Clinical and Molecular Effects of GnRH Agonist and Antagonist on The Cumulus Cells in The In Vitro Fertilization Cycle

Document Type : Original Article

Authors

1 Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Anatomical Sciences, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

Abstract

Background:
Gonadotropin-releasing hormone (GnRH) analogues have been extensively utilized in the ovarian s timulation
cycle for suppression of endogenous rapid enhancement of luteinizing hormone (LH surge). Exclusive properties
and functional mechanisms of GnRH analogues in in vitro fertilization (IVF) cycles are clearly described. This s tudy was
performed to evaluate clinical and molecular impacts of the GnRH agonis t and antagonis t protocols in IVF cycles. For
this purpose, gene expression of cumulus cells (CCs) as well as clinical and embryological parameters were evaluated
and compared between two groups (GnRH agonis t and antagonis t) during the IVF cycle.
Materials and Methods:
Twenty-one infertile individuals were enrolled in this s tudy. Subjects were
selected from two groups of GnRH agonis t (n=10) treated patients and GnRH antagonis t (n=11) treated individuals.
The defined clinical embryological parameters were compared between the two groups. Expression of BAX, BCL-2,
SURVIVIN, ALCAM, and VCAN genes were assessed in the CCs of the participants using the real-time polymerase
chain reaction (PCR) technique.
Results:
The mean number of cumulus oocyte complex (COC), percentage of metaphase II (MII) oocytes, grade A
embryo and clinical parameters did not show noticeable differences between the two groups. BAX gene expression in
the CCs of the group treated with GnRH agonis t was remarkably higher than those received GnRH antagonis t treatment
(P<0.001). The mRNA expression of BCL-2 and ALCM genes were considerably greater in the CCs of patients
who underwent antagonis t protocol in comparison to the group that received agonis t protocol (P<0.001).
Conclusion:
Despite no considerable difference in the oocyte quality, embryo development, and clinical outcomes between
the group treated with GnRH agonis t and the one treated with antagonis t protocol, the GnRH antagonis t protocol
was slightly more favorable. However, further clinical s tudies using molecular assessments are required to elucidate
this controversial subject.

