Clinical and Experimental Reproductive Medicine

  • 제48권3호
  • /
  • Pages.245-254
  • /
  • 2021
  • /
  • 2233-8233(pISSN)
  • /
  • 2233-8241(eISSN)
대한생식의학회 (The Korean Society for Reproductive Medicine)
권호 표지
DOI QR코드

DOI QR Code

Alteration of TGFB1, GDF9, and BMPR2 gene expression in preantral follicles of an estradiol valerate-induced polycystic ovary mouse model can lead to anovulation, polycystic morphology, obesity, and absence of hyperandrogenism

  • Asghari, Reza (Department of Anatomical Sciences and Histology, Faculty of Medicine, Tabriz University of Medical Sciences) ;
  • Shokri-Asl, Vahid (Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences) ;
  • Rezaei, Hanieh (Medical School, Hamedan University of Medical Sciences) ;
  • Tavallaie, Mahmood (Human Genetic Research Center, Baqiyatallah University of Medical Sciences) ;
  • Khafaei, Mostafa (Human Genetic Research Center, Baqiyatallah University of Medical Sciences) ;
  • Abdolmaleki, Amir (Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences) ;
  • Seghinsara, Abbas Majdi (Department of Anatomical Sciences and Histology, Faculty of Medicine, Tabriz University of Medical Sciences)
  • 투고 : 2020.09.25
  • 심사 : 2021.05.12
  • 발행 : 2021.09.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Objective: In humans, polycystic ovary syndrome (PCOS) is an androgen-dependent ovarian disorder. Aberrant gene expression in folliculogenesis can arrest the transition of preantral to antral follicles, leading to PCOS. We explored the possible role of altered gene expression in preantral follicles of estradiol valerate (EV) induced polycystic ovaries (PCO) in a mouse model. Methods: Twenty female balb/c mice (8 weeks, 20.0±1.5 g) were grouped into control and PCO groups. PCO was induced by intramuscular EV injection. After 8 weeks, the animals were killed by cervical dislocation. Blood serum (for hormonal assessments using the enzyme-linked immunosorbent assay technique) was aspirated, and ovaries (the right ovary for histological examinations and the left for quantitative real-time polymerase) were dissected. Results: Compared to the control group, the PCO group showed significantly lower values for the mean body weight, number of preantral and antral follicles, serum levels of estradiol, luteinizing hormone, testosterone, and follicle-stimulating hormone, and gene expression of TGFB1, GDF9 and BMPR2 (p<0.05). Serum progesterone levels were significantly higher in the PCO animals than in the control group (p<0.05). No significant between-group differences (p>0.05) were found in BMP6 or BMP15 expression. Conclusion: In animals with EV-induced PCO, the preantral follicles did not develop into antral follicles. In this mouse model, the gene expression of TGFB1, GDF9, and BMPR2 was lower in preantral follicles, which is probably related to the pathologic conditions of PCO. Hypoandrogenism was also detected in this EV-induced murine PCO model.

