【作者】 王媛媛；

【导师】 徐雯；

【作者基本信息】 广州中医药大学 ， 中医儿科学， 2008， 硕士

【摘要】 研究背景:性早熟系一种生长发育异常疾病,表现为青春期提前启动,第二性征提前出现。其中以特发性中枢性性早熟（ICPP）患儿最为多见,占性早熟患儿的92%,目前研究表明,该病对患儿生理、心理、生活及学习均有不同程度的影响,并可影响其骨龄的发育及最终身高。近年来性早熟发病率逐年上升,性早熟已成为儿童内分泌科常见病之一,且患病女孩80%～90%为ICPP,因此女童ICPP的研究成为性早熟研究中的焦点。目前,ICPP的病因尚未完全明确,现认为主要是由于下丘脑-垂体-性腺轴（HPGA）功能提前激活所致。西医药对于ICPP女童的治疗,临床应用最多的为促性腺激素释放激素拟似物（GnRHa）。GnRHa价格昂贵,投放临床应用时间较短,其药物安全性尚待进一步考证,且近年有报道其可同时抑制生长激素（GH）分泌,影响身高。中医认为人体正常的生长发育及性腺的成熟,主要靠肾气的充盛及天癸的期至。若各种原因致肾阴阳失衡,天癸早至,则可引起儿童性成熟的提前而发病。目前认为性早熟的病因病机主要有:肾阴不足;肝郁化火;脾虚痰凝;湿浊下注等。但临床ICPP女童以肾阴不足、阴虚火旺者居多,且在临床实践中我们发现ICPP患儿除有阴虚火旺的症候表现外,多伴有多食易饥、面部痤疮等胃热炽盛、虚火上炎的表现。在运用中医药治疗本病的实践中,我们发现中药不仅可使患儿第二性征消退,亦可降低血清性激素水平,且对患儿治疗期间的生长发育无明显影响。故本研究根据小儿具有“阴常不足,阳常有余”,“肝常有余,肾常虚”的病理特点,提出以滋阴降火清胃为治则,自拟早熟一方治疗ICPP,选取促卵泡生成素（FSH）、黄体生成素（LH）、雌二醇（E₂）和生长激素（GH）水平为主要的研究指标,及盆腔B超、骨龄、体重、身高、临床症状等多方面进行临床疗效的观察,以期进一步了解中药对HPGA、促生长激素轴的功能活动、血清激素水平及生长发育的影响。研究目的:通过观察治疗前后患儿青春期性征、体重、身高、骨龄等的变化,进一步对早熟一方治疗ICPP临床疗效进行科学的论证;通过观察治疗前后患儿血清FSH、LH、E₂水平的变化,了解早熟一方对患儿激素水平的影响;通过观察治疗前后患儿血清中GH变化,了解早熟一方对患儿生长激素水平的影响;并试图探讨促生长激素轴及促性腺轴之间的相互关系,以及它们在ICPP发病机制中的作用,从而进一步探讨早熟一方的作用机制。本研究从患儿血清中GH的变化以及与FSH、LH、E₂的变化间的相互关系,试图了解促生长激素轴和促性腺轴之间的相互关系,并从这些全新的角度探讨ICPP的发病机制及早熟一方治疗ICPP的作用机理,证实滋阴降火清胃法治疗本病的优势所在和特点及其药物安全性,为中医药治疗本病提供新的治疗思路和途径。研究方法:研究对象共50例女童,均为2006年1月—2008年3月在广州市中医医院儿科门诊就诊并确诊为ICPP的女童,按就诊先后顺序随机分为治疗组和对照组各25例,治疗组予早熟一方口服,每日2次;对照组予知柏地黄丸,每次6丸,每日2次。两组用药时间均为6个月,治疗期间均无合并其他疗法。治疗前后对临床症状、体征、FSH、LH、E₂、GH、盆腔B超、骨龄、体重、身高、肝肾功能等进行比较。全部数据以均数±标准差（（?）±s）表示,组间比较:方差齐的采用两组独立样本的t检验,方差不齐的采用秩和检验;治疗前后比较采用配对样本的t检验;计数资料采用x²检验。分析均由SPSS11.3软件包完成。结果:1.两组疗效比较:两组总有效率分别为:治疗组88%,对照组56%,两组比较有显著性差异（P＜0.05）。2.两组临床症状缓解的起效时间:两组头晕、五心烦热、多食善饥、面部痤疮的缓解起效时间比较有显著性差异（P＜0.05）,而潮热、盗汗的缓解起效时间比较无显著性差异（P＞0.05）。3.两组治疗前后乳房直径:两组治疗前后乳房大小比较均有显著性差异（P＜0.05）。但两组治疗前乳房大小比较无显著性差异（P＞0.05）,而治疗后比较差异有显著性（P＜0.05）。4.子宫、卵巢体积:治疗组治疗前后子宫体积比较有显著性差异（P＜0.05）,而对照组治疗前后比较差异无显著性（P＞0.05）。且两组治疗前子宫体积比较无显著性差异（P＞0.05）,而治疗后比较差异有显著性（P＜0.05）。5.血清FSH水平:治疗组治疗前后血清FSH比较有显著性差异（P＜0.05）,而对照组治疗前后比较差异无显著性（P＞0.05）。且两组治疗前血清FSH比较无显著性差异（P＞0.05）,而治疗后比较差异有显著性（P＜0.05）。6.血清LH水平:治疗组治疗前后血清LH比较有显著性差异（P＜0.05）,而对照组治疗前后比较差异无显著性（P＞0.05）。而两组治疗前后血清LH比较无显著性差异（P＞0.05）。7.血清E₂水平:两组治疗前后血清E₂比较均有显著性差异（P＜0.05）。但两组治疗前血清E₂比较无显著性差异（P＞0.05）,而治疗后比较差异有显著性（P＜0.05）。8.GH水平:两组治疗前后血清生长激素比较均无显著性差异（P＞0.05）。两组治疗前后血清生长激素比较亦无显著性差异（P＞0.05）。9.BA/CA（骨龄/实际年龄）:治疗组治疗前后BA/CA比较有显著性差异（P＜0.05）,而对照组治疗前后比较差异无显著性（P＞0.05）。两组治疗前血清BA/CA比较无显著性差异（P＞0.05）,而治疗后比较差异有显著性（P＜0.05）。10.两组治疗前后身高、体重比较无显著性差异（P＞0.05）。11.药物的不良反应:治疗组不良反应总发生率8%,对照组不良反应总发生率16%,两组比较无显著性差异（P＞0.05）。结论:1.早熟一方对头晕、五心烦热、多食善饥、面部痤疮等肾阴亏虚、胃火旺盛等症状的疗效优于知柏地黄丸。2.早熟一方可缩小患儿肿大的乳房及增大的子宫和卵巢体积,且效果优于知柏地黄丸。3.早熟一方不仅可降低ICPP患儿体内E₂水平,还可降低其血清FSH、LH水平,说明其可能具有抑制ICPP患儿HPGA轴的功能。4.早熟一方在降低ICPP患儿体内性激素水平的同时GH水平没有降低。且患儿骨龄增长速度低于知柏地黄丸组。间接证明其对于生长激素轴没有明显的抑制,且患儿骨龄超前得以一定程度缓解,生长潜力增高。5.早熟一方治疗组不良反应发生率低,应用本方治疗女童ICPP是安全可行的。更多还原

【Abstract】 Background:Precocious puberty is a kind of growth and developmental abnormality that is characterized as premature start of adolescence and secondary sexual character,among which idiopathic central precocious puberty（ICPP）is the most common one（92%of children with precocious puberty）.Researches show it has impact on children’ s physiology,mental health,lives and study;it can also effect the development of bone age and body height.In recent years, prevalence of precocious puberty increases steadily and it has become a common endocrine disease in children.80%-90%of endocrine disease in girls is ICPP, so ICPP in girls has become the focus in the study of precocious puberty.Until now its etiology is unclear,which is believed to be the result of activation of HPGA in advance.In western medicine,gonadotropin releasing hormone analogues（GnRHa）are the usual agent in treating ICPP of girls.GnRHa are expensive and its safety needs further appraisal because of its short application period in clinics,further more,it is report to inhibit secretion of GH and has negative impact to body height in recent years.It is thought from the point of TCM that normal growth and development and maturation of genital gland mainly depend on sufficient kidney-qi and menstruation