Effect of Metformin on Premature Luteinization and Pregnancy Outcomes in ICSI-Fresh Embryo Transfer Cycles: A Randomized Double-Blind Controlled Trial

Background: Premature luteinization (PL) is not unusual in IVF and could not be wholly avoided with either gonadotrophin-releasing hormone (GnRH) agonists or GnRH antagonist regimens. The study aims to evaluate the metformin's efficacy in preventing PL in fresh GnRH antagonist intracytoplasmic sperm injection (ICSI) cycles with cleavage-stage embryo transfer. Materials and methods: A randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov: NCT03088631) 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, p=0.002, respectively) were demonstrated in women receiving metformin. Metformin group generated a better rate of good-quality embryos (p=0.005) and ongoing pregnancy (43.8% vs. 31.8%, p=0.026). A similar trend, through 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.