Polycystic Ovary Syndrome (PCOS) and In Vitro Fertilization (IVF): A Comparison Between Standard Long Protocol Versus an Antagonist Protocol Starting on Day 1

Polycystic Ovary Syndrome Clinical Trial

Official title:

PCOS and IVF: A Comparison Between Standard Long Protocol Versus an Antagonist Protocol Starting on Day 1

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00883766
• Other study ID #: DEX002
• Status: Terminated
• Phase: N/A
• First received: April 17, 2009
• Last updated: July 19, 2012
• Start date: April 2009
• Est. completion date: June 2012

Study information

• Verified date: October 2010
• Source: Institut Universitari Dexeus
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

The aim of this study is to compare two different IVF-stimulation protocols in patients affected by PCOS: the use of a Gonadotropin-releasing hormone (GnRH) - antagonist starting on day 1 of controlled ovarian hyperstimulation (COH) versus a standard long agonist protocol; in order to assess whether it affects the number and quality of Metaphase II (MII) oocytes while reducing the risk of hyperstimulation. Since PCOS patients are also likely to be insulin resistant we also aim to evaluate how metformin affects tha IVF stimulation outcome.

Description:

Hejinen et al (1) recently conducted a meta-analysis to compare outcomes of conventional IVF in women presenting with polycystic ovary syndrome (PCOS) and non-PCOS patients. They compared nine RCTs reporting data on 458 PCOS patients (793 cycles) and 694 matched controls (1116 cycles) and concluded that in PCOS there is an increased cancellation rate, but more oocytes retrieved per pick-up and a lower fertilization rate. Overall, PCOS and control patients achieved similar pregnancy and live birth rates per cycle. The incidence of ovarian hyperstimulation syndrome (OHSS) after oocyte retrieval was rarely reported.

Our results are in accordance with this meta-analysis. Therefore, if the pregnancy and abortion rates in PCOS and controls do not differ, the main problem when dealing with PCOS in IVF is OHSS. This condition can be approached by using an antagonist instead of an agonist, by changing the kind of ovulation trigger and by co-treating patients with metformin.

• One of the currently debatable issues regarding the use of GnRH antagonists refers to the timing of GnRH antagonist initiation. A fixed protocol starting antagonist arbitrarily on Day 6 of stimulation has been used in all introductory comparative trials employing a daily antagonist administration (2). Following these trials, a flexible antagonist initiation by a follicle of 14-15 mm has been evaluated. Currently, initiation of antagonist in the early follicular phase in PCOS patients has been performed by Lainas and coll. (3) who treated patients with PCOS either with a long GnRH agonist scheme or a fixed day-1 GnRH antagonist protocol and concluded that initiation of GnRH antagonist concomitantly with recombinant FSH on day 1 is associated with an earlier follicular growth and a different hormonal environment during the follicular phase when compared with the long agonist protocol. This may lead to a reduction in the incidence of OHSS.

• Over the past 15 years, it has become increasingly recognized that insulin resistance is central to the pathogenesis of the PCOS (4). Metformin, a biguanide insulin-lowering agent, has been extensively investigated in the management of PCOS. Two recent systematic reviews (5, 6) demonstrated that metformin improves reproductive function of some women with PCOS. Metformin also appeared to improve the outcomes of ovulation induction therapies when combined with clomiphene and gonadotrophin. Tang et al. recently studied PCOS overweight patients undergoing IVF to whom they administered 850 mg bid or placebo 28 days prior to the stimulation (7). They concluded that short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS.

The aim of this study is to verify if using an antagonist the number and quality of MII oocytes is equal compared to a standard long agonist protocol while reducing the risk of hyperstimulation.

Outcome measures:

Primary endpoints:

• Oocytes MII Secondary endpoints

• Fertilization rates

• Pregnancy rates

• Miscarriage rates

• Incidence of OHSS

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 172
• Est. completion date: June 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 37 Years

Eligibility

Inclusion Criteria:

• PCOS patients according to the Rotterdam consensus criteria

• Presence of both ovaries

• Absence of endometriomas detected at ultrasound

• FSH < 10 IU/L on day 3 of the cycle

• E2 < 80 pg/mL, and Pg < 1.6 ng/mL at initiation of stimulation

Exclusion Criteria:

• Congenital adrenal hyperplasia

• Cushing's syndrome

• Androgen-producing tumours

• Hyperprolactinaemia and thyroid dysfunction

• Age > 38 years

• Serum FSH levels > 10 mIU/ml

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• In Vitro Fertilization
• Polycystic Ovary Syndrome

