Análise imunoistoquímica e histomorfométrica do endométrio de ratas em estro permanente tratadas com melatonina, metformina e citrato de clomifeno

Leandro Sabará de Mattos; Leonardo Augusto  Lombardi; Marcio Luis Alves  Moura; Ana Paula Espindula; Ricardo Santos  Simões; Rinaldo  Florencio-Silva; Paulo Celso  Franco; Gisela Rodrigues da Silva  Sasso; Manuel de Jesus  Simões

doi:10.33448/rsd-v11i7.29995

Autores

Leandro Sabará de Mattos Universidade Nove de julho https://orcid.org/0000-0003-3041-7344
Leonardo Augusto Lombardi Universidade Federal do Triângulo Mineiro https://orcid.org/0000-0002-9735-8804
Marcio Luis Alves Moura Universidade Cruzeiro do Sul https://orcid.org/0000-0003-1259-2202
Ana Paula Espindula Universidade Federal do Triângulo Mineiro https://orcid.org/0000-0002-9282-4482
Ricardo Santos Simões Universidade de São Paulo https://orcid.org/0000-0002-7207-4856
Rinaldo Florencio-Silva Universidade Federal do São Paulo https://orcid.org/0000-0002-2956-6230
Paulo Celso Franco Universidade Federal do São Paulo https://orcid.org/0000-0002-6372-1492
Gisela Rodrigues da Silva Sasso Universidade Federal do São Paulo https://orcid.org/0000-0002-6583-1329
Manuel de Jesus Simões Universidade Federal do São Paulo https://orcid.org/0000-0003-2770-8618

DOI:

https://doi.org/10.33448/rsd-v11i7.29995

Palavras-chave:

Endométrio; Estro permanente; Ensino em Saúde; Melatonina; Metformina; Citrato de clomifeno; Ratas.

Resumo

Objetivo: Avaliar os efeitos da melatonina, metformina e citrato de clomifeno no endométrio de ratas modelo de síndrome dos ovários policísticos. Métodos: Setenta e oito ratas foram divididas em 13 grupos e dois experimentos (prevenção e tratamento). Após as exposições todos os animais foram anestesiados e tiveram retirados os cornos uterinos e submetidos a coloração pela hematoxilina e eosina e imunoistoquímica (Ki-67 e Vegf). Os dados obtidos foram submetidos ao teste t de Student (p<0,05). Resultados/Conclusão: A melatonina, a metformina e o citrato de clomifeno não promovem efeitos proliferativos e angiogênicos no endométrio de ratas em estro permanente, porém, a melatonina tem efeito trófico mais significativo no estroma endometrial, o que não interferiu na sua espessura, enquanto que a metformina apresentou efeito trófico mais significante no epitélio glandular do endométrio, portanto, estes efeitos são semelhantes tanto antes quanto após a indução de SOP por exposição à luz contínua.

Referências

Almeida, J. P., Pinelo, S., Serra, H., Barbosa, A., Felgueira, E., Pires, I., et al. (2011). Controlled ovarian stimulation and intrauterine insemination: an actual therapy?. Rev Bras Ginecol Obstet, 33(11), 341-347.

Berson, D. M. (2003). Strange vision: ganglion cells as circadian photoreceptors. Trends Neurosci, 26(6), 314-320.

Cakmak, H., & Taylor, H. S. (2011). Implantation failure: molecular mechanisms and clinical treatment. Hum Reprod Update, 17(2), 242-253.

Camano, L., & Giuffrida, R. (1970). Cytological and histological modifications of the rat vaginal epithelium. Matern Infanc (Sao Paulo), 29(2), 231-234.

Commentz, J. C., & Helmke, K. (1995). Precocious puberty and decreased melatonin secretion due to a hypothalamic hamartoma. Horm Res, 44(6), 271-275.

Costello, M. F. (2004). Systematic review of the treatment of ovulatory infertility with clomiphene citrate and intrauterine insemination. Aust N Z J Obstet Gynaecol, 44(2), 93-102.

Donaghay, M., & Lessey, B. A. (2007). Uterine receptivity: alterations associated with benign gynecological disease. Semin Reprod Med, 25(6), 461-475.

Elia, E., Sander, V., Luchetti, C. G., Solano, M. E., Di Girolamo, G., Gonzalez, C., et al. (2006). The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice. Mol Hum Reprod, 12(8), 475-481.