beginning on time.If there are imbalance between kidney-yin and kidney-yang and menstruation is ahead of time,it will cause disease by bringing sexual maturity of children forward.It is regarded that the main etiology and pathogenesis of precocious puberty is:inefficiency of kidney-yin;pathogenic fire derived from stagnation of liver-QI;stagnation of phlegm caused by splenic asthenia;flowing down of pathogenic damp and etc.But in clinic inefficiency of kidney-yin and asthenic yin causing excessive pyrexia are the main symptoms of girls with ICPP.In clinic,we find that children with ICPP are always accompanied with symptoms of excessive gastric heat and hyperactivity of deficient fire such as polyphagia,easy to be hungry and acne in the face besides asthenic yin causing excessive pyrexia.During treatment of the disorder with traditional Chinese medicine（TCM）,we found that TCM can not only decrease secondary sexual character of children patients,but also decrease serum level of sex hormone（FSH,LH,E₂）and has no impact to growth and development of the children during treating period.In the study, based on pathologic character of "yin frequently in deficiency,yang frequently in excess" and "liver frequently in excess,asthenic susceptibility of kidney" in children,we propose nourishing yin to lessen fire and clear stomach as therapeutical principle and prescribed Zaoshu Yifang to treat ICPP.We choose hormone（FSH,LH,E₂,GH）level in serum as the main index and ultrasound examination Of pelvic cavity,bone age,body weight,body height and clinical symptoms as parameters of curative effect.From the study, we hope to further investigate influence of TCM to functional activity of HPGA and somatotropic hormone-axle,hormone level in serum,growth and development.Objective:Appraisal clinical curative effect of Zaoshu Yifang to ICPP in scientific manner by observation of changes of sexual characteristics during adolescence, body weight,body height and bone age before and after the treatment; investigate impact of Zaoshu Yifang to hormone level of children patients by observation of changes of FSH,LH and E2 before and after the treatment;by observation of changes of GH level,study impact of Zaoshu Yifang to growth hormone of children patients,investigate interrelationship between somatotropic hormone-axle and gonadotropic hormone-axle and their role in pathogenesis of ICPP and further study the mechanism of action of Zaoshu Yifang.In the study,we try to study interrelationship between somatotropic hormone-axle and gonadotropic hormone-axle from changes of GH level and its relationship with changes of FSH,LH and E2,investigate pathogenesis of ICPP and mechanism of action of Zaoshu Yifang to ICPP from these fresh new point of view,verify advantages of nourishing yin to lessen fire and clear kidney in treating the disorder and drug safety and provide new therapeutic method in treating the disorder by TCM. Methods:50 girls diagnosed to be ICPP in outpatient pediatric clinic in Guangzhong Hospital of Chinese Medicine（from January,2006 to April,2008）were randomly divided into treatment group and control group with 25 girls in each group. Treatment group were treated with Zaoshu Yifang,twice per day;Control group were treated with Zhibaidihuang Pill,6 pills per time,twice per day.Treating time is 6 months in both groups and without additional treatment.Clinical symptoms and signs,FSH,LH,E₂,GH,ultrasound examination of pelvic cavity, bone age,body weight,body height,liver function and renal function were compared before and after treatment.Results were showed as X±s.Group comparison:independent t test was used for homogeneity of variance and rank sum test was used for heterogeneity of variance.Comparison before and after treatment:paired t test was used for measurement data andχ² test was used for enumeration data.SPSS11.3 software was used for analysis.Results:1.Comparison of therapeutic effect:There is significant difference