CNP在GH促进GnRHa治疗中大骨龄、青春中后期CPP/EFP女孩线性生长机制中的作用

 目的:探讨生长激素（growth hormone,GH）改善促性腺激素释放激素类似物（gonadotropin-releasing hormone analogue,GnRHa）治疗中大骨龄、青春中后期中枢性性早熟（central precocious puberty,CPP）或快速进展型早发育（early and fast puberty,EFP）女孩线性生长的近期疗效,以及C型利钠肽（C-type natriuretic peptide,CNP）在GH促线性生长机制中的作用。方法:22例骨龄≥11.5岁、预测成年身高（predicted adult height,PAH）严重受损、青春中后期的特发性CPP或EFP女孩分为2组各11例：（1）单用GnRHa组:仅用GnRHa（每4周缓释型曲普瑞林60～80 μg/kg,im）治疗;（2）联用GH组:联用GnRHa和GH（每周1 U/kg,分6~7次睡前sc）治疗。每3个月测量身高和体重,检查性征;治疗开始和治疗6个月末行骨龄检查,并检测血清CNP氨基端前体（amino-terminal pro-C-type natriuretic peptide,NTproCNP）、胰岛素样生长因子1（insulin-like growth factor 1,IGF-1）及1型前胶原氨基端伸展肽（procollagen type 1 amino-terminal propeptide,P1NP）的浓度。比较治疗前及治疗后6个月的身高增长速度（height velocity,HV)、按骨龄身高的标准差分值（height SD score for bone age,HtSDSBA）、PAH及上述血清指标的变化。结果:（1）联用GH组治疗6个月的HV、HtSDSBA增值（ΔHtSDSBA）和PAH增值（ΔPAH）均显著高于单用GnRHa组(P<0.01)。（2）联用GH组治疗6个月末与治疗开始时比较,血清NTproCNP、P1NP浓度和IGF-1浓度均无显著性差异。（3）单用GnRHa组治疗6个月末的血清NTproCNP和P1NP浓度则均较治疗开始时显著下降（P<0.05),IGF-1浓度则无显著差异。结论: 对于大骨龄、青春中后期的特发性CPP或EFP女孩,GnRHa联用GH能促进线性生长,有效改善预测成年身高。GH的促生长作用不依赖于血清IGF-1水平的变化,而可能部分与CNP介导的长骨生长加速有关。     

儿童青少年血清IGF-1及IGFBP-3的 正常参考值研究

目的 探讨儿童青少年血清胰岛素生长因子-1（IGF-1）及胰岛素因子结合蛋白-3（IGFBP-3）的正常参考值。方法 选取2018年1月~2019年1月在我院体检的312例健康的儿童、青少年为研究对象,分别测定其IGF-1、IGFBP-3水平,并分析IGF-1、IGFBP-3与年龄、性别、发育阶段的关系。结果 男孩血清IGF-1峰值为13岁,女孩为11岁;男孩血清IGFBP-3峰值为14岁,女孩为11岁;高峰值出现后,IGF-1、IGFBP-3水平随年龄增长缓慢下降或维持高峰值;同年龄比较男孩血清IGF-1水平高于女孩、IGFBP-3水平低于女孩,差异有统计学意义（P＜0.05）;年龄、发育阶段与血清IGF-1值呈正相关（r=0.241,P＜0.01）,IGFBP-3与年龄呈正相关（r=0.323,P＜0.01）。结论 建立儿童青少年IGF-1、IGFBP-3水平正常参考值,可与监测其生长、临床症状以及生长激素治疗后随访具有重要的参考价值。     