Ferreira, C. S., Carvalho, K. C., Maganhin, C. C., Paiotti, A. P., Oshima, C. T., Simões, M. J., et al. (2016). Does melatonin influence the apoptosis in rat uterus of animals exposed to continuous light? Apoptosis, 21(2), 155-162.

Franciosi, M., Lucisano, G., Lapice, E., Strippoli, G. F., Pellegrini, F., & Nicolucci, A. (2013). Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One, 8(8), e71583.

Kang, X., Jia, L., & Shen, X. (2015). Manifestation of Hyperandrogenism in the Continuous Light Exposure-Induced PCOS Rat Model. Biomed Res Int, 2015, 943694.

Leanza, V., Coco, L., Grasso, F., Leanza, G., Zarbo, G., & Palumbo, M. (2014). Ovulation induction with clomiphene citrate and metformin in women with polycystic ovary syndrome. Minerva Ginecol, 66(3), 299-301.

Legro, R. S., Barnhart, H. X., Schlaff, W. D., Carr, B. R., Diamond, M. P., Carson, S. A., et al. (2007). Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med, 356(6), 551-566.

Lombardi, L. A., Simões, R. S., Maganhin, C. C., da Silva, C. F., Maciel, G. A., Baracat, E. C., et al. (2012). [Morphology of the interstitial cells of rat polycystic ovaries: an experimental study]. Rev Bras Ginecol Obstet, 34(7), 323-328.

Lombardi, L. A. ., Mattos, L. S. ., Moura, M. L. A. ., Espindula, A. P. ., Simões, R. S. ., Florencio-Silva, R. ., Simões, M. de J., Franco, P. C. ., Sasso, G. R. da S., & Soares-Jr, J. M. . (2021). Histomorphometric and immunohistochemical changes in interstitial cells and ovarian follicles of rats treated with metformin during and after induction of permanent estrus . Research, Society and Development, 10(6), e5110615536. https://doi.org/10.33448/rsd-v10i6.15536.

Maganhin, C. C., Carbonel, A. A., Hatty, J. H., Fuchs, L. F., Oliveira-Júnior, I. S., Simões, M. e. J., et al. (2008). [Melatonin effects on the female genital system: a brief review]. Rev Assoc Med Bras (1992), 54(3), 267-271.

Mahajan, D. K. (1988). Polycystic ovarian disease: animal models. Endocrinol Metab Clin North Am, 17(4), 705-732.

Mathur, R., Alexander, C. J., Yano, J., Trivax, B., & Azziz, R. (2008). Use of metformin in polycystic ovary syndrome. Am J Obstet Gynecol, 199(6), 596-609.

Michalany, J. (1998). Técnica Histológica em Anatomia Patológica. Editora Michalany (3ª ed.). São Paulo.

Moll, E., Korevaar, J. C., Bossuyt, P. M., & van der Veen, F. (2008). Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome? Hum Reprod, 23(8), 1830-1834.

Montes, G. S., & Luque, E. H. (1988). Effects of ovarian steroids on vaginal smears in the rat. Acta Anat (Basel), 133(3), 192-199.

Musi, N., Hirshman, M. F., Nygren, J., Svanfeldt, M., Bavenholm, P., Rooyackers, O., et al. (2002). Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes, 51(7), 2074-2081.

Ortega, I., Cress, A. B., Wong, D. H., Villanueva, J. A., Sokalska, A., Moeller, B. C., et al. (2012). Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells. Biol Reprod, 86(1), 1-9.

Pereira, A.S., Shitsuka, D.M., Parreira, F.J 7 Shitsuka, R. (2018). Metodologia da pesquisa científica. [free e-book]. Santa Maria/RS. Ed. UAB/NTE/UFSM.

Pertsov, S. S. (2006). The behavior of rats in response to changes in the light regime and administration of melatonin. Neurosci Behav Physiol, 36(7), 767-772.

Prapas, N., Karkanaki, A., Prapas, I., Kalogiannidis, I., Katsikis, I., & Panidis, D. (2009). Genetics of polycystic ovary syndrome. Hippokratia, 13(4), 216-223.

Quezada, S., Avellaira, C., Johnson, M. C., Gabler, F., Fuentes, A., & Vega, M. (2006). Evaluation of steroid receptors, coregulators, and molecules associated with uterine receptivity in secretory endometria from untreated women with polycystic ovary syndrome. Fertil Steril, 85(4), 1017-1026.

Regan, K. S., Cline, J. M., Creasy, D., Davis, B., Foley, G. L., Lanning, L., et al. (2005). STP position paper: ovarian follicular counting in the assessment of rodent reproductive toxicity. Toxicol Pathol, 33(3), 409-412.

