More than 500 genes associated with uterine receptivity

Changes in the expression of 556 genes within uterine gland cells may explain why embryo implantation can fail repeatedly in some fertility patients.

Even with top-quality, chromosomally-normal embryos, only about half of IVF transfers result in a live birth. In some cases a miscarriage occurs, but in up to 35 percent of cases the embryo fails to implant in the uterus lining (endometrium). A study identified 556 genes, concentrated in endometrial gland cells, whose expression changes around the time of the cycle at which implantation would occur. The changes were more prevalent in endometrial samples from fertile women, compared to those who have experienced infertility.

'This was one of the first attempts to really look at the menstrual cycle in women who are fertile and try and understand how the endometrium is changing, how it becomes briefly receptive to embryo attachment at the most fundamental level,' said Dr Nataki Douglas, director of reproductive endocrinology and infertility at Rutgers New Jersey Medical School and the senior author of the study published in JCI Insight.

Because it is not possible to take endometrial samples around the time of implantation from women undergoing IVF or actively trying to conceive, the project recruited 30 women with regular menstrual cycles and proven fertility. Participants used ovulation predictor kits and worked with the researchers so tissue samples were taken at precise points in the cycle. Blood hormone levels and microscopic checks were used to confirm timing.

To track the endometrium's changes across the cycle, the team used two approaches: one measuring gene activity across the whole tissue and another measuring it cell by cell. Both pointed to the same pattern.

The largest molecular transition occurred as the menstrual cycle entered the mid-secretory phase: the stage typically linked with implantation. The changes were most pronounced in specialised uterine gland cells that produce molecules thought to nourish an embryo and help coordinate implantation.

From these patterns, the researchers defined a 556-gene signature they called the 'glandular epithelium receptivity module'. When they applied a score based on this signature to published datasets, it was consistently lower in women with recurrent implantation failure or pregnancy loss than in fertile controls.

The researchers hope that understanding uterine readiness could, in future, allow clinicians to identify when a woman's endometrium is contributing to infertility and offer solutions.

'Once we can identify those who are at risk and the genes that are the most important in this group of 556 that we know code for particular proteins that we might be able to add synthetically, then we may be able to work on therapeutic approaches,' said Dr Douglas.