Improving Implantation Rate in 2nd ICSI Cycle through Ovarian Stimulation with FSH and LH in GNRH Antagonist Regimen

Amanda Souza Setti; Daniela Paes de Almeida Ferreira Braga; Assumpto Iaconelli Júnior; Edson Borges Júnior

doi:10.1055/s-0041-1736306

Revista Brasileira de Ginecologia e Obstetrícia / RBGO Gynecology and Obstetrics, Table of Contents

CC BY 4.0 · Rev Bras Ginecol Obstet 2021; 43(10): 749-758
DOI: 10.1055/s-0041-1736306

Original Article

Assisted Fertilization

Improving Implantation Rate in 2nd ICSI Cycle through Ovarian Stimulation with FSH and LH in GNRH Antagonist Regimen

Melhorando a taxa de implantação no 2° ciclo de ICSI através do estímulo ovariano com FSH e LH no regime com antagonista do GnRH

Amanda Souza Setti

¹Fertility Medical Group, São Paulo, SP, Brazil

,

Daniela Paes de Almeida Ferreira Braga

¹Fertility Medical Group, São Paulo, SP, Brazil

,

Assumpto Iaconelli Júnior

¹Fertility Medical Group, São Paulo, SP, Brazil

,

Edson Borges Júnior

¹Fertility Medical Group, São Paulo, SP, Brazil

› Author Affiliations

Abstract

Objective To investigate whether patients with a previous recombinant follicle stimulating hormone (rFSH)-stimulated cycle would have improved outcomes with rFSH + recombinant luteinizing hormone (rLH) stimulation in the following cycle.

Methods For the present retrospective case-control study, 228 cycles performed in 114 patients undergoing intracytoplasmic sperm injection (ICSI) between 2015 and 2018 in an in vitro fertilization (IVF) center were evaluated. Controlled ovarian stimulation (COS) was achieved with rFSH (Gonal-f, Serono, Geneva, Switzerland) in the first ICSI cycle (rFSH group), and with rFSH and rLH (Pergoveris, Merck Serono S.p.A, Bari, Italy) in the second cycle (rFSH + rLH group). The ICSI outcomes were compared among the groups.

Results Higher estradiol levels, oocyte yield, day-3 high-quality embryos rate and implantation rate, and a lower miscarriage rate were observed in the rFSH + rLH group compared with the rFSH group. In patients < 35 years old, the implantation rate was higher in the rFSH + rLH group compared with the rFSH group. In patients ≥ 35 years old, higher estradiol levels, oocyte yield, day-3 high-quality embryos rate, and implantation rate were observed in the rFSH + rLH group. In patients with ≤ 4 retrieved oocytes, oocyte yield, mature oocytes rate, normal cleavage speed, implantation rate, and miscarriage rate were improved in the rFSH + rLH group. In patients with ≥ 5 retrieved oocytes, higher estradiol levels, oocyte yield, and implantation rate were observed in the rFSH + rLH group.

Conclusion Ovarian stimulation with luteinizing hormone (LH) supplementation results in higher implantation rates, independent of maternal age and response to COS when compared with previous cycles stimulated with rFSH only. Improvements were also observed for ICSI outcomes and miscarriage after stratification by age and retrieved oocytes.

Resumo

Objetivo: Investigar se há algum efeito da suplementação com hormônio luteinizante (LH, na sigla em inglês) no regime com antagonista do hormônio liberador de gonadotropina (GnRH, na sigla em inglês) sobre os resultados dos ciclos consecutivos de injeção intracitoplasmática de espermatozoides (ICSI, na sigla em inglês).

Métodos Para o presente estudo retrospectivo de caso-controle, foram avaliados 228 ciclos de microinjeção intracitoplasmática de espermatozoides (ICSI, na sigla em inglês) realizados em 114 pacientes entre 2015 e 2018 em um centro privado de fertilização in vitro (FIV) afiliado a uma universidade. O estímulo ovariano controlado (EOC) foi feito com hormônio folículo- estimulante recombinante (rFSH, na sigla em inglês) (Gonal-f, Serono, Genebra, Suíça) no primeiro ciclo de ICSI (grupo rFSH), e com rFSH e rLH (Pergoveris, Merck Serono S.p.A, Bari, Itália) no segundo ciclo (grupo rFSH + rLH). Os desfechos dos ciclos de ICSI foram comparados entre os grupos.

