The Effect of Follitropin Alfa in Controlled Ovarian Stimulation Protocol for In Vitro Fertilization Cycles

Prasetiawati, Novitai; Sundari, Ayu; Supriyadi, Agus; Sjarbaini, Hadi; Tarigan, Sudirmanto; Suardana, Gde; Pariyanti, Gangsar; Indah, Deana; Purwatyningsih, Euis; Bowolaks, Anom

doi:10.18502/jri.v24i2.12499

The Effect of Follitropin Alfa in Controlled Ovarian Stimulation Protocol for In Vitro Fertilization Cycles

Authors

Novitai Prasetiawati ¹

Ayu Sundari ²

Agus Supriyadi ³

Hadi Sjarbaini ³

Sudirmanto Tarigan ³

Gde Suardana ³

Gangsar Pariyanti ³

Deana Indah ³

Euis Purwatyningsih ³

Anom Bowolaks ²

¹ Graduate School of Biology, Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Indonesia, Depok, Indonesia

² Graduate School of Biology, Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Indonesia, Depok, Indonesia; Cellular and Molecular Mechanisms in Biological Systems (CEMBIOS) Research Group, Department

³ Melati Infertility Clinic, Harapan Kita Women and Children Hospital, Jakarta, Indonesia

10.18502/jri.v24i2.12499

Abstract

Background: Follitropin alfa (FA) is one of the most widely used exogenous gonadotropins in both agonist and antagonist protocols for controlled ovarian stimulation (COS) and in vitro fertilization (IVF). However, reports of its effectiveness are limited, particularly in terms of its impact on overall IVF outcomes and ovarian hyperstimulation syndrome (OHSS). Therefore, in this study, FA competency was investigated by evaluating its effect on IVF outcomes and OHSS, administering agonist and antagonist COS protocols. Methods: A retrospective study with 120 subjects was conducted. Outcomes comprising the number of retrieved and fertilized oocytes, quality of embryos, and clinical pregnancies were assessed. Statistical correlation between FA dose, IVF outcomes, and the incidence of OHSS was also analyzed. All statistical analyses were performed at 95% confidence level. Results: There was no significant difference in both protocols regarding retrieved oocytes (p=0.604), fertilized oocytes (p=0.761), embryo quality including good, average, poor embryo (p=0.875, p=0.565, p=0.785), and clinical pregnancy (p=0.844). However, FA doses in the agonist protocol were shown notably higher (p=0.001). Negative correlations were also observed between FA dose and the number of retrieved oocytes (r=-0.255, p<0.01), fertilized oocytes (r=-0.296, p<0.01), and good quality embryos (r=-0.231, p<0.05). Conclusion: Our study suggested that FA yields similar outcomes in both COS protocols, but agonist protocols require higher doses of FA and evaluation of its effect on OHSS is an important area of research for further investigation.

Keywords

Agonist

Antagonist

Follitropin alfa

Gonadotropin releasing hormone (GnRH)

In vitro fertilization

OHSS

Lindenberg S, Almind GJ, Lindenberg FB. Is gonadotropin stimulation bad for oocytes? Curr Opin Obstet Gynecol. 2018;30(3):151-4.

Wang H, May J, Butnev V, Shuai B, May JV, Bousfield GR, et al. Evaluation of in vivo bioactivities of recombinant hypo- (FSH21/18) and fully- (FSH24) glycosylated human FSH glycoforms in Fshb null mice. Mol Cell Endocrinol. 2016;437:224-36.

Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, et al. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007;22(4):980-8.

Friedler S, Meltzer S, Saar-Ryss B, Rabinson J, Lazer T, Liberty G. An upper limit of gonadotropin dose in patients undergoing ART should be advocated. Gynecol Endocrinol. 2016;32(12):965-9.

Xu GF, Zhang JY, Pan HT, Tian S, Liu ME, Yu TT, et al. Cardiovascular dysfunction in offspring of ovarian-hyperstimulated women and effects of estradiol and progesterone: a retrospective cohort study and proteomics analysis. J Clin Endocrinol Metab. 2014;99(12):E2494-503.

