Effects Of Long-Acting GnRH Agonist Down Regulation On Assisted Reproductive Outcomes In Patients With Adenomyosis

Chapter Ⅰ The effect of long-acting GnRH agonist pretreatment on IVF/ICSI outcomes in patients with adenomyosis:a systematic review and meta-analysisBackgroundAdenomyosis is an estrogen-dependent gynecological disease,which is closely related to infertility and might be a risk factor for adverse pregnancy outcomes in in vitro fertilization/intracytoplasmic sperm injection(IVF/ICSI)treatment.Adenomyosis might also increase the occurrence of maternal and neonatal complications,such as preterm birth,preeclampsia,small for gestational age,preterm premature rupture of membranes,postpartum hemorrhage and neonatal intensive care unit admission rate.Currently,long-acting gonadotropin releasing hormone agonist(GnRHa)pretreatment is widely used in patients with adenomyosis receiving IVF/ICSI treatment.Long-acting GnRHa can make pituitary downregulate to induce hypoestrogenic state,directly inhibit proliferation and induce apoptosis of adenomyotic lesions,simultaneously relieve inflammation reaction and aberrant angiogenesis.Thus,it might optimize the environment of uterine cavity,and improve IVF/ICSI outcomes in patients with adenomyosis.However,previous studies on the benefits of long-acting GnRHa pretreatment are still controversial.The existence of the divergences might be associated with heterogeneity among different studies.ObjectiveTo systematically evaluate the effect of long-acting GnRHa pretreatment on pregnancy outcomes in patients with adenomyosis receiving IVF/ICSI treatment.MethodsAn electronic-based search was performed in PubMed,Web of Science,and Cochrane library databases from inception to May 2022.Comparative studies on IVF/ICSI outcomes in adenomyosis patients with and without long-acting GnRHa pretreatment(3.75mg GnRHa monthly for ≥one month)were included.The odds ratio(OR)and 95%confidence interval(CI)were calculated to assess pregnancy outcomes.The methodological quality was evaluated using the guidelines of the Newcastle-Ottawa Scale.Further subgroup analysis was conducted in fresh embryo transfer(ET)cycles and frozen embryo transfer(FET)cycles.The main outcome was clinical pregnancy rate(CPR),and the secondary outcomes included implantation rate(IR),live birth rate(LBR),miscarriage rate(MR),early MR and late MR.ResultsTen eligible studies were included eventually,consisting of 1716 cycles with long-acting GnRHa pretreatment and 1299 cycles without it.In IVF/ICSI cycles,long-acting GnRHa pretreatment could significantly improve IR(OR 1.57;95%CI 1.22-2.01)and CPR(OR 1.57;95%CI 1.18-2.08),however,no benefits were observed in early MR(OR 0.73;95%CI 0.35-1.54),late MR(OR 3.01;95%CI 0.69-13.08)and MR(OR 0.72;95%CI 0.52-1.00).LBR(OR 1.46;95%CI 1.01-2.13)might be improved after long-acting GnRHa pretreatment,whereas subsequent sensitivity analysis showed that the difference was no longer significant after excluding the study with high heterogeneity.The subgroup analysis indicated that long-acting GnRHa pretreatment brought significant improvements on IR in either fresh ET cycles(OR 1.31;95%CI 1.06-1.60)or FET cycles(OR 2.10;95%CI 1.31-3.36)and CPR in fresh ET cycles(OR 1.42;95%CI 1.04-1.93).ConclusionIn patients with adenomyosis,long-acting GnRHa pretreatment before embryo transfer was associated with improved IR and CPR,whereas no association was found in miscarriage.The improvement effect of long-acting GnRHa pretreatment on LBR needed further study to validate.Chapter Ⅱ Effects of duration of long-acting GnRH agonist downregulation on assisted reproductive outcomes in patients with adenomyosisBackgroundAdenomyosis could contribute to enlarged uterus,severe dysmenorrhea,menorrhagia and infertility.Previous meta-analysis indicated that adenomyosis was related to adverse pregnancy outcomes of IVF.Long-acting