Metformin in Intracytoplasmic Sperm Injection Cycles

Study Overview
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Brief Summary
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The relationship between serum progesterone level on the day of human chorionic gonadotropin administration and outcome of in vitro fertilization /intracytoplasmic sperm injection and embryo transfer has been controversial for several decades. some studies presented data against the negative effect of premature luteinization and reported that elevated serum progesterone had no adverse effect on pregnancy rates in fresh embryo-transfer cycles within different ovarian responses. However, most studies have evaluated the association between serum progesterone level and clinical outcome in fresh in vitro fertilization /intracytoplasmic sperm injection cycles and advocated that serum progesterone elevation on the day of human chorionic gonadotropin administration may adversely affect the clinical outcome by jeopardizing endometrial receptivity. In addition, the underlying mechanism through which premature luteinization influences clinical outcomes is elusive. some proposed that premature luteinization cause impairment of the endometrial receptivity, which may indicate a change in the implantation window, is more likely to be affected than the oocyte.whereas some documented that the compromised quality of oocytes might also be a cause. The cut-off point of premature luteinization is not well established until now. Premature luteinization has been variously defined based on serum P levels, with thresholds of 0.9-1.5 ng/mL being used. Previous studies have shown that metformin inhibits the first steps of steroidogenesis dose-dependently reducing granulosa cells progesterone output. Moreover, other authors have recently reported that low dose metformin could improve in vitro fertilization outcome in non poly-cystic ovarian syndrome repeaters. So, considering the safety of this drug before pregnancy, metformin can be given to consenting patients from first ultrasound monitoring until ovulation triggering.

Official Title
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Role of Metformin in Prevention of Premature Luteinization in Intracytoplasmic Sperm Injection Cycles

Conditions
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Intracytoplasmatic Sperm Injection

Intervention / Treatment
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* Drug: Metformin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: First or second trial ICSI cycle. Age: 20 -38 years BMI: patients with BMI ≥ 30 kg/m2 were advised to lose weight for 6 months through lifestyle modifications. AMH ≥1 ng/ml Basal FSH < 10 IU/ml. Normal uterine cavity evidenced by HSG or office hysteroscopy Normal levels of prolactin and TSH before starting COS cycle Exclusion Criteria: Patients with recurrent two or more failed intra-cytoplasmic sperm injection cycles. Uterine anomalies or Synechiae. Severe male factor infertility Patients known to have diabetes, renal, liver disease, alcoholism, or drug abuse were excluded Patients who were on metformin treatment were asked to have a one month washout period before study participation. Poor responders

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 38 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible women who gave their informed consent were randomized into two groups: (I) metformin group and (II) placebo group. Randomization was conducted using a computer generated table of random numbers with allocation concealment. Randomization was not changed after it had been done.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin group<br> | Drug: Metformin<br>* will receive metformin (1500 mg/day) starting with the commencement of oral contraceptive pills in the preceding cycle until the day of human chorionic gonadotropin triggering.<br>|
| Placebo Comparator: Placebo group<br> | Other: Placebo<br>* will receive corn-flour placebo tablets (three tablets daily).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of premature luteinization in both groups | Serum progesterone measurement ≥ 1.5 ng/ml by Mini-vidas assay was used to diagnose cases of premature luteinization. | 12 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ongoing pregnancy rate | The number of cases with pregnancy more than 12 weeks of gestation divided by the cycles initiated per 100. | 12 weeks | 
| Good quality embryo rate | The number of good day 3 embryos per all two-pronuclear embryos. | 20 days | 
| Progesterone-to-mature oocyte index (PMOI) | calculated by dividing the serum P level (ng/ml) by the number of mature oocytes. | 17 days | 
| Progesterone/estradiol ratio | calculated as [progesterone (ng/mL) × 1000]/esatradiol (pg/mL) | 12 days | 
| Implantation rate | The number of gestational sacs observed by trans-vaginal ultrasound divided by the number of embryos transferred. | 7 weeks |