Animal Reproduction (AR)
Animal Reproduction (AR)

Impact of GnRH agonist and GnRH antagonist on GDF9 and BMP15 expression in mouse ovaries and oocyte development

Xin-Yu Guo; Yan Huang; Ying Ou; Xiao-Yan Chen; Ye-Xing Xian; Shi-Qin Chen; Su-Yan Xie

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GnRH analogues were widely used for controlld ovary stimulation, but their effects on oocyte quality remain contradictory. This study aimed to explore the influence of GnRH analogues on oocyte quality in mice. A total of 120 mice were randomly assigned to four groups:(i)GnRH-a+PMSG group; (ii) GnRH-ant+PMSG group; (iii) PMSG group; (iv) Control group. Ovaries were collected for quantitative real-time polymerase chain reaction (qRT-PCR) to assess GDF9 and BMP15 mRNA expression, and protein expression were evaluated by western blotting. Moreover, embryo developmental progress in vitro and implantation rate in vivo were recorded. Compared with control group, both GDF9 mRNA and protein expressions were strengthened in PMSG group, but reduced in the presence of GnRH-a or GnRH-ant. The GnRH-a group exhibited decreased BMP15 mRNA expression compared to PMSG group, while the GnRH-ant group did not show the same pattern. BMP15 protein expression were not statisticlly different among the four groups. Notably, there was no statistically difference in the expression of these two factors between GnRH-a and GnRH-ant groups. The percentage of zygotes progressing to the 2-cell stage and percentage of 2-cell advancing to the blastocyst stage were similar in the PMSG group and control group. However, both the GnRH-a and GnRH-ant groups showed decreased embryos development rates compared to other two groups. The embryonic implantation rate in control group (53.3%) was higher than that in the GnRH-a and GnRH-ant groups (33.3% and 30.8%, P<0.05). The difference between the PMSG (45.0%) and GnRHa group was statistically significant (P value of 0.023), but not between the PMSG and GnRH-ant group (P value of 0.486). No statistical difference was confirmed between GnRH-a and GnRH-ant groups. Our findings shed light on the safety of GnRH analogues in ovary stimulation, and highlight the need for further research to establish optimal and effective controlled ovary stimulation protocol.


GnRH analogue, GnRH agonist, GnRH antagonist, GDF9, BMP15


Aboulghar M, Mansour R, Al-Inany H, Abou-Setta AM, Mourad L, Serour G. Paternal age and outcome of intracytoplasmic sperm injection. Reprod Biomed Online. 2007;14(5):588-92. PMid:17509198.

Alama P, Bellver J, Vidal C, Giles J. GnRH analogues in the prevention of ovarian hyperstimulation syndrome. Int J Endocrinol Metab. 2013;11(2):107-16. PMid:23825982.

Azizollahi S, Bagheri M, Haghollahi F, Mohammadi SM, Hossein Rashidi B. Clinical and molecular effects of gnrh agonist and antagonist on the cumulus cells in the in vitro fertilization cycle. Int J Fertil Steril. 2021;15(3):202-9. PMid:34155867.

Bodri D, Sunkara SK, Coomarasamy A. Gonadotropin-releasing hormone agonists versus antagonists for controlled ovarian hyperstimulation in oocyte donors: a systematic review and meta-analysis. Fertil Steril. 2011;95(1):164-9. PMid:20684954.

Check JH, Choe JK, Cohen R, Wilson C. A study to determine the efficacy of controlled ovarian hyperstimulation regimen using a gonadotropin releasing hormone agonist versus antagonist in women of advanced reproductive age with varying degrees of oocyte reserve on outcome following in vitro fertilization-embryo transfer. Clin Exp Obstet Gynecol. 2013;40(2):191-2. PMid:23971234.

Cota AM, Oliveira JB, Petersen CG, Mauri AL, Massaro FC, Silva LF, Nicoletti A, Cavagna M, Baruffi RL, Franco JG Jr. GnRH agonist versus GnRH antagonist in assisted reproduction cycles: oocyte morphology. Reprod Biol Endocrinol. 2012;10(1):33. PMid:22540993.

D’Occhio MJ, Campanile G, Baruselli PS. Transforming growth factor-β superfamily and interferon-τ in ovarian function and embryo development in female cattle: review of biology and application. Reprod Fertil Dev. 2020;32(6):539-52. PMid:32024582.

