Extra Luteinizing Hormone Improve Embryo Quality in IVF Patients With Low LH During Long GnRH-Agonist Treatment

Official title

Exogenous Luteinizing Hormone Supplementation to Improve Embryo Quality in Patients With Excessive LH Suppression During a Long GnRH-Agonist Protocol: A Randomized Controlled Trial

Overview

This randomized controlled trial aims to evaluate whether supplementation with exogenous luteinizing hormone (LH) can improve embryo quality in patients undergoing in vitro fertilization (IVF) with a long gonadotropin-releasing hormone agonist (GnRH-a) protocol who have excessive suppression of LH. Eligible participants will be randomly assigned to receive either exogenous LH supplementation or standard care. The primary outcome is embryo quality, and secondary outcomes include pregnancy rates and safety assessments. The study is conducted at Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University.

Detailed description

Excessive suppression of luteinizing hormone (LH) during ovarian stimulation with a long gonadotropin-releasing hormone agonist (GnRH-a) protocol has been associated with suboptimal follicular development, impaired oocyte maturation, and reduced embryo quality. LH plays a critical role in the final stages of folliculogenesis, steroidogenesis, and ovulation, and its deficiency during controlled ovarian hyperstimulation may adversely affect the developmental competence of oocytes.

This randomized controlled trial is designed to evaluate whether supplementation with exogenous LH can improve embryo quality in patients undergoing in vitro fertilization (IVF) with excessive LH suppression during a long GnRH-a protocol. Eligible participants are women meeting predefined hormonal suppression criteria prior to or during stimulation. Participants will be randomly assigned to receive either exogenous LH supplementation in addition to standard ovarian stimulation or standard care without LH supplementation.

The primary endpoint is the proportion of high-quality embryos obtained per cycle. Secondary endpoints include clinical pregnancy rate, implantation rate, live birth rate, and safety outcomes such as incidence of ovarian hyperstimulation syndrome (OHSS) and adverse events.

The study aims to provide high-quality evidence to guide the optimal management of patients with profound LH suppression during controlled ovarian stimulation. Findings from this trial may contribute to refining stimulation protocols and improving reproductive outcomes in assisted reproductive technology (ART).

Interventions

• Drug Recombinant Luteinizing Hormone (rLH)
  Recombinant LH administered subcutaneously in combination with recombinant FSH (rFSH) at a ratio of 2:1 starting on stimulation day, continued throughout controlled ovarian hyperstimulation. Dosage adjusted according to follicular growth and serum hormone levels.
• Drug Recombinant Follicle-Stimulating Hormone (rFSH)
  Recombinant FSH administered subcutaneously for controlled ovarian hyperstimulation after pituitary downregulation with a long-acting GnRH agonist. Dosage adjusted based on follicular development and hormone monitoring.
• Drug Gonadotropin-Releasing Hormone Agonist (GnRH-a)
  Long-acting GnRH agonist (3.75 mg) administered subcutaneously on menstrual cycle day 2-4 for pituitary downregulation before controlled ovarian hyperstimulation.

Primary outcome measures

• Proportion of cycles with no usable embryos [Time frame: 7 days after oocyte retrieval]

Secondary outcome measures (7)

• Number of high-quality Day 3 embryos [Time frame: 7 days after oocyte retrieval]
• Total gonadotropin dose used [Time frame: At the end of ovarian stimulation (average 8-12 days)]
• Duration of gonadotropin stimulation [Time frame: At the end of ovarian stimulation (average 8-12 days)]
• Number of oocytes retrieved [Time frame: At oocyte retrieval (36-38 hours after trigger)]
• Clinical pregnancy rate [Time frame: 30 days after embryo transfer]
• Early miscarriage rate [Time frame: Within 12 weeks of gestation]
• Live birth rate [Time frame: At delivery (up to 1 year after embryo transfer)]

Eligibility criteria

Inclusion criteria

• Women aged 20 to 37 years (inclusive). Diagnosed with infertility and undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment using the long-acting GnRH agonist protocol.

Serum luteinizing hormone (LH) level <0.5 U/L after pituitary downregulation. Normal uterine cavity as confirmed by hysteroscopy, sonohysterography, or hysterosalpingography within 6 months.

Written informed consent provided prior to participation.

Exclusion criteria

• Polycystic ovary syndrome (PCOS). History of recurrent implantation failure (RIF). Presence of endometriosis or adenomyosis. History of ovarian surgery. Ovarian cysts ≥3 cm or with suspected malignancy. Poor ovarian reserve (antral follicle count <5, anti-Müllerian hormone <1.1 ng/mL, or baseline FSH >10 IU/L).

Chromosomal abnormalities in either partner. Systemic diseases such as uncontrolled hypertension, diabetes, thyroid disorders, or autoimmune diseases.

Contraindications to ovarian stimulation medications or pregnancy.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Nanjing Drum Tower Hospital, Nanjing University Medical School — Nanjing

Publications

• 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
• Tesarik J, Mendoza C. Effects of exogenous LH administration during ovarian stimulation of pituitary down-regulated young oocyte donors on oocyte yield and developmental competence. Hum Reprod. 2002 Dec;17(12):3129-37. doi: 10.1093/humrep/17.12.3129. PMID 12456612
• Wu KK, Papp AC, Manner CE, Hall ER. Interaction between lymphocytes and platelets in the synthesis of prostacyclin. J Clin Invest. 1987 Jun;79(6):1601-6. doi: 10.1172/JCI112995. PMID 3108319
• Kan O, Simsir C, Atabekoglu CS, Sonmezer M. The impact of adding hp-hMG in r-FSH started GnRH antagonist cycles on ART outcome. Gynecol Endocrinol. 2019 Oct;35(10):869-872. doi: 10.1080/09513590.2019.1600667. Epub 2019 Apr 11. PMID 30973022
• Propst AM, Hill MJ, Bates GW, Palumbo M, Van Horne AK, Retzloff MG. Low-dose human chorionic gonadotropin may improve in vitro fertilization cycle outcomes in patients with low luteinizing hormone levels after gonadotropin-releasing hormone antagonist administration. Fertil Steril. 2011 Oct;96(4):898-904. doi: 10.1016/j.fertnstert.2011.06.069. Epub 2011 Aug 11. PMID 21839437
• Tayyar AT, Kahraman S. Comparison between cycles of the same patients when using recombinant luteinizing hormone + recombinant follicle stimulating hormone (rFSH), human menopausal gonadotropin + rFSH and rFSH only. Arch Med Sci. 2019 May;15(3):673-679. doi: 10.5114/aoms.2017.72408. Epub 2018 Jan 8. PMID 31110533
• Fleming R, Rehka P, Deshpande N, Jamieson ME, Yates RW, Lyall H. Suppression of LH during ovarian stimulation: effects differ in cycles stimulated with purified urinary FSH and recombinant FSH. Hum Reprod. 2000 Jul;15(7):1440-5. doi: 10.1093/humrep/15.7.1440. PMID 10875848
• Westergaard LG, Laursen SB, Andersen CY. Increased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction. Hum Reprod. 2000 May;15(5):1003-8. doi: 10.1093/humrep/15.5.1003. PMID 10783342

Identifiers

NCT: NCT07128394 · SZ-ELH-2025 · BJHPA-2023-SZHYXZHQN-006

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