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

May 10, 2017 updated by: Chung-Hoon Kim

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Korea, Republic of
    • Songpa-gu
      • Seoul, Songpa-gu, Korea, Republic of, 05505
        • Asan Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Metformin
Metformin 500mg tablet by mouth, every 12 hours, from the first day of oral contraceptive pills taken to the day of oocyte retrieval
Drug: Metformin
Other Names:
  • Glucophage Tab 500mg, National Drug Code(NDC) 0087-6060-05
Placebo Comparator: 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
Drug: Metformin
Other Names:
  • Glucophage Tab 500mg, National Drug Code(NDC) 0087-6060-05

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of mature(MII) oocyte
Time Frame: Day1(from the day of oocyte retrieval to fertilization confirmation)
using polarized light microscopy
Day1(from the day of oocyte retrieval to fertilization confirmation)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical pregnancy rate in %
Time Frame: 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.
Clinical pregnancy was defined as a viable pregnancy beyond 12 weeks gestation by ultrasonographic visualization.
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.
Miscarriage rate in %
Time Frame: 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.
Miscarriage was defined as a early loss of a pregnancy before 20 weeks of pregnancy.
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 dose of follicle-stimulating hormone(FSH) used(IU)
Time Frame: average of 10 days, From the day of stimulation start with FSH to the day of oocyte retrieval
compare the ovarian response to controlled ovarian stimulation between two groups
average of 10 days, From the day of stimulation start with FSH to the day of oocyte retrieval
Total duration of FSH used(day)
Time Frame: average of 10 days, From the day of stimulation start with FSH to the day of oocyte retrieval
compare the ovarian response to controlled ovarian stimulation between two groups
average of 10 days, From the day of stimulation start with FSH to the day of oocyte retrieval
Number of oocytes retrieved
Time Frame: Day1(the day of oocyte retrieval)
using polarized light microscopy
Day1(the day of oocyte retrieval)
Number of frozen 2 pronucleus(2PN) embryos
Time Frame: Day1((from the day of oocyte retrieval to fertilization confirmation)
using polarized light microscopy
Day1((from the day of oocyte retrieval to fertilization confirmation)
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
Time Frame: Day 1
At the day of oocyte retrieval, follicular fluids were collected from the follicles with a diameter over than 15mm. The fluids were frozen within 4 hours for the future analysis. All the samples were stored at -20℃ and were analysed in the biochemistry department of the study centre.
Day 1
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
Time Frame: Day 1
Serum samples were obtained on the day of Metformin commencement and ovum pick up. Levels are measured by means of solid-phase enzyme-linked immunosorbent assay.
Day 1

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Chung-Hoon Kim

Investigators

  • Study Chair: CHUNG-HUN KIM, Professor, Asan Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 12, 2011

Primary Completion (Actual)

May 4, 2015

Study Completion (Actual)

July 23, 2015

Study Registration Dates

First Submitted

February 15, 2017

First Submitted That Met QC Criteria

March 15, 2017

First Posted (Actual)

March 22, 2017

Study Record Updates

Last Update Posted (Actual)

May 11, 2017

Last Update Submitted That Met QC Criteria

May 10, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2010-Metformin for PCOS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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