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
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Number of mature(MII) oocyte
Study Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 20 Years to 40 Years (Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
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
- •Oligo - or anovulation
- •Clinical or/and biochemical hyperandrogenism
- •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
Arms & Interventions
Metformin
Metformin 500mg tablet by mouth, every 12 hours, from the first day of oral contraceptive pills taken to the day of oocyte retrieval
Intervention: Metformin (Drug)
Placebo
Placebo(identical in appearance to metformin), every 12 hours, from the first day of oral contraceptive pills taken to the day of oocyte retrieval
Intervention: Metformin (Drug)
Outcomes
Primary Outcomes
Number of mature(MII) oocyte
Time Frame: Day1(from the day of oocyte retrieval to fertilization confirmation)
using polarized light microscopy
Secondary Outcomes
- Miscarriage rate in %(Pregnancy test was carried out at 11 days after embryo transfer and was classified as positive when the serum beta-human chorionic gonadotropin(hCG) level was over 5 IU/L. Than follow up to 20 weeks of gestation.)
- Total duration of FSH used(day)(average of 10 days, From the day of stimulation start with FSH to the day of oocyte retrieval)
- Number of frozen 2 pronucleus(2PN) embryos(Day1((from the day of oocyte retrieval to fertilization confirmation))
- Clinical pregnancy rate in %(Pregnancy test was carried out at 11 days after embryo transfer and was classified as positive when the serum beta-human chorionic gonadotropin(hCG) level was over 5 IU/L. Than follow up to 12 weeks of gestation.)
- Serum TNF-α level in pg/ml and serum Adiponectin level in pg/ml and serum Interleukin-6 level in pg/ml and serum AMH level in pg/ml and serum Testosterone level in pg/ml and serum Estradiol level in pg/ml(Day 1)
- Total dose of follicle-stimulating hormone(FSH) used(IU)(average of 10 days, From the day of stimulation start with FSH to the day of oocyte retrieval)
- Number of oocytes retrieved(Day1(the day of oocyte retrieval))
- Follicular fluid Tumor necrosis factor(TNF)-α level in pg/ml and follicular fluid Adiponectin level in pg/ml and follicular fluid Interleukin-6 level in pg/ml and follicular fluid Anti-mullerian hormone(AMH) level in pg/ml(Day 1)
Investigators
Chung-Hoon Kim
Asan Medical Center
Asan Medical Center