Resultados Níveis mais elevados de estradiol, de recuperação oocitária, taxa de embriões de alta qualidade no 3° dia e taxa de implantação, e menor taxa de aborto foram observados no grupo rFSH + rLH. Em pacientes < 35 anos, a taxa de implantação foi maior no grupo rFSH + rLH em comparação com o grupo rFSH. Em pacientes com ≥ 35 anos, maiores níveis de estradiol, recuperação oocitária, a taxa de embriões de alta qualidade no 3° dia e a taxa de implantação foram observados no grupo rFSH + rLH. Em pacientes com baixa resposta ao EOC (≤ 4 oócitos recuperados), a recuperação oocitária, a taxa de oócitos maduros, a taxa de velocidade normal de clivagem, a taxa de implantação e a taxa de aborto foram melhoradas no grupo rFSH + rLH. Em pacientes com resposta normal ao EOC (≥ 5 oócitos recuperados), níveis mais elevados de estradiol, recuperação oocitária e taxa de implantação foram observados no grupo rFSH + rLH.

Conclusão A estimulação ovariana com suplementação de LH resultou em taxas de implantação mais altas, independentemente da idade materna e da resposta ao EOC, em comparação com os ciclos anteriores estimulados apenas com rFSH. Melhorias também foram observadas nos resultados da ICSI e na taxa de aborto quando as pacientes foram estratificadas por idade e número de oócitos recuperados.

Keywords

follicle-stimulating hormone - intracytoplasmic sperm injection implantation - luteinizing hormone - ovarian stimulation

Palavras-chave

hormônio folículo- estimulante - microinjeção intracitoplasmática de espermatozoides - hormônio luteinizante - estímulo ovariano

