الفهرس 
ACKNOWLEDGMENTSOnly 14 pages are availabe for public view
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Abstract
An obstacle in studying PL is that authors are not speaking the same language regarding the P cut-off, measurement methods, days of measurement, and even the terminology. Meanwhile, it is widely accepted that P level at ≥ 1.5 ng/ml on the final day of oocyte maturation could reduce the pregnancy rates when embryos are freshly transferred in this cycle. Tailored cut-off levels according to the degree of ovarian responsiveness or the day of embryo transfer were suggested.
The critical threshold for the PL-induced detrimental effect on pregnancy was found to be lower in cleavage-stage than in blastocyst embryo transfers. It could be assumed that the endometrial advancement due to PL could be balanced by the transfer of embryo at an advanced stage, which has a higher chance to synchronize with the endometrium.
Various studies have reported different levels of P/E or progesterone/oocyte ratios to be more predictive than the use of serum P level alone. The rationale proposed behind these ratios is to consider the degree of ovarian response and to differentiate the source of P in hyper-responders than poor responders.
PL incidence was shown to be linked to different factors such as type of COS protocol, daily FSH dose, number of retrieved oocytes, peak estradiol level, cycle duration and the patient profile characteristics.
PL deleteriously affects IVF cycles through causing advancement of the endometrium which blocks the essential synchrony between the endometrium and the developing embryos. This was supported by the differences discovered in the endometrial gene expression profiles between patients having serum P ≥1.5 ng/ml, and patients with P ≤1.5 ng/ml.
In contrast to the well-established adverse effect of PL on endometrial receptivity, the impact of PL on embryo or oocyte quality is still debatable. In literature, several reports have proposed that PL does not affect oocyte or embryo quality. The data of oocyte donation cycles and the success of frozen embryo transfers for embryos originating from ovarian cycles with PL have supported this judgment. However, there is growing evidence about the negative impact of PL on the rate of TQE formation regardless of the degree of ovarian response. Future large multicenter randomized trials are needed to evaluate the potential effect of PL on oocyte/embryo quality.
The freeze-all policy with deferring embryo transfers on artificial endometrium is the widely accepted rescue strategy to eliminate the hazards of PL on endometrial receptivity. However, embryo freezing has an extra burden on IVF laboratory, increase IVF cost, and may be complicated by embryo damage during freezing or thawing.
Several measures were demonstrated to reduce the incidence of PL on IVF cycles: 1) addition of corticosteroids to COS in patients with higher basal progesterone, 2) optimal timing of HCG triggering, 3) aromatase inhibitors, 4) metformin, and 5) step-down stimulation approach and avoidance of enhanced ovarian stimulation toward the late follicular phase. Nevertheless, further well-designed studies are needed to prove their success in prevention of PL in IVF cycle.
b) For the Metformin Trial
Objectives: 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
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 cases with potential PL to improve pregnancy rates by preventing PL