GnRHa could reduce uterine volume and improve the environment of uterine cavity,so patients with adenomyosis commonly used long-acting GnRHa downregulation protocol when undergoing assisted reproductive technology(ART)treatment.However,in fresh ET and FET cycles,the efficacy of downregulation was still controversial.In fresh ET cycles,downregulation might excessively inhibit ovarian function,thereby increasing the risk of poor ovarian response.Previous studies suggested that the use of long-acting GnRHa downregulation did not necessarily significantly increase CPR of patients with adenomyosis compared to the non-downregulation protocol,and the duration of downregulation was clinically heterogeneous,ranging from 1 to 6 months.ObjectiveTo elucidate the relationship between long-acting GnRHa downregulation and pregnancy outcomes and identify the optimal duration of downregulation in patients with adenomyosis undergoing ART treatment.MethodsThis retrospective cohort study included patients with adenomyosis who underwent ART treatment at the Center for Reproductive Medicine,Shandong University from January 2016 to December 2020,and excluded patients with uterine malformation and those who underwent preimplantation genetic testing cycles.The downregulation group was the usage of 1 to 6 months long-acting GnRHa before ET,and the non-downregulation group was those without long-acting GnRHa.After a 1:1 propensity score matching approach using nearest neighbor matching(caliper value=0.03)to deal with the confounding factors,it respectively involved 272 cycles in the downregulation group and non-downregulation group.According to the duration of long-acting GnRHa downregulation,the downregulation group was further divided into 1 month(147 cycles),2 months(72 cycles)and>3 months(53 cycles)downregulation subgroups,and subgroup analysis was conducted.Additionally,stratification analysis was performed on pregnancy outcomes in 239 fresh ET cycles and 305 FET cycles.The primary outcome was CPR,and the secondary outcomes included IR,biochemical pregnancy rate(BPR),ectopic pregnancy rate(EPR),MR,early MR,late MR and LBR.ResultsIn patients with adenomyosis,compared to the non-downregulation group,the downregulation group had larger mean diameter of initial uterus(6.32 vs.5.50cm,P<0.001),higher proportion of severe dysmenorrhea(36.03%vs.17.28%,P<0.001),however,there were no significant differences in IR,BPR,EPR,CPR,MR,early MR and LBR between two groups,but late MR(13.4%vs.3.1%,P=0.003)was higher in the downregulation group.The results of stratification analysis showed that in fresh ET cycles,IR(75.0%vs.39.2%,P=0.002),BPR(91.7%vs.56.0%,P=0.036)and CPR(83.3%vs.47.0%,P=0.016)increased significantly in the ≥3 months downregulation group compared to the non-downregulation group,whereas late MR was difficult to be reversed(30.0%vs.3.2%,P=0.017).There were no significant differences in pregnancy outcome in the 1 month and 2 months downregulation groups compared to the non-downregulation group,respectively.In FET cycles,higher MR(53.6%vs.29.9%,P=0.029;58.8%vs.29.9%,P=0.026)and lower LBR(18.8%vs.34.1%,P=0.023;17.1%vs.34.1%,P=0.037)were observed in the 1 month and>3 months downregulation groups,whereas no differences were found in the 2 months downregulation group compared to the non-downregulation group.There were no significant differences in IR,BPR,CPR,early MR and late MR between the downregulation subgroups and the non-downregulation group.ConclusionIn patients with severer adenomyosis receiving ART treatment,long-acting GnRHa downregulation had beneficial effects on pregnancy outcomes.In fresh ET cycles,prolonged downregulation(≥3 months)could significantly improve IR,BPR and CPR,but increased late MR was still intractable.In FET cycles,downregulation for one month might be not sufficient,prolonged downregulation(≥2 months)might bring potential advantages.