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proceedings of the National Academy of Sciences, 93(12): 5925–5930. http://dx.doi.org/10.1073/pnas.93.12.5925

Kuiper G.G., Carlsson B., Grandien K., Enmark E., Haggblad J., Nilsson S. & Gustafsson J.A. (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology, 138(3): 863–870. http://dx.doi.org/10.1210/endo.138.3.4979

Maekawa R., Tamura H., Taniguchi K., Taketani T. & Sugino A. (2007) Role and regulation of maternal melatonin during pregnancy in rats. Biology of Reproduction, 77: 105–110. https://doi.org/10.1093/biolreprod/77.s1.105b

Maganhin C.C., Ferraz A.A.C., Halley J.H., Fuchs L.F.P., Oliveira-Júnior I.S. & Simões M.J. (2008) Efeitos da melatonina no sistema genital feminino: breve revisão. Revista da Associação Medica Brasileira, 54(3): 267–271. https://doi.org/10.1590/S0104-42302008000300022

Martin I., Torres Neto R., Oba E., Buratini J.Jr., Binelli M. & Laufer-Amorim R. (2008) Immunohistochemical detection of receptors for oestrogen and progesterone in endometrial glands and stroma during the oestrous cycle in Nelore (Bos taurus indicus) cows. Reproduction in Domestic Animal, 43(4): 415–421. https://doi.org/10.1111/j.1439-0531.2007.00928.x

Medeiros J.P., Wanderley-Teixeira V., Teixeira A.A.C., Baratella-Evencio L. & Evencio Neto J. (2003) Ultrastructural analysis of pinealectomy and lack of light influence over collagen in the endometrium of rats. International Journal of Morphology, 21(3): 231–235. http://dx.doi.org/10.4067/S0717-95022003000300008

Michnovicz J.J. & Galbraith R.A. (1991) Cimetidine inhibits catechol estrogen metabolism in women. Metabolism Clinical and Experimental, 40(2): 170–174. https://doi.org/10.1016/0026-0495(91)90169-W

Mosselman S., Polman J. & Dijkema R. (1996) ERb: identification and characterization of a novel human estrogen receptor. FEBS Letters, 392: 49–53. http://dx.doi.org/10.1016/0014-5793(96)00782-x

Myllyharrju J. & Kivirikko K.L. (2004) Collagens, modifying enzymes and their mutations in humans, flies and worms. Trens in Genetics, 20: 33–43. http://dx.doi.org/10.1016/j.tig.2003.11.004

Nahas E.A.P., Nahás-Neto J., Pontes A., Dias R. & Fernandes C.E. (2006) Estados hiperprolactinêmicos – inter-relações com o psiquismo. Revista de Psiquiatria Clínica, 33: 68–73. http://dx.doi.org/10.1590/S0101-60832006000200006

Oxlund B.S., Ortoft G., Brüel A., Danielsen C., Bor P. & Oxlund H. (2010) Collagen concentration and biomechanical properties of samples from the lower uterine cervix in relation to age and parity in non-pregnant women. Reproductive Biology and Endocrinology, 8: 82–90. http://dx.doi.org/10.1186/1477-7827-8-82

Robinson R.S., Mann G.E., Lamming G.E. & Wathes D.C. (2010) Expression of oxytocin, oestrogen and progesterone receptors in uterine biopsy samples throughout the oestrous cycle and early pregnancy in cows. Journal of Reproduction and Fertility, 122: 965–979. http://dx.doi.org/10.1530/rep.0.1220965

Rosselli M., Reinhart K., Imthurn B., Keller P.J. & Dubey R.K. (2000) Cellular and biochemical mechanisms by which environmental estrogens may influence the reproduction function. Human Reproduction, 6: 332–350. http://dx.doi.org/10.1093/humupd/6.4.332

Saiyn U. (2012) EPR analysis of gamma irradiated single crystal cimetidine. Journal of Molecular Structure, 1031: 132–137. http://dx.doi.org/10.1016/j.molstruc.2012.07.022

Sasso-Cerri E. & Cerri O.S. (2008) Morphological evidences indicate that the interference of cimetidine on the peritubular components is responsible for detachment and apoptosis of Sertoli cells. Reproductive Biology and Endocrinology, 6:18. http://dx.doi.org/10.1186/1477-7827-6-18

Silva R.D., Glazebrook M.A., Campos V.N. & Vascocelos A.C. (2011) Achilles tendinosis – a morphometricalstydy in a rat model. International Journal of Clinical and Experimental Pathology, 4: 683–691.

