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


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


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).


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