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.

Purpose: To evaluate the effect of endometrial scratching on in vitro fertilization (IVF) success rates in women undergoing frozen embryo transfer with preimplantation genetic testing for aneuploidy (PGT-A). Methods: Biopsy was performed at oocyte retrieval in cases and compared to those who did not undergo scratching (controls). Endpoints included pregnancy loss, total pregnancy, clinical pregnancy rate (CPR), ongoing pregnancy rate/live birth rate (OPR), and the incidence of chronic endometritis (CE). Results: Women in case and control groups had similar characteristics, such as age, body mass index, and parity. Overall total pregnancy rate was 82.43% following single euploid embryo transfer in cases compared to 85.7% in controls (p = 0.57; OR = 1.27; 95% CI = 0.565 to 2.78). CPR was 73.3% and 76.2% (p = 0.62; OR = 1.18; 95% CI = 0.594 to 2.29), and OPR between groups was 64.8% and 72.3% (p = 0.28; OR = 1.42; 95% CI = 0.74 to 2.7). First trimester loss rate was similar at 16.9%% and 15.5%%, respectively (p = 0.82). Subjects who underwent scratching closer to their frozen embryo transfer (≤ 3 months) had a similar overall pregnancy rate to those with a longer delay between retrieval and frozen embryo transfer (> 3 months 81.4% vs.87.5%; p = 0.56). CE incidence was 10.8% (8 out of 74; 95% CI = 5.5% to 19.9%). The odds of having a second trimester loss were significantly higher in the scratch group compared to controls (p = 0.03; OR = infinity; 95% CI = 1.3 to infinity). Conclusions: Endometrial scratching before frozen euploid embryo transfer did not influence pregnancy outcome but increased the chances of second trimester loss. CE was a frequent finding in those undergoing endometrial scratching at the time of retrieval.