Impact of sitagliptin on endometrial mesenchymal stem-like progenitor cells: A randomised, double-blind placebo-controlled feasibility trial
Shreeya Tewary,
Emma S. Lucas,
Risa Fujihara,
Peter K. Kimani,
Angela Polanco,
Paul J. Brighton,
Joanne Muter,
Katherine J. Fishwick,
Maria José Minhoto Diniz Da Costa,
Lauren J. Ewington,
Lauren Lacey,
Satoru Takeda,
Jan J. Brosens,
Siobhan Quenby
Affiliations
Shreeya Tewary
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, UK
Emma S. Lucas
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, UK
Risa Fujihara
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Department of Obstetrics & Gynaecology, Juntendo University, Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Peter K. Kimani
Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Angela Polanco
Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, UK
Paul J. Brighton
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK
Joanne Muter
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, UK
Katherine J. Fishwick
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK
Maria José Minhoto Diniz Da Costa
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, UK
Lauren J. Ewington
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, UK
Lauren Lacey
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, UK
Satoru Takeda
Department of Obstetrics & Gynaecology, Juntendo University, Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Jan J. Brosens
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, UK
Siobhan Quenby
Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire, Coventry CV2 2DX, UK; Corresponding author at: Division of Biomedical Sciences, Warwick Medical School, University Hospitals Coventry and Warwickshire, Coventry, CV2 2DX, United Kingdom.
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. Thirty-eight 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: 1.32–1.75, 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. Clinical trial registration: EU Clinical Trials Register no. 2016-001120-54. Keywords: Pregnancy, Miscarriage, Sitagliptin, Endometrium stem cells, Randomised clinical trial, Decidualization
