Granulocyte Macrophage Colony Stimulating Factor Supplementation in Culture Media for Subfertile Women Undergoing Assisted Reproduction Technologies: A Systematic Review

Abstract

Granulocyte macrophage colony stimulating factor (GM-CSF) is a cytokine/growth factor produced by epithelial cells that exerts embryotrophic effects during the early stages of embryo development. We performed a systematic review, and six studies that were performed in humans undergoing assisted reproduction technologies (ART) were located. We wanted to evaluate if embryo culture media supplementation with GM-CSF could improve success rates. As the type of studies and the outcome parameters investigated were heterogeneous, we decided not to perform a meta-analysis. Most of them had a trend favoring the supplementation with GM-CSF, when outcomes were measured in terms of increased percentage of good-quality embryos reaching the blastocyst stage, improved hatching initiation and number of cells in the blastocyst, and reduction of cell death. However, no statistically significant differences were found in implantation and pregnancy rates in all apart from one large multicenter trial, which reported favorable outcomes, in terms of implantation and live birth rates. We propose properly conducted and adequately powered randomized controlled trials (RCTs) to further validate and extrapolate the current findings with the live birth rate to be the primary outcome measure.

Effects of granulocyte-macrophage colony-stimulating factor supplementation in culture medium on embryo quality and pregnancy outcome of women aged over 35 years

“…Unfortunately, compared to the control group, no significant benefit to embryo quality was observed. The present result differed from several previous preclinical studies in which the developmentpromoting and apoptosis-decreasing effect of GM-CSF on human embryos was observed [20,29]. The main causes of this difference might be the following.…”

“…Thus, it might be speculated that GM-CSF exerts beneficial effects on implantation competence of the embryos derived from elderly subfertile women. Several previous clinical researches also confirmed the beneficial role of GM-CSF addition in pregnancy rate and/or live birth rate in patients who experienced at least one previous miscarriage or unsuccessful IVF cycles [1,20]. In the present study, all patients recruited were aged over 35 and the probability to achieve successful pregnancy was greatly reduced compared to the normal population.…”

“…Comparing our results with previous researches, we could conclude the possibility that GM-CSF possessed embryotrophic properties, especially to congenitally deficient embryos derived from elderly subfertile women. Contrary to previous studies [20] and owing to extraneous expenses for GM-CSF addition, only a relatively lower concentration of GM-CSF (0.2 ng/mL) was employed in this study. It was confirmed that a culture with 2 ng/mL GM-CSF did not disturb the chromosomal constitution of embryos when compared with the control [22].…”

“…Among various embryokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) has attracted much attention. GM-CSF is expressed in female genital tract, and as a developmental programming agent, it enhances cell proliferation, embryo progression, blastocyst hatching, and embryo implantation [1,3,[16][17][18][19][20][21][22][23]. Especially, some existing data have indicated a link between decreased GM-CSF levels and reproductive pathologies in women, including miscarriage, intrauterine fetal growth retardation, preeclampsia, and preterm delivery Capsule Although no benefit of GM-CSF on embryo quality was observed, the addition of this factor significantly decreased the occurrence of chemical pregnancy of women aged over 35 years, indicating the role of GM-CSF in improving implantation competence of embryos derived from elderly infertile women.…”

“…These researches suggest GM-CSF as an attractable candidate for improving the quality of the present culture medium. However, most of these results are from animal studies [1,3,[16][17][18], and the effect of GM-CSF on human preimplantation embryo, especially the clinical perinatal outcome and offspring health, has yet to be elucidated [20][21][22][23]. Moreover, the present concentration of GM-CSF (2 ng/mL) applied in human researches is chosen mainly based on animal data [19,21,22], which cannot be exactly equal to human oocytes or embryos.…”