Intervention

Other:
• Controlled ovarian hyperstimulation for IVF with a long agonist protocol
Day 1 of 1st menstruation: OC for 18-21 days (Microdiol ®) + Metformin (Dianben ®) 850 x 2/day if: BMI>30, HOMA >3.8, G/I ratio <4.5 Day 18-24 of cycle: Leuprorelin (Procrin ®) 0.1 s.c. for 14-21 days Day 1 of 2nd menstruation (=Day 1 COH cycle): Hormonal profile (FSH, LH, E2, Pg, T, SHBG), Ultrasonography to exclude cyst >10 mm Day 2of COH cycle: rFSH (Gonal F ®) 150 IU/day for 4 days; Leuprorelin (Procrin ®) 0.1 s.c. (and following days) Day 7 of COH (and following): Measure FSH, LH, E2, Pg + Ultrasound Day before HCG: stop rFSH Day HCG: measure FSH, LH, E2, Pg, administer 250 mcg Choriogonadotropin-alfa ( Ovitrelle®) Day of pick-up: Follicular fluid from 1st follicle to be centrifuged and stored at -20°C Day 7 after pick-up: ultrasound, patient evaluation. Day 14 after pick-up: HCG in blood Day 28 after pick-up: Ultrasound to visualize heart beat if pregnancy test positive (OC= oral contraceptive; COH= Controlled Ovarian Hyperstimulation)
• Controlled ovarian hyperstimulation for IVF with an antagonist protocol
Day 1 of pre COH-cycle: OC for 18-21 days (Microdiol ®) + Metformin (Dianben ®) 850 x 2/day if: BMI>30, HOMA >3.8, G/I ratio <4.5 Day 3 of free-pill interval: Hormonal profile (FSH, LH, E2, Pg, T, SHBG), Ultrasonography to exclude cyst >10 mm Day 5 of free-pill interval (=Day 1 COH cycle): Cetrorelix acetate (Cetrotide®) 0.25 mg s.c. + rFSH (Gonal F ®) 150 IU/day (and following days) Day 3-4-10 of COH cycle: measure FSH, LH, E2, Pg + ECO Day before HCG: stop rFSH + cetrorelix Day HCG: measure FSH, LH, E2, Pg, administer 250 mcg Choriogonadotropin-alfa ( Ovitrelle®) Day of pick-up: Follicular fluid from 1st follicle to be centrifuged and stored at -20°C Day 7 after pick-up: ultrasound, patient evaluation. Day 14 after pick-up: HCG in blood Day 28 after pick-up: Ultrasound to visualize heart beat if pregnancy test positive (OC= oral contraceptive; COH= Controlled Ovarian Hyperstimulation)

Locations

Country	Name	City	State
Spain	Institut Universitari Dexeus	Barcelona

Sponsors (1)

Lead Sponsor	Collaborator
Institut Universitari Dexeus

Country where clinical trial is conducted

Spain, 

References & Publications (7)

Al-Inany H, Aboulghar M. GnRH antagonist in assisted reproduction: a Cochrane review. Hum Reprod. 2002 Apr;17(4):874-85. — View Citation

Costello MF, Eden JA. A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertil Steril. 2003 Jan;79(1):1-13. Review. — View Citation

Heijnen EM, Eijkemans MJ, Hughes EG, Laven JS, Macklon NS, Fauser BC. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update. 2006 Jan-Feb;12(1):13-21. Epub 2005 Aug 25. — View Citation

Lainas TG, Petsas GK, Zorzovilis IZ, Iliadis GS, Lainas GT, Cazlaris HE, Kolibianakis EM. Initiation of GnRH antagonist on Day 1 of stimulation as compared to the long agonist protocol in PCOS patients. A randomized controlled trial: effect on hormonal levels and follicular development. Hum Reprod. 2007 Jun;22(6):1540-6. Epub 2007 Mar 8. — View Citation

Moll E, van der Veen F, van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update. 2007 Nov-Dec;13(6):527-37. Epub 2007 Sep 1. Review. — View Citation

Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod. 2006 Jun;21(6):1416-25. Epub 2006 Feb 24. — View Citation

Tsilchorozidou T, Overton C, Conway GS. The pathophysiology of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2004 Jan;60(1):1-17. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Oocytes MII retrieved per patient		1 Day	No
Secondary	Fertilization rates		24 hours after pick-up	No
Secondary	Clinical pregnancy rates		4 weeks after pick-up	No
Secondary	Incidence of OHSS		From ovulation triggering to two weeks after pick-up	Yes

External Links

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