0~16岁儿童IGF-1的变化及其正常参考范围的建立

目的探讨本地区0~16岁儿童胰岛素样生长因子-1(IGF-1)的变化并建立其正常参考范围。方法 2009年至2014年共筛选276例0~16岁正常儿童(男156例,女120例),采用化学发光法检测检测其血清的IGF-1浓度,分析血清IGF-1随年龄增长的变化趋势并建立婴儿期、幼儿期、学龄前期、学龄初期、学龄中期、青春期6个时期的正常参考范围。结果儿童血清IGF-1水平随着年龄的增长而升高,男、女孩分别于14岁和13岁时出现高峰;高峰值后,IGF-1水平随年龄增长缓慢下降或为平台期;276例儿童按婴儿期、幼儿期、学龄前期、学龄初期、学龄中期、青春期的结果依次为中位数40.5,79.0,117,184,284,342;参考范围分别为30.4-62.5;29.7-156;63.7-201;123-322;156-508;211-532,各年龄组间IGF-1浓度差异有统计学意义(P0.05)。结论建立了本地区儿童血清IGF-1的正常参考范围,对于生长监测、临床诊断及GH治疗后随访有重要参考价值。     

GnRHa通过影响大鼠子宫内膜异位症Tspan5的表达影响内膜容受性

目的 探讨Tspan5和OPN与子宫内膜容受性的相关性,阐明Tspan5作为评估内异症患者子宫内膜容受性的参考指标的意义。方法 40只实验大鼠随机分为GnRHa降调模型组（n=20）和对照组（n=20）。GnRHa降调模型组：按0.04 mg/kg进行肌内注射,注射浓度为0.25 mg/mL的长效GnRHa的生理盐水1 d,28 d在当日17点按1∶1的比例和正常雄鼠合笼,第2天早晨8点检查,出现阴栓标为怀孕第1日,按此类推。对照组以等量生理盐水代替GnRHa,余同GnRHa降调模型组。子宫内膜标本进行WB、real time-PCR和免疫组化以检测Tspan5和OPN的mRNA表达和蛋白定位。ELISA法检测血清E2、P、CA125水平,分析Tspan5和OPN与血清E2、P、CA125水平的相关性。结果 Q-PCR、免疫组化和免疫印迹均显示,GnRHa降调模型组GnRHa降调前子宫内膜中Tspan5及OPN蛋白的表达显著高于对照组,差异有统计学意义（P<0.05）。GnRHa降调模型组GnRHa降调后Tspan5及OPN的表达明显下降,接近对照组的表达量（P>0.05）...     

2型糖尿病血管病变时血浆ANP、BNP及CNP的变化及临床意义

目的：探讨血浆心钠素(ANP)、脑利钠肽(BNP)、C型利钠肽(CNP)在2型糖尿病血管病变时的变化及其临床意义。方法:应用酶联免疫吸附法(ELISA)测定正常对照组(9例)、2型糖尿病无血管病变组(34例)及2型糖尿病血管病变组(23例)血浆proANP、BNP fragment及NT-proCNP浓度，分析各组间血浆利钠肽水平的变化及相关因素。结果:2型糖尿病血管病变组血浆ANP、BNP明显高于另外2组（P<0.01），而血浆CNP明显降低（P<0.01），2型糖尿病血管病变组各亚组(微血管病变组、大血管病变组及微血管合并大血管病变组)间血浆利钠肽水平无明显差异（P>0.05）。2型糖尿病血管病变组血浆ANP与BNP间存在显著正相关（r=0.309, P<0.05），ANP与CNP（r=-0.374, P<0.05）以及BNP与CNP（r=-0.653, P<0.01）间存在显著负相关。结论:血浆ANP、BNP及CNP的联合检测可以作为简便、价廉、可靠的糖尿病血管病变的筛选指标。     

