BACKGROUND Modern lifestyle has led to an increase in the age at conception. Advanced age is one of the critical risk factors for female-related infertility. It is well known that maternal age positively correlates with the deterioration of oocyte quality and chromosomal abnormalities in oocytes and embryos. The effect of age on endometrial function may be an equally important factor influencing implantation rate, pregnancy rate, and overall female fertility. However, there are only a few published studies on this topic, suggesting that this area has been under-explored. Improving our knowledge of endometrial aging from the biological (cellular, molecular, histological) and clinical perspectives would broaden our understanding of the risks of age-related female infertility. OBJECTIVE AND RATIONALE The objective of this narrative review is to critically evaluate the existing literature on endometrial aging with a focus on synthesizing the evidence for the impact of endometrial aging on conception and pregnancy success. This would provide insights into existing gaps in the clinical application of research findings and promote the development of treatment options in this field. SEARCH METHODS The review was prepared using PubMed (Medline) until February 2023 with the keywords such as ‘endometrial aging’, ‘receptivity’, ‘decidualization’, ‘hormone’, ‘senescence’, ‘cellular’, ‘molecular’, ‘methylation’, ‘biological age’, ‘epigenetic’, ‘oocyte recipient’, ‘oocyte donation’, ‘embryo transfer’, and ‘pregnancy rate’. Articles in a language other than English were excluded. OUTCOMES In the aging endometrium, alterations occur at the molecular, cellular, and histological levels suggesting that aging has a negative effect on endometrial biology and may impair endometrial receptivity. Additionally, advanced age influences cellular senescence, which plays an important role during the initial phase of implantation and is a major obstacle in the development of suitable senolytic agents for endometrial aging. Aging is also accountable for chronic conditions associated with inflammaging, which eventually can lead to increased pro-inflammation and tissue fibrosis. Furthermore, advanced age influences epigenetic regulation in the endometrium, thus altering the relation between its epigenetic and chronological age. The studies in oocyte donation cycles to determine the effect of age on endometrial receptivity with respect to the rates of implantation, clinical pregnancy, miscarriage, and live birth have revealed contradictory inferences indicating the need for future research on the mechanisms and corresponding causal effects of women’s age on endometrial receptivity. WIDER IMPLICATIONS Increasing age can be accountable for female infertility and IVF failures. Based on the complied observations and synthesized conclusions in this review, advanced age has been shown to have a negative impact on endometrial functioning. This information can provide recommendations for future research focusing on molecular mechanisms of age-related cellular senescence, cellular composition, and transcriptomic changes in relation to endometrial aging. Additionally, further prospective research is needed to explore newly emerging therapeutic options, such as the senolytic agents that can target endometrial aging without affecting decidualization. Moreover, clinical trial protocols, focusing on oocyte donation cycles, would be beneficial in understanding the direct clinical implications of endometrial aging on pregnancy outcomes.

Hyperandrogenic women with PCOS show disrupted decidualization (DE) and placentation. Dihydrotestosterone (DHT) is reported to enhance DE in non-PCOS endometrial stromal cells (eSCCtrl); however, this has not been assessed in PCOS cells (eSCPCOS). Therefore, we studied the transcriptome profile of non-decidualized (non-DE) and DE eSCs from women with PCOS and Ctrl in response to short-term estradiol (E2) and/or progesterone (P4) exposure with/without (±) DHT. The non-DE eSCs were subjected to E2 ± DHT treatment, whereas the DE (0.5 mM 8-Br-cAMP, 96 h) eSCs were post-treated with E2 and P4 ± DHT, and RNA-sequenced. Validation was performed by immunofluorescence and immunohistochemistry. The results showed that, regardless of treatment, the PCOS and Ctrl samples clustered separately. The comparison of DE vs. non-DE eSCPCOS without DHT revealed PCOS-specific differentially expressed genes (DEGs) involved in mitochondrial function and progesterone signaling. When further adding DHT, we detected altered responses for lysophosphatidic acid (LPA), inflammation, and androgen signaling. Overall, the results highlight an underlying defect in decidualized eSCPCOS, present with or without DHT exposure, and possibly linked to the altered pregnancy outcomes. We also report novel factors which elucidate the mechanisms of endometrial dysfunction in PCOS.

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