Full Text

References

References
1 Raju GA, Chavan R, Deenadayal M, Gunasheela D, Gutgutia R, Haripriya G. et al. Luteinizing hormone and follicle stimulating hormone synergy: A review of role in controlled ovarian hyper-stimulation. J Hum Reprod Sci 2013; 6 (04) 227-234 DOI: 10.4103/0974-1208.126285.
2 Mochtar MH, Van der Veen F, Ziech M, van Wely M. Recombinant Luteinizing Hormone (rLH) for controlled ovarian hyperstimulation in assisted reproductive cycles. Cochrane Database Syst Rev 2007; (02) CD005070 DOI: 10.1002/14651858.CD005070.pub2.
3 Hill MJ, Levens ED, Levy G, Ryan ME, Csokmay JM, DeCherney AH. et al. The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and meta-analysis. Fertil Steril 2012; 97 (05) 1108-14.e1 DOI: 10.1016/j.fertnstert.2012.01.130.
4 Alviggi C, Clarizia R, Mollo A, Ranieri A, De Placido G. Who needs LH in ovarian stimulation?. Reprod Biomed Online 2011; 22 (Suppl. 01) S33-S41 DOI: 10.1016/S1472-6483(11)60007-2.
5 Alviggi C, Humaidan P, Ezcurra D. Hormonal, functional and genetic biomarkers in controlled ovarian stimulation: tools for matching patients and protocols. Reprod Biol Endocrinol 2012; 10: 9 DOI: 10.1186/1477-7827-10-9.
6 Bosch E, Labarta E, Crespo J, Simón C, Remohí J, Pellicer A. Impact of luteinizing hormone administration on gonadotropin-releasing hormone antagonist cycles: an age-adjusted analysis. Fertil Steril 2011; 95 (03) 1031-1036 DOI: 10.1016/j.fertnstert.2010.10.021.
7 Hill MJ, Levy G, Levens ED. Does exogenous LH in ovarian stimulation improve assisted reproduction success? An appraisal of the literature. Reprod Biomed Online 2012; 24 (03) 261-271 DOI: 10.1016/j.rbmo.2011.12.005.
8 Humaidan P, Bungum M, Bungum L, Yding Andersen C. Effects of recombinant LH supplementation in women undergoing assisted reproduction with GnRH agonist down-regulation and stimulation with recombinant FSH: an opening study. Reprod Biomed Online 2004; 8 (06) 635-643 DOI: 10.1016/s1472-6483(10)61643-4.
9 Matorras R, Prieto B, Exposito A, Mendoza R, Crisol L, Herranz P. et al. Mid-follicular LH supplementation in women aged 35-39 years undergoing ICSI cycles: a randomized controlled study. Reprod Biomed Online 2009; 19 (06) 879-887 DOI: 10.1016/j.rbmo.2009.09.016.
10 Wong PC, Qiao J, Ho C, Ramaraju GA, Wiweko B, Takehara Y. et al; Asia Pacific Fertility Advisory Group. Current opinion on use of luteinizing hormone supplementation in assisted reproduction therapy: an Asian perspective. Reprod Biomed Online 2011; 23 (01) 81-90 DOI: 10.1016/j.rbmo.2011.03.023.
11 Mochtar MH, Danhof NA, Ayeleke RO, Van der Veen F, van Wely M. Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles. Cochrane Database Syst Rev 2017; 5 (05) CD005070 DOI: 10.1002/14651858.CD005070.pub3.
12 Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992; 340 (8810): 17-18 DOI: 10.1016/0140-6736(92)92425-f.
13 Balasch J, Creus M, Fábregues F, Carmona F, Puerto B, Casamitjana R. et al. The effect of exogenous luteinizing hormone (LH) on oocyte viability: evidence from a comparative study using recombinant human follicle-stimulating hormone (FSH) alone or in combination with recombinant LH for ovarian stimulation in pituitary-suppressed women undergoing assisted reproduction. J Assist Reprod Genet 2001; 18 (05) 250-256 DOI: 10.1023/a:1016662100572.
14 Caserta D, Lisi F, Marci R, Ciardo F, Fazi A, Lisi R. et al. Does supplementation with recombinant luteinizing hormone prevent ovarian hyperstimulation syndrome in down regulated patients undergoing recombinant follicle stimulating hormone multiple follicular stimulation for IVF/ET and reduces cancellation rate for high risk of hyperstimulation?. Gynecol Endocrinol 2011; 27 (11) 862-866 DOI: 10.3109/09513590.2010.544133.
15 Wiser A, Hourvitz A, Yinon Y, Levron J, Dor J, Elizur S. Recombinant human luteinizing hormone supplementation may improve embryo quality in in vitro fertilization/intracytoplasmic sperm injection cycles with gonadotropin-releasing hormone antagonist protocol. Open J Obstet Gynecol 2011; 1 (02) 31-35 DOI: 10.4236/ojog.2011.12007.
16 Cédrin-Durnerin I, Grange-Dujardin D, Laffy A, Parneix I, Massin N, Galey J. et al. Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study. Hum Reprod 2004; 19 (09) 1979-1984 DOI: 10.1093/humrep/deh369.
17 Griesinger G, Schultze-Mosgau A, Dafopoulos K, Schroeder A, Schroer A, von Otte S. et al. Recombinant luteinizing hormone supplementation to recombinant follicle-stimulating hormone induced ovarian hyperstimulation in the GnRH-antagonist multiple-dose protocol. Hum Reprod 2005; 20 (05) 1200-1206 DOI: 10.1093/humrep/deh741.
18 Levi-Setti PE, Cavagna M, Bulletti C. Recombinant gonadotrophins associated with GnRH antagonist (cetrorelix) in ovarian stimulation for ICSI: comparison of r-FSH alone and in combination with r-LH. Eur J Obstet Gynecol Reprod Biol 2006; 126 (02) 212-216 DOI: 10.1016/j.ejogrb.2005.11.023.
