| BackgroundPremature ovarian insufficiency(POI)is a common reproductive endocrine disorder defined by cessation of ovarian function before the age of 40 years.POI is characterized by oligomenorrhea or amenorrhea with raised gonadotrophins(FSH>25 IU/L)and low estradiol(E2).POI was once subdivided into three stages by the American Association of Reproductive Medicine(ASRM):occult,biochemical and overt stage.However,there remains unclear for the diagnosis criteria of occult POI and biochemical POI.Therefore,the clinicians are still confused about the early diagnosis of POI.Either a small primordial follicle pool or a rapid follicle exhaustion,is associated with ovarian dysfunction and fecundity decline and results in POI.Currently the main ovarian reserve indicators widely used in clinics include FSH,E2,inhibin B,anti-Müllerian hormone(AMH)and antral follicle count(AFC).However,none has been proven optimal to predict the residual follicle pool and reproductive lifespan.Their dynamics and predictive value during the progressive ovarian insufficiency remain unclear.In addition,POI is highly heterogeneous in etiology.Whether POI patients with different etiologies presented distinct phenotype and endocrine hormones,and ovarian reserve markers could be potential indicators for etiology classification in women with POI needs further exploration.ObjectiveTo identify the characteristics of ovarian reserve indicators for POI at different ovarian reserve stages and find the early predicting indicators of POI.To analyze the characteristics of ovarian reserve for POI with different etiologies and evaluate the significance of different ovarian reserve indicators in etiological classification of POI.MethodsA total of 1998 women less than 40 years old with different ovarian reserve were retrospectively recruited from the Reproductive Hospital Affiliated to Shandong University between July 2014 and July 2019.According to the FSH level and menstrual conditions,all participants were sub-grouped into normal ovarian reserve(NOR,n=987),pre-POI(n=410),early POI(n=147),and POF(n=454)group.According to known etiologies,patients with POI were subdivided into four groups:genetic POI(n=61),iatrogenic POI(n=35),autoimmune POI(n=102)and idiopathic POI(n=403),as previously reported.The indicators of ovarian reserve were compared within different subgroups,and the predictive value of ovarian reserve markers was analyzed.Results1.The ovarian reserve indicators consecutively deteriorated with the progress of ovarian insufficiency,indicated as an increase of FSH and LH but decrease of AMH,inhibin B,AFC,E2 and T(P<0.01).Most of them changed significantly from NOR to pre-POI while remained relatively stable at low level or even undetectable at early POI and POF stage.2.FSH showed a 2-fold increase steadily in each stage along with ovarian function decline(6.81±1.17 IU/L vs.14.90±4.23 IU/L vs.31.73±4.35 IU/L vs.70.77±23.11 IU/L,P<0.001).The decrease pattern of AMH,inhibin B and AFC was quite similar,with significance among NOR,pre-POI and early POI stages(P<0.001)but comparable between early POI and POF(P>0.05).From NOR to pre-POI,AMH showed the most significant decline and relatively high sensitivity with approximately 6 times of decrease(from 2.513 ng/mL to 0.424 ng/mL),compared to an approximately 2-fold decline of inhibin B(from 65.18 pg/mL to 37.05 pg/mL)and AFC(from 8 to 4).3.AMH showed the highest predictive value for pre-POI(AUC 0.932,95%CI 0.9180.945)and POI(AUC 0.944,95%CI 0.933-0.954),and the combination of AMH and AFC was highly promising for early prediction.The AUC is 0.948 and the 95%confidence interval is 0.935 to 0.959.4.POI patients with different etiologies showed distinct characteristics of endocrine hormones,and genetic POI had much smaller AFC and lower level of inhibin B.Conclusions1.Ovarian function decline is a continuum and progressive progress,in analogy to a shortened chronological aging associated menopausal transition.When ovarian dysfunction started,the ovarian reserve indicators have begun deteriorating,especially the highly sensitive markers,such as AMH,AFC,inhibin B and FSH/LH ratio;once entered the POI stage,these indicators remained stable at extremely low levels.2.The quantitative changes and cutoff values of AMH and AFC(AMH=1.211 ng/mL and AFC=5)could provide new insights in early prediction and diagnosis of POI.3.POI patients with different etiologies showed distinct characteristics of endocrine hormones,and genetic POI had the worst ovarian reserve status. |
