卵巢早衰的病因学研究进展
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摘要
卵巢早衰(premature ovarian failure,POF)是导致女性不孕症的一个重要原因,但病因和发病机制尚不十分明确。近年来的研究结果表明,POF的病因包括遗传学因素、免疫因素、医源性因素和环境因素等。遗传学因素可能是导致POF的一个重要因素,包括染色体数目与结构的异常、基因突变,都可导致POF。免疫因素导致的POF可能是卵巢内或者体液内存在抗原,使得机体在其他部位产生的抗体同时作用于卵巢产生损害,也可能为自身免疫性疾病导致的异常激素水平影响到女性内分泌。医源性因素主要是有盆腔手术史以及术后放化疗者均有可能导致POF。此外,环境中的一些物质可能破坏卵泡从而导致POF。现将近年来POF的病因学研究进展,尤其是在遗传学因素和免疫学方面的研究进展进行综述,以期为POF的治疗及预防提供依据。
Premature ovarian failure(POF) is an important cause of female infertility. However, the etiology and pathogenesis of POF is not very clear. Recent studies have shown that the etiological factors of POF include genetics, immune, iatrogenic and environmental factors. Genetic factor as an important factor of POF includes numerous abnormalities in chromosome number and structure as well as gene mutation. Immune factor may be due to the presence of antigens in ovaries or body fluids, so that antibodies produced in other parts of the body cause ovarian damage, or the abnormal hormone level caused by autoimmune diseases that may affect female endocrine. Iatrogenic factors of POF mainly include pelvic surgery history and postoperative chemoradiotherapy. In addition, some substances in the environment may damage the follicles and thus cause POF. Recent advances in the etiology of POF, especially in genetic and immunological factors, are reviewed so as to provide a useful reference for the treatment and prevention of POF.
Premature ovarian failure(POF) is an important cause of female infertility. However, the etiology and pathogenesis of POF is not very clear. Recent studies have shown that the etiological factors of POF include genetics, immune, iatrogenic and environmental factors. Genetic factor as an important factor of POF includes numerous abnormalities in chromosome number and structure as well as gene mutation. Immune factor may be due to the presence of antigens in ovaries or body fluids, so that antibodies produced in other parts of the body cause ovarian damage, or the abnormal hormone level caused by autoimmune diseases that may affect female endocrine. Iatrogenic factors of POF mainly include pelvic surgery history and postoperative chemoradiotherapy. In addition, some substances in the environment may damage the follicles and thus cause POF. Recent advances in the etiology of POF, especially in genetic and immunological factors, are reviewed so as to provide a useful reference for the treatment and prevention of POF.
引文
[1]谢幸,苟文丽.妇产科学[M].8版.北京:人民卫生出版社,2013.
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[24]Zhou L,Wang J,Wang T.Functional study on new FOXL2mutations found in Chinese patients with blepharophimosis,ptosis,epicanthus inversus syndrome[J].BMC Med Genet,2018,19(1):121.
[25]Li F,Chai P,Fan J,et al.A Novel FOXL2 Mutation Implying Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Type I[J].Cell Physiol Biochem,2018,45(1):203-211.
[26]Lin B,Zeng B,Zhao J,et al.Seven Novel and Three Known Mutations in FOXL2 in 10 Chinese Families with Blepharophimosis Syndrome[J].Curr Mol Med,2018,18(3):152-159.
[27]Reato G,Morlin L,Chen S,et al.Premature ovarian failure in patients with autoimmune Addison's disease:clinical,genetic,and immunological evaluation[J].J Clin Endocrinol Metab,2011,96(8):E1255-E1261.
[28]Gao J,Jiao X,Dang Y,et al.Identification of patients with primary ovarian insufficiency caused by autoimmunity[J].Reprod Biomed Online,2017,35(4):475-479.
[29]Kosir Pogacnik R,Meden Vrtovec H,Vizjak A,et al.Possible role of autoimmunity in patients with premature ovarian insufficiency[J].Int J Fertil Steril,2014,7(4):281-290.
[30]Yuzyuk T,Viau K,Andrews A,et al.Biochemical changes and clinical outcomes in 34 patients with classic galactosemia[J].JInherit Metab Dis,2018,41(2):197-208.
[31]Apperley JF,Reddy N.Mechanism and management of treatmentrelated gonadal failure in recipients of high dose chemoradiotherapy[J].Blood Rev,1995,9(2):93-116.
[2]Jiao X,Qin C,Li J,et al.Cytogenetic analysis of 531 Chinese women with premature ovarian failure[J].Hum Reprod,2012,27(7):2201-2207.
[3]Shankar RK,Backeljauw PF.Current best practice in the management of Turner syndrome[J].Ther Adv Endocrinol Metab,2018,9(1):33-40.
[4]Ledig S,Preisler-Adams S,Morlot S,et al.Premature ovarian failure caused by a heterozygous missense mutation in POF1B and a reciprocal translocation 46,X,t(X;3)(q21.1;q21.3)[J].Sex Dev,2015,9(2):86-90.
[5]Lee Y,Kim C,Park Y,et al.Next generation sequencing identifies abnormal Y chromosome and candidate causal variants in premature ovarian failure patients[J].Genomics,2016,108(5/6):209-215.
[6]Mohamadhashem F,Rafati M,Hoseininasab F,et al.Primary ovarian insufficiency with t(5;13):a case report and literature review on disrupted genes[J].Climacteric,2017,20(5):498-502.
