P-319 Opposite functional alterations between aged endometria and that of women with uterine disorders offer plausible explanations to the increased incidence of uterine disorders with age
Authors: Devesa Peiro A , Sebastian-Leon P , Garcia-Garcia F , Pellicer A , Saez-Rodriguez J , Diaz-Gimeno P 
Published: June 2022

Abstract

Study question
Which is the functional relationship between age and uterine disorders at endometrial level?

Summary answer
Ciliogenesis and cell cycle processes were oppositely altered between the endometrium of patients with uterine disorders and that of &gt; 35 y.o. women.

What is known already
Uterine disorders are complex and multifactorial conditions which incidence increases with age affecting women's reproductive health and fertility. Uterine disorders and age have been transcriptomically researched to identify potential biomarkers and underlying mechanisms in independent studies. However, there is a lack of studies comparing the effects caused by uterine disorders and age in endometrium to understand the functional relationship between them. The objective of this research was to compare the mechanisms underlying uterine disorders and age in the endometrium to understand the molecular relationship behind the increased incidence of these disorders with age.

Study design, size, duration
In silico study performed between 2016-2021 involving a systematic review at Gene Expression Omnibus sample repository to identify datasets with endometrial gene expression raw data associated to uterine disorders and age for answering the research question. Samples were preprocessed and analyzed with the same transcriptomic procedures for comparable analysis of functions affecting gene expression. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, DoRothEA and OmniPath functional databases were consulted for identifying functions/transcription factors involved.

Participants/materials, setting, methods
Nine endometrial transcriptomic datasets evaluating uterine disorders (123 cases, 127 controls) and one including control women with different ages (23–49 y.o., n = 27) were downloaded. Differentially expressed genes and gene set enrichment functional results related to uterine disorders or age for each dataset were calculated and integrated between uterine disorders under a meta-analysis with a random effects model to account for study heterogeneity. Upstream transcription factors and pathways were identified with footprinting methods.

Main results and the role of chance
All evaluated uterine disorders (adenocarcinoma (ADC), recurrent implantation failure (RIF), recurrent pregnancy loss (RPL) and eutopic endometriosis) shared a significant downregulation of six ciliary functions (FDR&lt;0.03) with 186 associated genes. Moreover, the EGFR proliferative pathway and its downstream transcription factors MYC and/or E2F, involved in cell cycle progression, were significantly upregulated in ADC, RIF and endometriosis but downregulated in RPL (all FDR&lt;0.05). Conversely, the endometrium of women &gt;35 y.o. presented an opposite functional profile in comparison with the effect of uterine disorders - with a significant upregulation of 22 ciliary functions (FDR&lt;0.03) and a downregulation of epithelial cell proliferation (FDR=0.014) - with the exception of RPL which also presented a significant downregulation of the cell cycle (FDR&lt;0.05). We identified 91 significantly upregulated genes as major contributors of cilia alterations with age (49.5% of them being shared with the 186 cilia-related genes detected in uterine disorders); and 37 significantly downregulated cell cycle genes, including EGFR (all FDR&lt;0.05). Since ciliogenesis and cell cycle progression present an antagonistic relationship, upregulation of ciliary functions could be related to the downregulation of cell cycle processes and viceversa.

Limitations, reasons for caution
This study depends on publicly available datasets to analyze. Although we considered potential confounding variables (time of biopsy collection, presence of benign pathologies in aged women) and study heterogeneity (using random effects models accounting for study variability), further studies are needed to corroborate our findings and test the proposed hypothesis.

Wider implications of the findings
A new hypothesis was generated regarding the molecular mechanisms behind the increased incidence of uterine disorders with age: With aging, the endometrium exhibits cell cycle arrest, inhibiting ciliogenesis. Consequently, compensatory mechanisms are activated to counteract aging-related alterations, but these mechanisms could be unbalanced towards the other extreme, originating distinct disorders.

Trial registration number
Not applicable