P-322 Does endometrium age? The endometrial transcriptome of advanced reproductive age patients reveals the signs of cellular ageing, altered immune response and compromised receptivity
Authors: Loid M , Obukhova D , Derks K , Meltsov A , Kask K , Altmäe S , Saare M , Peters M , Esteki M Z , Salumets A 
Published: June 2022

Abstract

Study question
What changes occur in the endometrium during ageing and how they may affect fertility?

Summary answer
The endometrial transcriptome of women of advanced maternal age is significantly different from the young women, indicating specific pathways involved in endometrial ageing.

What is known already
A woman’s peak reproductive years are considered in her twenties. Trending postponed family planning, unfortunately, brings more women in their late forties to fertility specialists to seek for assisted conception. In vitro fertilization (IVF) using donated oocytes is a common approach to overcome the impact of maternal age on ovarian reserve. However, even with the implementation of embryo that underwent pre-implantation genetic testing, the IVF success rate drops significantly in the late forties. It still remains unclear which age-related molecular processes take place in the endometrium and whether it may impact the ability to support embryo implantation.

Study design, size, duration
Endometrial transcriptome profiling was done in 44 women undergoing endometrial receptivity evaluation at hormonal replacement therapy before IVF. Patients younger than 29 were considered as young maternal age group (YMA, age 23-27) and women older than 45 were considered as advanced maternal age group (AMA, age 47-50).

Participants/materials, setting, methods
Endometrial biopsies were obtained on day 5 of progesterone treatment and RNA was extracted. All endometrial samples were evaluated as receptive based on the expression of 57 common endometrial receptivity markers. Study group samples (12 YMA + 12 AMA) were subject to Illumina RNA sequencing. The sequences were annotated using the RefSeq database and differential expression analysis was performed using DeSeq2.We validated our results (10 YMA + 10 AMA) usingquantitative-PCR and histological validation.

Main results and the role of chance
A total of 37228 mRNA transcripts were expressed in the analyzed endometrial samples. After multiple testing corrections, 144 significantly differentially expressed(DE) transcripts (92 up-regulated, 52 down-regulated) were identified in the endometrium of the AMA versus YMAgroup. Overexpressed genes were associated with decidualization (ALDH3A1), endometrial receptivity (EML5, GALNT12), cell cycle (CDKN2A) and signal transduction, while down-regulated genes included sugar metabolism and inflammation (C2CD4B, NFKB), cellular motility (SPAG6)and progesterone signaling (RPL9). The pathways most affected by age were cellular remodeling, cell motility and migration, and immune response. Interestingly, some of the identified DE genes have been previously associated with ageing. Our results suggest the involvement of p16-associated cellular senescence and the suppression of metabolic and inflammatory processes essential for endometrial preparation for embryo transfer.

Limitations, reasons for caution
The study includes only patients undergoing hormonal replacement therapy and it is unclear whether the same processes are affected by age in the natural cycles.

Wider implications of the findings
These findings allow us to explain the age-related molecular changes that take place in the endometrial tissue. Understanding these alterations and using them in assisted reproductive technology may help to improve infertility management in women with advanced reproductive age.

Trial registration number
None