Endocrine Abstracts

Objective: Obesity and polycystic ovary syndrome (PCOS) affect endomertial receptivity and may cause implantation failure, defective placentation, and pregnancy loss. Glucagon-like peptide-1 (GLP-1) receptor agonist (RA) improved the endometrial function in animal models, presumably by anti-inflammatory action and reduction of endometrial fibrosis. The impact of GLP-1RA on human endometrioum has not yet been investigated.

Aim: We compared endometrial transcriptome of women with obesity and PCOS pre-treated with liraglutide and endometrial transcriptome of treatment-naive BMI and age-matched controls.

Design: Cross-sectional study.

Methods: Endometrial biopsies were collected during the window of implantation from 20 infertile women with PCOS and BMI ≥30 kg/m² before in-vitro fertilization (IVF) procedure. The endometrium transcriptome of ten women who had been pretreated with low-dose liraglutide 1.2 mg QD for 12-weeks and achieved at least 5% weight loss from baseline were compared with 10 BMI and age matched PCOS controls who were treatment naïve and had a stable weight over the previous 12 weeks. Next-generation sequencing was conducted using the Illumina HiSeq 2000 platform to analyze RNA samples. The resulting data were processed through Ingenuity® Pathway Analysis to discern key canonical pathways and predict activations or inhibitions. Additionally, gene networks were constructed based on established published associations to further interpret the findings.

Results: Endometrial biopsy analysis demonstrated distinct gene expression profiles between both groups. A total of 1036 genes displayed differential expression with statistical significance (P-value <0.05); 478 genes were upregulated, and 558 genes downregulated in the treatment group, including ones already demonstrated to be associated with liraglutide treatment (PCSK2, ACTN3, NOS2). Functional analysis identified that the most important canonical pathways that differed between the comparison groups included GLP-1 receptor activation, modulation of inflammation and oxidative stress response, alterations in glucose homeostasis and energy consumption, with YWHAG being a notable central gene in the associated network. The results indicate a possible involvement of the AKT pathway in the liraglutide’s mode of action.

Conclusions: Short-term low-dose liraglutide treatment prior to IVF was associated with changes in the endometrial transcriptome that could potentially be important for improving endometrial receptivity and fertility in infertile women with obesity and PCOS.