Keywords

References

 
1. Xia L, Tian L, Tan J, Zhang S, Wu QF. GnRH antagonis t versus modified prolonged GnRH agonis t protocol in polycys tic ovary syndrome (pcos): analysis using propensity score matching. 2020. Available from: https://www.researchsquare.com/article/rs-63654/ v1. (31 Aug 2020)
2. Wu HM, Chang HM, Leung PC. Gonadotropin-releasing hormone analogs: mechanisms of action and clinical applications in female reproduction. Front Neuroendocrinol. 2020; 60: 100876.
3. Lin MH, Wu FSY, Hwu YM, Lee RKK, Li RS, Li SH. Dual trigger with gonadotropin releasing hormone agonis t and human chorionic gonadotropin significantly improves live birth rate for women with diminished ovarian reserve. Reprod Biol Endocrinol. 2019; 17: 7.
4. Chen Q, Yu F, Li Y, Zhang AJ, Zhu XB. Comparative proteomics reveal negative effects of gonadotropin-releasing hormone agonis t and antagonis t on human endometrium. Drug Des Devel Ther. 2019; 13: 1855-1863.
5. Güzel Y. Follicle-s timulating hormone induced in vitro growth of small antral follicles are not affected by gonadotropin-releasing hormone agonis t or antagonis t treatment in mice. Eur Arch Med Res. 2019; 35(4): 211-214.
6. Tabibnejad N, Sheikhha MH, Ghasemi N, Fesahat F, Soleimani M, Aflatoonian A. Association between early embryo morphokinetics plus cumulus cell gene expression and assis ted reproduction outcomes in polycys tic ovary syndrome women. Reprod Biomed Online. 2019; 38(2): 139-151.
7. Li Q, McKenzie LJ, Matzuk MM. Revisiting oocyte–somatic cell interactions: in search of novel intrafollicular predictors and regulators of oocyte developmental competence. Mol Hum Reprod. 2008; 14(12): 673-678.
8. Adriaenssens T, Segers I, Wathlet S, Smitz J. The cumulus cell gene expression profile of oocytes with different nuclear maturity and potential for blas tocys t formation. J Assis t Reprod Genet. 2011; 28(1): 31-40.
9. Nagyova E, Salus tri A, Nemcova L, Scsukova S, Kalous J, Camaioni A. Versican G1 fragment es tablishes a s trongly s tabilized interaction with hyaluronan-rich expanding matrix during oocyte maturation. Int J Mol Sci. 2020; 21(7): 2267.
10. Wei LL, Pan YS, Tang Q, Yang ZJ, Song WQ, Gao YF, et al. Decreased ALCAM expression and promoter hypermethylation is associated with preeclampsia. Hypertens Res. 2019; 43(1): 13-22.
11. Adriaenssens T, Van Vaerenbergh I, Coucke W, Segers I, Verheyen G, Anckaert E, et al. Cumulus-corona gene expression analysis combined with morphological embryo scoring in single embryo transfer cycles increases live birth after fresh transfer and decreases time to pregnancy. J Assis t Reprod Genet. 2019; 36(3): 433-443.
12. Jančar N, Kopitar AN, Ihan A, Klun IV, Bokal EV. Effect of apoptosis and reactive oxygen species production in human granulosa cells on oocyte fertilization and blas tocys t development. J Assis t Reprod Genet. 2007; 24(2-3): 91-97.
13. Chermuła B, Kranc W, Jopek K, Budna-Tukan J, Hutchings G, Dompe C, et al. Human cumulus cells in long-term in vitro culture reflect differential expression profile of genes responsible for planned cell death and aging—a s tudy of new molecular markers. Cells. 2020; 9(5): 1265.
14. Faramarzi A, Khalili MA, Jahromi MG. Is there any correlation between apoptotic genes expression in cumulus cells with embryo morphokinetics? Mol Biol Rep. 2019; 46: 3663-3670.
15. Johnson AL, Langer JS, Bridgham JT. Survivin as a cell cycle-related and antiapoptotic protein in granulosa cells. Endocrinology. 2002; 143(9): 3405-3413.
16. Jiang Z, Hu M, Wang Z, Huang L, Lin F, Qi S, et al. Survivin is essential for fertile egg production and female fertility in mice. Cell Death Dis. 2014; 5(3): e1154.
17. Demiray SB, Goker ENT, Tavmergen E, Yilmaz O, Calimlioglu N, Soykam HO, et al. Differential gene expression analysis of human cumulus cells. Clin Exp Reprod Med. 2019; 46(2): 76-87.
18. Hussein MR. Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update. 2005; 11(2): 162-178.
19. Chi XX, Zhang T, Chu XL, Zhen JL, Zhang DJ. The regulatory effect of Genis tein on granulosa cell in ovary of rat with PCOS through Bcl-2 and Bax signaling pathways. J Vet Med Sci. 2018; 80(8): 1348-1355.
20. Mathyk BA, Cetin BA, Vardagli D, Zengin E, Sofiyeva N, Irez T, et al. Comparison of antagonis t mild and long agonis t protocols in terms of follicular fluid total antioxidant capacity. Taiwan J Obs tet Gyne. 2018; 57(2): 194-199.