Sinha R.B., Banerjee P. & Ganguly A.K. (2006) Serum concentration of testosterone, epididymal mast cell population and histamine content in relation to sperm count and their motility in albino rats following H2 receptor blocker treatment. Nepal Medical College Journal, 8: 36–39.

Surazynski A., Miltyk W., Wolczynski S. & Palka J. (2013) The effect of prolactin and estrogen cross-talk on prolidase-dependent signaling in MCF-7 cells. Neoplasma, 60: 355–363. http://dx.doi.org/10.4149/neo_2013_047

Takeshi S., Kai H. & Suita S. (2002) Effects of the prenatal administration of cimetidine on testicular descent and genital differentiation in rats. Surgery 131: 301–305. http://dx.doi.org/10.1067/msy.2002.119961

Taketani T., Tamura H., Takasaki A., Lee L., Kizuka F. & Tamura I. (2011) Protective role of melatonin in progesterone production by human luteal cells. Journal Pineal Research, 51(2): 207–213. http://dx.doi.org/10.1111/j.1600-079X.2011.00878.x

Teixeira A.A.C., Simoes M.J., Evencio-Neto J. & Wanderley-Teixeira V. (2002) Morphologic aspects of endometrium in the estrus phase, of pinealectomized rats. Revista Chilena de Antomia, 20(2): 145–159. http://dx.doi.org/10.4067/S0716-98682002000200005

Teixeira A.A.C., Simões M.J., Wanderley-Teixeira V. & Soares J.M.Jr. (2004) Evaluation of the implantation in pinealectomized and/or submitted to the constant illumination rats. International Journal of Morphology, 22(3): 189–194. http://dx.doi.org/10.4067/S0717-95022004000300003

Uygur R., Aktas C., Caglar V., Uigur E., Erdogan H. & Ozen A.O. (2013) Protective effects of melatonin against arsenic-induced apoptosis and oxidative stress in rat testes. Toxicology and Industrial Health, 32(5): 848–859. http://dx.doi.org/10.1177/0748233713512891

Xiang S., Mao L., Yuan L., Duplessis T., Jones F., Hoyle G.W., Frasch T., Dauchy R., Blask D., Chakravarty G. & Hill S.M. (2012) Impaired mouse mammary gland growth and development is mediated by melatonin and its MT1 G protein-coupled receptor via repression of ERα, Akt1, and Stat5. Journal of Pineal Research, 53: 307–318. http://dx.doi.org/10.1111/j.1600-079X.2012.01000.x

Zarazaga L., Celi I., Guzmán J.L. & Malpaux B. (2011) The effect of nutrition on the neural mechanisms potentially involved in melatonin-stimulated LH secretion in female Mediterranean goats. The Journal of Endocrinology, 211: 263–272. http://dx.doi.org/10.1530/JOE-11-0225

Zarazaga L., Celi I., Guzmán J.L. & Malpaux B. (2012) Reproductive performance is improved during seasonal anoestrus when female and male Murciano-Granadina goats receive melatonin implants and in Payoya goats when females are thus treated. Reproduction in Domestic Animals, 47(3): 436–442. https://doi.org/10.1111/j.1439-0531.2011.01899.x

Zhong L., Xiang X., Lu W., Zhau P. & Wang (2013) Interference of xenoestrogen o,p'-DDT on the action of endogenous estrogens at environmentally realistic concentrations. Bulletin of Environmental Contamination and Toxicology, 90: 591–595. https://doi.org/10.1007/s00128-013-0976-9

Zuloaga G.Z., Zuloaga K.L., Hinds L.R., Carbone D.L. & Handa R.J. (2013) Estrogen receptor β expression in the mouse forebrain: Age and sex differences. Journal of Comparative Neurology, 522: 358–371. https://doi.org/10.1002/cne.23400

Downloads

Publicado

20-12-2020

Edição

Seção

CIÊNCIAS DA SAÚDE / HEALTH SCIENCES