Fleming R. Gonadotropin releasing hormone analogs as part of controlled ovarian stimulation. Fertil Steril Rep. 2022;4(2, Suppl):8-14. PMid:37223758.

Garcia-Ispierto I, De Rensis F, Pérez-Salas JA, Nunes JM, Pradés B, Serrano-Pérez B, López-Gatius F. The GnRH analogue dephereline given in a fixed-time AI protocol improves ovulation and embryo survival in dairy cows. Res Vet Sci. 2019;122:170-4. PMid:30513410.

Gong Y, Li-Ling J, Xiong D, Wei J, Zhong T, Tan H. Age-related decline in the expression of GDF9 and BMP15 genes in follicle fluid and granulosa cells derived from poor ovarian responders. J Ovarian Res. 2021;14(1):1-10. PMid:33397408.

Hoseini FS, Noori Mugahi SM, Akbari-Asbagh F, Eftekhari-Yazdi P, Aflatoonian B, Aghaee-Bakhtiari SH, Aflatoonian R, Salsabili N. A randomized controlled trial of gonadotropin-releasing hormone agonist versus gonadotropin-releasing hormone antagonist in Iranian infertile couples: oocyte gene expression. Daru. 2014;22(1):67-75. PMid:25288473.

Huirne JA, Homburg R, Lambalk CB. Are GnRH antagonists comparable to agonists for use in IVF? Hum Reprod. 2007;22(11):2805-13. PMid:17872909.

Kadoura S, Alhalabi M, Nattouf AH. Conventional GnRH antagonist protocols versus long GnRH agonist protocol in IVF/ICSI cycles of polycystic ovary syndrome women: a systematic review and meta-analysis. Sci Rep. 2022;12(1):4456. PMid:35292717.

Kousheh F, Ghasemian F, Zahiri Z. Association between glucose consumption and oocyte maturation competence in mice with polycystic ovarian syndrome. Int J Fertil Steril. 2022;16(4):292-8. PMid:36273316.

Kristensen SG, Andersen K, Clement CA, Franks S, Hardy K, Andersen CY. Expression of TGF‐beta superfamily growth factors,their receptors, the associated SMADs and antagonists in five isolatedsize‐matched populations of pre‐antral follicles from normal humanovaries. MHR: Basic Sci Reproductive Med. 2014;20(4):293-308. PMid:24270394.

Lambalk CB, Banga FR, Huirne JA, Toftager M, Pinborg A, Homburg R, van der Veen F, van Wely M. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type. Hum Reprod Update. 2017;23(5):560-79. PMid:28903472.

Li F, Zhang M, Zhang YZ, Liu T, Qu XL. GnRH analogues may increase endometrial Hoxa10 promoter methylation and affect endometrial receptivity. Mol Med Rep. 2015;11(1):509-14. PMid:25323439.

Lv M, Yu JJ, Chen PQ, Xiao QM, Lou LQ, Luo YF, Yuan M, Xu Y, Feng YJ, Bai MZ, Zhang ZB, Li LX. Ovarian stimulation in IVF couples with severe male factor infertility: GnRH antagonist versus long GnRH agonist. Front Endocrinol. 2022;13:1037220. PMid:36277710.

Murber A, Fancsovits P, Ledo N, Gilan ZT, Rigo J Jr, Urbancsek J. Impact of GnRH analogues on oocyte/embryo quality and embryo development in in vitro fertilization/intracytoplasmic sperm injection cycles: a case control study. Reprod Biol Endocrinol. 2009;7(1):103. PMid:19781070.

Rabati BK, Zeidi SN. Investigation of pregnancy outcome and ovarian hyper stimulation syndrome prevention in agonist and antagonist gonadotropin-releasing hormone protocol. J Res Med Sci. 2012;17(11):1063-6. PMid:23833582.

Riepsamen AH, Donoghoe MW, Indran IR, Hechtman L, Robertson DM, Gilchrist RB, Ledger WL, Yong EL. Serum GDF9 and BMP15 as potential markers of ovarian function in women with and without polycystic ovary syndrome. Clin Endocrinol (Oxf). 2023;98(4):567-77. PMid:36372988.

