第三代芳香化酶抑制剂治疗女孩外周性性早熟的临床分析

发布时间：2018-07-14 20:01

【摘要】：背景:性早熟是指男童在9岁前出现第二性征,女童在8岁前出现第二性征或10岁前月经初潮。按照发病机理及临床表现的不同,可以分为中枢性性早熟及外周性性早熟。中枢性性早熟(Central precocious puberty CPP)即下丘脑-垂体-性腺轴提前发动、成熟,从而使内、外生殖器发育和第二性征呈现,为促性腺激素释放激素依赖性性早熟。外周性性早熟(Peripheral precocious puberty PPP)则是由于体内性甾体激素水平升高至青春期水平,并无性腺轴的真正发动,所以只有第二性征的出现,而没有完整的性发育程序性的过程。目前主张应用第三代芳香化酶抑制剂来曲唑或选择性雌激素受体调节剂他莫昔芬治疗,通过抑制雄激素向雌激素的转化而降低雌激素水平,或阻断雌激素对相应器官的影响,使阴道出血停止、防止骨骺提前闭合导致患儿最终身高受影响。目的:探讨第三代芳香化酶抑制剂治疗女孩外周性性早熟的疗效及安全性方法:选择于2013年9月至2016年12月就诊于我院儿科内分泌门诊的11名1.2-6.8岁的外周性性早熟女孩,就诊症状为乳房发育,阴道出血或分泌物,LH和FSH水平低下,除外分泌雌激素的肿瘤、先天性肾上腺皮质增生症、原发性甲状腺功能低下、摄入过多外源性雌激素所致等情况。给予来曲唑片(江苏省恒瑞医药股份有限公司,国药准字H19991001,规格为每片2.5 mg)口服治疗,剂量为1-2mg/m2.d,分别于治疗1月、3月后复查,通过比较治疗前后性激素水平、Tanner分期,以及患者、家属的主观反映来评价来曲唑治疗的有效性,若患儿治疗期间乳房恢复正常,阴道出血或分泌物停止则予停药。治疗过程中,密切观察患儿的一般情况,记录来曲唑口服过程中出现的不良反应,以评估来曲唑治疗女孩外周性性早熟的安全性。采用SPSS21.0统计学软件对所观察到的结果及实验室数据行数据处理分析。由于外周性性早熟发病率低,而且缺乏对照组数据,所以每个病例都通过自身对照行前瞻性研究。结果:1入组儿童的基本资料本项研究共纳入11例女孩,均为非促性腺激素释放激素依赖性性早熟,发病年龄在1.2-6.8岁之间(4.6±2.0岁),表现为乳房发育、阴道出血或分泌物,LH和FSH水平低下,盆腔B超可见卵巢囊肿,5例女孩有骨龄资料,均为骨龄提前,其中2例女孩有显著高的生长速率标准差。6例女孩有皮肤牛奶咖啡斑,9号女孩既往有骨折病史,且存在甲状腺功能亢进症,10号女孩胫腓骨X片示骨纤维化,且存在甲状腺功能亢进症。所有女孩均无肾上腺功能亢进史,垂体MR检测未见明显异常。4名女孩曾接受过达那唑的治疗,1名女孩曾接受过他莫昔芬治疗,均在停药半年到2年半后复发,再次出现乳房发育,阴道出血或分泌物。2来曲唑治疗1月后2.1基本情况的变化及比较经过1个月的治疗,6号女孩的乳房分期较前下降,其余女孩无明显变化,除4号女孩外,所有女孩阴道出血或分泌物均较前减少或停止,2号、8号、11号病人在治疗1月后卵巢囊肿消失,其余患儿,除4号、10号外卵巢囊肿均较前变小,4号病人治疗1月后乳房较前增大,出血较前增多,盆腔B超示卵巢暗区较前增大,予停用来曲唑,10号病人治疗1月后无变化,予来曲唑口服剂量加量。2.2盆腔超声及性激素水平的变化患儿的平均卵巢容积(MOV)、雌二醇(E2)较前显著下降,卵泡刺激素(FSH)较治疗前升高,睾酮(T)、黄体生成素(LH)、子宫容积没有变化。3来曲唑治疗3月后3.1基本情况的变化及比较治疗前后体重、Ht-SDS无显著变化,身高较治疗前增长,体质指数(BMI)较治疗前降低,经过3个月的治疗,6号、7号女孩的乳房分期较前下降,其余女孩无明显变化,所有病例均未再出现阴道出血及分泌物。3.2盆腔超声及性激素水平的变化6号、7号、11号女孩的MOV、子宫容积及卵巢囊肿均较前减小。1号女孩的MOV、子宫容积、卵巢囊肿在治疗1月后较前降低,但在治疗3月后有高于治疗前的趋势。与治疗前相比,E2显著降低(P=0.018),FSH有所升高(P=0.018),T、LH无变化(分别为P=0.735,P=1.0)。结论:1来曲唑治疗外周性性早熟是有效的,可以减少阴道出血的量及频率,降低雌激素水平,缩小平均卵巢容积,为治疗女孩外周性性早熟提供了新的选择。2来曲唑治疗的安全性尚有待进一步研究,治疗过程中可能出现FSH水平的增高、卵巢囊肿的增大,需定期复查,除外中枢性性早熟及预防卵巢囊肿破裂或扭转。3来曲唑治疗外周性性早熟的剂量、疗程仍需更多样本及更长时间的研究来进一步明确。
[Abstract]:Background: precocious precocious puberty refers to the second sex sex sign before 9 years of age. The girl has the secondary sex sign before the age of 8 or the menarche before the age of 10. According to the pathogenesis and the clinical manifestation, it can be divided into central precocious puberty and peripheral precocious puberty. Central precocious puberty CPP, the hypothalamus hypophysis - gonadal axis Dynamic and mature, so that the internal and external genitals are developed and the secondary sex is present, the gonadotropin releasing hormone dependent precocious puberty. Peripheral sexual precocious puberty (Peripheral precocious puberty PPP) is due to the level of steroid hormone levels in the body to puberty, and the real launch of the gonadotropin axis, so only the second sex sign appears. There is no complete procedural process of sexual development. Currently, the third generation aromatase inhibitor, trazole or selective estrogen receptor modulator tamoxifen, is used to reduce estrogen level by inhibiting the conversion of androgen to estrogen, or blocking the effect of estrogen on the corresponding organs, stopping the vaginal bleeding and preventing epiphysis. Objective: To explore the effect and safety of third generation aromatase inhibitors in the treatment of peripheral sexual precocious puberty in girls: 11 1.2-6.8 years old peripheral precocious girls aged from September 2013 to December 2016 in the pediatric endocrinology clinic of our hospital were selected for the symptoms of breast development and vagina Bleeding or secretions, low levels of LH and FSH, except for estrogen secreting tumors, congenital adrenocortical hyperplasia, primary hypothyroidism, excessive intake of exogenous estrogen, etc., were given to Letrozol Tablets (Jiangsu Heng Rui medical Limited by Share Ltd, Chinese medicine quasi word H19991001, specification for 2.5 mg per slice), The dose of 1-2mg/m2.d was treated in January and March respectively. The efficacy of letrozole was evaluated by comparing the level of sex hormone before and after treatment, Tanner