Changes in the expression of 556 genes within uterine gland cells may explain why embryo implantation repeatedly fails for some patients undergoing fertility treatment, according to a new study published in JCI Insight.
Despite the leverage of high-quality, chromosomally normal embryos, approximately half of in vitro fertilization (IVF) transfers do not result in a live birth. While some pregnancies conclude in miscarriage, a significant proportion – up to 35 percent of cases – involve a failure of the embryo to implant in the uterine lining, known as the endometrium.
Researchers identified the 556 genes whose expression levels change around the time implantation would normally occur. These changes were more pronounced in endometrial samples taken from women with proven fertility, compared to those who had experienced infertility.
“This was one of the first attempts to really look at the menstrual cycle in women who are fertile and attempt 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 study’s senior author.
Obtaining endometrial samples around the time of implantation is challenging, particularly from women undergoing IVF or actively trying to conceive. To overcome this, the research team recruited 30 women with regular menstrual cycles and confirmed fertility. Participants used ovulation predictor kits, and tissue samples were collected at precise points in their cycles, with blood hormone levels and microscopic checks used to verify timing.
The team employed two approaches to track changes in the endometrium throughout the cycle: one measuring gene activity across the entire tissue sample, and another analyzing it at the single-cell level. Both methods revealed the same pattern of gene expression.
The most significant molecular changes occurred during the mid-secretory phase of the menstrual cycle, the period typically associated with implantation. These changes were most prominent in specialized uterine gland cells, which produce molecules believed to nourish the embryo and coordinate the implantation process.
Based on these patterns, the researchers defined a 556-gene signature, termed the “glandular epithelium receptivity module.” When this signature was applied to existing datasets, it consistently showed lower scores in women with recurrent implantation failure or pregnancy loss compared to fertile controls.
According to the CNY Fertility website, successful implantation requires preparing the endometrium with hormones, carefully timing the embryo transfer, and ensuring an optimal uterine environment. The site notes that estrogen and progesterone are commonly used to thicken and prepare the endometrium before embryo transfer, and these medications are often continued into the early stages of pregnancy.
Dr. Douglas expressed hope that a deeper understanding of uterine readiness could eventually allow clinicians to identify women whose endometrium is contributing to infertility and offer targeted solutions.
“Once One 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,” she said.
