Effect of Metformin on Premature Luteinization and Pregnancy Outcomes in Intracytoplasmic Sperm Injection-Fresh Embryo Transfer Cycles: A Randomized Double-Blind Controlled Trial

Hussein, Reda S.; Elnashar, Ihab; Amin, Ahmed F; Zhao, Yulian; Abdelmagied, Ahmed M.; Abbas, Ahmed M.; Abdelaleem, Ahmed A.; Farghaly, Tarek A.; Abdalmageed, Osama S; Youssef, Ahmed A.; Badran, Esraa; Abou-Taleb, Hisham A.

doi:10.22074/ijfs.2020.134643

Effect of Metformin on Premature Luteinization and Pregnancy Outcomes in Intracytoplasmic Sperm Injection-Fresh Embryo Transfer Cycles: A Randomized Double-Blind Controlled Trial

Document Type : Original Article

Authors

¹ Department of Obstetrics and Gynecology, Faculty of Medicine, Assiut University, Assiut, Egypt

² Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, USA

³ Department of Obstetrics and Gynecology, Taibah University, Medina, KSA

10.22074/ijfs.2020.134643

Abstract

Background: Premature luteinization (PL) is not unusual in in vitro fertilization (IVF) and could not be wholly
avoided by using either gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonist regimens. The study
aims to evaluate metformin’s efficacy in preventing PL in fresh GnRH antagonist intracytoplasmic sperm injection
(ICSI) cycles with cleavage-stage embryo transfer.

Materials and Methods: This randomized, double-blind, placebo-controlled trial was conducted in a tertiary university
IVF center. We recruited infertile women who were scheduled to perform their first or second ICSI trial. Eligible
women were recruited and randomized in a 1:1 ratio into two groups. Metformin was administered in a dose of 1500
mg per day since the start of contraceptive pills in the cycle antecedent to stimulation cycle until the day of ovulation
triggering, while women in the placebo group received a placebo for the same regimen and duration. The primary
outcome was the incidence of PL, defined as serum progesterone (P) on the triggering day ≥1.5 ng/mL. Secondary
outcomes comprised the live birth, ongoing pregnancy, implantation, and good-quality embryos rates.

Results: The trial involved 320 eligible participants (n=160 in each group). Both groups had comparable stimulation
days, endometrial thickness, peak estradiol levels, number of oocytes retrieved, and number of mature oocytes. Metformin
group experienced lower level of serum P (p <0.001) and incidence of PL (10 vs. 23.6%, P=0.001). Moreover,
lower progesterone/estradiol (P/E) ratio and progesterone to mature oocyte index (PMOI) (P=0.002 and P=0.002,
respectively) were demonstrated in women receiving metformin. Metformin group generated a better rate of goodquality
embryos (P=0.005) and ongoing pregnancy (43.8 vs. 31.8%, P=0.026). A similar trend, though of borderline
significance, was observed in the live birth rate in favor of metformin administration (38.15 vs. 27.5%, P=0.04).

Conclusion: Metformin could be used in patients with potential PL to improve fresh cycle outcomes by preventing PL
(Registration number: NCT03088631).

Keywords

20.1001.1.2008076.2021.15.2.5.1

References

1. Hussein RS, Elnashar I, Amin AF, Abou-Taleb HA, Abbas AM, Abdelmageed AM, et al. Revisiting debates of premature luteinization and its effect on assisted reproductive technology outcome. J Assist Reprod Genet. 2019; 36(11): 2195-2206.

2. Santos-Ribeiro S, Polyzos NP, Haentjens P, SmitzJ, Camus M, Tournaye H. et al. Live birth rates after IVF are reduced by both low and high progesterone levels on the day of human chorionic gonadotrophin administration. Hum Reprod. 2014; 29(8): 1698-1705

3. Venetis CA, Kolibianakis EM, Bosdou JK, Tarlatzis BC. Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles. Hum Reprod Update. 2013; 19(5): 433-457.

4. Shanker U, Lawrenz B, Bungum L, Depret Bixio L, Ruiz F, Coughlan C, et al. Significant serum progesterone variations on the day of final oocyte maturation in stimulated IVF cycles. Front Endocrinol (Lausanne). 2019; 10: 806.