PMO患者血清E2、IL-6及IGF-Ⅰ水平的临床观察

目的：通过观察绝经后骨质疏松症（PMO）患者血清E2、IL-6及IGF-Ⅰ含量的变化,探讨E2、IL-6及IGF-Ⅰ在绝经后骨质疏松症发病机理中的作用。方法：根据腰椎骨密度（BMD）扫描结果,将受试者分为三组,即绝经后骨质疏松组32例、绝经后非骨质疏松组30例、绝经前健康组30例。采用放免法测定血清IL-6、BGP、IGF-Ⅰ水平,用化学发光免疫分析法测定血清E2水平,同时测定血清P、Ca、AKP水平。结果：绝经后妇女血清IL-6水平高于绝经前妇女,骨质疏松组又高于非骨质疏松组。IL-6与BMD、E2呈负相关关系（r分别为-0．587、-0．438,P〈0．05）,与BGP呈正相关关系（r=0．545,P〈0．05）。绝经后妇女IGF-Ⅰ含量降低,骨质疏松组IGF-Ⅰ含量最低。IGF-Ⅰ与BMD、E2呈显著正相关关系（相关系数r分别为0．569、0．433,P〈0．01）,与年龄呈显著负相关关系（r=-0．538,P〈0．01）。结论：绝经后骨质疏松为高转换率骨质疏松,IL-6高表达与骨质疏松症发病以及雌激素减少有关,雌激素水平下降可导致IL-6分泌的增多。体内雌激素还有助于维持IGF-Ⅰ的水平,绝经后骨质疏松患者体内IGF-Ⅰ水平明显下降。IL-6分泌增多、IGF-Ⅰ水平下降均可以导致骨吸收超过骨形成,引起骨丢失和骨质疏松症的发生。因此,IL-6、IGF-Ⅰ可作为一种预测骨质疏松症发病的检测手段。合理应用雌激素、IGF-Ⅰ可预防绝经后骨质疏松症的发生。     

原发性高血压患者循环中IGF-1水平与心肌肥厚的研究

目的：探讨原发性高血压（EH）患者循环中的胰岛素生长因子-1（IGF-1）与心肌肥厚的关系。 方法： 采取酶免疫分析方法测定53例为原发性高血压患者和16例正常人的血清IGF-1水平。 结果： 发现原发性高血压患者循环中的IGF-1水平显著高于正常组（P<0．05）。高血压病心肌肥厚组的血清IGF-1水平显著高于非心肌肥厚组，275．5±116．4 vs 203．8±82．9，P＜0．01。左室重量指数与血清IGF-1存在相关性（r=0．45，P<0．01）。从IGF-1的水平可以看出在原发性高血压患病时间＜15年的LVH患者IGF-1升高明显，而原发性高血压患病时间（≥15年）IGF-1水平有下降的趋势。以脉压≤60 mmHg、>60 mmHg划分为2个组，脉压≤60 mmHg心肌肥厚有10人；脉压>60 mmHg心肌肥厚有20人，占该组患者的65%，2组比较P<0．05；2组的血清IGF-1浓度无显著差异(P>0．05)。 结论： ①原发性高血压IGF-1的升高，提示IGF-1 可能参与高血压某些病理生理过程。②高血压病心肌肥厚组的血清IGF-1浓度的显著升高、左室重量指数与血清IGF-1存在相关性，提示血清IGF-1有促进心肌肥厚作用。③以患病时间长短来划分，血清IGF-1在患病时间≥15年出现有意义降低。④脉压＞60 mmHg患心肌肥厚病人较多，说明脉压增大与心肌肥厚有关。⑤血清IGF-1水平并没有随脉压增大而增高，可能在促进心肌肥厚方面有各自作用途径。     

绝经后妇女骨质疏松患者血清IGF-1、IGFBP-3与骨密度及骨代谢指标的关系

目的： 探讨胰岛素样生长因子-1（IGF-1）和胰岛素样生长因子结合蛋白-3（IGFBP-3）与绝经后妇女骨密度及骨代谢指标之间的关系。方法： 通过检测90例绝经后妇女骨质疏松患者及70例绝经后骨量正常的健康对照组血清IGF-1、IGFBP-3、骨钙素（BGP）、I型胶原异构C端肽（β-CTX）、雌激素（E₂）、降钙素（CT）、甲状旁腺激素（PTH）、钙（Ca）、磷（P）等指标，然后同用双能X线骨密度仪检测的两组研究对象的腰椎（L2-L4）侧位、左股骨颈骨密度进行比较。结果： 绝经后骨质疏松组妇女腰椎、股骨颈骨密度显著低于对照组（均P<0.01）；血清IGF-1、IGFBP-3、E₂、CT、BGP水平均低于对照组（均P<0.01）；血清β-CTX、PTH均高于对照组（均P<0.01），血清Ca、P两组之间无差异（均P>0.05）。骨质疏松组和对照组腰椎侧位、左股骨颈BMD均与IGF-1、IGFBP-3、E₂、BGP、CT水平呈正相关，与β-CTX、PTH水平呈负相关，而与血钙、血磷无明显关系。结论： IGF-1、IGFBP-3、E₂、BGP、CT、β-CTX、PTH血清水平与腰椎、左股骨质具有明显的相关性，通过检测上述指标可考虑作为筛查绝经后妇女是否容易患有骨质疏松症的一项有价值的生化参考指标。     

