This study is a prospective, single-blinded (to the outcomes assessor), randomized controlled trial conducted at the In Vitro Fertilization ( IVF) centers of the Departments of Obstetrics & Gynecology, Kasr El-Ainy Hospital and Beni-suef hospital in Cairo University and Beni-suef university,respectively, Egypt, to determine the clinical effect of metformin on ICSI outcomes in non PCO patients. Ethical committee approval was obtained. The study will include 400 infertile patients.~Inclusion criteria :~Patients subjected to IVF/ICSI aged 20-35 years with long agonist protocol~history of infertility for at least two years (either primary or secondary)~normal Thyroid stimulating Hormone (TSH) and prolactin~Exclusion criteria :~Patients who used metformin in the past 3-months before study~having medical problems such as kidney or liver diseases~Severe endometriosis.~hypo-thalamic amenorrhea.~Severe male factor( patients with testicular biopsy or those with azoo-spermia).~Associated uterine factor.~IVF/ ICSI for sex selection. All patients are informed about the study and consent is given by those who accept to participate.~Careful history taking include infertility type, duration , cause, obstetric history, medical and surgical history and demographic distribution is taken. Full physical examination and 2 dimensional (2D) transvaginal sonography (TVS) are done on day 2 to 5 of menses to assess antral follicle count, uterus and adnexa . Body mass index (BMI) and waist/hip ratio (WHR) are calculated, Blood samples are taken for AntiMullerian Hormone (AMH), Basal Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), Estradiol (E2), thyroid stimulating hormone ( TSH), Prolactin and free testosterone.~All 400 participants will be randomized by withdrawing closed envelopes for each patient into group A and group B .~Group A ( involves 200 patients ) will receive metformin 850 mg twice daily along the cycle of ICSI Group B ( involve 200 patients) will not receive metformin.~They will undergo a cycle of ICSI.The agonist protocol is followed.Long protocol steps:~Start from day 19th - 20th by GnRH agonist ;Triptorelin 0.1mg subcutaneous (Decapeptyl, Ferring). -1st visit : after 2 weeks of start of GnRH agonist or day 2 of cycle, we confirm down regulation by a serum level of E2to be <50 pg/ml, endometrial thickness <5mm, no ovarian cyst by ultrasound. Then we add Gonadotropins as Intramuscular (I.M.) injections of 150-300 I.U. of highly purified Human Menopausal Gonadotropins daily (Merional, 75 I.U. /vial, IBSA). The dose is adjusted according to the age, BMI, AFC, serum levels of anti-mullerian hormone (AMH), follicle stimulating hormone (FSH) and ovarian response.~2nd visit : on 6th - 7 th days of Gonadotrophins and then every other day to do folliculometry by TVS and E2 level in serum.~We do trigger by Human Chorionic Gonadotrophin (HCG)10000 IU I.M.(Pregnyl, Organon) when at least 3 follicles reach 18mm in mean diameter or more and E2 level is less than 2500 pg/ml. Ovum pickup is done 34 hours after HCG injection and embryo transfer using Wallace catheter on day 2 to 3.~-Luteal support: Natural Progesterone 400 mg 1x2, Folic acid once daily, Amoxicillin-Clavulanic Acid 1gm 1x2x7 ,Progesterone 100mg I.M. daily for 10 days, Acetylsalicylic Acid once daily~-Quantitative ß- HCG in serum after 14 days of embryo transfer. -TVS to detect clinical pregnancy at 6-7 weeks of gestation.~Primary outcome of this trial is to detect occurrence of Ovarian Hyper-stimulation Syndrome (OHSS) , while secondary outcomes include quality & number of retrieved follicles fertilization rate ,ongoing pregnancy rate & endometrial thickness.
400 Patients will be randomly assigned into two groups after informed consent from every patient.~They will be classified into 2 groups:~Group A ( involves 200 patients ) will receive metformin 850 mg twice daily along the cycle of Intra-cytoplasmic sperm injection (ICSI) Group B ( involve 200 patients) will not receive metformin. They will undergo a cycle of ICSI. Primary outcome of this trial is to detect occurrence of Ovarian Hyper-stimulation Syndrome (OHSS) , while secondary outcomes include quality & number of retrieved~follicles fertilization rate ,ongoing pregnancy rate & endometrial thickness.