Inflammatory Changes after Medical Suppression of Suspected Endometriosis for Implantation Failure: Preliminary Results

Abstract

Unexplained euploid embryo transfer failure (UEETF) is a frustrating and unanswered conundrum accounting for 30 to 50% of failures in in vitro fertilization using preimplantation genetic testing for aneuploidy (PGT-A). Endometriosis is thought by many to account for most of such losses and menstrual suppression or surgery prior to the next transfer has been reported to be beneficial. In this study, we performed endometrial biopsy in a subset of women with UEETF, testing for the oncogene BCL6 and the histone deacetylase SIRT1. We compared 205 PGT-A cycles outcomes and provide those results following treatment with GnRH agonist versus controls (no treatment). Based on these and previous promising results, we next performed a pilot randomized controlled trial comparing the orally active GnRH antagonist, elagolix, to oral contraceptive pill (OCP) suppression for 2 months before the next euploid embryo transfer, and monitored inflammation and miRNA expression in blood, before and after treatment. These studies support a role for endometriosis in UEETF and suggest that medical suppression of suspected disease with GnRH antagonist prior to the next transfer could improve success rates and address underlying inflammatory and epigenetic changes associated with UEETF.

Keywords: endometriosis; implantation; infertility; inflammation; recurrent pregnancy loss.

Figure 1

(a) Normal endometrial receptivity is largely regulated by progesterone which down-regulates estrogen receptors and initiates an extensive list of activated genes, along with stromal decidualization which is critical for successful pregnancy (left). In endometriosis, due to immune activation and inflammatory cytokines, progesterone action is suppressed and estrogen signaling amplified, contributing to infertility and pregnancy loss. (b) Pregnancy success rates (live birth and ongoing pregnancy) in first attempt PGT-A (First PGTA), compared to those with prior failure and GnRH agonist suppression for 2 months (GnRHa) or no further treatment (NoTx). The pregnancy success rate (95% CI) was 71.65% (63.27% to 78.77%), 68.09% (53.83% to 79.6%), and 35.71% (16.34% to 61.24%), respectively. No treatment was inferior to either GnRHa suppression or first time PGT-A success rates (p = 0.02, chi-squared).

Figure 2

Differential expression of inflammation-related genes comparing pre- and post- treatment. (a) Heatmap of 10 differentially expressed transcripts (DETs; p ≤ 0.05) in peripheral blood detected using the Nanostring Inflammation panel before and after OCPs treatment. (b) Heatmap of 42 DETs (p ≤ 0.05) detected before and after elagolix treatment. Principal component analysis (PCA) plot for the OCP group (c) before and after treatment, and a PCA plot for the elagolix group (d).

Figure 3

Differential expression of miRNAs comparing pre- and post- treatment. (a) Heatmap of 10 differentially expressed miRNA transcripts (DETs; p ≤ 0.05) in peripheral blood detected using the Nanostring Human miRNA panel before and after OCPs treatment. (b) Heatmap of 337 DETs (p ≤ 0.05) detected before and after elagolix treatment. Principal component analysis (PCA) plot for the OCP group (c) before and after treatment, and a PCA plot for the elagolix group (d).