키워드

참고문헌

  1. Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, et al. Polycystic ovary syndrome. Nat Rev Dis Primers 2016;2:16057. https://doi.org/10.1038/nrdp.2016.57
  2. Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med 2010;8:41. https://doi.org/10.1186/1741-7015-8-41
  3. Huang A, Brennan K, Azziz R. Prevalence of hyperandrogenemia in the polycystic ovary syndrome diagnosed by the National Institutes of Health 1990 criteria. Fertil Steril 2010;93:1938-41. https://doi.org/10.1016/j.fertnstert.2008.12.138
  4. Bani Mohammad M, Majdi Seghinsara A. Polycystic ovary syndrome (PCOS), diagnostic criteria, and AMH. Asian Pac J Cancer Prev 2017;18:17-21.
  5. Erickson GF, Shimasaki S. The physiology of folliculogenesis: the role of novel growth factors. Fertil Steril 2001;76:943-9. https://doi.org/10.1016/S0015-0282(01)02859-X
  6. Karagul MI, Aktas S, Coskun Yilmaz B, Yilmaz M, Orekici Temel G. GDF9 and BMP15 expressions and fine structure changes during folliculogenesis in polycystic ovary syndrome. Balkan Med J 2018;35:43-54. https://doi.org/10.4274/balkanmedj.2016.1110
  7. Piotrowska H, Kempisty B, Sosinska P, Ciesiolka S, Bukowska D, Antosik P, et al. The role of TGF superfamily gene expression in the regulation of folliculogenesis and oogenesis in mammals: a review. Vet Med 2013;58:505-15. https://doi.org/10.17221/7082-VETMED
  8. Sanfins A, Rodrigues P, Albertini DF. GDF9 and BMP15 direct the follicle symphony. J Assist Reprod Genet 2018;35:1741-50. https://doi.org/10.1007/s10815-018-1268-4
  9. Persani L, Rossetti R, Di Pasquale E, Cacciatore C, Fabre S. The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders. Hum Reprod Update 2014;20:869-83. https://doi.org/10.1093/humupd/dmu036
  10. Shi J, Yoshino O, Osuga Y, Koga K, Hirota Y, Hirata T, et al. Bone morphogenetic protein-6 stimulates gene expression of follicle-stimulating hormone receptor, inhibin/activin beta subunits, and anti-Mullerian hormone in human granulosa cells. Fertil Steril 2009;92:1794-8. https://doi.org/10.1016/j.fertnstert.2009.05.004
  11. Wei LN, Huang R, Li LL, Fang C, Li Y, Liang XY. Reduced and delayed expression of GDF9 and BMP15 in ovarian tissues from women with polycystic ovary syndrome. J Assist Reprod Genet 2014;31:1483-90. https://doi.org/10.1007/s10815-014-0319-8
  12. Shi D, Vine DF. Animal models of polycystic ovary syndrome: a focused review of rodent models in relationship to clinical phenotypes and cardiometabolic risk. Fertil Steril 2012;98:185-93. https://doi.org/10.1016/j.fertnstert.2012.04.006
  13. Ben-Or S. Morphological and functional development of the ovary of the mouse. I. Morphology and histochemistry of the developing ovary in normal conditions and after FSH treatment. J Embryol Exp Morphol 1963;11:1-11.
  14. Makker A, Goel MM, Das V, Agarwal A. PI3K-Akt-mTOR and MAPK signaling pathways in polycystic ovarian syndrome, uterine leiomyomas and endometriosis: an update. Gynecol Endocrinol 2012;28:175-81. https://doi.org/10.3109/09513590.2011.583955
  15. Hu L, Zhang Y, Chen L, Zhou W, Wang Y, Wen J. MAPK and ERK polymorphisms are associated with PCOS risk in Chinese women. Oncotarget 2017;8:100261-8. https://doi.org/10.18632/oncotarget.22153
  16. Franks S. Can animal models of PCOS help point the way towards early and effective therapeutic intervention in women with the syndrome? Endocrinology 2015;156:2371-3. https://doi.org/10.1210/en.2015-1420
  17. Maliqueo M, Benrick A, Stener-Victorin E. Rodent models of polycystic ovary syndrome: phenotypic presentation, pathophysiology, and the effects of different interventions. Semin Reprod Med 2014;32:183-93. https://doi.org/10.1055/s-0034-1371090
  18. Divyashree S, Janhavi P, Ravindra PV, Muthukumar SP. Experimental models of polycystic ovary syndrome: an update. Life Sci 2019;237:116911. https://doi.org/10.1016/j.lfs.2019.116911