Huirne JA, van Loenen AC, Schats R, McDonnell J, Hompes PG, Schoemaker J, et al. Dose-finding study of daily gonadotropin-releasing hormone (GnRH) antagonist for the prevention of premature luteinizing hormone surges in IVF/ICSI patients: antide and hormone levels. Hum Reprod. 2004;19(10):2206-15.

Newton CL, Riekert C, Millar RP. Gonadotropin-releasing hormone analog therapeutics. Minerva Ginecol. 2018;70(5):497-515.

Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2016;4(4):CD001750.

Lambalk CB, Banga FR, Huirne JA, Toftager M, Pinborg A, Homburg R, et al. 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.

Gay LR, Mills GE, Airasian P. Educational research: Competencies for analysis and application. United State of America: Pearson education; 2012. p. 145.

ESHRE special interest group of embryology and alpha scientists in reproductive medicine. The Vienna consensus: report of an expert meeting on the development of ART laboratory performance indicators. Reprod Biomed Online. 2017;35(5):494-510.

Golan A, Weissman A. Symposium: update on prediction and management of OHSS. a modern classification of OHSS. Reprod Biomed Online. 2009;19(1):28-32.

Lunenfeld B, Bilger W, Longobardi S, Alam V, D'Hooghe T, Sunkara SK. The development of gonadotropins for clinical use in the treatment of infertility. Front Endocrinol (Lausanne). 2019;10:429.

Mochtar MH, Dutch Ganirelix Study Group. The effect of an individualized GnRH antagonist protocol on folliculogenesis in IVF/ICSI. Hum Reprod. 2004;19(8):1713-8.

Stimpfel M, Vrtacnik-Bokal E, Pozlep B, Virant-Klun I. Comparison of GnRH agonist, GnRH antagonist, and GnRH antagonist mild protocol of controlled ovarian hyperstimulation in good prognosis patients. Int J Endocrinol. 2015;2015:385049.

Hsieh YY, Chang CC, Tsai HD. Comparisons of different dosages of gonadotropin-releasing hormone (GnRH) antagonist, short-acting form and single, half-dose, long-acting form of GnRH agonist during controlled ovarian hyperstimulation and in vitro fertilization. Taiwan J Obstet Gynecol. 2008;47(1):66-74.

Velthuis E, Hubbard J, Longobardi S, D'Hooghe T. The frequency of ovarian hyperstimulation syndrome and thromboembolism with originator recombinant human follitropin alfa (GONALl-f) for medically assisted reproduction: a systematic review. Adv Ther. 2020;37(12):4831-47.

Xiao JS, Su CM, Zeng XT. Comparisons of GnRH antagonist versus GnRH agonist protocol in supposed normal ovarian responders undergoing IVF: a systematic review and meta-analysis. PLoS One. 2014;9(9):e106854.

Sydow P, Gmeinwieser N, Pribbernow K, Keck C, Wiegratz I. Effectiveness and safety of follitropin alfa (Ovaleap®) for ovarian stimulation using a GnRH antagonist protocol in real-world clinical practice: a multicenter, prospective, open, non-interventional assisted reproductive technology study. Reprod Biol Endocrinol. 2020;18(1):54.

Lunenfeld B, Bilger W, Longobardi S, Kirsten J, D'Hooghe T, Sunkara SK. Decision points for individualized hormonal stimulation with recombinant gonadotropins for treatment of women with infertility. Gynecol Endocrinol. 2019;35(12):1027-36.

Iaconelli CAR, Setti AS, Braga DPAF, Maldonado LGL, Iaconelli A Jr, Borges E Jr, et al. Concomitant use of FSH and low-dose recombinant hCG during the late follicular phase versus conventional controlled ovarian stimulation for intracytoplasmic sperm injection cycles. Hum Fertil (Camb). 2017;20(4):285-92.

Hovatta O, McVeigh E, Lass A, Homburg R. A large Northern European observational study of follitropin alpha filled-by-mass pre-filled pen. Reprod Biomed Online. 2009;18(4):502-8.