Optimal Stimulation of Hypo-responders Undergoing in Vitro Fertilization (IVF)

Summary

Stimulation is a key step of in vitro fertilization (IVF). Typically, injectable gonadotropins are used for stimulation, and their dose is individually determined to avoid hypo- as well as hyper-response. Despite the individualization some patients respond with a lower-than-expected number of oocytes. If the low response is unexpected based on the baseline parameters or if an unusually high dose of gonadotropins is needed to achieve a proper response we talk about "hypo-response". In such cases if the first treatment fails and a repeat attempt is planned typically even more gonadotropins, the combination of luteinizing hormone (LH) with follicle stimulating hormone (FSH) or the use of the more potent recombinant preparations are considered. The benefits of these approaches however have not been studied properly in hypo-responders. The studies have used various criteria to identify hypo-responders, have used various gonadotropin doses and have evaluated different outcome parameters. Live birth was only studied in one trial. It is also known that in a different cycle the same patient is likely to have a slightly different response to the same type and dose of drugs. Therefore, the question arises whether a hypo-responder in one treatment is expected to have hypo-response again if the treatment is similarly carried out in a different cycle. Do we need to change/ increase the gonadotropin dose if based on age and ovarian reserve otherwise we would expect a normal response? Furthermore, if we consider a change should we increase the dose of FSH or should we combine it with LH? Therefore the aim of this randomized controlled trial is compare an unchanged medication regimen to increased dose of FSH vs the combination of FSH and LH in hypo-responder patients identified based on POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) criteria (Gr 1 and 2: retrieval of 9 or fewer oocytes in patients with an anti-Müllerian hormone (AMH) level ≥ 1.2 ng/ml or antral follicle count (AFC) ≥ 5 and age \<35 years \[Group (Gr) 1\] or ≥35 years \[Gr2\]). Hypo-responder patients will be randomized to: 1. Same gonadotropin dose as in previous treatment (recombinant(r) FSH) \['control group'\] 2. The same dose as in the previous cycle but in the form of FSH + LH combination (rFSH:rLH 2:1 ratio) \['additional LH group'\] 3. A dose increase of 75 international unit (IU) compared to the dose in the previous treatment. \['higher dose FSH group'\] The primary outcome parameter to study is live clinical pregnancy. In addition, baseline demographic, stimulation and further clinical outcomes (pregnancy rate, miscarriage rate, live birth rate) will be compared.

Timeline

Start

2025-09-01

Primary completion

2026-08-31

Completion

2027-03-01

Publications

• Background Yazici Yilmaz F, Gorkemli H, Colakoglu MC, Aktan M, Gezginc K. The evaluation of recombinant LH supplementation in patients with suboptimal response to recombinant FSH undergoing IVF treatment with GnRH agonist down-regulation. Gynecol Endocrinol. 2015 Feb;31(2):141-4. doi: 10.3109/09513590.2014.965675. Epub 2014 Sep 19.
• Background 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 Mar;87(3):542-6. doi: 10.1016/j.fertnstert.2006.06.059. Epub 2006 Nov 27.
• Background De Placido G, Alviggi C, Perino A, Strina I, Lisi F, Fasolino A, De Palo R, Ranieri A, Colacurci N, Mollo A; Italian Collaborative Group on Recombinant Human Luteinizing Hormone. Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum Reprod. 2005 Feb;20(2):390-6. doi: 10.1093/humrep/deh625. Epub 2004 Dec 2.
• Background 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 Dec;82(6):1521-6. doi: 10.1016/j.fertnstert.2004.06.041.
• Background Lisi F, Rinaldi L, Fishel S, Lisi R, Pepe GP, Picconeri MG, Campbell A. Use of recombinant LH in a group of unselected IVF patients. Reprod Biomed Online. 2002 Sep-Oct;5(2):104-8. doi: 10.1016/s1472-6483(10)61610-0.
• Background Lisi F, Rinaldi L, Fishel S, Lisi R, Pepe G, Picconeri MG, Campbell A, Rowe P. Use of recombinant FSH and recombinant LH in multiple follicular stimulation for IVF: a preliminary study. Reprod Biomed Online. 2001;3(3):190-194. doi: 10.1016/s1472-6483(10)62034-2.
• Background Lehert P, Kolibianakis EM, Venetis CA, Schertz J, Saunders H, Arriagada P, Copt S, Tarlatzis B. 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 Feb 20;12:17. doi: 10.1186/1477-7827-12-17.
• Background Santi D, Casarini L, Alviggi C, Simoni M. Efficacy of Follicle-Stimulating Hormone (FSH) Alone, FSH + Luteinizing Hormone, Human Menopausal Gonadotropin or FSH + Human Chorionic Gonadotropin on Assisted Reproductive Technology Outcomes in the "Personalized" Medicine Era: A Meta-analysis. Front Endocrinol (Lausanne). 2017 Jun 1;8:114. doi: 10.3389/fendo.2017.00114. eCollection 2017.
• Background Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 1996 Apr;17(2):121-55. doi: 10.1210/edrv-17-2-121. No abstract available.
• Background Conforti A, Esteves SC, Di Rella F, Strina I, De Rosa P, Fiorenza A, Zullo F, De Placido G, Alviggi C. The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2019 Feb 6;17(1):18. doi: 10.1186/s12958-019-0460-4.
• Background Poseidon Group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number); Alviggi C, Andersen CY, Buehler K, Conforti A, De Placido G, Esteves SC, Fischer R, Galliano D, Polyzos NP, Sunkara SK, Ubaldi FM, Humaidan P. A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril. 2016 Jun;105(6):1452-3. doi: 10.1016/j.fertnstert.2016.02.005. Epub 2016 Feb 26. No abstract available.
• Background Ovarian Stimulation TEGGO, Bosch E, Broer S, Griesinger G, Grynberg M, Humaidan P, Kolibianakis E, Kunicki M, La Marca A, Lainas G, Le Clef N, Massin N, Mastenbroek S, Polyzos N, Sunkara SK, Timeva T, Toyli M, Urbancsek J, Vermeulen N, Broekmans F. ESHRE guideline: ovarian stimulation for IVF/ICSIdagger. Hum Reprod Open. 2020 May 1;2020(2):hoaa009. doi: 10.1093/hropen/hoaa009. eCollection 2020.
• Background Polyzos NP, Drakopoulos P, Parra J, Pellicer A, Santos-Ribeiro S, Tournaye H, Bosch E, Garcia-Velasco J. Cumulative live birth rates according to the number of oocytes retrieved after the first ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection: a multicenter multinational analysis including approximately 15,000 women. Fertil Steril. 2018 Sep;110(4):661-670.e1. doi: 10.1016/j.fertnstert.2018.04.039.
• Background Fanton M, Cho JH, Baker VL, Loewke K. A higher number of oocytes retrieved is associated with an increase in fertilized oocytes, blastocysts, and cumulative live birth rates. Fertil Steril. 2023 May;119(5):762-769. doi: 10.1016/j.fertnstert.2023.01.001. Epub 2023 Jan 10.

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