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Impact of sitagliptin on endometrial mesenchymal stem-like progenitor cells: A randomised, double-blind placebo-controlled feasibility trial.
EBioMedicine ( IF 9.7 ) Pub Date : 2020-01-02 , DOI: 10.1016/j.ebiom.2019.102597
Shreeya Tewary 1 , Emma S Lucas 1 , Risa Fujihara 2 , Peter K Kimani 3 , Angela Polanco 4 , Paul J Brighton 5 , Joanne Muter 1 , Katherine J Fishwick 5 , Maria José Minhoto Diniz Da Costa 1 , Lauren J Ewington 1 , Lauren Lacey 1 , Satoru Takeda 6 , Jan J Brosens 1 , Siobhan Quenby 1
Affiliation  

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.

中文翻译:

西格列汀对子宫内膜间充质干样祖细胞的影响:一项随机、双盲安慰剂对照的可行性试验。

背景 复发性妊娠丢失(RPL)与子宫内膜间充质干样祖细胞(eMSC)的丢失有关。DPP4 抑制剂可能会增加骨髓来源细胞向组织损伤部位的归巢和植入。在这里,我们评估了 DPP4 抑制剂西他列汀对 RPL 女性 eMSC 的影响,确定了对子宫内膜蜕膜化的影响,并评估了全面临床试验的可行性。方法 对 18 至 42 岁、有 3 次或以上流产史、月经周期规律且无西格列汀禁忌症的女性进行双盲、随机、安慰剂对照可行性试验。38 名受试者被随机分配每天服用 100 毫克西格列汀,连续 3 个周期,或服用相同的安慰剂胶囊。使用计算机生成的排列区组随机化来分配治疗包。集落形成单位 (CFU) 测定用于量化黄体中期子宫内膜活检中的 eMSC。主要结果指标是 CFU 计数。次要结果指标是子宫内膜厚度、研究可接受性以及研究后 12 个月内的首次妊娠结果。对组织样本进行了探索性研究。结果 仅在根据基线 CFU 计数和年龄进行调整后,西他列汀治疗后的 CFU 计数才高于安慰剂(RR:1.52,95% CI:1.32-1.75,P<0.01)。西他列汀组的 CFU 计数变化为 1.68,安慰剂组为 1.08。试验招募、可接受性和药物依从性都很高。没有发生严重的不良事件。探索性研究表明,西格列汀可抑制衰老蜕膜细胞标记基因 DIO2 的表达。解释 西他列汀可增加 eMSC 并减少蜕膜衰老。评估孕前西他列汀治疗对 RPL 妊娠结局影响的大规模临床试验是可行且有必要的。资助汤米婴儿慈善机构。临床试验注册 欧盟临床试验注册号 2016-001120-54。
更新日期:2020-01-09
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