Ruan HC, Zhu XM, Luo Q, Liu AX, Qian YL, Zhou CY, Jin F, Huang HF, Sheng JZ. Ovarian stimulation with GnRH agonist, but not GnRH antagonist, partially restores the expression of endometrial integrin 3 and leukaemia-inhibitory factor and improves uterine receptivity in mice. Hum Reprod. 2006;21(10):2521-9. PMid:16790614.

Sbracia M, Colabianchi J, Giallonardo A, Giannini P, Piscitelli C, Morgia F, Montigiani M, Schimberni M. Cetrorelix protocol versus gonadotropin-releasing hormone analog suppression long protocol for superovulation in intracytoplasmic sperm injection patients older than 40. Fertil Steril. 2009;91(5):1842-7. PMid:18501900.

Schachter M, Friedler S, Raziel A, Strassburger D, Bern O, Ron-el R. Improvement of IVF outcome in poor responders by discontinuation of GnRH analogue during the gonadotropin stimulation phase--a function of improved embryo quality. J Assist Reprod Genet. 2001;18(4):197-204. PMid:11432110.

Trenkić M, Popović J, Kopitović V, Bjelica A, Živadinović R, Pop-Trajković S. Flexible GnRH antagonist protocol vs. long GnRH agonist protocol in patients with polycystic ovary syndrome treated for IVF: comparison of clinical outcome and embryo quality. Ginekol Pol. 2016;87(4):265-70. PMid:27321097.

Uddin AHMM, Petrovski KR, Song Y, Garg S, Kirkwood RN. Application of exogenous GnRH in food animal production. Animals (Basel). 2023;13(12):1891. PMid:37370402.

Verpoest W, De Vos A, De Rycke M, Parikh S, Staessen C, Tournaye H, De Vos M, Vloeberghs V, Blockeel C. Gonadotropin releasing hormone agonists or antagonists for Preimplantation Genetic Diagnosis (PGD)? A prospective randomised trial. Curr Pharm Biotechnol. 2017;18(8):622-7. PMid:28786358.

Virant‐Klun I, Leicht S, Hughes C, Krijgsveld J. Identification of maturation‐specific proteins by single‐cell proteomics of humanoocytes. Mol Cell Proteomics. 2016;15(8):2616-27. PMid:27215607.

Wang J, Zhang J, Zhao N, Ma Y, Wang XY, Gou XQ, Ju Y, Zhang HD, Chen SQ, Wang XH. The effect of ovarian stimulation on aneuploidy of early aborted tissues and preimplantation blastocysts: comparison of the GnRH agonist long protocol with the GnRH antagonist protocol. J Assist Reprod Genet. 2022;39(8):1927-36. PMid:35767166.

Wei LN, Li LL, Fang C, Huang R, Liang XY. Inhibitory effects of controlled ovarian stimulation on the expression of GDF9 and BMP15 in oocytes from women with PCOS. J Assist Reprod Genet. 2013;30(10):1313-8. PMid:23912750.

Yang JW, Zhang XD, Ding XY, Wang YT, Huang GN, Ye H. Cumulative live birth rates between GnRH-agonist long and GnRH-antagonist protocol in one ART cycle when all embryos transferred: real-word data of 18,853 women from China. Reprod Biol Endocrinol. 2021;19(1):124-32. PMid:34384445.

Yang QY, Zhu LX, Jin L. Human follicle in vitro culture including activation, growth, and maturation: a review of research progress. Front Endocrinol. 2020;11:548. PMid:32849312.

Zanetti BF, Braga DPAF, Setti AS, Iaconelli A Jr, Borges E Jr. Effect of GnRH analogues for pituitary suppression on oocyte morphology in repeated ovarian stimulation cycles. JBRA Assist Reprod. 2020;24(1):24-9. PMid:31436072.

Zhang Y, Yan Z, Qin Q, Nisenblat V, Chang HM, Yu Y, Wang T, Lu C, Yang M, Yang S, Yao Y, Zhu X, Xia X, Dang Y, Ren Y, Yuan P, Li R, Liu P, Guo H, Han J, He H, Zhang K, Wang Y, Wu Y, Li M, Qiao J, Yan J, Yan L. Transcriptome landscape of humanfolliculogenesis reveals oocyte and granulosa cell interactions. Mol Cell. 2018;72(6):1021-34. PMid:30472193.

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