Animal studies suggest that the insulin-like growth factors play an important role in preimplantation embryo development. Human preimplantation embryos express mRNA for insulin-like growth factor-I receptor (IGF-IR) but the ligand, insulin-like growth factor-I (IGF-I), is not expressed by the embryo until after implantation. We tested the hypothesis that IGF-I produced by the female reproductive tract may bind to these receptors, augmenting embryo survival, growth and development. Transcripts of mRNA for IGF1 were detected using reverse transcription-polymerase chain reaction in midcycle human Fallopian tube. Immunohistochemistry localized immunoreactive IGF-I to the cytoplasm of all the major structures of the Fallopian tube, with the most intense staining seen in the tubal epithelial lining. Maternally produced IGF-I was present in the fluid found in the human tube and uterus at concentrations of 8.0 and 10.9 nM respectively. Supplementation of culture medium with IGF-I increased the proportion of embryos developing to the blastocyst stage from 35% in controls to 60% in the presence of IGF-I. In addition the total number of cells in day 6 blastocysts was increased by 19% (64.44 versus 54.08% in control, not significant), due entirely to a statistically significant 59% increase (25 versus 15.75%, P = 0.020) in the number of cells in the inner cell mass. The effect of IGF-I was mediated through the IGF-I receptor. Immunocytochemistry using an alphaIR3 antibody confirmed the presence of IGF-I receptor in human blastocysts and the same antibody completely inhibited the stimulation of blastocyst formation by IGF-I. These data suggest that human preimplantation development is enhanced by maternal IGF-I. Mimicking this in-vivo paracrine relationship may improve clinical in-vitro embryo culture and IVF pregnancy rates.

Insulin, insulin‐like growth factor‐I (lgf‐I), and insulin‐like growth factor‐II (lgf‐II) are known to enhance growth in mouse preimplantation embryos. The addition of insulin, lgf‐I, and lgf‐II to mouse embryos in culture results in an increase in protein synthesis, cell number, and the proportion of embryos developing to the blastocyst stage. To study the role of the insulin‐like growth factors in early human development, the timing of gene expression of insulin, IGF1, IGF2, and their receptors was analysed. Reverse transcription‐polymerase chain reaction (RT‐PCR) was used to examine the presence of transcripts in preimplantation embryos. Following reverse transcription, strategically designed nested primers were used for amplification from cDNA. Transcripts for all three receptors (insulin receptor, IGF1R, IGF2R) were present in human oocytes and preimplantation embryos. However, of the ligands, only IGF2 transcripts were detected. This is consistent with expressed patterns seen in the mouse. As in the human, mouse lgf2 is the only ligand in the family expressed and has been shown to have an autocrine effect on preimplantation development. It has previously been shown that insulin and lgf‐1 are produced by the mouse maternal reproductive tract and have a paracrine effect on the preimplantation embryo. We speculate that a similar relationship exists in the human and that preimplantation development may be regulated by IGFs from both embryonic (IGF‐II) and maternal (insulin and IGF‐I) sources. Mol. Reprod. Dev. 47:134–139, 1997. © 1997 Wiley‐Liss, Inc.

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There appears to be no benefit in metformin co-treatment before and during IVF in women with PCO without any other features of PCOS. Clinical Trials.gov: NCT01046032.

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