骨灵汤对绝经期前后骨质疏松患者血清IGF-1、TGFβ1与OPG／RANKL水平的影响

目的观察绝经期前后骨质疏松（osteoporosis,OP）患者血清胰岛素样生长因子（IGF-1）、转化生长因子（TGFβ1）与OPG-RANKL系统的关系以及骨灵汤对IGF-1和TGFβ1表达的影响。方法将80例OP患者分为绝经前组和绝经后组,每组各40例,均给予抗OP中药骨灵汤（骨碎补、鹿角胶、菟丝子等）治疗。采用ELISA方法检测血清TGFβ1、OPG和RANKL。采用包被放免法（IRMA）检测血清IGF-1。结果绝经后组血清IGF和RANKL的水平显著低于绝经前组（P〈0．01）,绝经后组血清OPG水平显著高于绝经前组（P〈0．01）;血清IGF-1、TGFβ1浓度与血清OPG浓度呈负相关,相关系数为r=0．003、P=-0．622和r=0．000、P=-0．713;血清IGF-1、TGFβ1浓度与血清RANKL浓度呈正相关,相关系数为r=0．012、P=0．549和r=0．001、P=0．667;绝经前妇女骨灵汤治疗后,血清IGF和TGFβ1水平升高（P〈0．05）,OPG水平明显升高（P〈0．01）,RANKL浓度下降（P〈0．05）;绝经后妇女骨灵汤治疗后IGF、TGFβ和OPG水平升高（P〈0．05）,RANKL浓度下降（P〈0．05）。结论骨灵汤可以通过上调IGF-1和TGFβ1的表达,影响OPG-RANKL系统,从而调节骨代谢,达到防治OP的目的。     

急性颅脑损伤患者血清NSE、IL-8和CNP水平的变化及临床意义

目的：探讨了急性颅脑损伤患者治疗前后血清NSE、IL-8和CNP水平的变化及临床意义。方法：应用放免法对30例急性颅脑损伤患者进行了血清NSE、IL-8和CNP的检测,并与35名正常健康人作比较。结果：急性颅脑损伤患者在治疗前血清NSE、IL-8水平非常显著地高于正常人组,而CNP水平又非常显著地低于正常人组（P〈0.01）。经治疗2周后则与正常人组比较无显著性差异（P〉0.05）,且血清NSE水平与IL-8水平呈正相关（r=0.6188,P〈0.01）,与CNP水平呈显著负相关（r=-0.578,P〈0.01）。结论：检测血清NSE、IL-8和CNP水平的变化有助于估计急性颅脑损伤患者病情的轻重及预后。     

Serum dehydroepiandrosterone sulphate and pubertal development in Chinese girls

Serum dehydroepiandrosterone sulphate (DHEAS), estradiol (E2), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured by radioimmunoassay in 170 healthy school girls from 7–16 years old. Blood samples from postmenarcheal girls were taken on days 6–10 of the menstrual cycle. Bone age, height, weight, breast and pubic hair development were also investigated. Of the four hormones measured, serum DHEAS displayed the earliest elevation, at 7 years and upwards. A significant DHEAS increment at chronological age 13 years was observed. Girls with earlier menarche had higher DHEAS level than girls having later menarche. Serum DHEAS levels also correlated with bone age, height, weight, subcutaneous fat and pubertal stages. The results suggest that adrenal androgen might be involved in the initiation of puberty and female maturation.     

