Insulin Growth Factor-1 (IGF-1) and Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) in PCOS IVF Patients: Correlations With Outcome

Abstract

Protocols incorporating OCP/GnRH-agonist dual suppression followed by low-dose gonadotropin therapy are commonly utilized to induce ovulation for IVF in PCOS patients. Follicular recruitment in PCOS patients demonstrates that IGF-1 and IGFBP-3 are predictive of ovarian response. The purpose of this study was to observe IGF-1 and IGFBP-3 levels during the course of dual suppression/ low dose gonadotropin stimulation in PCOS patients and evaluate their value as predictive factors for IVF outcome. Prospective analysis of serial serum levels of IGF-1 and IGFBP-3 from PCOS patients undergoing IVF Serum was prospectively collected and cryopreserved for analysis at a later date from PCOS patients cycles (n=77) undergoing IVF with the dual suppression /low dose gonadotropin protocol over a two year period. Twenty patients (29.0%) were concurrently treated with metformin. Growth Hormone was not used. Serum IGF-1 and IGFBP-3 levels were measured by ELISAs (R&D Systems, MN) on day 3 of GnRH-agonist withdrawal bleed and on the day of hCG administration. Statistical analysis included non-parametric and Chi-Square tests. The mean age of patients was 30.6±2.9 years, and the mean BMI was 24.1±4.7. Peak mean estradiol levels were 1578 ± 912 pg/mL on day of hCG. An average of 13.3±3 oocytes with 9.7±4.9 mature oocytes were retrieved per cycle, with 6.9±3.8 normally fertilized oocytes per cycle. Clinical and ongoing pregnancy rates were 58.5% and 50.9%, respectively. IGF-1 and IGFBP-3 levels increased during stimulation (IGF-1, 187.4±78.1ng/mL vs. 243.5±146.0[day 3 vs. day of hCG], p<.0001; IGFBP-3, 1204.2±897.0 ng/mL vs. 1710.8±1532.5,[day 3 vs. day of hCG], p<.002). Metformin treatment did not significantly affect day 3 or day of hCG levels of IGF-1 or IGFBP-3, or the significant trend of increasing levels of IGF-1 and IGFBP-3 during stimulation. Those patients who had a decrease in IGF-1 levels from day 3 to day of hCG had higher mean numbers of oocytes retrieved (15.6±7.6 vs. 11.5±4.9, p=.02). However, patients whose IGF-1 levels fell during stimulation also had a significant increase in the number of immature oocytes; consequently, those whose IGF-1 levels rose had a higher percentage of mature oocytes (79.8% vs. 62.5% mature oocytes, rise vs. fall of IGF1 day 3 to day of hCG, p= 0.02). An increase in IGFBP-3 levels during stimulation was associated with a greater likelihood of becoming pregnant (IGFBP-3, p=.03) and of ongoing pregnancy (IGFBP-3, p=.02). For the first time we report on the dynamic changes of IGF-1 and IGFBP-3 during ovarian hyperstimulation for PCOS IVF patients. In this patient population we found a mean increase in levels of IGF-1 and IGFBP-3 during stimulation. Increasing levels of IGF-1 were associated with a higher percentage of mature oocytes, suggesting its higher bioavailability to maturing follicles. Increasing levels of IGFBP-3 during stimulation were associated with a higher likelihood of pregnancy and ongoing pregnancy. It is possible that this stimulation protocol creates a unique intraovarian environment affecting the important regulatory roles that IGF-1 and IGFBP-3 play in follicular recruitment and maturation. Interestingly, in this setting treatment with an insulin sensitizing agent did not affect ovarian responsiveness. Future studies into the Growth hormone/IGF-1 axis in the intraovarian environment during suppression and stimulation for IVF are needed.