New research published online in Developmental Cell indicates that higher expression of certain developmental genes at precise times in the uterus might improve pregnancy rates from in vitro fertilization-embryo transfers (IVF-ET). So far, these rates remain low at around 30%.

Researchers at Cincinnati Children’s Hospital Medical Center focused on Msx1 and Msx2, genes that play integral roles in organ formation during fetal development and are essential for ensuring that the uterus is in a receptive phase. Sudhansu K. Dey, PhD, director of the Division of Reproductive Sciences in the Perinatal Institute at Cincinnati Children’s Hospital Medical Center, said compromised uterine receptivity is a major cause of pregnancy failure in IVF programs.

The risk of premature birth is higher for babies successfully conceived through IVF. Premature births can lead to various potential short and long- term health risks for the child, but recognizing essential molecular signaling pathways during the critical stages of early pregnancy in IVF patients could open the door for new approaches to optimize pregnancy outcome.

Dey comments:

“Our findings raise the possibility that clinicians may be able to develop new strategies to improve implantation rates in IVF programs by temporarily increasing uterine levels of Msx. This could allow clinicians to potentially extend the window of uterine receptivity and grant transferred embryos more time to implant.”

The researchers determined in a series of experiments involving engineered mice, that the loss of Msx genes is linked to detrimental reproductive consequences in a key molecular signaling pathway that involves Wnt signaling. This Wnt pathway plays a key role in the development of the embryo. Because of the Msx loss, uterine luminal epithelial cell respond incorrectly and fail to develop a slit-like structure that forms a crypt, called nidus, which is necessary for placing the embryo for successful implantation.

The researchers observed that depending on whether they deleted a single or double Msx gene in mice, these mice showed graded levels of compromised fertility, for example, mice with a single deleted Msx1 produced either smaller than normal litter sizes or no litters at all, whilst deletion of both Msx1 and Msx2 genes lead to complete infertility due to the embryos failing to implant.

Gene analysis has revealed that during the menstrual cycle in women, Msx genes are differentially expressed in the uterus, suggesting that it could be possible that genes identified in this study may play important roles during human implantation.

The researchers also discovered that Msx genes conduct and maintain uterine receptivity without altering uterine sensitivity to these hormones or ovarian hormone levels. Dey and his team suggest that Msx could be likely to assist in the development of non-steroidal contraceptives in addition to potentially improving IVF-derived pregnancy outcomes.

The researchers say that although they achieved an advance in gaining a better understanding of the molecular network that regulates female fertility, which is subject to manipulation, further research is needed to apply the findings to human fertility.

Takiko Daikoku, PhD, a faculty member in the Division of Reproductive Sciences, and Jeeyeon Cha, an MD/PhD student in Dey’s laboratory were the first co-authors of the study, which was partly funded by the National Institutes of Health, including a training grant from the National Institutes of Child Health and Development and a pre-doctoral National Research Service Award; the Cincinnati Children’s Perinatal Institute Pilot/Feasibility grant; a Lalor Foundation Post-doctoral Fellowship, and the Japan Society for the Promotion of Science Fellowship for Research Abroad.

Written by Petra Rattue