21. Lee SH, Oh HJ, Kim MJ, Lee BC. Exosomes derived from oviduct cells mediate the EGFR/MAPK signaling pathway in cumulus cells. J Cell Physiol. 2020; 235(2): 1386-1404.
22. S tamperna K, Giannoulis T, Nanas I, Kalemkeridou M, Dadouli K, Moutou K, et al. Short term temperature elevation during IVM affects embryo yield and alters gene expression pattern in oocytes, cumulus cells and blas tocys ts in cattle. Theriogenology. 2020; 156: 36-45.
23. Devjak R, Papler TB, Verdenik I, Tacer KF, Bokal EV. Embryo quality predictive models based on cumulus cells gene expression. Balkan J Med Genet. 2016; 19(1) :5-12.
24. Clavero A, Cas tilla JA, Núñez AI, Garcı́a-Peña ML, Maldonado V, Fontes J, et al. Apoptosis in human granulosa cells after induction of ovulation in women participating in an intracytoplasmic sperm injection program. Eur J Obs tet Gynecol Reprod Biol. 2003; 110(2):181-185.
25. Lee KS, Joo BS, Na YJ, Yoon MS, Choi OH, Kim WW. Clinical assis ted reproduction: cumulus cells apoptosis as an indicator to predict the quality of oocytes and the outcome of IVF–ET. J Assis t Reprod Genet. 2001; 18(9): 490-498.
26. Van Montfoort AP, Dumoulin JC, Kes ter AD, Evers JL. Early cleavage is a valuable addition to exis ting embryo selection parameters: a s tudy using single embryo transfers. Hum Reprod. 2004; 19(9): 2103-2108.
27. Varras M, Polonifi K, Mantzourani M, S tefanidis K, Papadopoulos Z, Akrivis C, et al. Expression of antiapoptosis gene survivin in luteinized ovarian granulosa cells of women undergoing IVF or ICSI and embryo transfer: clinical correlations. Reprod Biol Endocrinol. 2012; 10(1): 74.
28. Assou S, Haouzi D, Mahmoud K, Aouacheria A, Guillemin Y, Pantesco V, et al. A non-invasive tes t for assessing embryo potential by gene expression profiles of human cumulus cells: a proof of concept s tudy. Mol Hum Reprod. 2008; 14(12): 711-719.
29. Geng Y, Xun Y, Hu S, Lai Q, Jin L. GnRH antagonis t versus follicular-phase single-dose GnRH agonis t protocol in patients of normal ovarian responses during controlled ovarian s timulation. Gynecol Endocrinol. 2019; 35(4): 309-313.
30. Kara M, Aydin T, Aran T, Turktekin N, Ozdemir B. Comparison of GnRH agonis t and antagonis t protocols in normoresponder patients who had IVF-ICSI. Arch Gynecol Obs tet. 2013; 288(6): 1413-1416.
31. Prapas Y, Petousis S, Dagklis T, Panagiotidis Y, Papatheodorou A, Assunta I, et al. GnRH antagonis t versus long GnRH agonis t protocol in poor IVF responders: a randomized clinical trial. Eur J Obs tet Gynecol Reprod Biol. 2013; 166(1): 43-46.
32. Takahashi K, Mukaida T, Tomiyama T, Goto T, Oka C. GnRH antagonis t improved blas tocys t quality and pregnancy outcome after multiple failures of IVF/ICSI–ET with a GnRH agonis t protocol. J Assis t Reprod Genet. 2004; 21(9): 317-322.
33. de Souza Jordão ÉV, Nakagawa HM, Es trela FS, de Morais RB, Gomes-Sobrinho DB, de Carvalho BR. Outcomes of GnRH agonis t and GnRH antagonis t regimens for IVF in women aged up to 40. Acta Med. 2016; 3(1): 46-49.
34. Xiao Js, Su Cm, Zeng Xt. Comparisons of GnRH antagonis t versus GnRH agonis t protocol in supposed normal ovarian responders undergoing IVF: a sys tematic review and meta-analysis. PLoS One. 2014; 9(9): e106854.
35. Adriaenssens T, Wathlet S, Segers I, Verheyen G, De Vos A, Van der Els t J, et al. Cumulus cell gene expression is associated with oocyte developmental quality and influenced by patient and treatment characteris tics. Hum Reprod. 2010; 25(5): 1259-1270.
36. Fujiwara H, Tatsumi K, Kosaka K, Sato Y, Higuchi T, Yoshioka S, et al. Human blas tocys ts and endometrial epithelial cells express activated leukocyte cell adhesion molecule (ALCAM/CD166). J Clin Endocrinol Metab. 2003; 88(7): 3437-3443.
37. Hernandez-Gonzalez I, Gonzalez-Robayna I, Shimada M, Wayne CM, Ochsner SA, White L, et al. Gene expression profiles of cumulus cell oocyte complexes during ovulation reveal cumulus cells express neuronal and immune-related genes: does this expand their role in the ovulation process? Mol Endocrinol. 2006; 20(6): 1300-1321.
International Journal of Fertility and Sterility
Volume 15, Issue 3
July 2021
Pages 202-209

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