Study reveals potential causes of infertility

A 556-gene signature in the uterine lining may help explain why some embryo transfers fail, even when clinics use chromosomally normal embryos, new research suggests.

Even in the best-case scenario, when clinics transfer embryos with a normal number of chromosomes into a woman’s uterus, only about half result in a live birth.

Some transfers lead to pregnancy followed by miscarriage, but in 30 to 35 per cent of cases the embryo does not implant in the uterus at all.

For decades, fertility research has focused heavily on embryo quality, but some scientists suspect the problem can lie in the uterus itself. New findings support that view.

Researchers at Rutgers Health and Michigan State University identified genes concentrated in gland cells in the uterine lining, known as the endometrium, that rise in fertile women during the brief window when the womb can accept an embryo.

The team enrolled 30 patients with regular menstrual cycles and proven fertility.

Participants used ovulation predictor kits and worked with researchers so tissue samples were taken at precise points in the cycle.

Blood hormone levels and microscopic checks were used to confirm timing, adding rigour the researchers said was missing from earlier work.

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

The biggest molecular shift came as the cycle entered the mid-secretory phase, the stage typically linked with implantation.

The sharpest changes were seen in specialised uterine gland cells that produce molecules thought to nourish an embryo and help coordinate implantation.

Earlier studies had shown these glands matter in mice and sheep, but the authors said this is the first human evidence pointing to a central role for this glandular tissue.

They also noted that their results in mostly Black and Hispanic patients matched findings from mostly white patients in past research, suggesting similar factors may drive infertility across races.

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 work is not yet ready for clinical use.

Nataki Douglas, an associate professor of obstetrics, gynaecology and reproductive health at Rutgers New Jersey Medical School and senior author of the study, said the next steps include shortening the gene list and recruiting patients with implantation failure to test whether the signature predicts outcomes.

“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,” Douglas said.

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