Metabolomic profiles of receptive-phase endometrium in women with different infertility diagnosis

Abstract Study question What is the entire metabolomic profile of receptive-phase human endometrium and does the metabolic composition differ between women with different infertility diagnosis? Summary answer Human endometrium contains 925 different metabolites from diverse chemical classes, and the metabolomic signature varies between women with different infertility diagnosis. What is known already Different metabolites have been identified in human endometrium, including amino acids, nucleosides/nucleotides, organic acids, lipids, and sugars, with main focus on lipid profiles in endometriosis. Metabolic dysregulation in the uterus has been shown to provoke complex effects in the endometrium, leading to a low rate of embryo implantation and endometriosis. These are the first studies highlighting the importance of metabolites (metabolic routes) in endometrial functions and more research in the field is warranted. Further, the previous studies have focussed on specific metabolite classes, and we lack the knowledge of the whole metabolome composition in human uterus. Study design, size, duration This cross-sectional study included in total 47 women (age= 34.7±3.8 years, BMI= 24.5±4.2 kg/m²) who attended the Reproduction Unit at the University Hospital Granada from March 2019 to April 2021. Women with endometriosis (n = 13), unexplained infertility (n = 10), recurrent implantation failure (RIF) (n = 15) and male factor infertility (n = 9) were included. The study was approved by the Ethics Committee of Investigación Biomédica de Andalucia. Participants/materials, setting, methods Endometrial biopsies were collected at the mid-secretory phase (LH + 7) of a natural cycle using Pipelle curette. The complete metabolome from endometrial samples was analysed by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Raw data were extracted, peak-identified and quality control processed using Metabolon’s hardware and software (metabolon.com). Multiple regression models controlling for age and BMI were applied using R software. Main results and the role of chance We provide the whole metabolome profile of endometrium, where 925 different metabolites were identified. Among these metabolites, lipid metabolites comprised the largest percentage (44%), where long chain fatty acids such as myristate (14:0), palmitoleate (16:1n7), nonadecanoate (19:0), arachidate (20:0), and dihomo-linolenate (20:3n3 or n6) prevailed. The endometrial metabolomic profiles differed significantly between women with different infertility diagnosis (p <0.05). Overall, the metabolites of the lipid and protein metabolism were less present, while carbohydrates, nucleotides, and xenobiotics were predominant in the uterus of women with unexplained infertility, endometriosis, and RIF when compared to women with male factor infertility. Specifically, the metabolites linoleate (18:2n6), linolenate (18:3n3 or n6), and dihomo-linolenate (20:3n3 or n6) were less abundant in women with indication of dysfunctional endometrium (endometriosis and RIF) (FDR p -value<0.05). Limitations, reasons for caution This is the first study presenting the complete metabolome of human endometrium on a limited sample size, which might have been underpowered to detect all differences in metabolite composition between groups. Wider implications of the findings This study identifies a metabolomic profiles associated with infertility diagnoses where altered endometrial functions are suspected (RIF and endometriosis). Our study findings could help to understand the molecular background of female infertility and lead to identification of potential molecular biomarkers of endometrial functions involved in embryo implantation and infertility. Trial registration number not applicable