中枢性性早熟女童血清miR-125b与维生素D联合检测的临床意义研究
|
摘要
背景下丘脑-垂体-性腺轴过早激活是中枢性性早熟(CPP)的主要发生机制,但其激活的机制尚不明确。微小核糖核酸可能参与了性早熟的发生发展。目的分析CPP女童血清miR-125b与维生素D、激素指标的关系,并分析血清miR-125b与维生素D联合检测的临床意义。方法收集2013—2016年每年的7—9月在南方医科大学附属中山博爱医院就诊的102例CPP女童(CPP女童组)及同时期年龄匹配的体检健康女童102例(健康女童组),记录两组的临床指标[年龄、身高、体质量、体质指数(BMI)、乳房发育年龄、卵巢体积、骨龄、骨龄与年龄差、体质量标准差分数(WSDS)、身高标准差分数(HSDS)、体质指数标准差分数(BMI SDS)]、乳腺Tanner分期;采用实时荧光定量PCR检测血清miR-125b;采用化学发光法检测血清25-羟基维生素D(25-OH-D)及激素指标(游离甲状腺素、促甲状腺素、雌二醇、泌乳素、黄体生成素、卵泡刺激素)。结果 CPP女童组血清miR-125b高于健康女童组(P<0.05)。CPP女童组血清miR-125b与25-OH-D呈负相关(r=-0.809 5,P<0.01)。将CPP女童分为miR-125b高表达亚组(54例)和miR-125b中/低表达亚组(48例)。miR-125b高表达亚组与miR-125b中/低表达亚组年龄、卵巢体积、骨龄、骨龄与年龄差、WSDS、HSDS、BMI SDS比较,差异无统计学意义(P>0.05);miR-125b高表达亚组与miR-125b中/低表达亚组乳房发育年龄和乳腺Tanner分期比较,差异有统计学意义(P<0.05)。miR-125b高表达亚组雌二醇高于miR-125b中/低表达亚组(P<0.05)。经促性腺激素释放激素类似物(GnRHa)治疗后,miR-125b高表达亚组中维生素D正常者乳房发育消退比例高于维生素D缺乏者(P<0.05);miR-125b高表达亚组中维生素D正常者与维生素D缺乏者生长速率恢复、骨龄减速比例比较,差异无统计学意义(P>0.05)。miR-125b中/低表达亚组中维生素D正常者与维生素D缺乏者乳房发育消退、生长速率恢复、骨龄减速比例比较,差异均无统计学意义(P>0.05)。结论血清miR-125b在CPP女童中升高,与维生素D呈负相关,影响乳腺发育年龄,这可能与雌二醇的升高相关。血清miR-125b与维生素D联合检测可判定GnRHa治疗对CPP女童乳房发育消退的疗效。
Background Premature activation of hypothalamic-pituitary-gonadal axis is the main mechanism of central precocious puberty(CPP),but the mechanism of its activation is still unclear.mi-RNA may be involved in the development of precocious puberty.Objective To explore the relationships of serum microRNA-125 b and vitamin D and hormone parameters,and analysis the clinical significance of combined detection of serum miR-125 b and vitamin D.Methods We enrolled 102 CPP female children(CPP group) and 102 age-and sex-matched physical examinees(control group) from Boai Hospital of Zhongshan Affiliated to Southern Medical University from July to September,from 2013 to 2016.The clinical parameters,such as age,height,weight,body mass index(BMI),breast development age,ovarian volume,bone age,bone age and age difference,WSDS,HSDS,and BMI SDS and distribution of Tanner stage were recorded.The expression level of miR-125 b was detected by qRT-PCR.And the levels of 25-hydroxy-vitamin D(25-OH-D) and hormone parameters(free thyroxine,thyrotropin,estradiol,prolactin,luteinizing hormone and follicle-stimulating hormone)were detected using chemiluminiscence assay.Results The expression level of serum miR-125 b was higher in CPP group than that in the control group(P<0.05).The serum miR-125 b expression level was negatively correlated with 25-OH-D level in CPP group(r=-0.809 5,P<0.01).CPP children with high miR-125 b expression(high miR-125 b expression subgroup,n=54) and those with low to medium miR-125 b expression(low to medium miR-125 b expression subgroup,n=48) showed significant differences in the mammogenesis age and distribution of Tanner stage(P<0.05),but not in the age,ovarian volume,bone age,bone age and age difference,WSDS,HSDS,and BMI SDS(P>0.05).Moreover,high miR-125 b expression subgroup had higher estradiol level than low to medium miR-125 b expression subgroup(P<0.05).After treated by gonadotropin-releasing hormone analogues(GnRHa),high miR-125 b expression patients with normal vitamin D level had higher proportion of regression of breast development than those patients with decreased vitamin D level(P<0.05),but similar improvement in decreased growth velocity and early bone development(P>0.05).Low to medium miR-125 b expression patients with normal vitamin D level and