Metformin in High Responder Polycystic Ovary Syndrome (PCOS) Patients Undergoing IVF Cycles

Metformin Addition to Gonadotropins Ovarian Stimulation in High Responder Patients With PCOS Undergoing In-vitro Fertilization

The use of metformin pre-treatment and co-administration was recently proposed in infertile women affected by polycystic ovary syndrome (PCOS) treated with gonadotropins.

Data from meta-analyses showed that metformin administration significantly reduced the stimulation length and the total dose of gonadotropins used in PCOS women undergoing gonadotropins stimulation for non in-vitro fertilization (IVF) cycles. On the other hand, in IVF cycles metformin was demonstrated to significantly reduce the ovarian hyperstimulation syndrome (OHSS) rate in infertile patients with PCOS treated with gonadotropins.

The metformin regulating effect on the ovarian response was also observed in a randomized controlled trial (RCT) on young non-obese insulin-resistant women with PCOS receiving gonadotropins for mono-ovulation induction. In particular, metformin increased the mono-ovulatory cycles, the duration of stimulation and the amount of gonadotropins used, while it reduced the number of dominant follicles and the estradiol (E2) levels.

The aim of the present study was to evaluate the effect of metformin administration in high responder PCOS patients undergoing gonadotropins ovarian stimulation for IVF cycles.

Study Overview

• Status: Completed
• Conditions: Infertility; Polycystic Ovary Syndrome (PCOS)
• Intervention / Treatment: Drug: Metformin; Drug: Placebo administration

Detailed Description

Infertile young non-obese insulin-resistant patients with PCOS who had a background of the first IVF treatment cycle cancelled because of high risk for OHSS will be enrolled and randomized in two treatment arms.

In their second IVF attempt, the experimental group will receive metformin (500 mg, 3 times daily) pre-treatment for two weeks and co-administration during gonadotropins ovarian stimulation; the control group will be treated with placebo (2 cps daily) pre-treatment and co-administration by using the same schedule of the experimental group. In all patients, ovarian stimulation will be carried out with a personalized step-down gonadotropin in association with a minidose flare-up GnRH agonist protocol.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Catanzaro, Italy, 88100
    • Pugliese" Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• History of one previous cancelled cycle for high-risk of OHSS, or history of moderate/severe OHSS during their previous IVF cycle
• Infertility
• Polycystic ovary syndrome (PCOS)
• insulin resistance
• hyperandrogenism

Exclusion Criteria:

• BMI>30 kg/m2
• age >35 years
• FSH>9UI/L

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control group; Placebo	Drug: Placebo administration; Placebo pre-treatment and co-administration
Experimental: Experimental group; Patients receiving metformin pretreatment and co-administration	Drug: Metformin; Metformin pre-treatment and co-administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rate of OHSS	one month

Secondary Outcome Measures

Outcome Measure	Time Frame
Stimulation length	one month
Gonadotropins dose	one month
Dominant follicles on day of ovulation triggering	one month
Ovulation rate	one month
Peak estradiol levels on day of ovulation triggering	one month
Embryo quality	one month
pregnancy rate	one month
multiple pregnancy rate	one month
Live birth rate	ten months

Collaborators and Investigators

• Sponsor: University Magna Graecia
• Investigators: Principal Investigator: Stefano Palomba, University Magna Graecia; Study Chair: Fulvio Zullo, University Magna Graecia

Publications and helpful links

General Publications

• Palomba S, Falbo A, Orio F Jr, Manguso F, Russo T, Tolino A, Annamaria C, Dale B, Zullo F. A randomized controlled trial evaluating metformin pre-treatment and co-administration in non-obese insulin-resistant women with polycystic ovary syndrome treated with controlled ovarian stimulation plus timed intercourse or intrauterine insemination. Hum Reprod. 2005 Oct;20(10):2879-86. doi: 10.1093/humrep/dei130. Epub 2005 Jun 15.
• 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.
• Palomba S, Falbo A, Carrillo L, Villani MT, Orio F, Russo T, Di Cello A, Cappiello F, Capasso S, Tolino A, Colao A, Mastrantonio P, La Sala GB, Zullo F, Cittadini E; METformin in High Responder Italian Group. Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: a randomized, controlled trial. Fertil Steril. 2011 Dec;96(6):1384-1390.e4. doi: 10.1016/j.fertnstert.2011.09.020. Epub 2011 Oct 7.

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: October 8, 2010
• First Submitted That Met QC Criteria: November 2, 2010
• First Posted (Estimate): November 3, 2010

Study Record Updates

• Last Update Posted (Estimate): June 10, 2011
• Last Update Submitted That Met QC Criteria: June 9, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Keywords: Infertility; PCOS; Polycystic ovary syndrome; Cancelled cycles; OHSS
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Polycystic Ovary Syndrome; Syndrome; Infertility; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 04/2010