Study to Assess the Effect of Metformin Supplementation on IVF Outcome in Patients With Polycystic Ovarian Syndrome.

A Multicenter, Prospective, Randomized Study to Assess the Effect of Metformin Supplementation on IVF Outcome and Intrafollicular Environment in Patients With Polycystic Ovarian Syndrome Undergoing In Vitro Fertilization/Embryo Transfer

This study was performed to investigate the effects of metformin on controlled ovarian stimulation (COS), in vitro fertilization (IVF) outcomes, pregnancy outcomes, and comparison of serum and follicular fluid cytokines and hormones in patients with polycystic ovary syndrome (PCOS) undergoing IVF using gonadotropin-releasing hormone(GnRH) antagonist protocol.

Polycystic ovary syndrome is the common cause of the female infertility that features insulin resistance and hyperinsulinemia participate in the reproductive as well as metabolic disturbances.

In many studies, metformin treatment reduces androgen levels and attenuates hyperinsulinemia in women with PCOS. This favorable effect on insulin and androgens levels, justifies the use of metformin in reproductive disturbances in PCOS women. Metformin treatment was shown to diminish ovarian androgen secretion, while lowering insulin levels in women with PCOS.

In women with PCOS, metformin treatment may increase ovulation, improve menstrual cyclicity, and reduce seum androgen levels. Metformin has direct effects on the ovary and also reduces the level of insulin that act upon the ovary. It has been indicated that metformin has direct, insulin-independent actions on theca cell steroidogenesis, because in human ovarian theca-like tumor cells, metformin suppressed androstenedione production. Metformin also exert a direct effect on granulosa cells and subsequent reduction of steroid production.

Metformin was shown to improve endothelium dependent vasodilation in insulin resistant patients and potentially protect against atherogenesis and cardiovascular disease.

Considering gonadotropin ovulation induction or IVF in women with PCOS, metformin coadministration improves the pregnancy outcome and reduces the risk of ovarian hyperstimulation syndrome. Metformin therapy throughout pregnancy can reduce the risk of early miscarriage or the incidence of gestational diabetes.

All patients were pretreated for 3 weeks with monophasic oral contraceptive (OC)(Yasmin; Bayer Schering Pharma, Berlin, Germany) before COS. Five days after OC discontinuation, COS for IVF/ICSI was commenced. GnRH antagonist protocol was used for COS in all subjects. Patients were randomly allocated into the metformin or control groups, using sealed envelopes.

Inclusion Criteria:

• PCOS diagnostic criteria

  • 2003 American Society for Reproductive Medicine(ARSM)/European Society of Human Reproduction and Embryology(ESHRE) consensus meeting guideline

  • include two out of three

    1. Oligo - or anovulation
    2. Clinical or/and biochemical hyperandrogenism
    3. Polycystic ovaries on ultrasound, exclusion of other etiologies( ≥ 12 follicles(2-9 mm diameter) in each ovary or ovarian volume(0.5 x length x width x thickness) ≥ 10cm3)

• Anatomical normal uterus

• Normal level of thyroid hormone

Exclusion Criteria:

• Severe endometriosis(stageIII, IV)
• Endometrial thickness less than 7mm in late follicular phase
• Severe male infertility factor, non-obstructive azoospermia
• History of ectopic pregnancy or abortion over the last 3 months
• Unexplained abnormal uterine bleeding
• Congenital adrenal hyperplasia
• Androgen secreting tumor
• Cushing syndrome
• Concurrent administration of metformin, ovulation induction drugs, oral contraceptives within previous 3 months
• Chronic disease(liver, kidney, severe heart failure, DM)
• Any pathology of genital tract
• History of alcohol abuse
• Refuse of study participate consent