Richter, K. S., Bugge, K. R., Bromer, J. G., & Levy, M. J. (2007). Relationship between endometrial thickness and embryo implantation, based on 1,294 cycles of in vitro fertilization with transfer of two blastocyst-stage embryos. Fertil Steril, 87(1), 53-59.

Rossi, A.G., Soares, J.M. J.R., Motta, E.L., Simões, M.J., Oliveira-Filho, R.M., Sainz, R.M., Mayo, J.C., Reiter, R.J., Antolin, L., Esteban, M.M., & Rodriguez, C. (2006). Melatonin regulates glucocorticoid receptor: an answer to its antiapoptotic action in thymus. FASEB J, 13 (12),1547-1556.

Salamonsen, L. A., Nie, G., Hannan, N. J., & Dimitriadis, E. (2009). Society for Reproductive Biology Founders' Lecture 2009. Preparing fertile soil: the importance of endometrial receptivity. Reprod Fertil Dev, 21(7), 923-934.

Salvetti, N. R., Panzani, C. G., Gimeno, E. J., Neme, L. G., Alfaro, N. S., & Ortega, H. H. (2009). An imbalance between apoptosis and proliferation contributes to follicular persistence in polycystic ovaries in rats. Reprod Biol Endocrinol, 7, 68.

Savaris, R. F., Groll, J. M., Young, S. L., DeMayo, F. J., Jeong, J. W., Hamilton, A. E., et al. (2011). Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles. J Clin Endocrinol Metab, 96(6), 1737-1746.

Schibler, U., & Sassone-Corsi, P. (2002). A web of circadian pacemakers. Cell, 111(7), 919-922.

Scholzen, T., & Gerdes, J. (2000). The Ki-67 protein: from the known and the unknown. J Cell Physiol, 182(3), 311-322.

Shorr, E. (1941). A new technic for staining vaginal smears: iii, a single differential stain. Science, 94(2449), 545-546.

Smaniotto, S., & Simões, M.J. (1996). Morphological aspects of the endometrial epithelium of persistent estrous rats under estrogenic action. Braz J Morphol Sci, 13(103).

Soares, J. M., Simões, M. J., Oshima, C. T., Mora, O. A., De Lima, G. R., & Baracat, E. C. (2003). Pinealectomy changes rat ovarian interstitial cell morphology and decreases progesterone receptor expression. Gynecol Endocrinol, 17(2), 115-123.

Sára, L., Nádasy, G., Antal, P., Szekeres, M., Monori-Kiss, A., Horváth, E. M., et al. (2012). Arteriolar biomechanics in a rat polycystic ovary syndrome model - effects of parallel vitamin D3 treatment. Acta Physiol Hung, 99(3), 279-288.

Tan, X., Li, S., Chang, Y., Fang, C., Liu, H., Zhang, X., et al. (2016). Effect of metformin treatment during pregnancy on women with PCOS: a systematic review and meta-analysis. Clin Invest Med, 39(4), E120-131.

Tang, T., Lord, J. M., Norman, R. J., Yasmin, E., & Balen, A. H. (2012). Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev(5), CD003053.

Teixeira, A.A.C., Simões, M.J., Wanderley-Teixeira, V., & Soares, J.R. J.M. (2004). Evaluation of the implantation in pinealectomized and/or submitted to the constant illumination rats. International Journal of Morphology, 22(3), 189-194.

Unfer, V., Casini, M. L., Costabile, L., Mignosa, M., Gerli, S., & Di Renzo, G. C. (2004). Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil Steril, 82(1), 145-148, quiz 265.

Wu, B., Li, S., Sheng, L., Zhu, J., Gu, L., Shen, H., et al. (2012). Metformin inhibits the development and metastasis of ovarian cancer. Oncol Rep, 28(3), 903-908.

Zhang, Y., Li, M. X., Wang, H., Zeng, Z., & Li, X. M. (2015). Metformin down-regulates endometrial carcinoma cell secretion of IGF-1 and expression of IGF-1R. Asian Pac J Cancer Prev, 16(1), 221-225.

Análise imunoistoquímica e histomorfométrica do endométrio de ratas em estro permanente tratadas com melatonina, metformina e citrato de clomifeno

Autores

DOI:

Palavras-chave:

Resumo

Referências

Downloads

Publicado

Como Citar

Edição

Seção

Licença

JOURNAL METRICS

Idioma

Enviar Submissão