The Significance Of AMH In Patients With Different PCOS Phenotypes Undergoing Assisted Reproductive Treatment

Background:Polycystic ovarian syndrome(PCOS)is a common endocrine and metabolic disorder in women,with an incidence of about 6%-21%in women of reproductive age.The clinical manifestations of PCOS are highly heterogeneous,mainly manifested as Oligo-and/or anovulation,Clinical and/or biochemical signs of hyperandrogenism,infertility and metabolic dysfunction.PCOS is the most common cause of female ovulation disorders.In recent years,with the progress of assisted reproductive technology(ART),in vitro fertilization-embryos transfer(IVF-ET)has been widely applied,so it has become a hot topic for clinicians to predict the outcome of IVF-ET before treatment.Ovarian reserve test is the important means to predict the outcome of ART,and anti-Mullerian hormone(AMH)is considered as an early and sensitive indicator of ovarian reserve(OR).AMH is mainly secret by the granulosa cells(GCs)in pre-antral follicles and small antral follicles and plays an important role in the process of follicular development.Recently,it was found that serum AMH level increased to different degrees in different PCOS phenotypes,and the differences among individuals with different PCOS phenotypes led to different responses of ovaries in controlled ovarian hyperstimulation(COH),thus affecting the outcome of ART.Objective:The purpose of this study is to explore the value of AMH in assisted reproductive treatment for patients with different PCOS phenotypes in order to develop individualized treatment plans before ART,follow up after pregnancy,and optimized pregnancy outcomes for clinicians.Materials and methods:This study retrospectively analyzed the clinical data of 6732 patients who underwent the first cycle of IVF/Intracytoplasmic Sperm Injection(ICSI)treatment in the outpatient department of Reproductive Hospital Affiliated to Shandong University from January 2017 to July 2018.According to the Rotterdam standard of PCOS,the patients were divided into the PCOS group and the control group,and the PCOS group was divided into four subgroups based on the different phenotypes:PCOS-A group(HA+OA+PCO),PCOS-B group(HA+OA),PCOS-C group(HA+PCO),PCOS-D group(OA+PCO).Baseline data and data on ovarian response and pregnancy outcomes of all patients during IVF/ICSI cycles were collected.The serum AMH level,ovarian response and pregnancy outcome of different PCOS phenotype groups were compared,the relationship between AMH level and three diagnostic bases of PCOS was analyzed,the main factors affecting pregnancy outcome of different PCOS phenotypes and the influence of AMH level on pregnancy outcome of different PCOS phenotypes were analyzed.Results:The incidence of different PCOS phenotypes from high to low was PCOS-D(OA+PCO),PCOS-A(HA+OA+PCO),PCOS-C(HA+PCO),PCOS-B(HA+OA).(1)The comparison among different PCOS phenotype groupsThe serum AMH levels,basic LH,LH/FSH,serum total testosterone(To)in PCOS four phenotype groups significantly higher than the control group,and PCOS-A group was the highest(P<0.05).The serum AMH level of different PCOS phenotype groups ranged from high to low was PCOS-A group(12.35±6.03 ng/mL),PCOS-D group(9.37±4.80 ng/mL),PCOS-C group(8.86±4.37 ng/mL),PCOS-B group(7.05±3.91 ng/mL).The correlation between AMH levels and the three diagnostic criteria of PCOS in PCOS patients:In PCOS women,serum AMH level was significantly positively correlated with HA and PCO(P<0.05),among which,the correlation with HA was stronger than with PCO,and there was no significant correlation with OA(P>0.05).(2)The comparison of ovarian response among different PCOS phenotypesPriming dose and total dose of gonadotropin(Gn)in PCOS-A,C and D groups were lower than those in PCOS-B and control groups(P<0.05).The number of follicles with diameter ≥14mm on the trigger day,E2 level on the trigger day and the number of retrieved oocytes were significantly higher in PCOS-A and C groups compared with other phenotypes and control groups(P<0.05).In PCOS-C group was observed an higher number of good quality embryos compared to the PCOS-D and control groups(P<0.05).(3)AMH predicted the cycle cancellation rate in different PCOS phenotypesThe serum AMH level could predict the cycle cancellation rate only in PCOS-A and D groups(P<0.05),but not in the PCOS-B and C groups(P>0.05).In the PCOS-A group,the optimal AMH threshold for predicting the cycle cancellation rate was 10.438 ng/mL(with sensitivity 66.8%and specificity 65.1%).In the PCOS-D group,the optimal AMH threshold was 8.637 ng/mL(with sensitivity 58.2%and specificity 61.4%).