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

NCT07121751 | Not Yet Recruiting Phase 4

• 1 other identifier: NNGYK/22108-7/2025
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 4

Brief 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. 1.Same gonadotropin dose as in previous treatment (recombinant(r) FSH) \['control group'\]
2. 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. 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.

Conditions

Hypo-responder; Infertility (IVF Patients); OVARIAN STIMULATION

Keywords

ovarian stimulation; in vitro fertilization; hypo-responder; gonadotropin; luteinizing hormone

Outcome Measures

Primary Outcomes (1)

• live clinical pregnancy

  intrauterine gestational sac with an embryo with heartbeat at week 10-12

  up to 3 months after the embryo transfer; starting with the first patient who has a positive pregnancy test after transfer and up to 3 months after the completion of the study (last transfer with positive result)

Secondary Outcomes (1)

• live birth

  from up to 9 month after the embryo transfer; starting with the first patient who has a positive pregnancy test after the embryo transfer and up to 8 months after the completion of the study (last transfer with positive result)

Other Outcomes (8)

• Biochemical pregnancy

  starting 2 weeks after the first transfer and up to 2 weeks after the last embryo transfer

• Early miscarriage

  starting 4 weeks after the first positive pregnancy test and up to 12 weeks after the last positive pregnancy test after the completion of the study (last transfer with positive result)

• late miscarriage

  starting 12 weeks plus 1 day after the first positive pregnancy test and up to 24 weeks after the last positive pregnancy test after the completion of the study (last transfer with positive result)

Study Arms (3)

Control group

OTHER

In this arm the hypo-responder patient will undergo stimulation using the same gonadotropin dose as in her previous treatment. Treatment steps: 1. Stimulation using the same recombinant FSH dose as in her prevoius cycle is started on day 2 or 3 of the menstrual cycle and is continued for 5 days. On day 6 the patient is seen for US and bloodwork. If indicated the dose can be increased by max. 75 IU every 2 days to a maximum of 300 IU/day. 2. GnRH antagonist is started at follicle size 12-14 m. 3. Trigger is administered once the largest follicle gets \>17 mm. Retrieval is scheduled 36 hrs later. IVF or ICSI fertilization. Luteal support from day past retrieval. 4. Transfer of 1-2 embryos on day 3 or 5. 5. Pregnancy test 12 days after ET.

Drug: unchanged dose

Additional LH group (Pergoveris, Merck)

ACTIVE COMPARATOR

In this arm the hypo-responder patient will undergo stimulation using the same gonadotropin dose as in her previous treatment but in the form of rec FSH and recLH 2:1 ratio (e.g.: if 150 IU rec FSH was used then 150 IU recFSH and recLH (2:1 ratio). Treatment steps: 1. Stimulation using the same dose as in her previuos cycle but in the form of recombinant FSH and recombinant LH 2:1 ratio is started on day 2 or 3 of the menstrual cycle and is continued for 5 days. On day 6 the patient is seen for US and bloodwork. If indicated the dose can be increased by max. 75 IU every 2 days to a maximum of 300 IU/day. 2. GnRH antagonist is started at follicle size 12-14 m. 3. Trigger is administered once the largest follicle gets \>17 mm. Retrieval is scheduled 36 hrs later. IVF or ICSI fertilization. Luteal support from day past retrieval. 4. Transfer of 1-2 embryos on day 3 or 5. 5. Pregnancy test 12 days after ET.

Drug: use of combination of recombinant FSH and recombinant LH

higher dose FSH group (follitropin alpha (Gonal-F, Ovaleap) or follitropin delta (Rekovelle)

ACTIVE COMPARATOR

In this arm the hypo-responder patient will undergo stimulation using recombinant FSH but with a dose increase of 75 IU/day compared to the gonadotropin dose used in her previous treatment (e.g.: if 150 IU/d rec FSH was used then 225 IU/d will be used). Treatment steps: 1. Stimulation using an additional 75 IU recombinant FSH per day compared to her previous treatment is started on day 2 or 3 of the menstrual cycle and is continued for 5 days. On day 6 the patient is seen for US and bloodwork. If indicated the dose can be increased by max. 75 IU every 2 days to a maximum of 300 IU/day. 2. GnRH antagonist is started at follicle size 12-14 m. 3. Trigger is administered once the largest follicle gets \>17 mm. Retrieval is scheduled 36 hrs later. IVF or ICSI fertilization. Luteal support from day past retrieval. 4. Transfer of 1-2 embryos on day 3 or 5. 5. Pregnancy test 12 days after ET.

Drug: higher dose recFSH

Interventions

use of combination of recombinant FSH and recombinant LH DRUG

in this arm the patients will use the combination of recFSH:recLH in the same dose as in her prior cycle

Additional LH group (Pergoveris, Merck)

higher dose recFSH DRUG

in this arm the patient will use an additional 75 IU/day recFSH compared to her previous drug dose

higher dose FSH group (follitropin alpha (Gonal-F, Ovaleap) or follitropin delta (Rekovelle)

unchanged dose DRUG

in this groups the patient will receive the same recFSH dose as in her prior cycle

Control group

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• indication for IVF-ICSI
• age 18-40 years
• \<9 oocytes in a previous IVF cycle and having an AMH ≥1.2 ng/ml and/or AFC ≥5 (POSEIDON 1,2)
• The use of ≤225 IU FSH (either rFSH alone or the combination of rFSH+hMG) in the previous cycle
• regular 24-35 day cycles
• Intact uterine cavity
• motile sperm from ejaculate or testicular biopsy

You may not qualify if:

• the use of rFSH:rLH (2:1 ratio) in the previous cycle
• the use of clomiphene citrate or aromatase inhibitor in the previous cycle
• \>225 IU gonadotropin in the previous cycle
• \>3 failed previous treatments
• patient with recurrent miscarriages
• presence of a hydrosalpinx
• positive HIV or hepatitis screening test
• planned preimplantation genetic testing of the embryos
• planned elective cryopreservation
• lack of consent

Sponsors & Collaborators

• Dunamenti REK Istenhegyi IVF Center: lead
• Dunamenti REK Gyor Clinic: collaborator
• Dunamenti REK Pannon Clinic: collaborator
• University of Szeged, Hungary: collaborator

Study Sites (4)

Dunamenti REK Istenhegyi IVF Center

Budapest, 1125, Hungary

Location

Dunamenti REK Gyor IVF Center

Győr, 9026, Hungary

Location

University of Szeged, Reproductive Medicine Institute

Szeged, 6723, Hungary

Location

Dunamenti REK Tapolca IVF Center

Tapolca, 8300, Hungary

Location

Related Publications (14)

• 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.

  PMID: 25237892 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.

  PMID: 17126339 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.

  PMID: 15576390 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.

  PMID: 15589853 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.

  PMID: 12419032 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.

  PMID: 12513853 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.

  PMID: 24555766 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.

  PMID: 28620352 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.

  PMID: 8706629 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.

  PMID: 30728019 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.

  PMID: 26921622 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.

  PMID: 32395637 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.

  PMID: 30196963 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.

  PMID: 36634732 BACKGROUND

MeSH Terms

Conditions

Infertility

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases

Central Study Contacts

Peter Kovacs, MD, PhD

CONTACT

+3612022802; peterkovacs1970@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: medical director Dunamenti REK Istenhegyi IVF Center

Study Record Dates

• First Submitted: July 25, 2025
• First Posted: August 13, 2025
• Study Start: September 1, 2025
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): March 1, 2027
• Last Updated: August 13, 2025

Record last verified: 2025-08

Locations

HU (4)