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

Polycystic Ovary Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03086005
• Other study ID #: 2010-Metformin for PCOS
• Status: Completed
• Phase: Phase 3
• First received: February 15, 2017
• Last updated: May 10, 2017
• Start date: October 12, 2011
• Est. completion date: July 23, 2015

Study information

• Verified date: May 2017
• Source: Asan Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: July 23, 2015
• Est. primary completion date: May 4, 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 20 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Polycystic Ovary Syndrome
• Syndrome

Intervention

Drug:
• Metformin

Locations

Country	Name	City	State
Korea, Republic of	Asan Medical Center	Seoul	Songpa-gu

Sponsors (1)

Lead Sponsor	Collaborator
Chung-Hoon Kim

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (7)

Ardawi MS, Rouzi AA. Plasma adiponectin and insulin resistance in women with polycystic ovary syndrome. Fertil Steril. 2005 Jun;83(6):1708-16. — View Citation

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. Review. — View Citation

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. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. Erratum in: Hum Reprod. 2008 Jun;23(6):1474. — View Citation

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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of mature(MII) oocyte	using polarized light microscopy	Day1(from the day of oocyte retrieval to fertilization confirmation)
Secondary	Clinical pregnancy rate in %	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.
Secondary	Miscarriage rate in %	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.
Secondary	Total dose of follicle-stimulating hormone(FSH) used(IU)	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
Secondary	Total duration of FSH used(day)	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
Secondary	Number of oocytes retrieved	using polarized light microscopy	Day1(the day of oocyte retrieval)
Secondary	Number of frozen 2 pronucleus(2PN) embryos	using polarized light microscopy	Day1((from the day of oocyte retrieval to fertilization confirmation)
Secondary	Follicular fluid Tumor necrosis factor(TNF)-a 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	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
Secondary	Serum TNF-a 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	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