  19. Newbold RR, Jefferson WN, Padilla-Banks E. Prenatal exposure to bisphenol A at environmentally relevant doses adversely affects the murine female reproductive tract later in life. Environ Health Perspect 2009;117:879-85. https://doi.org/10.1289/ehp.0800045
  20. Alonso-Magdalena P, Ropero AB, Carrera MP, Cederroth CR, Baquie M, Gauthier BR, et al. Pancreatic insulin content regulation by the estrogen receptor ER alpha. PLoS One 2008;3:e2069. https://doi.org/10.1371/journal.pone.0002069
  21. Davis BJ, Maronpot RR, Heindel JJ. Di-(2-ethylhexyl) phthalate suppresses estradiol and ovulation in cycling rats. Toxicol Appl Pharmacol 1994;128:216-23. https://doi.org/10.1006/taap.1994.1200
  22. Decherf S, Demeneix BA. The obesogen hypothesis: a shift of focus from the periphery to the hypothalamus. J Toxicol Environ Health B Crit Rev 2011;14:423-48. https://doi.org/10.1080/10937404.2011.578561
  23. Grun F, Blumberg B. Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling. Endocrinology 2006;147(6 Suppl):S50-5. https://doi.org/10.1210/en.2005-1129
  24. Wu XY, Li ZL, Wu CY, Liu YM, Lin H, Wang SH, et al. Endocrine traits of polycystic ovary syndrome in prenatally androgenized female Sprague-Dawley rats. Endocr J 2010;57:201-9. https://doi.org/10.1507/endocrj.K09E-205
  25. Poornima R, Saranya P, Bhuvaneshwari S, Averal HI. Evaluation of Pergularia daemia and metformin in the treatment of PCOS in testosterone propionate induced albino wistar rats (Rattus norvegicus). Int J Sci Res Pub 2015;5:503-9.
  26. Mahesh VB, Greenblatt RB. Isolation of dehydroepiandrosterone and 17alpha-hydroxy-delta5-pregenolone from the polycystic ovaries of the Stein-Leventhal syndrome. J Clin Endocrinol Metab 1962;22:441-8. https://doi.org/10.1210/jcem-22-4-441
  27. Kim EJ, Jang M, Choi JH, Park KS, Cho IH. An improved dehydroepiandrosterone-induced rat model of polycystic ovary syndrome (PCOS): post-pubertal improve PCOS's features. Front Endocrinol (Lausanne) 2018;9:735. https://doi.org/10.3389/fendo.2018.00735
  28. Manneras L, Cajander S, Holmang A, Seleskovic Z, Lystig T, Lonn M, et al. A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology 2007;148:3781-91. https://doi.org/10.1210/en.2007-0168
  29. van Houten EL, Kramer P, McLuskey A, Karels B, Themmen AP, Visser JA. Reproductive and metabolic phenotype of a mouse model of PCOS. Endocrinology 2012;153:2861-9. https://doi.org/10.1210/en.2011-1754
  30. Johansson J, Feng Y, Shao R, Lonn M, Billig H, Stener-Victorin E. Intense electroacupuncture normalizes insulin sensitivity, increases muscle GLUT4 content, and improves lipid profile in a rat model of polycystic ovary syndrome. Am J Physiol Endocrinol Metab 2010;299:E551-9. https://doi.org/10.1152/ajpendo.00323.2010
  31. Pinilla L, Trimino E, Garnelo P, Bellido C, Aguilar R, Gaytan F, et al. Changes in pituitary secretion during the early postnatal period and anovulatory syndrome induced by neonatal oestrogen or androgen in rats. J Reprod Fertil 1993;97:13-20. https://doi.org/10.1530/jrf.0.0970013
  32. Stener-Victorin E, Ploj K, Larsson BM, Holmang A. Rats with steroid-induced polycystic ovaries develop hypertension and increased sympathetic nervous system activity. Reprod Biol Endocrinol 2005;3:44. https://doi.org/10.1186/1477-7827-3-44
  33. Norman RJ, Noakes M, Wu R, Davies MJ, Moran L, Wang JX. Improving reproductive performance in overweight/obese women with effective weight management. Hum Reprod Update 2004;10:267-80. https://doi.org/10.1093/humupd/dmh018
  34. Ikeda K, Baba T, Morishita M, Honnma H, Endo T, Kiya T, et al. Longterm treatment with dehydroepiandrosterone may lead to follicular atresia through interaction with anti-Mullerian hormone. J Ovarian Res 2014;7:46. https://doi.org/10.1186/1757-2215-7-46
  35. Mesbah F, Moslem M, Vojdani Z, Mirkhani H. Estradiol valerate-induced polycystic ovary syndrome: an animal model study. Armaghane Danesh 2011;15:325-34.