of total effective rate between two groups （88%in treatment group and 56%in control group,P＜0.05）.2.Symptomatic relief time:There is significant difference of symptomatic relief time between two groups in the symptom such as dizziness,burning sensation of five centres, polyphagia,boutimia,prosopo-acne（P＜0.05）.But,there is no significant difference of symptomatic relief time between two groups in the symptom such as hectic fever、night sweat（P＞0.05）.3.Breasts diameter:There is significant difference in breasts diameter before and after treatment both in two groups（P＜0.05）.But,there is no significant difference between two groups before treatment（P＞0.05）,there is significant difference between two groupsafter treatment（P＜0.05）.4.Volume of womb and ovaries:There is significant difference in volume of womb and ovaries before and after treatment in treatment group（P＜0.05）.But,there is no significant difference in volume of womb and ovaries before and after treatment in control group（P＞0.05）.There is no significant difference between two groups before treatment（P＞0.05）.And,there is significant difference between two groups after treatment（P＜0.05）5.FSH level:There is significant difference in FSH level before and after treatment in treatment group（P＜0.05）But,there is no significant difference in FSH level before and after treatment in control group（P＞0.05）There is no significant difference between two groups before treatment（P＞0.05）But, there is significant difference between two groups after treatment（P＜0.05）.6.LH level:There is significant difference in LH level before and after treatment in treatment group（P＜0.05）.But,there is no significant difference in LH level before and after treatment in control group（P＞0.05）.There is no significant difference between two groups before and after treatment（P＞0.05）.7.E₂ level:There is significant difference in E₂ level before and after treatment both in two groups（P＜0.05）.There is no significant difference between two groups before treatment（P＞0.05）But,there is significant difference between two groups after treatment（P＜0.05）.8.GH level:There is significant difference in E₂ level before and after treatment both in two groups（P＞0.05）.And there is no significant difference between two groups before and after treatment（P＞0.05）.9.BA/CA（bone age/actual age）:There is significant difference in BA/CA before and after treatment in treatment group（P＜0.05）.But,there is no significant difference in BA/CA before and after treatment in control group（P＞0.05）.There is no significant difference between two groups before treatment（P＞0.05）,But,there is significant difference between two groups after treatment（P＜0.05）.10.There is no significant difference of body height and body weight between two groups before and after treatment（P＞0.05）.11.idverse effect of the drug:Total incidence of adverse effect is 8%in treatment group and 16%in control group,there is no significant difference between two groups, （P＞0.05）.Conclusions:1.Zaoshu Yifang is better than Zhibaidihuang Pill in treating symptoms of deficiency of kidney-YIN and excessive stomach-fire such as dizziness,burning sensation of five centres,polyphagia,boulimia, prosopo-acne.2.Zaoshu Yifang can significantly diminish enlarged breasts,womb and ovaries,and its therapeutic effect is better than that of Zhibaidihuang Pill.3.Zaoshu Yifang not only can decrease the E₂ level in the body but also can decrease the FSH and LH level,which maybe is a proof that it can inhibit HPGi axle of ICPP sufferers.4.Zaoshu Yifang has no impact to GH while decreasing sex hormone level in children with ICPP.And growth rate of bone age in ICPP sufferers is lower than that in Zhibaidihuang Pill group.It is a proof that it has little inhibition effect to growth hormone axle,further more,advanced bone age in ICPP sufferers is slowed down,which will increase growth potential of the children.5.Zaoshu Yifang is a safe method in treating girls with ICPP.更多还原