those with decreased vitamin D level had no significant differences in the improvement in prepubertal mammogenesis,decreased growth velocity and early bone development(P>0.05).Conclusion The expression level of miR-125 b was increased in CPP female children,which was negatively correlated with vitamin D level,and affected mammogenesis age.These may be related to the upregulation of estradiol.Combined detection of miR-125 b and vitamin D could predicate the effect of GnRHa therapy on allometric growth of mammary parenchyma before puberty.
Background Premature activation of hypothalamic-pituitary-gonadal axis is the main mechanism of central precocious puberty(CPP),but the mechanism of its activation is still unclear.mi-RNA may be involved in the development of precocious puberty.Objective To explore the relationships of serum microRNA-125 b and vitamin D and hormone parameters,and analysis the clinical significance of combined detection of serum miR-125 b and vitamin D.Methods We enrolled 102 CPP female children(CPP group) and 102 age-and sex-matched physical examinees(control group) from Boai Hospital of Zhongshan Affiliated to Southern Medical University from July to September,from 2013 to 2016.The clinical parameters,such as age,height,weight,body mass index(BMI),breast development age,ovarian volume,bone age,bone age and age difference,WSDS,HSDS,and BMI SDS and distribution of Tanner stage were recorded.The expression level of miR-125 b was detected by qRT-PCR.And the levels of 25-hydroxy-vitamin D(25-OH-D) and hormone parameters(free thyroxine,thyrotropin,estradiol,prolactin,luteinizing hormone and follicle-stimulating hormone)were detected using chemiluminiscence assay.Results The expression level of serum miR-125 b was higher in CPP group than that in the control group(P<0.05).The serum miR-125 b expression level was negatively correlated with 25-OH-D level in CPP group(r=-0.809 5,P<0.01).CPP children with high miR-125 b expression(high miR-125 b expression subgroup,n=54) and those with low to medium miR-125 b expression(low to medium miR-125 b expression subgroup,n=48) showed significant differences in the mammogenesis age and distribution of Tanner stage(P<0.05),but not in the age,ovarian volume,bone age,bone age and age difference,WSDS,HSDS,and BMI SDS(P>0.05).Moreover,high miR-125 b expression subgroup had higher estradiol level than low to medium miR-125 b expression subgroup(P<0.05).After treated by gonadotropin-releasing hormone analogues(GnRHa),high miR-125 b expression patients with normal vitamin D level had higher proportion of regression of breast development than those patients with decreased vitamin D level(P<0.05),but similar improvement in decreased growth velocity and early bone development(P>0.05).Low to medium miR-125 b expression patients with normal vitamin D level and those with decreased vitamin D level had no significant differences in the improvement in prepubertal mammogenesis,decreased growth velocity and early bone development(P>0.05).Conclusion The expression level of miR-125 b was increased in CPP female children,which was negatively correlated with vitamin D level,and affected mammogenesis age.These may be related to the upregulation of estradiol.Combined detection of miR-125 b and vitamin D could predicate the effect of GnRHa therapy on allometric growth of mammary parenchyma before puberty.