(4)The comparison of AMH level and pregnancy outcomes in different PCOS phenotypes and control groupThe AMH level,biochemical pregnancy rate,implantation rate,clinical pregnancy rate(CPR)and premature birth rate in the PCOS group were higher than in the control group,and the differences were statistically significant(P<0.05).The ectopic pregnancy rate,abortion rate and live birth rate(LBR)in the PCOS group were higher than in the control group,but the differences were not statistically significant(P>0.05).There were statistically significant differences in the cycle cancellation rate,the number of 2PN,fertilization rate,the number of transferred embryos and transferred good quality embryos and implantation rate in different PCOS phenotype groups and control group(P<0.05),but no statistically significant differences in biochemical rate,CPR,ectopic pregnancy rate,abortion rate,premature birth rate and LBR(P>0.05).(5)The major influence factors of LBR among different PCOS phenotype groupsThe major influence factors of LBR in PCOS-A group were stimulation protocol(OR=3.040,P=0.012)and HCG dose(OR=0.960,P=0.015).The major influence factor of LBR in PCOS-B group was fasting blood glucose(FBG)(OR=0.140,P=0.048).The major influence factors of LBR in PCOS-C group were FBG(OR=0.960,P=0.025)and total testosterone(To)level(OR=0.830,P=0.012).The major influence factors of LBR in PCOS-D group were endometrial thickness on the trigger day(OR=1.225,P=0.000),E2 level on the trigger day(OR=1.021,P=0.028),number of transferred embryos(OR=1.804,P=0.012)and freeze embryo(OR=1.119,P=0.043).(6)Effects of serum AMH level of pregnancy outcomes in different PCOS phenotype groupsSerum AMH level only affected the premature birth rate in PCOS-B and D group.AMH level was a protective factor for premature birth rate in the PCOS-B group(OR=0.575,P=0.042)and a risk factor for premature birth rate in the PCOS-D group(OR=1.115,P=0.009).Conclusions:1.The incidence of different PCOS phenotypes from high to low was PCOS-D,A,C and B.The serum AMH level of different PCOS phenotype groups ranged from high to low was PCOS-A,D,C and B.2.In PCOS women,serum AMH level was positively correlated with HA and PCO,among which,the correlation with HA was stronger than that with PCO,there was no significant correlation with O A.3.Serum AMH level can predict the cycle cancellation rate only in PCOS-A and D phenotypes,but the sensitivity and specificity are weak.4.The PCOS-A and C phenotypes both with HA and PCO were superior to other phenotypes in ovarian response,requiring less Gn.Although there were no significant differences in pregnancy outcomes among different PCOS phenotypes,the abortion rate and premature birth rate in PCOS-A and B phenotypes were higher.High AMH levels tend to increase the premature birth rate in PCOS-D phenotype,and close follow-up after pregnancy in this population should be strengthened to reduce the incidence of premature birth.Due to differences in individuals with different phenotypes of Polycystic ovary syndrome(PCOS),the ovary has different responsiveness to gonadotropin(Gn),which in turn affects the outcome of assisted reproductive technology(ART).Therefore,predicting ovarian response and ART outcomes in patients with different phenotypes of PCOS before controlled ovarian hyperstimulation(COH)can help clinicians develop individualized treatment options to optimize ART outcomes.Anti-Mullerian hormone(AMH)is now considered as an adjunct to diagnosis of PCOS,and increases in different levels in different PCOS populations.Exiting studies suggest that AMH has certain predictive value for ovarian response in patients with different PCOS phenotypes during COH;the PCOS phenotype with polycystic ovaries(PCO)has the risk of ovarian hyperstimulation syndrome(OHSS)and the tendency to use low Gn;the PCOS phenotype with HA may yield more good quality embryos;AMH has predictive value only for the ART outcome of partial PCOS phenotypes.However,the specific predicted values or ranges still need to be determined by further research.The purpose of this review is to investigate the predictive value of AMH for ovarian response and ART outcome of patients with different PCOS phenotypes in COH,in order to develop individual treatment strategies for patients with different PCOS phenotypes through the determination of AMH before COH and obtain an ideal pregnancy outcome.