5. Venetis CA, Kolibianakis EM, Bosdou JK, Lainas GT, Sfontouris IA, Tarlatzis BC, et al. Estimating the net effect of progesterone elevation on the day of hCG on live birth rates after IVF: a cohort analysis of 3296 IVF cycles. Hum Reprod. 2015; 30(3): 684-691.

6. Xu B, Li Z, Zhang H, Jin L, Li Y, Ai J, et al. Serum progesterone level effects on the outcome of in vitro fertilization in patients with different ovarian response: an analysis of more than 10,000 cycles. Ferti Steril. 2012; 97(6): 1321-1327. e1-4

7. Simon C, Branet L, Moreau J, Gatimel N, Cohade C, Lesourd F, et al. Association between progesterone to number of mature oocytes index and live birth in GnRH antagonist protocols. Reprod Biomed Online. 2019; 38(6): 901-907.

8. Kaponis A, Chronopoulou E, Decavalas G. The curious case of premature luteinization. J Assist Reprod Genet. 2018; 35(10): 1723-1740.

9. Fatemi HM, Garcia-Velasco J. Avoiding ovarian hyperstimulation syndrome with the use of gonadotropin-releasing hormone agonist trigger. Fertil Steril. 2015; 103: 870-873.

10. Manno M, Tomei F. Can we prevent premature luteinization in IVF cycles? Med Hypotheses. 2014; 82(1): 122-123.

11. Refuerzo JS, Viteri OA, Hutchinson M, Pedroza C, Blackwell SC, Tyson JE, et al. The effects of metformin on weight loss in women with gestational diabetes: a pilot randomized, placebo-controlled trial. Am J Obstet Gynecol. 2015; 212(3): 389. e1-9.

12. Mansfield R, Galea R, Brincat M, Hole D, Mason H. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril. 2003; 79(4): 956-962.

13. Wu Y, Tu M, Huang Y, Liu Y, Zhang D. Association of metformin with pregnancy outcomes in women with polycystic ovarian syndrome undergoing in vitro fertilization: a systematic review and meta-analysis. JAMA Netw Open. 2020; 3(8): e2011995.

14. Busnelli A, Somigliana E. Prognosis and cost-effectiveness of IVF in poor responders according to the Bologna Criteria. Minerva Ginecol. 2018; 70(1): 89-98.

15. Volpes A, Sammartano F, Coffaro F, Mistretta V, Scaglione P, Allegra A. Number of good quality embryos on day 3 is predictive for both pregnancy and implantation rates in in vitro fertilization/intracytoplasmic sperm injection cycles. Fertil Steril. 2004; 82(5): 1330-1336.

16. Yang X, Lin G, Lu G, Gong F. Letrozole supplementation during controlled ovarian stimulation in expected high responders: a pilot randomized controlled study. Reprod Biol Endocrinol. 2019; 17(1): 43.

17. Rose BI, Laky DC, Rose SD. A comparison of the use of clomiphene citrate and letrozole in patients undergoing IVF with the objective of producing only one or two embryos. Facts Views Vis Obgyn. 2015;

7(2): 119-126.

18. Abbara A, Vuong LN, Ho VNA, Clarke SA, Jeffers L, Comninos AN, et al. Follicle size on day of trigger most likely to yield a mature oocyte. Front Endocrinol (Lausanne). 2018; 9: 193.

19. Bedaiwy MA, Shokry M, Mousa N, Claessens A, Esfandiari N, Gotleib L, et al. Letrozole co-treatment in infertile women 40 years old and older receiving controlled ovarian stimulation and intrauterine insemination. Fertil Steril. 2009; 91(6): 2501-2507.

20. Golbasi H, Ince O, Golbasi C, Ozer M, Demir M, Yilmaz B. Effect of progesterone/estradiol ratio on pregnancy outcome of patients with high trigger-day progesterone levels undergoing gonadotropin-releasing hormone antagonist intracytoplasmic sperm injection cycles: a retrospective cohort study. J Obstet Gynaecol. 2019; 39(2): 157-163.

21. Xiong Y, Hu L, Zhang T, Wang M, Xu H, Li TC, et al. Effects of high progesterone in in-vitro fertilization cycle on DNA methylation and gene expression of adhesion molecules on endometrium during implantation window. J Assist Reprod Genet. 2020; 37(1): 33-43.

22. Baldini D, Savoia MV, Sciancalepore AG, Malvasi A, Vizziello D, Beck R, et al. High progesterone levels on the day of HCG administration do not affect the embryo quality and the reproductive outcomes of frozen embryo transfers. Clin Ter. 2018; 169(3): e91-e95.