引文
[1]中华医学会儿科学分会内分泌遗传代谢学组.中枢性性早熟诊断与治疗共识(2015)[J].中华儿科杂志,2015,53(6):412-418.DOI:10.3760/cma.j.issn.0578-1310.2015.06.004.
[2]SORENSEN K,MOURITSEN A,AKSGLAEDE L,et al.Recent secular trends in pubertal timing:implications for evaluation and diagnosis of precocious puberty[J].Horm Res Paediatr,2012,77(3):137-145.DOI:10.1159/000336325.
[3]LOMNICZI A,WRIGHT H,OJEDA S.Epigenetic regulation of female puberty[J].Front Neuroendocrinol,2015,36:90-107.DOI:10.1016/j.yfrne.2014.08.003.
[4]唐家彦,黄娟,上官予梅,等.检测中枢性性早熟女童血清维生素D水平的临床意义[J].中国妇幼保健,2015,30(18):2997-2998.DOI:10.7620/zgfybj.j.issn.1001-4411.2015.18.36.
[5]SINGH T,ADAMS B D.The regulatory role of miRNAs on VDR in breast cancer[J].Transcription,2017,8(4):232-241.DOI:10.1080/21541264.2017.1317695.
[6]SUI M,JIAO A,ZHAI H,et al.Upregulation of miR-125b is associated with poor prognosis and trastuzumab resistance in HER2-positive gastric cancer[J].Exp Ther Med,2017,14(1):657-663.DOI:10.3892/etm.2017.4548.
[7]GAO Q L,MA Y X,YUAN D W,et al.MicroRNA-125b in peripheral blood:a potential biomarker for severity and prognosis of children with viral encephalitis[J].Neurol Sci,2017,38(8):1437-1444.DOI:10.1007/s10072-017-2982-x.
[8]WANG S,LIU J,LI X,et al.miR-125b regulates primordial follicle assembly by targeting activin receptor type 2a in neonatal mouse ovary[J].Biol Reprod,2016,94(4):83.DOI:10.1095/biolreprod.115.131128.
[9]HU Z,SHEN W J,CORTEZ Y,et al.Hormonal regulation of microRNA expression in steroid producing cells of the ovary,testis and adrenal gland[J].PLoS One,2013,8(10):e78040.DOI:10.1371/journal.pone.0078040.
[10]WANG W L,WELSH J,TENNISWOOD M.1,25-Dihydroxy vitamin D3 modulates lipid metabolism in prostate cancer cells through miRNA mediated regulation of PPARA[J].J Steroid Biochem Mol Biol,2013,136:247-251.DOI:10.1016/j.jsbmb.2012.09.033.
[11]SANWALKA N,KHADILKAR A,CHIPLONKAR S,et al.Vitamin D receptor gene polymorphisms and bone mass indices in post-menarchal Indian adolescent girls[J].J Bone Miner Metab,2013,31(1):108-115.DOI:10.1007/s00774-012-0390-0.
[12]SANTOS B R,MASCARENHAS L P G,SATLER F,et al.Vitamin D receptor gene polymorphisms and sex steroid secretion in girls with precocious pubarche in Southern Brazil:a pilot study[J].J Endocrinol Invest,2012,35(8):725-729.DOI:10.3275/7979.
[13]BI X,SHI Q,ZHANG H,et al.c-Jun NH2-teminal kinase 1interacts with vitamin D receptor and affects vitamin D-mediated inhibition of cancer cell proliferation[J].J Steroid Biochem Mol Biol,2016,163:164-172.DOI:10.1016/j.jsbmb.2016.05.009.
[14]锡顶,朱蓓,李珍,等.LHRH激发试验对性早熟女童GnRHa治疗的评估[J].临床儿科杂志,2013,31(12):1121-1124.DOI:10.3969/j.issn.1000-3606.2013.12.006.
