Metformin in Intracytoplasmic Sperm Injection Cycles

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

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.

Study Overview

• Status: Completed
• Conditions: Intracytoplasmatic Sperm Injection
• Intervention / Treatment: Drug: Metformin; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 320
• Phase: Phase 2

Contacts and Locations

Study Locations

• Egypt
  • Assiut, Egypt, 71111
    • Women Health Hospital - Assiut university

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 38 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo group	Other: Placebo; will receive corn-flour placebo tablets (three tablets daily).
Active Comparator: Metformin group	Drug: Metformin; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assiut University

Publications and helpful links

General Publications

• Hussein RS, Elnashar I, Amin AF, Zhao Y, Abdelmagied AM, Abbas AM, Abdelaleem AA, Farghaly TA, Abdalmageed OS, Youssef AA, Badran E, Abou-Taleb HA. Effect of Metformin on Premature Luteinization and Pregnancy Outcomes in Intracytoplasmic Sperm Injection-Fresh Embryo Transfer Cycles: A Randomized Double-Blind Controlled Trial. Int J Fertil Steril. 2021 Apr;15(2):108-114. doi: 10.22074/IJFS.2020.134643. Epub 2021 Mar 11.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Actual): March 1, 2019
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: March 18, 2017
• First Submitted That Met QC Criteria: March 18, 2017
• First Posted (Actual): March 23, 2017

Study Record Updates

• Last Update Posted (Actual): September 17, 2019
• Last Update Submitted That Met QC Criteria: September 14, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: MICSI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No