23. Racca A, Santos-Ribeiro S, Munck ND, Mackens S, Drakopoulos P, Camus M, et al. Impact of late-follicular phase elevated serum progesterone on cumulative live birth rates: is there a deleterious effect on embryo quality? Hum Reprod. 2018; 33(5): 860-868.

24. Bu Z, Zhao F, Wang K, Guo Y, Su Y, Zhai J,et al. Serum progesterone elevation adversely affects cumulative live birth rate in different ovarian responders during in vitro fertilization and embryo transfer: a large retrospective study. PLoS One. 2014; 9(6): e100011.

25. Huang B, Ren X, Wu L, Zhu L, Xu B, Li Y, et al. Elevated progesterone levels on the day of oocyte maturation may affect top quality embryo IVF cycles. PLoS One. 2016; 11(1): e0145895.

26. Vanni VS, Somigliana E, Reschini M, Pagliardini L, Marotta E, Faulisi S, et al. Top quality blastocyst formation rates in relation to progesterone levels on the day of oocyte maturation in GnRH antagonist IVF/ICSI cycles. PLoS One. 2017; 12(5): e0176482.

27. Jinno M, Kondou K, Teruya K. Low-dose metformin improves pregnancy rate in in vitro fertilization repeaters without polycystic ovary syndrome: Prediction of effectiveness by multiple parameters related to insulin resistance. Hormones (Athens). 2010; 9(2): 161-170.

28. Christianson MS, Wu H, Zhao Y,Yemini M, Leong M, Shohamet Z. Metformin use in patients undergoing in vitro fertilization treatment: results of a worldwide web-based survey. J Assist Reprod Genet. 2015; 32(3): 401-406.

29. Kollmann M, Martins WP, Lima MLS, Craciunas L, Nastri CO, Richardson A, et al. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2016; 48(6): 709-718.

30. Sharpe A, Morley LC, Tang T, Norman RJ, BalenAH. Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2019; 12(12): CD013505.

31. Tso LO, Costello MF, Albuquerque LET, Andriolo RB, Macedo CR. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2014; 2014(11): CD006105.

32. Singh N, Kaur SD, Malik N, Malhotra N, Vanamail P. Do increased levels of progesterone and progesterone/estradiol ratio on the day of human chorionic gonadotropin affects pregnancy outcome in long agonist protocol in fresh in vitro fertilization/intracytoplasmic sperm injection cycles? J Hum Reprod Sci. 2015; 8(2): 80-85.

33. Esteves SC, Khastgir G, Shah J, Murdia K, Gupta SM, Rao DG, et al. Association between progesterone elevation on the day of human chronic gonadotropin trigger and pregnancy outcomes after fresh embryo transfer in in vitro fertilization/intracytoplasmic sperm injection cycles. Front Endocrinol. 2018; 9: 201.

34. Smitz J, Platteau P. Influence of human chorionic gonadotrophin during ovarian stimulation: an overview. Reprod Biol Endocrinol. 2020; 18: 80.

35. Kolibianakis EM, Albano C, Camus M, Tournaye H, Steirteghem ACV, Devroey P. Prolongation of the follicular phase in in vitro fertilization results in a lower ongoing pregnancy rate in cycles stimulated with recombinant follicle-stimulating hormone and gonadotropin-releasing hormone antagonists. Fertil Steril. 2004; 82(1): 102-107

36. Ji Z, Quan X, Lan Y, Zhao M, Tian X, Yang X. Gonadotropin versus follicle-stimulating hormone for ovarian response in patients undergoing in vitro fertilization: a retrospective cohort comparison. Curr Ther Res Clin Exp. 2020; 92: 100572.

37. Herbemont C, Sarandi S, Boujenah J, Cedrin-Durnerin I, Sermondade N, Vivot A, et al. Should we consider day-2 and day-3 embryo morphology before day-5 transfer when blastocysts reach a similar good quality? Reprod Biomed Online. 2017; 35(5): 521- 528.

38. Mizobe Y, Tokunaga M, Oya N, Iwakiri R, Yoshida N, Sato Y, et al. Synchrony of the first division as an index of the blastocyst formation rate during embryonic development. Reprod Med Biol. 2018; 17(1): 64-70.