The Effect Of High Ovarian Response In Controlled Ovarian Hyperstimulation Of IVF On Uterine Endometrial Receptivity And The Related Mechanism

In recent decades,the incidence of infertility is rising.About 10%-15%couples of childbearing age in our country suffer from infertity,IVF-ET has become an very important treatment to offer the opportunity of for them.Along with the social development and progress of science and technology,assisted reproductive medicines are increasingly optimized and controlled ovulation hyperstimulation protocols are increasingly individualized,but the clinical outcomes of IVF are in bottleneck situation.In most cases,according to patients’age,AFC,d3 FSH and AMH,clinical physicians evaluate women’s ovarian reserve function before ovarian stimulation,and select an apprortiate protocle and Gn doze for stimulation,but not all of the patients show expected the ideal responses.Compared with natural pregnancy,stimulated ovulation drugs application results not only increasing egg number,but also effect on the hormone balance inevitably,the compatibility of the embryo and endometrial receptivity can not be ignored on the status of high ovarian response.In the process of controlled ovarian ovulation,serum estrogen levels are several times or even dozens of timeshigher than the natural cycle.Such a high level of estrogen not only increases the risk of OHSS,but also has an detrimental impact on clinical outcome in IVF.The purpose of this study is to illustrate the effect of implantation-related intima ultrastructure、cytokines、genes HOXA-10 about endometrial receptivity under the condition of high estrogen and to explore the possible mechanism.Part I:Effect of high ovarian response after controlled ovarian htyperstimulation on the pregnancy outcome of women undergoing IVF-ETObjectives:To observe the IVF pregnancy outcome of women with different ovarian responses after controlled ovarian hyperstimulation(COH),and to evaluated the affection of serum E2 levels on the day of hCG administration on the development of oocytes and embryos,and(ER).Materials and Methods:Retrospective analysis of 680 women accepted their first cycle of in vitro fertilization/intracytoplasmic sperm injection-embryo transfer(IVF/ICSI-ET)due to male and/or tubal factor.Three groups were set according to cut-off concentrations of serum E2 levels on the the day of hCG administration,including poor ovarian response,mid ovarian response group,and high ovarian response.Number of oocytes retrieved,embryos development and pregnancy outcome were compared among the groups.Results:The number of obtained oocytes、MII oocytes and high quality embryos were significantly increased from low ovarian response group to high ovarian response group while no significant difference of fertilization rate、cleavage rate and high quality embryo rate in three groups.Embryo transfer cancellation rate was 12.62%in high response group,which was significantly higher than normal ovarian response group(P<0.01).But embryo implanting rate and clinical pregnancy rate significantly were reduced in high response group than in normal reaction group(P<0.01).There were no significant difference of abortion rate between groups(P>.0.05).In moderate response group,the incidence of OHSS was lower than the high group,but significant difference was observed in low response group and high response group(P<0.01).Conclusions:Ideal IVF pregnancy outcome need an optimal range of serum E2 level.Both low and high ovarian responses are detrimental to IVF pregnancy outcome,which are possibly due to the smaller number of transferable embryos caused by fewer oocytes acquired in low response groups and impaired ER in high response groups.Part II:The effects of high ovarian hyperstimulation on endometrial secretory phase transformation,pinopode development and related molecular expression in IVF womenObjectives:To analyse the effects of high ovarian response in COH on endometrial secretory phase transformation,pinopode development and related molecular expression during the peri-implantation period in patients undergoing in vitro fertilization/intracytoplastic sperm injection-embryo transfer(IVF/ICSI-ET).Materials and Methods:Peripheral blood and endometrial biopsies were obtained from infertile women on days 6±1 after oocytes retrieval or ovulation in 18 stimulated cycles(SC)and 18 natural cycles(NC)respectively.Serum levels of estradiol(E2)’ and progesterone(P4)were measured by chemiluminescence detection.All endometrial samples were stained with hematoxylin and eosin(HE)staining for histological dating.Pinopode was observed by scanning electron microscope(SEM).Expression of integrin β3;LIF were observed by immunohistochemical method.Results:Serum levels of both E2 and P4 were significantly higher in the peripheral blood in SC than in NC(P<0.01).The development of endometrium was advanced 1 to 2 days in SC1 than SC2 and NC,and gland expansion and edema in stroma was more significant than in NC.Pinopodes with different developmental degrees were observed in all women,but the pinopodes were the most abundant during the mid-sectory phase in the NC group and during the early-sectory phase in the NC group(P<0.05).The expression of integrin 0 3 in SC1 group is lower than in SC2 group,but obviously lower than in NC group while LIF expression level was lower than in NC group but no significant differnce with SC2 group.Conclusions:High E2 and P4 in high ovarian response women by COH may advance the transformation of sectory phase and the development of pinopodes.High estrogen can also reduce the expression of integrin β3 and LIF in the implantation period.The abnormal expression of integrin β3 and LIF may affect ER in high ovarian response women in COH cycle.PART Ⅲ:Expression of gene HOXA10 in endometrinm from women with high ovarian responseObjectives:To observe the expression of gene HOXA10 in endometrium from women with high ovarian response and moderate response for in vitro fertilization/intracytoplasmic sperm injection-embryo transfer(IVF/ICSI-ET),and to analyze the association with endometrial receptivity(ER).Materials and Methods:Peripheral blood and endometrial biopsies were obtained from infertile women on days 6±1 after oocytes retrieval in 13 women while 8 with high ovarian response and 5 with moderate ovarian response respectively.All endometrial samples were stained with HE for histological dating.The protein and mRNA of HOXA10 were assayed by immunohistochemistry,RT-PCR and Wertern-blot.Results:The protein and mRNA levels in the endometrium of HOXA10 were detected.But the level in high response group were significantly lower than in moderate group(P<0.01).Conclusions:High E2 and P4 secreted by high ovarian response women in COH may inhibit the expression of both mRNA and protein of HOXA10.This may be the gene mechanism of decreased ER in high ovarian response group.