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

July 19, 2012 updated by: Institut Universitari Dexeus

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed 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

Study Type

Interventional

Enrollment (Anticipated)

172

Phase

  • Not Applicable

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

  • Spain
      • Barcelona, Spain, 08028
        • Institut Universitari Dexeus

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

14 years to 33 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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 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: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Long agonist protocol
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)
Experimental: Antagonist protocol
Other: 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Number of Oocytes MII retrieved per patient
Time Frame: 1 Day
1 Day

Secondary Outcome Measures

Outcome Measure
Time Frame
Fertilization rates
Time Frame: 24 hours after pick-up
24 hours after pick-up
Clinical pregnancy rates
Time Frame: 4 weeks after pick-up
4 weeks after pick-up
Incidence of OHSS
Time Frame: From ovulation triggering to two weeks after pick-up
From ovulation triggering to two weeks after pick-up

Collaborators and Investigators

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

Sponsor

Institut Universitari Dexeus

Investigators

  • Principal Investigator: Fulvia Mancini, M.D. PhD, Department of Obstetric, Gynecology and Reproductive Medicine

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

Helpful Links

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

April 1, 2009

Primary Completion (Actual)

June 1, 2012

Study Completion (Actual)

June 1, 2012

Study Registration Dates

First Submitted

April 17, 2009

First Submitted That Met QC Criteria

April 17, 2009

First Posted (Estimate)

April 20, 2009

Study Record Updates

Last Update Posted (Estimate)

July 20, 2012

Last Update Submitted That Met QC Criteria

July 19, 2012

Last Verified

October 1, 2010

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DEX002

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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