Serum dehydroepiandrosterone sulphate and pubertal development in Chinese girls

Serum dehydroepiandrosterone sulphate (DHEAS), estradiol (E2), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured by radioimmunoassay in 170 healthy school girls from 7-16 years old. Blood samples from postmenarcheal girls were taken on days 6-10 of the menstrual cycle. Bone age, height, weight, breast and pubic hair development were also investigated. Of the four hormones measured, serum DHEAS displayed the earliest elevation, at 7 years and upwards. A significant DHEAS increment at chronological age 13 years was observed. Girls with earlier menarche had higher DHEAS level than girls having later menarche. Serum DHEAS levels also correlated with bone age, height, weight, subcutaneous fat and pubertal stages. The results suggest that adrenal androgen might be involved in the initiation of puberty and female maturation.     

Growth, bone maturation and pubertal development in children with the EMG-syndrome

In 7 patients (5 girls, 2 boys) with the EMG or Wiedemann-Beckwith syndrome, statural growth, bone age (BA), weight and pubertal development were studied longitudinally. Height was above the 90th percentile (%) for chronological age (CA) after age 2 years, reaching an average of 2.5 SD above the mean at or after puberty. Adult or attained height also exceeded significantly (P<0.015) parental (genetic) target height by 13.2 cm on the average. In one girl, adult height prognosis (190 cm) could be reduced to an adult height of 183 cm by high-dose estrogen treatment. In most children, growth velocity remained above the 90th % up to 4–6 years of age and normalized thereafter. In all patients studied, bone age was markedly advanced and particularly so during the first 4 years after birth. Weight was above the 90th–97th % during infancy and early childhood and remained there, appropriate or slightly subnormal for height, until adulthood, except for 3 girls who reached and maintained the 50th % during or after puberty. Spontaneous pubertal development occurred within normal limits for CA and around the 50th % for BA. Except for the marked bone age acceleration, the reason for the increased statural growth and adult height in patients with the EMG syndrome is still unknown.     

急性颅脑外伤患者血清NSE及血浆ET、IGF-Ⅱ、CNP水平分析

目的：探讨急性脑外伤患者血清及血浆相关标志物水平的变化及临床意义。方法：血清NSE采用化学发光法;血浆ET、IGF-Ⅱ和CNP采用放射免疫分析。结果：NSE水平颅脑外伤轻型组水平与正常对照组比较差异无显著性（P〉0.05）;中型组显著高于正常对照组;重型组患者较正常对照组升高更为显著（P均〈0.01）。该指标水平的变化明显随病情的加重而呈递增性升高。ET水平的变化规律与NSE基本相同。IGF-Ⅱ的变化则显示轻型组与正常对照组差异无显著性（P〉0.05）;中型组和正常对照组比较显著差异（P〈0.05）;重型组则差异更为显著（P〈0.01）。CNP水平其测定值显示较正常对照组低;轻型组CNP水平降低不太明显,与正常对照组比较无显著差异（P〉0.05）;而中型组和重型组两组患者血浆CNP水平均下降极为显著（P均〈0.01）。其递降规律与颅脑外伤的加重呈显著的平行关系。结论：血清NSE及血浆ET、IGF-Ⅱ及CNP的变化与急性颅脑外伤的病理生理过程关系密切,其测定对于早期评估脑损伤的严重程度和预后有重要的临床意义。     

Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia

To determine the timing of pubertal development and the frequency of gonadal dysfunction in children who survive acute lymphoblastic leukemia, we assessed pubertal status and the plasma levels of sex steroids, gonadotropin, and inhibin in 45 children (20 girls and 25 boys) who had received combination chemotherapy along with 24 Gy of irradiation to the cranium (modified LSA2L2 protocol). We also reexamined testicular biopsy specimens, obtained at the time of the cessation of chemotherapy, for the presence of germ cells. Germ-cell damage, indicated by marked elevations in the plasma level of follicle-stimulating hormone (P less than 0.001 for the comparison with normal children), was evident in both sexes and was confirmed in the boys by the absence of germ cells in the testicular biopsy specimens and by the small size of the testes for pubic-hair stage. Only 44 percent of the pubertal girls had measurable plasma inhibin levels, as compared with more than 93 percent of normal pubertal girls. Although plasma sex-steroid levels were normal, the secretion of luteinizing hormone in response to stimulation with gonadotropin-releasing hormone was elevated in the pubertal children (P less than 0.01 for the comparison with normal controls)--a finding that suggests compensation for decreased gonadal function. Despite clear evidence of gonadal damage, girls had early menarche at a mean age (+/- SD) of 11.95 +/- 0.91 years, as compared with the Australian standard of 12.98 +/- 1.11 years (P less than 0.01). Thus, in girls, puberty was early despite primary gonadal damage. Thirteen of 23 boys reached puberty at a mean age of 12.36 +/- 0.73 years. We conclude that treatment for acute lymphoblastic leukemia may lead to primary gonadal damage in both sexes, regardless of the age at treatment, but that the secondary characteristics of puberty develop at a normal age or, in girls, relatively early.     

Diurnal changes in FSH-regulatory peptides and their relationship to gonadotrophins in pubertal girls

BACKGROUND: FSH-regulatory peptides participate with GnRH and sex steroids to regulate serum FSH concentrations. We hypothesized that day/night variations in FSH serum concentrations would be associated with diurnal variation in FSH-regulatory peptides. METHODS: Blood was obtained every 15 min for 24 h beginning at 08:00 h in eight girls [seven with variations in growth or puberty and one with idiopathic hypogonadotrophic hypogonadism (IHH)] and for 12 h beginning at 20:00 h in 12 additional girls with variant puberty, eight with gonadal dysgenesis or ovarian failure (GD/OF) and one with IHH. Samples across 3 h blocks were pooled for determination of LH, FSH, activin-A, inhibin-B and follistatin 288. RESULTS: LH and FSH concentrations increased from 23:00 to 08:00 h with respect to daytime concentrations in pubertal girls (P<0.005) but only LH increased (P=0.002) in girls with GD/OF. In pubertal girls, inhibin-B declined during the day (P=0.019), reaching a nadir between 17:00 and 22:45 h just prior to the night-time increase in FSH. Follistatin concentrations exhibited diurnal variation (P=0.028), with the greatest concentrations occurring between 05:00 and 11:00 h. Activin-A concentrations declined coincident with the night-time increase in FSH in pubertal girls (P<0.0001) but not in girls with GD/OF. CONCLUSIONS: The directionality of changes in FSH-regulatory proteins supports the notion that FSH-regulatory peptides may contribute to the night-time augmentation of circulating FSH during puberty in girls.     

多囊卵巢综合征患者血清IGF-1水平与胰岛素抵抗

目的探讨血清胰岛素样生长因子1(IGF-1)、胰岛素敏感指数(ISI)与多囊卵巢综合征(PCOS)的关系。方法采集90例PCOS患者和41例正常对照组血清,应用电化学发光法检测胰岛素水平,葡萄糖氧化酶终点法检测空腹葡萄糖(FPG)水平,酶联免疫吸附试验(ELISA)检测IGF-1水平。结果 1.PCOS患者FPG、血清胰岛素、IGF-1水平明显高于正常对照组(t=16.72,2.24,4.51;P<0.01),且均与患者是否肥胖高度相关(t=5.08,2.07,3.30;P<0.01);2.PCOS患者胰岛素敏感性明显低于对照组,差别有显著性意义(t=3.12,P<0.05);3.PCOS患者血清IGF-1的含量与胰岛素敏感指数呈显著负相关,差别有显著性意义(r=-0.57,P<0.05);对照组血清IGF-1含量与胰岛素敏感指数无明显相关性(r=0.14,P>0.05)。结论多囊卵巢综合征患者存在不同程度的胰岛素抵抗(IR),IGF-1水平增高与PCOS患者发生IR有关,IGF-1可能与PCOS发生、发展有一定的内在联系并起协同作用。