Impact of Sitagliptin on Endometrial Mesenchymal Stem-Like Progenitor Cells: A Randomised, Double-Blind Placebo-Controlled Feasibility Trial

Abstract

Background: Recurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury. Here, we evaluated the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, determined the impact on endometrial decidualization, and assessed the feasibility of a full-scale clinical trial. Methods: A double-blind, randomised, placebo-controlled feasibility trial on women aged 18 to 42 years with a history of 3 or more miscarriages, regular menstrual cycles, and no contraindications to sitagliptin. Thirtyeight subjects were randomised to either 100 mg sitagliptin daily for 3 consecutive cycles or identical placebo capsules. Computer generated, permuted block randomisation was used to allocate treatment packs. Colony forming unit (CFU) assays were used to quantify eMSC in midluteal endometrial biopsies. The primary outcome measure was CFU counts. Secondary outcome measures were endometrial thickness, study acceptability, and first pregnancy outcome within 12 months following the study. Tissue samples were subjected to explorative investigations. Findings: CFU counts following sitagliptin were higher compared to placebo only when adjusted for baseline CFU counts and age (RR: 1.52, 95% CI: 1.32À1.75, P<0.01). The change in CFU count was 1.68 in the sitagliptin group and 1.08 in the placebo group. Trial recruitment, acceptability, and drug compliance were high. There were no serious adverse events. Explorative investigations showed that sitagliptin inhibits the expression of DIO2, a marker gene of senescent decidual cells. Interpretation: Sitagliptin increases eMSCs and decreases decidual senescence. A large-scale clinical trial evaluating the impact of preconception sitagliptin treatment on pregnancy outcome in RPL is feasible and warranted. Funding: Tommy's Baby Charity.

Characterization of Highly Proliferative Decidual Precursor Cells During the Window of Implantation in Human Endometrium

“…In this context, a recent pilot trial demonstrated that sitagliptin, a dipeptidyl-peptidase IV inhibitor used in the management of diabetes, increases endometrial clonogenicity and decreases decidual senescence during the implantation window in recurrent miscarriage patients. 74 The efficacy of sitagliptin, and other potential interventions that target BDMSC and decidual precursor cells, 28 in mitigating the risk of adverse pregnancy outcome warrants further evaluation in clinical trials.…”

Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids

“…Clinically, recurrent pregnancy loss, defined as multiple miscarriages, is associated with loss of endometrial clonogenicity (Lucas et al, 2016, Diniz-da-Costa et al, In press), uNK cell deficiency and excessive decidual senescence (Lucas et al, 2020, Tewary et al, 2020), and rapid conceptions (also referred to as ‘superfertility’) (Dimitriadis et al, 2020, Ticconi et al, 2020). Conversely, lack of a proliferative gene signature in midluteal endometrium and premature expression of decidual PRL have been linked to recurrent implantation failure (Berkhout et al, 2020b, Koler et al, 2009, Koot et al, 2016), a pathological condition defined by a failure to achieve a pregnancy following transfer of one or more high-quality embryos in multiple IVF cycles (Polanski et al, 2014).…”

“…Turnover of senescent decidual cells likely promotes recruitment of bone marrow-derived decidual precursor cells, which confer tissue plasticity for rapid decidual expansion in early pregnancy (Diniz-da-Costa et al, In press). Importantly, lack of clonogenic decidual precursor cells and a pro-senescent decidual response are linked to recurrent pregnancy loss (Lucas et al, 2016, Lucas et al, 2020, Tewary et al, 2020).…”

Jointly modelling longitudinally measured urinary human chorionic gonadotrophin and early pregnancy outcomes

“…Monitoring from first detection has the potential to be useful in cases of recurrent miscarriage, particularly as research into treatment gains traction. A recently published feasibility study assessing the effectiveness of the diabetes drug sitagliptin as a treatment for recurrent miscarriage, presented promising findings 24 . This trial builds on previous research, which found that in some cases of recurrent miscarriage it is the deterioration of stem-like cells in the uterus which contribute to pregnancy loss.…”