[15]SEN A,PRIZANT H,LIGHT A,et al.Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression[J].Proc Natl Acad Sci U S A,2014,111(8):3008-3013.DOI:10.1073/pnas.1318978111.
[2]SORENSEN K,MOURITSEN A,AKSGLAEDE L,et al.Recent secular trends in pubertal timing:implications for evaluation and diagnosis of precocious puberty[J].Horm Res Paediatr,2012,77(3):137-145.DOI:10.1159/000336325.
[3]LOMNICZI A,WRIGHT H,OJEDA S.Epigenetic regulation of female puberty[J].Front Neuroendocrinol,2015,36:90-107.DOI:10.1016/j.yfrne.2014.08.003.
[4]唐家彦,黄娟,上官予梅,等.检测中枢性性早熟女童血清维生素D水平的临床意义[J].中国妇幼保健,2015,30(18):2997-2998.DOI:10.7620/zgfybj.j.issn.1001-4411.2015.18.36.
[5]SINGH T,ADAMS B D.The regulatory role of miRNAs on VDR in breast cancer[J].Transcription,2017,8(4):232-241.DOI:10.1080/21541264.2017.1317695.
[6]SUI M,JIAO A,ZHAI H,et al.Upregulation of miR-125b is associated with poor prognosis and trastuzumab resistance in HER2-positive gastric cancer[J].Exp Ther Med,2017,14(1):657-663.DOI:10.3892/etm.2017.4548.
[7]GAO Q L,MA Y X,YUAN D W,et al.MicroRNA-125b in peripheral blood:a potential biomarker for severity and prognosis of children with viral encephalitis[J].Neurol Sci,2017,38(8):1437-1444.DOI:10.1007/s10072-017-2982-x.
[8]WANG S,LIU J,LI X,et al.miR-125b regulates primordial follicle assembly by targeting activin receptor type 2a in neonatal mouse ovary[J].Biol Reprod,2016,94(4):83.DOI:10.1095/biolreprod.115.131128.
[9]HU Z,SHEN W J,CORTEZ Y,et al.Hormonal regulation of microRNA expression in steroid producing cells of the ovary,testis and adrenal gland[J].PLoS One,2013,8(10):e78040.DOI:10.1371/journal.pone.0078040.
[10]WANG W L,WELSH J,TENNISWOOD M.1,25-Dihydroxy vitamin D3 modulates lipid metabolism in prostate cancer cells through miRNA mediated regulation of PPARA[J].J Steroid Biochem Mol Biol,2013,136:247-251.DOI:10.1016/j.jsbmb.2012.09.033.
[11]SANWALKA N,KHADILKAR A,CHIPLONKAR S,et al.Vitamin D receptor gene polymorphisms and bone mass indices in post-menarchal Indian adolescent girls[J].J Bone Miner Metab,2013,31(1):108-115.DOI:10.1007/s00774-012-0390-0.
[12]SANTOS B R,MASCARENHAS L P G,SATLER F,et al.Vitamin D receptor gene polymorphisms and sex steroid secretion in girls with precocious pubarche in Southern Brazil:a pilot study[J].J Endocrinol Invest,2012,35(8):725-729.DOI:10.3275/7979.
[13]BI X,SHI Q,ZHANG H,et al.c-Jun NH2-teminal kinase 1interacts with vitamin D receptor and affects vitamin D-mediated inhibition of cancer cell proliferation[J].J Steroid Biochem Mol Biol,2016,163:164-172.DOI:10.1016/j.jsbmb.2016.05.009.
[14]锡顶,朱蓓,李珍,等.LHRH激发试验对性早熟女童GnRHa治疗的评估[J].临床儿科杂志,2013,31(12):1121-1124.DOI:10.3969/j.issn.1000-3606.2013.12.006.
[15]SEN A,PRIZANT H,LIGHT A,et al.Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression[J].Proc Natl Acad Sci U S A,2014,111(8):3008-3013.DOI:10.1073/pnas.1318978111.