The Effects Of High Concentration Of Progesterone On Endometrial Receptivity And Decidualization

Progesterone(P)is an extremely important steroid hormone that regulates the establishment and maintenance of pregnancy in mammals.P is often clinically used as a first-line drug for the conservative treatment of luteal phase deficiency.However,there are limited solid evidences available for the optimal timing and dose of P therapy,and especially for the possible adverse effects on implantation and decidualization when P is administrated empirically.A superphysiological dose of estrogen leads to a premature closure of the window of embryo implantation,but it has not been reported whether excess P supplementation is harmful to pregnancy outcome.Moreover,whether the high P serum level at the end of follicular phase has any adverse impacts on the ongoing pregnancy outcome is confused owing to the differences in test methods and cut-off levels in human IVF clinical practices until now.In this study,the effects and the molecular mechanism of P at different concentrations on embryo implantation and decidualization are evaluated in mouse models,and,effects of excess P on human in vitro decidualization are also examined.When pregnant mice were treated with 1,4 and 8 mg P/mouse on day 3 9:00,compared to control,the level of Lif mRNA expression in the whole uterus and phosphorylated Stat3 in the luminal epithelium on day 4 9:00 was inhibited by 4 or 8 mg/mouse P,so as to estrogen receptor(ER),P receptor(PR)and P target genes including Ihh and Areg.In order to analyze the effects of excess P on mouse decidualization,day 3 pregnant mice were treated with different dose of P daily(from days 3 to7).Compared to control,the weight of implantation sites on day 8 was significantly declined by 1,4 and 8 mg/mouse P.Additionally,for excluding effects of excess P on embryonic development,artificial decidualization mouse model was adopted,treatment of 4 mg/mouse P caused a significant decrease on the weight of deciduoma.Besides,the morphology of blastocysts from different dose of P treated mice is normal and similar to vehicle control.Under in vitro decidualization,Dtprp,a marker for mouse decidualization,was significantly induced,while Dtprp expression was significantly suppressed by 4 and 20 ?M,but not by 0.8 ?M P.We also found that birth weight of P treated mice was significantly reduced by 1 and 8 mg/mouse P.Meanwhile,the expression levels of IGFBP-1,FOXO1 and PLZF were significantly suppressed by excess P in a dosage dependent manner.When ovariectomized mice were treated with different concentrations of P daily for 3 days,the level of total PRAB and PRB were significantly inhibited,both of Ihh and Areg were up-regulated,estrogen target gene Ltf was significantly suppressed and endoplasmic reticulum stress was activated,especially for GRP78/p-eIF2a/ATF4 pathway by different concentrations of P.Accordingly,we found that GRP78/eIF2a/ATF4 pathway was aberrantly upregulated by excess P in decidua of day 8 when day 3 pregnant mice were treated with 4 mg/mouse P daily from day 3 to day 5 for 5 days,which indicated that excess P dysregulated mouse physiological endoplasmic reticulum stress during decidualization.In conclusion,our study indicates that excess P has a detrimental effect on endometrium receptivity and decidualization.Excess P treatment may cause fetal growth restriction through compromising embryo implantation and decidualization in mouse models.Data from our study might be helpful for clinicians to better interpret the negative influences of elevation P levels on ongoing pregnant outcomes after fresh cycle embryo transfer,but also imply that P should be administrated more carefully.