[7]Asadi R,Omrani MD,Ghaedi H,et al.Premutations of FMR1 CGGrepeats are not related to idiopathic premature ovarian failure in Iranian patients:A case control study[J].Gene,2018,676:189-194.
[8]Rehnitz J,Alcoba DD,Brum IS,et al.FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve[J].Reprod Biol Endocrinol,2018,16(1):65.
[9]Guo T,Qin Y,Jiao X,et al.FMR1 premutation is an uncommon explanation for premature ovarian failure in Han Chinese[J].PLoSOne,2014,9(7):e103316.
[10]Rehnitz J,Alcoba DD,Brum IS,et al.FMR1 and AKT/mTORsignalling pathways:potential functional interactions controlling folliculogenesis in human granulosa cells[J].Reprod Biomed Online,2017,35(5):485-493.
[11]Sanfins A,Rodrigues P,Albertini DF.GDF-9 and BMP-15 direct the follicle symphony[J].J Assist Reprod Genet,2018,35(10):1741-1750.
[12]Dixit H,Rao LK,Padmalatha VV,et al.Missense mutations in the BMP15 gene are associated with ovarian failure[J].Hum Genet,2006,119(4):408-415.
[13]Wang B,Wen Q,Ni F,et al.Analyses of growth differentiation factor 9(GDF9)and bone morphogenetic protein 15(BMP15)mutation in Chinese women with premature ovarian failure[J].Clin Endocrinol(Oxf),2010,72(1):135-136.
[14]Fonseca DJ,Ortega-Recalde O,Esteban-Perez C,et al.BMP15 c.-9C>G promoter sequence variant may contribute to the cause of non-syndromic premature ovarian failure[J].Reprod Biomed Online,2014,29(5):627-633.
[15]Kumar R,Alwani M,Kosta S,et al.BMP15 and GDF9 Gene Mutations in Premature Ovarian Failure[J].J Reprod Infertil,2017,18(1):185-189.
[16]Gallardo TD,John GB,Bradshaw K,et al.Sequence variation at the human FOXO3 locus:a study of premature ovarian failure and primary amenorrhea[J].Hum Reprod,2008,23(1):216-221.
[17]Wang B,Mu Y,Ni F,et al.Analysis of FOXO3 mutation in 114Chinese women with premature ovarian failure[J].Reprod Biomed Online,2010,20(4):499-503.
[18]Zhang BF,Hu Y,Liu X,et al.The role of AKT and FOXO3 in preventing ovarian toxicity induced by cyclophosphamide[J].PLoSOne,2018,13(8):e0201136.
[19]Jang H,Na Y,Hong K,et al.Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27Kip1promoter in primordial follicles[J].J Pineal Res,2017,63(3).doi:10.1111/jpi.12432.
[20]Park M,Shin E,Won M,et al.FOXL2 interacts with steroidogenic factor-1(SF-1)and represses SF-1-induced CYP17 transcription in granulosa cells[J].Mol Endocrinol,2010,24(5):1024-1036.
[21]Xue M,Zheng J,Zhou Q,et al.Novel FOXL2 mutations in two Chinese families with blepharophimosis-ptosis-epicanthus inversus syndrome[J].BMC Med Genet,2015,16:73.
[22]Tan H,Yang P,Li H,et al.A novel FOXL2 mutation in a Chinese family with blepharophimosis,ptosis,epicanthus inversus syndrome[J].Hum Genome Var,2015,2:15008.
[23]Yang L,Li T,Xing Y.Identification of a novel FOXL2 mutation in a single family with both types of blepharophimosis-ptosisepicanthus inversus syndrome[J].Mol Med Rep,2017,16(4):5529-5532.
[24]Zhou L,Wang J,Wang T.Functional study on new FOXL2mutations found in Chinese patients with blepharophimosis,ptosis,epicanthus inversus syndrome[J].BMC Med Genet,2018,19(1):121.
[25]Li F,Chai P,Fan J,et al.A Novel FOXL2 Mutation Implying Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Type I[J].Cell Physiol Biochem,2018,45(1):203-211.
[26]Lin B,Zeng B,Zhao J,et al.Seven Novel and Three Known Mutations in FOXL2 in 10 Chinese Families with Blepharophimosis Syndrome[J].Curr Mol Med,2018,18(3):152-159.
[27]Reato G,Morlin L,Chen S,et al.Premature ovarian failure in patients with autoimmune Addison's disease:clinical,genetic,and immunological evaluation[J].J Clin Endocrinol Metab,2011,96(8):E1255-E1261.
[28]Gao J,Jiao X,Dang Y,et al.Identification of patients with primary ovarian insufficiency caused by autoimmunity[J].Reprod Biomed Online,2017,35(4):475-479.
[29]Kosir Pogacnik R,Meden Vrtovec H,Vizjak A,et al.Possible role of autoimmunity in patients with premature ovarian insufficiency[J].Int J Fertil Steril,2014,7(4):281-290.
[30]Yuzyuk T,Viau K,Andrews A,et al.Biochemical changes and clinical outcomes in 34 patients with classic galactosemia[J].JInherit Metab Dis,2018,41(2):197-208.
[31]Apperley JF,Reddy N.Mechanism and management of treatmentrelated gonadal failure in recipients of high dose chemoradiotherapy[J].Blood Rev,1995,9(2):93-116.