Research Sheds Light On Potential Causes of Infertility

Even in the best-case scenario, when fertility clinics transfer chromosomally normal embryos into a would-be mother’s uterus, the procedure only leads to a live birth half of the time. Some embryo transfers result in a pregnancy, and then miscarriage; but in 30 to 35% of cases, the embryo doesn’t even implant in the uterus.

For decades, fertility research has focused intensely on embryo quality, but some scientists have begun to suspect that the overlooked problem lies in the uterus itself. New research from Rutgers Health and Michigan State University supports that view. 

The study in JCI Insight identified 556 genes, concentrated in gland cells in the uterine lining (endometrium), that are increased in fertile women – but not in those who have struggled with infertility – when the uterus enters its brief window of receptivity.

“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 Nataki Douglas, an associate professor of obstetrics, gynecology and reproductive health at Rutgers New Jersey Medical School and senior author of the study.

The researchers couldn’t sample endometrial tissue just before the embryo transfer after in vitro fertilization and compare samples from patients whose treatments did and didn’t succeed, as such procedures could disrupt early pregnancy and create failures.

Instead, the team enrolled 30 patients from University Hospital in Newark, women with regular menstrual cycles and proven fertility. Participants used ovulation predictor kits and coordinated with the research team to ensure endometrial biopsies occurred precisely at different phases of the menstrual cycle. Blood hormone levels and microscopic examination confirmed the timing and thus provided a level of rigor the researchers said was lacking in previous work.

To read the endometrium’s shifting biology, the researchers used two sequencing approaches: one that measures gene activity in the tissue as a whole and another that measures it cell by cell.

Both approaches told the same story: The largest molecular transition occurred as the menstrual cycle entered the mid-secretory phase, which is usually the window for embryo implantation.

The most striking changes were in specialized cells in uterine glands that produce molecules thought to nourish an embryo and help orchestrate implantation. Previous research has established the importance of these glands in mice and sheep, but this is the first human evidence for the glandular epithelium’s central role, said the authors, who noted that the correlation of their findings from mostly Black and Hispanic patients at University Hospital with those from mostly white patients in past research is the first evidence that similar factors drive infertility across races.

From those patterns, the researchers defined a 556-gene signature they called the Glandular Epithelium Receptivity Module (GERM). When they applied a GERM score to published datasets, it was consistently lower in women with recurrent implantation failure or pregnancy loss than in fertile controls.

The work remains far from clinical application. Douglas, who is also a member of the Rutgers Center for Immunity and Inflammation, said the next steps include shrinking the gene list to something practical and prospectively recruiting patients with implantation failure to test whether the signature predicts outcomes.

The broader hope is that understanding uterine readiness could let clinicians identify when a patient’s endometrium is malfunctioning and eventually fix any problems they find.

“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,” Douglas said.