Clinical trial NCT03086005: Study to Assess the Effect of Metformin Supplementation on IVF Outcome in Patients With Polycystic Ovarian Syndrome.
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Polycystic Ovary Syndrome
Keywords: Metformin
Lead sponsor: Asan Medical Center
Sponsor class: OTHER
First posted: 2017-03-22
Enrollment: 24
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of mature(MII) oocyte
timeFrame: Day1(from the day of oocyte retrieval to fertilization confirmation)
Secondary outcomes:
measure: Clinical pregnancy rate in %
timeFrame: 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.
measure: Miscarriage rate in %
timeFrame: 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.
measure: Total dose of follicle-stimulating hormone(FSH) used(IU)
timeFrame: average of 10 days, From the day of stimulation start with FSH to the day of oocyte retrieval
measure: Total duration of FSH used(day)
timeFrame: average of 10 days, From the day of stimulation start with FSH to the day of oocyte retrieval
measure: Number of oocytes retrieved
timeFrame: Day1(the day of oocyte retrieval)
measure: Number of frozen 2 pronucleus(2PN) embryos
timeFrame: Day1((from the day of oocyte retrieval to fertilization confirmation)
measure: 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
timeFrame: Day 1
measure: 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
timeFrame: Day 1
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Songpa-gu
Study officials:
affiliation: Asan Medical Center
name: CHUNG-HUN KIM, Professor
role: STUDY_CHAIR
References:
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.
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.
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. doi: 10.1080/14767050600761893.
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.
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.
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.
citation: 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.
citation: 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.