  36. Franks S, Hardy K. Folliculogenesis in polycystic ovaries. In: Dunaif A, Chang RJ, Franks S, Legro RS, editors. Polycystic ovary syndrome: current controversies, from the ovary to the pancreas. Totowa: Humana Press; 2008. p. 1-7.
  37. Brawer JR, Munoz M, Farookhi R. Development of the polycystic ovarian condition (PCO) in the estradiol valerate-treated rat. Biol Reprod 1986;35:647-55. https://doi.org/10.1095/biolreprod35.3.647
  38. Haggstrom M. Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle. Wiki J Med 2014;1:1-5.
  39. Miri M, Karimi Jashni H, Alipour F. Effect of exercise intensity on weight changes and sexual hormones (androstenedione and free testosterone) in female rats with estradiol valerate-induced PCOS. J Ovarian Res 2014;7:37. https://doi.org/10.1186/1757-2215-7-37
  40. Pournaderi PS, Yaghmaei P, Khodaei H, Noormohammadi Z, Hejazi SH. The effects of 6-Gingerol on reproductive improvement, liver functioning and Cyclooxygenase-2 gene expression in estradiol valerate: induced polycystic ovary syndrome in Wistar rats. Biochem Biophys Res Commun 2017;484:461-6. https://doi.org/10.1016/j.bbrc.2017.01.057
  41. Venegas B, De Leon Gordillo LY, Rosas G, Espinoza JA, Moran C, Dominguez R, et al. In rats with estradiol valerate-induced polycystic ovary syndrome, the acute blockade of ovarian β-adrenoreceptors improve ovulation. Reprod Biol Endocrinol 2019;17:95. https://doi.org/10.1186/s12958-019-0539-y
  42. Laird M, Thomson K, Fenwick M, Mora J, Franks S, Hardy K. Androgen stimulates growth of mouse preantral follicles in vitro: interaction with follicle-stimulating hormone and with growth factors of the TGFβ superfamily. Endocrinology 2017;158:920-35. https://doi.org/10.1210/en.2016-1538
  43. Ghadami M, Makita Y, Yoshida K, Nishimura G, Fukushima Y, Wakui K, et al. Genetic mapping of the Camurati-Engelmann disease locus to chromosome 19q13.1-q13.3. Am J Hum Genet 2000;66:143-7. https://doi.org/10.1086/302728
  44. Raja-Khan N, Urbanek M, Rodgers RJ, Legro RS. The role of TGF-β in polycystic ovary syndrome. Reprod Sci 2014;21:20-31. https://doi.org/10.1177/1933719113485294
  45. Miao Zl, Wang ZN, Yang YD, Chen LQ, Rong CU, Wang XL, et al. Role of TGF-β1 in the formation of ovarian interstitial fibrosis in PCOS rat. J Reprod Contracept 2008;19:83-92. https://doi.org/10.1016/S1001-7844(08)60010-3
  46. Sugiura K, Su YQ, Eppig JJ. Does bone morphogenetic protein 6 (BMP6) affect female fertility in the mouse? Biol Reprod 2010;83:997-1004. https://doi.org/10.1095/biolreprod.110.086777
  47. Zhang XY, Chang HM, Zhu H, Liu RZ, Leung PC. BMP6 increases TGF-β1 production by up-regulating furin expression in human granulosa-lutein cells. Cell Signal 2019;55:109-18. https://doi.org/10.1016/j.cellsig.2019.01.002
  48. Moore RK, Shimasaki S. Molecular biology and physiological role of the oocyte factor, BMP15. Mol Cell Endocrinol 2005;234:67-73. https://doi.org/10.1016/j.mce.2004.10.012
  49. de Resende LO, Vireque AA, Santana LF, Moreno DA, de Sa Rosa e Silva AC, Ferriani RA, et al. Single-cell expression analysis of BMP15 and GDF9in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation. J Assist Reprod Genet 2012;29:1057-65. https://doi.org/10.1007/s10815-012-9825-8
  50. Otsuka F, McTavish KJ, Shimasaki S. Integral role of GDF9 and BMP15 in ovarian function. Mol Reprod Dev 2011;78:9-21. https://doi.org/10.1002/mrd.21265
  51. de Castro FC, Cruz MH, Leal CL. Role of growth differentiation factor 9 and bone morphogenetic protein 15 in ovarian function and their importance in mammalian female fertility: a review. Asian-Australas J Anim Sci 2016;29:1065-74. https://doi.org/10.5713/ajas.15.0797
  52. Teixeira Filho FL, Baracat EC, Lee TH, Suh CS, Matsui M, Chang RJ, et al. Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:1337-44. https://doi.org/10.1210/jcem.87.3.8316