All-trans retinoic acid and fibroblast growth factor-2 enhance the fertility rate and embryo development in polycystic ovary syndrome mouse model

Document Type : Original Article

Authors

1 Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

2 Cellular and Molecular Research Center, Research Institute for Non-communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran

3 Department of Anatomical Sciences, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran

4 Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran

5 Cellular and Molecular Research Center, Research Institute for Health Development, Department of Anatomical Sciences, Kurdistan University of Medical Sciences, Sanandaj, Iran

6 Medical Plants Research Center, Basic Health Sciences Institute, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran

7 Department of Epidemiology and Biostatistics, Shahrekord University of Medical Sciences, Shahrekord, Iran

10.22038/ijbms.2024.70509.15328

Abstract

Objective(s): Polycystic ovary syndrome (PCOS) causes a developmental arrest of antral follicles and disrupts oocyte maturation. Retinoic acid (RA) and Fibroblast Growth Factor-2 (FGF2) are effective in follicle growth, thus their effects on histopathology and in vitro fertility of oocytes were investigated in PCOS-induced mice.
Materials and Methods: Eighty female NMRI mice were randomly divided into 8 groups including 1-Normal mice, 2-PCOS mice without any treatment, 3-Normal mice treated with RA, 4-Normal mice treated with FGF2, 5-PCOS mice treated with RA, 6- PCOS mice treated with FGF2, 7- PCOS mice treated with RA and FGF2, and 8- Normal mice treated with RA and FGF2. Following PCOS induction, the mice were treated with intraperitoneal RA and FGF2 as a treatment. Then ovarian stimulation, for preparing the oocyte and embryo microscopic examinations was performed. After oocyte morphometry, through in vitro fertilization, the embryo formation was assessed. Data was analyzed by one-way ANOVA and Tukey tests.
Results: The results showed simultaneous injection of RA and FGF2 into PCOS-induced mice increases antral follicles and corpus luteum, but decreases cystic follicles. Simultaneous injection of these two substances into healthy mice increases the pre-antral follicles and corpus luteum. Simultaneous injection of RA and FGF2 increases the number of embryos in both control and intervention groups. 
Conclusion: It can be concluded that RA and FGF2 increase the maturity of ovarian follicles, the number of two-celled embryos, and the number of grade-A embryos in mice with PCOS, which is more effective when these two substances are injected simultaneously.

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Main Subjects


1. Venegas B, De León Gordillo LY, Rosas G, Espinoza JA, Morán C, Domínguez 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;17:95-104.
2. Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update 2008;14:367-378.
3. Tamadon A, Hu W, Cui P, Ma T, Tong X, Zhang F, et al. How to choose the suitable animal model of polycystic ovary syndrome? Tradit Med Mod Med 2018;1:95-113.
4. van Houten ELA, Visser JA. Mouse models to study polycystic ovary syndrome: A possible link between metabolism and ovarian function? Reprod Biol 2014;14:32-43.
5. Franks S, Hardy K. What causes anovulation in polycystic ovary syndrome? Curr Opin Endocr Metab Res 2020;12:59-65.
6. Abouzaripour M, Fathi F, Daneshi E, Mortezaee K, Rezaie MJ, Abdi M. Combined effect of retinoic acid and basic fibroblast growth factor on maturation of mouse oocyte and subsequent fertilization and development. Int J Fertil Steril 2018;12:68-71.    7. Barros RG, Lima PF, Soares ACS, Sanches L, Price CA, Buratini J. Fibroblast growth factor 2 regulates cumulus differentiation under the control of the oocyte. Journal of Assisted Reproduction and Genetics. 2019;36:905-913.
8. Livingston T, Eberhardt D, Edwards JL, Godkin J. Retinol improves bovine embryonic development in vitro. Reprod Biol Endocrinol 2004;2:1-7.
9.    Kamalipour F, Jalali H, Azarnia M. Comparison the Effect of Metformin and Clomiphene Citrate on Sirtuin3 gene Expression in the Oocytes of Mice with Polycystic Ovary Syndrome. Iran J Pharm Res 2020;19:160-168.
10.    Asunción M, Calvo RM, San Millán JL, Sancho J, Avila S, Escobar-Morreale HcF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000;85:2434-24348.
11.    Wang L, Potter JJ, Rennie-Tankersley L, Novitskiy G, Sipes J, Mezey E. Effects of retinoic acid on the development of liver fibrosis produced by carbon tetrachloride in mice. Biochim Biophys Acta Mol Basis Dis 2007;1772:66-71.
12.    March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010;25:544-551.
13.    Mehrabian F, Khani B, Kelishadi R, Ghanbari E. The prevalence of polycystic ovary syndrome in Iranian women based on different diagnostic criteria. Endokrynol Pol 2011;62:238-242.
14.    Tehrani FR, Simbar M, Tohidi M, Hosseinpanah F, Azizi F. The prevalence of polycystic ovary syndrome in a community sample of Iranian population: Iranian PCOS prevalence study. Reprod Biol Endocrinol 2011;9:1-7.
15.    Bolton VN, Hawes SM, Taylor CT, Parsons JH. Development of spare human preimplantation embryos in vitro: an analysis of the correlations among gross morphology, cleavage rates, and development to the blastocyst. J In vitro Fertil Embryo Transf 1989;6:30-35.
16.    Matos M, Lima-Verde I, Bruno J, Lopes C, Martins F, Santos K, et al. Follicle stimulating hormone and fibroblast growth factor-2 interact and promote goat primordial follicle development in vitro. Reprod Fertil Dev 2007;19:677-684.
17.    Salvetti NR, Panzani CG, Gimeno EJ, Neme LG, Alfaro NS, Ortega HH. An imbalance between apoptosis and proliferation contributes to follicular persistence in polycystic ovaries in rats.Reprod Biol Endocrinol 2009;7:1-10.
18.    Ghezelayagh Z, Abtahi NS, Valojerdi MR, Mehdizadeh A, Ebrahimi B. The combination of basic fibroblast growth factor and kit ligand promotes the proliferation, activity and steroidogenesis of granulosa cells during human ovarian cortical culture. Cryobiology 2020;96:30-36.
19.    Yang QE, Fields SD, Zhang K, Ozawa M, Johnson SE, Ealy AD. Fibroblast growth factor 2 promotes primitive endoderm development in bovine blastocyst outgrowths. Biol Reprod 2011;85:946-953.
20.    Kumar S, Singla SK, Manik R, Palta P, Chauhan MS. Effect of basic fibroblast growth factor (FGF2) on cumulus cell expansion, in vitro embryo production and gene expression in buffalo (Bubalus bubalis). Reprod Biol 2020;20:501-511.
21.    Jagtap S, Meganathan K, Wagh V, Natarajan K, Hescheler J, Sachinidis A. All-trans retinoic acid and basic fibroblast growth factor synergistically direct pluripotent human embryonic stem cells to extraembryonic lineages. Stem Cell Res 2013;10:228-240.