| BackgroundPremature ovarian insufficiency(POI)is a clinical syndrome that the ovarian function of the patents declines prematurely before 40 years old.The prevalence of POI is approximately 1% and increases with age.Women with POI get significantly declined fecundity and limited opportunity for natural pregnancy.However,few fertility intervention is reliably effective for increasing ovarian activity and natural pregnancy rate.Women with subclinical POI are at the early stage of POI and are more likely to develop into POI.Nevertheless,women with subclinical POI show more ovarian activity and have much more probability for conception than women with clinical POI.In recent years,women tend to postpone childbearing at later age,which increases the fertility needs of women with POI.Because of the lack of effective fertility intervention,it gets more and more important to screen and identify women with subclinical POI.The diagnostic criteria in Chines Consensus on Diagnosis and Management of POI is based on the elevation of serum basal follicle-stimulating hormone(b-FSH).But the f b-FSH elevates later than the decrease of serum Anti-Müllerian hormone(AMH)and Antral follicle count(AFC),which makes the diagnosis not sensitive enough for early screening.FSH also shows significant inter-and intra-cycle variability which brings inconvenience to clinical application while AMH show limited inter-and intra-cycle variability.Otherwise,this diagnostic criteria doesn’t show the age-related differences of ovarian function.This research will seek for and evaluate the Chinese age-related AMH-based criteria for screening women with subclinical POI.ObjectiveTo set up the Chinese age-related AMH-based criteria for screening women with subclinical POI and evaluate its effectiveness.MethodsThe inpatients who were admitted to the reproductive endocrinology department of Zhejiang Women’s Hospital affiliated with school of medicine,Zhejiang University during June 2019 to August 2020 were divided into non-subclinical POI population and subclinical POI population according to the inclusion criteria.After exclude by exclusion criteria,90% of the subclinical POI population were drawn at random into subclinical POI group,and the rest 10% were validation-subclinical POI group.Non-subclinical POI patients were selected with age-stratified random sampling based on subclinical population(1:2),90% of which were selected into non-subclinical POI group at random and the rest 10% made the validation-non-subclinical POI group.The subclinical POI group and the non-subclinical POI group were stratified respectively by 21～29 years old,30～34 years old and 35～39 years old.The best AMH cut-off value was found out by the receiver operating characteristic(ROC)curve.The age-related AMH based criteria for screening women with subclinical POI was set up by the best AMH cut-off value of each age stratification and the sensitivity,specificity,Youden index,positive likelihood rate(+LR),negative likelihood rate(-LR)and the Cohen’s Kappa of this screening criteria were computed.Then the age-related AMH based criteria was applied in the two validation group to validate the criteria.Results1.The subclinical and non-subclinical POI population got 329 and 384 patients respectively.The age composition and body mass index(BMI)composition were similar between the two population(P > 0.05).Subclinical,non-subclinical,validation subclinical and validation-non-subclinical POI group got 296,346,33,38 patients respectively.2.71 patients and 65 patients were included in 21～29-year-old non-subclinical POI group and subclinical POI group respectively.The age composition and the BMI composition were similar between the two groups(P>0.05).The AUC of the ROC curve was 0.969(0.945,0.993),P<0.001,and the best AMH cut-off value was ≤1.76ng/ml.With this cut-off value,the sensitivity of the screening test was 0.969.The specificity was0.887.The Youden index was 0.857.The accuracy was 92.6%.The +LR was 8.61.The –LR was 0.03.3.125 patients and 109 patients were included in 30～34-year-old non-subclinical POI group and subclinical POI group respectively.The age composition and the BMI composition were similar between the two groups(P>0.05).The AUC of the ROC curve was 0.959(0.935,0.983),P<0.001,and the best AMH cut-off value was ≤1.33ng/ml.With this cut-off value,the sensitivity of the screening test was 0.908.The specificity was0.904.The Youden index was 0.812.The accuracy was 90.6%.The +LR was 9.46.The –LR was 0.10.4.150 patients and 122 patients were included in 35～39-year-old non-subclinical POI group and subclinical POI group respectively.The age composition was similar between the two groups(P>0.05).The BMI have significant differences between the two groups,but the composition of BMI grades was similar.The AUC of the ROC curve was 0.918(0.887,0.950),P<0.001,and the best AMH cut-off value was ≤1.19ng/ml.With this cut-off value,the sensitivity of the screening test was 0.844.The specificity was0.867.The Youden index was 0.711.The accuracy was 85.7%.The +LR was 6.33.The –LR was 0.18.5.The age-related AMH-based screening criteria was 21～29 years old:≤1.76ng/ml,30～34 years old:≤1.33ng/ml,35～39 years old:≤1.19ng/ml.The sensitivity of the screening test was 0.895.The specificity was 0.884.The Youden index was 0.780.The accuracy was 88.9%.The +LR was 7.74.The –LR was 0.12.Compared with the inclusion criteria,the Cohen’s Kappa was 0.778,P<0.001,which meant that the new screening criteria was consistent with the inclusion criteria.6.38 patients and 33 patients were included in validation-non-subclinical POI group and validation-subclinical POI group respectively.The age composition and the BMI composition were similar between the two groups(P>0.05).With the age-related AMHbased screening criteria,the sensitivity of the screening test was 0.939.The specificity was 0.974.The Youden index was 0.913.The accuracy was 95.8%.The +LR was 35.70.The –LR was 0.06.Compared with the inclusion criteria,the Cohen’s Kappa was 0.915,P<0.001,which meant that the new screening criteria was consistent with the inclusion criteria.ConclusionThe Chinese age-related AMH-based criteria for screening subclinical POI is 21～29 years old:≤1.76ng/ml,30～34 years old:≤1.33ng/ml,35～39 years old:≤1.19ng/ml.The age-related AMH-based criteria shows good sensitivity,specificity and accuracy.However,multicenter prospective study is needed to establish a more reliable age-related AMH-based criteria for screening subclinical POI. |
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