staging, and the subjective reflection of the family members. In general, the adverse reactions occurring during the oral administration of letrozole were recorded to assess the safety of letrozole in the treatment of peripheral sexual precocious puberty. SPSS21.0 statistics software was used to analyze the observed results and laboratory data. The incidence of peripheral precocious puberty was low and the control group was lack of data. Results: a total of 11 girls were included in the basic data of 1 children, all of which were non gonadotropin releasing hormone dependent precocious puberty, the age of onset was between 1.2-6.8 years (4.6 + 2 years), showing breast development, vaginal bleeding or secretion, low levels of LH and FSH, and pelvic B ultrasound visible eggs. Nesting cysts, 5 girls have bone age data, all of which are early bone age, of which 2 girls have a significant high standard of growth rate,.6 girls have skin milk coffee spots, 9 girls have a history of fracture, hyperthyroidism, X shin and fibula in Girl 10, and hyperthyroidism. All girls have hyperthyroidism. No adrenal hyperfunction history, MR detection of pituitary MR had not been significantly abnormal.4 girls had been treated with dadazol, 1 girls had received tamoxifen treatment, all relapsed after half to 2 and a half years of drug withdrawal, recurrence of breast development, vaginal bleeding or secretion of.2 to cure 2.1 basic changes after the treatment of January, and compared 1 The breast staging of 6 girls declined more than that of the previous month, and the rest of the girls had no obvious changes. Except for girl No. 4, all the girls had vaginal bleeding or discharge more than before. The ovarian cysts disappeared after January, 2, 8 and 11. The remaining children, except 4 and 10, were all less ovarian cysts, and 4 patients were treated for the breast after January. More bleeding than before, pelvic B-ultrasound showed that the dark area of ovary was larger than before, and was given to trazole, and no change in 10 patients after January. The average ovarian volume (MOV), estradiol (E2) decreased significantly, and follicle stimulating hormone (FSH) was higher than that before the treatment in the patients with the oral dose of letrozole plus the changes of.2.2 pelvic ultrasound and sex hormone levels. Testosterone (T), luteinizing hormone (LH), the volume of uterus did not change.3, the changes in the 3.1 basic situation after March and the body weight before and after treatment, Ht-SDS had no significant change, the height was higher than before the treatment, the body mass index (BMI) was lower than before the treatment, after 3 months of treatment, 6, 7 girl's breast staging decreased, the rest of the girls were not clear. There was no recurrence of vaginal bleeding and the changes of.3.2 pelvic ultrasound and sex hormone levels in all cases, 6, 7, and 11 girls' MOV. The uterine volume and ovarian cysts were lower than the MOV, uterine volume and ovarian cysts in January. The ovarian cysts were lower than before in January, but after March, the trend was higher than that before treatment. E2 significantly decreased (P=0.018), FSH increased (P=0.018), T, LH did not change (P=0.735, P=1.0). Conclusion: 1 letrozole is effective in the treatment of peripheral sexual precocious puberty. It can reduce the amount and frequency of vaginal bleeding, reduce the level of estrogen, Suo Xiaoping's ovarian volume, and provide a new selection of.2 for the treatment of peripheral sexual precocious puberty in girls. The safety of letrozole still needs further study. The increase of FSH level and the increase of ovarian cysts in the treatment process should be reviewed regularly, except for central precocious puberty and prevention of rupture of ovarian cysts or reversing the dosage of.3 letrozole in the treatment of peripheral sexual precocious puberty. Step by step.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R725.8

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