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

NCT ID: NCT03086005

Last Updated: 2017-05-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-10-12
• Study Completion Date: 2015-07-23

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.

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.

Conditions

Polycystic Ovary Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Metformin

Metformin 500mg tablet by mouth, every 12 hours, from the first day of oral contraceptive pills taken to the day of oocyte retrieval

Group Type: EXPERIMENTAL

Metformin

Intervention Type: 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

Group Type: PLACEBO_COMPARATOR

Metformin

Intervention Type: DRUG

Interventions

Metformin

Intervention Type: DRUG

Other Intervention Names

Glucophage Tab 500mg, National Drug Code(NDC) 0087-6060-05

Eligibility Criteria

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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Chung-Hoon Kim

OTHER

Sponsor Role: lead

Responsible Party

Chung-Hoon Kim

Asan Medical Center

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

CHUNG-HUN KIM, Professor

Role: STUDY_CHAIR

Asan Medical Center

Locations

Asan Medical Center

Seoul, Songpa-gu, South Korea

Countries

South Korea

References

Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008 Mar;23(3):462-77. doi: 10.1093/humrep/dem426.

Reference Type: BACKGROUND

PMID: 18308833 (View on PubMed)

Diamanti-Kandarakis E, Economou F, Palimeri S, Christakou C. Metformin in polycystic ovary syndrome. Ann N Y Acad Sci. 2010 Sep;1205:192-8. doi: 10.1111/j.1749-6632.2010.05679.x.

Reference Type: BACKGROUND

PMID: 20840272 (View on PubMed)

Doldi N, Persico P, Di Sebastiano F, Marsiglio E, Ferrari A. Gonadotropin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro fertilization-embryo transfer. Gynecol Endocrinol. 2006 May;22(5):235-8. doi: 10.1080/14767050600761893.

Reference Type: BACKGROUND

PMID: 16785142 (View on PubMed)

Farrell K, Antoni MH. Insulin resistance, obesity, inflammation, and depression in polycystic ovary syndrome: biobehavioral mechanisms and interventions. Fertil Steril. 2010 Oct;94(5):1565-74. doi: 10.1016/j.fertnstert.2010.03.081. Epub 2010 May 14.

Reference Type: BACKGROUND

PMID: 20471009 (View on PubMed)

Katsiki N, Hatzitolios AI. Insulin-sensitizing agents in the treatment of polycystic ovary syndrome: an update. Curr Opin Obstet Gynecol. 2010 Dec;22(6):466-76. doi: 10.1097/GCO.0b013e32833e1264.

Reference Type: BACKGROUND

PMID: 20724929 (View on PubMed)

Toulis KA, Goulis DG, Farmakiotis D, Georgopoulos NA, Katsikis I, Tarlatzis BC, Papadimas I, Panidis D. Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Hum Reprod Update. 2009 May-Jun;15(3):297-307. doi: 10.1093/humupd/dmp006. Epub 2009 Mar 4.

Reference Type: BACKGROUND

PMID: 19261627 (View on PubMed)

Ardawi MS, Rouzi AA. Plasma adiponectin and insulin resistance in women with polycystic ovary syndrome. Fertil Steril. 2005 Jun;83(6):1708-16. doi: 10.1016/j.fertnstert.2004.11.077.

Reference Type: BACKGROUND

PMID: 15950640 (View on PubMed)

Tso LO, Costello MF, Albuquerque LET, Andriolo RB, Macedo CR. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2020 Dec 21;12(12):CD006105. doi: 10.1002/14651858.CD006105.pub4.

Reference Type: DERIVED

PMID: 33347618 (View on PubMed)

Other Identifiers

2010-Metformin for PCOS

Identifier Type: -

Identifier Source: org_study_id