19 Musters AM, van Wely M, Mastenbroek S, Kaajk EM, Repping S, van der Veen F. et al. The effect of recombinant LH on embryo quality: a randomized controlled trial in women with poor ovarian reserve. Hum Reprod 2012; 27 (01) 244-250 DOI: 10.1093/humrep/der371.
20 NyboeAndersen A, Humaidan P, Fried G, Hausken J, Antila L. Banhsbøll, et al; Nordic LH study group. Recombinant LH supplementation to recombinant FSH during the final days of controlled ovarian stimulation for in vitro fertilization. A multicentre, prospective, randomized, controlled trial. Hum Reprod 2008; 23 (02) 427-434 DOI: 10.1093/humrep/dem317.
21 Marrs R, Meldrum D, Muasher S, Schoolcraft W, Werlin L, Kelly E. Randomized trial to compare the effect of recombinant human FSH (follitropin alfa) with or without recombinant human LH in women undergoing assisted reproduction treatment. Reprod Biomed Online 2004; 8 (02) 175-182 DOI: 10.1016/s1472-6483(10)60513-5.
22 Berkkanoglu M, Isikoglu M, Aydin D, Ozgur K. Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders. Fertil Steril 2007; 88 (03) 665-669 DOI: 10.1016/j.fertnstert.2006.11.150.
23 Ferraretti AP, Gianaroli L, Magli MC, D'angelo A, Farfalli V, Montanaro N. Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. Fertil Steril 2004; 82 (06) 1521-1526 DOI: 10.1016/j.fertnstert.2004.06.041.
24 Motta E, Massaguer A, Serafini P, Beltrame A, Yadid I, Coslowsky M. Supplementation with rec-FSH or rec-LH is equally effective to modulate sub-optimal response for IVF cycles. A prospective randomized trial. Hum Reprod 2005; 20 (Suppl. 01) i125
25 Barrenetxea G, Agirregoikoa JA, Jiménez MR, de Larruzea AL, Ganzabal T, Carbonero K. Ovarian response and pregnancy outcome in poor-responder women: a randomized controlled trial on the effect of luteinizing hormone supplementation on in vitro fertilization cycles. Fertil Steril 2008; 89 (03) 546-553 DOI: 10.1016/j.fertnstert.2007.03.088.
26 Fábregues F, Creus M, Peñarrubia J, Manau D, Vanrell JA, Balasch J. Effects of recombinant human luteinizing hormone supplementation on ovarian stimulation and the implantation rate in down-regulated women of advanced reproductive age. Fertil Steril 2006; 85 (04) 925-931 DOI: 10.1016/j.fertnstert.2005.09.049.
27 Lisi F, Rinaldi L, Fishel S, Pepe GP, Picconeri MG, Campbell A. et al. Use of recombinant LH in a group of unselected IVF patients. Reprod Biomed Online 2002; 5 (02) 104-108 DOI: 10.1016/s1472-6483(10)61610-0.
28 Lahoud R, Ryan J, Illingworth P, Quinn F, Costello M. Recombinant LH supplementation in patients with a relative reduction in LH levels during IVF/ICSI cycles: A prospective randomized controlled trial. Eur J Obstet Gynecol Reprod Biol 2017; 210: 300-305 DOI: 10.1016/j.ejogrb.2017.01.011.
29 Oliveira JB, Mauri AL, Petersen CG, Martins AN, Cornicelli J, Cavanha M. et al. Recombinant luteinizing hormone supplementation to recombinant follicle-stimulation hormone during induced ovarian stimulation in the GnRH-agonist protocol: a meta-analysis. J Assist Reprod Genet 2007; 24 (2-3): 67-75 DOI: 10.1007/s10815-006-9095-4.
30 Baruffi RL, Mauri AL, Petersen CG, Felipe V, Mc Martins A, Cornicelli J. et al. Recombinant LH supplementation to recombinant FSH during induced ovarian stimulation in the GnRH-antagonist protocol: a meta-analysis. Reprod Biomed Online 2007; 14 (01) 14-25 DOI: 10.1016/s1472-6483(10)60758-4.
31 Kolibianakis EM, Kalogeropoulou L, Griesinger G, Papanikolaou EG, Papadimas J, Bontis J. et al. Among patients treated with FSH and GnRH analogues for in vitro fertilization, is the addition of recombinant LH associated with the probability of live birth? A systematic review and meta-analysis. Hum Reprod Update 2007; 13 (05) 445-452 DOI: 10.1093/humupd/dmm008.
32 Lehert P, Kolibianakis EM, Venetis CA, Schertz J, Saunders H, Arriagada P. et al. Recombinant human follicle-stimulating hormone (r-hFSH) plus recombinant luteinizing hormone versus r-hFSH alone for ovarian stimulation during assisted reproductive technology: systematic review and meta-analysis. Reprod Biol Endocrinol 2014; 12 (01) 17 DOI: 10.1186/1477-7827-12-17.
33 Ruvolo G, Bosco L, Pane A, Morici G, Cittadini E, Roccheri MC. Lower apoptosis rate in human cumulus cells after administration of recombinant luteinizing hormone to women undergoing ovarian stimulation for in vitro fertilization procedures. Fertil Steril 2007; 87 (03) 542-546 DOI: 10.1016/j.fertnstert.2006.06.059.
34 Hill MJ, Propst AM. The use of rLH, HMG and hCG in controlled ovarian stimulation for assisted reproductive technologies. In: Darwish A. ed. Enhancing success of assisted reproduction. Rijeka: InTechOpen; 2012: 53-76
35 Gutman G, Barak V, Maslovitz S, Amit A, Lessing JB, Geva E. Recombinant luteinizing hormone induces increased production of ovarian follicular adiponectin in vivo: implications for enhanced insulin sensitivity. Fertil Steril 2009; 91 (05) 1837-1841 DOI: 10.1016/j.fertnstert.2008.02.006.