| Part ?Premature Ovarian Insufficiency:Phenotypic Characterization within Different EtiologiesBackground:Premature ovarian insufficiency(POI),previously termed as premature ovarian failure(POF),is a complex clinical syndrome which is characterized by menstrual disturbance(amenorrhea or oligomenorrhea)with raised gonadotropins and low estradiol before the age of 40.Over the past few decades,ovarian insufficiency has become more common and drawn more concerns.POI is highly heterogeneous,both in phenotype and etiology.They are not yet clearly stated and correlated.Objective:To characterize clinical presentations of a large,well-phenotyped cohort of women with POI,and correlate phenotypes with etiologies to draw a comprehensive clinical picture of POI.Method:In this retrospective study,a total of 955 Chinese women with overt POI between 2006 and 2015 were systemically evaluated and analyzed.The phenotypic features,including menstrual characteristics,hormone profiles,ovarian ultrasonography/biopsy,pregnancy/family history,and genetic/autoimmune/iatrogenic etiologies were assessed,and further compared within different subgroups.According to the duration of reproductive age(years between menarche and amenorrhea),patients with SA were further divided into four groups:?5 years(Group 1,n=182);6-10 years(Group 2,n=243);11-15 years(Group 3,n=220);and>15 years(Group 4,n=176).Result:Among 955 women with POI,14.0%(N=134)presented with primary amenorrhea(PA)and 86.0%with secondary amenorrhea(SA).Compared with SA,patients with PA had significantly lower estradiol level[10.0(5.0-17.6)pg/ml vs.14.0(5.4-29.0)pg/ml,P<0.001]and significantly higher percentage of abnormal chromosomes(30.7%vs.11.6%,P<0.001).The decline of ovarian function in patients with SA progressed quickly.They had shortened reproductive periods(?10 years),and developed amenorrhea within 1-2 years after menstrual irregularity.The longer duration of reproductive age,the higher prevalence of pregnancy(G1:4.4%;G2:12.0%;G3:24.5%;G4:55.7%,P<0.001),and the higher percentage of family history were observed(G1:9.3%;G2:9.9%;G3:13.2%;G4:18.2%,P=0.036).The ovaries were invisible or small,and the presence of follicles(28.4%)was correlated with other good reproductive indicators.Familial patients(12.3%)manifested a better ovarian status and fewer chromosomal aberrations than sporadic patients.The plausible etiologies consisted of genetic(13.2%),autoimmune(12.0%)and iatrogenic(7.3%),?68%remaining idiopathic.There were significant differences among different etiologies,with genetic group representing the most severe phenotype.Conclusion:Our results that distinct phenotypic characteristics and association with different etiologies further confirmed the high heterogeneity of POI.Additional longitudinal clinical studies and pathogenesis research are warranted.There is highly heterogeneity of phenotype and etiology in women with overt POI.Phenotypic variabilities exist among patients,even when stratified by different etiological diagnosis.Part ?MicroRNAs Expression Profiles in Granulose Cells of Biochemical Premature Ovarian Insufficiency PatientsBackground:MicroRNAs(miRNAs)are a class of small(21-24 nucleotides)non-coding RNA molecules,which exist in human body tissues and fluids extensively.Through translational or cleavage repression of specific target mRNAs,miRNAs regulate gene expression post.transcriptionally.Numerous studies have confirmed that miRNAs play an important role in the pathogenesis of many diseases.It can be used as an effective marker for the diagnosis of a variety of cancers,diabetes,etc.MiRNA regulates the proliferation,differentiation and apoptosis of ovarian granule cells by regulating the transcription of target genes,and participates in controlling the secretion of steroid hormones,thereby affecting and regulating ovarian function.As miRNA continues to be studied in the field of reproduction,miRN A is becoming more and more concerned as the important regulatory factor of female reproductive system.Currently,there are few studies on miRNAs in this disease,and it is not fully elucidated the changes and effects of miRNAs in the pathogenesis of POI.Objective:To determine whether miRNAs in granulose cells are differentially expressed between normal controls women and biochemichal premature ovarian insufficiency(bPOI)patients.The miRNAs with significant differences were selected to be validated in the granulose cells of bPOI patients and healthy female controls,and to discuss the expression and significance of miRNAs in granule cells in POI patients.Methods:One hundred and two women undergoing assist reproduction technology treatment(IVF-ET/ICSI-ET)were recruited from June 2014 to September 2015 in the affiliated reproductive hospital of Shandong university.Among them,40 cases of bPOI patients in the stage of biochemical abnormality,and 62 of the women with normal ovarian function.Ovarian stimulation by long protocol or short protocol,the patient granulose cells were collected,the RNA is extracted from granulose cells.A total of 26 differentially expressed miRNAs,which were selected from our prior microarray data,were further validated by real-time PCR in an independently 102 granulosa cells.Results:Twenty-six miRNAs which was differentially expressed(13 miRNAs were up-regulated:miR-410-3p,miR-493-5p,m iR-4301,miR-4791,miR-875-3p,miR-136-5p,miR-451b,miR-376c-3p,miR-376c-5p,miR-487b-3p,miR-376b-5p,miR-889-3p,miR-944;while 13 miRNAs were up-regulated:miR-3197,miR-4434,miR-5584-5p,miR-758-5p,miR-4747-3p,miR-4476,miR-4650-5p,miR-3945,miR-4326,miR-4697-3p,miR-3648,miR-4673,miR-4694-5p)were selected and validated in 16 patients with POI and 16 normal control patients.Among which,six miRNAs(miR-493-5p,miR-4301,miR-4747-3p,miR-4650-5p,miR-3648,miR-4673)were significantly down-regulated in POI compared with controls(P<0.05).Then these six miRNAs were further validated in an independently 102 granulosa cells,and the results confirmed that 5 miRNAs(miR-493-5p,miR-4747-3p,miR-4650-5p,miR-3648,and miR-4673)were significantly down-regulated(P<0.05).Conclusion:This study revealed that miR-493-5p,miR-4747-3p,miR-4650-5p,miR-3648 and miR-4673 were significantly down-regulated in granulosa cells of bPOI patients. |
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