| CHAPTER Ⅰ.Bone age as an indicator facilitates the diagnosis ofcentral precocious pubertyBackgroundPrecocious puberty usually occurs in girls before the age of 8 or boys before the age of 9.In most cases,precocious puberty is caused by premature activation of the hypothalamic-pituitary-gonads axis,which is also known as central precocious puberty.Central precocious puberty is usually idiopathic unless there are identifiable causes of the disease,such as tumors,hydrocephalus,brain damage or intracranial trauma.In addition to secondary sexual characteristics,characteristics of precocious puberty also include pubic hair development,early skeletal maturity,linear growth acceleration and changes in pelvic ultrasonography,including abnormal changes in the volume of the ovaries,uterus and adrenal glands.Central precocious puberty can lead to premature closure of the epiphysis,which ultimately leads to other effects such as height loss and psychological stress.There are reports in the literature that girls with premature puberty have more behavioral problems than their peers.Therefore,detailed puberty development assessment is necessary for girls with suspected precocious puberty.Once a diagnosis is made,appropriate treatment should be performed.The luteinizing hormone stimulation test is an adjunct test to verify the activity of the gonadotropin axis and to distinguish between central precocious puberty and simple premature thelarche.For children with early signs of puberty,such as accelerated linear growth and early skeletal maturation,central precocious puberty can be diagnosed when premature activation of the gonad axis is determined.However,the luteinizing hormone releasing hormone stimulation test requires a lengthy and complicated sampling process.Sometimes,multiple tests are required before the diagnosis of central precocious puberty.It has been reported that two samples of luteinizing hormone levels need to be obtained at 45 minutes to accurately diagnose central precocious puberty.In this study,we sought to find a laboratory or clinical indicator that can predict the positive results of the luteinizing hormone-releasing hormone stimulation test.Because the understanding of these indicators can help determine the time of the trial,which can assist the diagnosis of central precocious puberty.We categorized and compared the clinical and laboratory parameters of patients with premature markers of puberty.The relevant parameters are associated with the initial and subsequent luteinizing hormone-releasing hormone stimulation test results,which can help find the most important factors that can predict the test results.The diagnosis of central precocious puberty has always faced challenges in clinical practice.As an important diagnostic tool for central precocious puberty,the luteinizing hormone-releasing hormone stimulation test is complex and time consuming.In many cases,the clinical features are inconsistent with the results of the luteinizing hormone-releasing hormone stimulation test,so the diagnostic results of the stimulation test alone are not reliable.In this study,we aimed to find a predictor of luteinizing hormone-releasing hormone stimulation test in subjects with premature signs of puberty.MethodsA total of 382 girls who had early breasts development before the age of 8 and conducted a luteinizing hormone releasing hormone stimulation test before the age of 9 were collected for subsequent trials.Patients whose luteinizing hormone peak level was greater than or equal to 5 IU/L and whose LH peak/FSH peak was greater than or equal to 0.6 were considered to be positive in the luteinizing hormone releasing hormone stimulation test,which can be diagnosed with central precocious puberty.Subjects’ chronological age,bone age,body weight,height,body mass index,and laboratory parameters were collected in an initial luteinizing hormone releasing hormone stimulation test.The Tanner rule was used in each case to assess breast development.We use the Greulich-Pyle method to assess bone age.The bone age is determined using X-rays of the wrist and left hand.The predicted adult height was calculated using the Bayley-Pinneau method.In addition,this study will also use the kit to determine the concentration of luteinizing hormone,follicle stimulating hormone,estradiol,insulin-like growth factor,carcinoembryonic antigen,human chorionic gonadotropin,alpha-fetoprotein,neuro-specific enolase in the blood of the subject.ResultsIn the initial luteinizing hormone-releasing hormone stimulation test,the average chronological age of the subjects was 7.8 ± 0.6 years;the mean bone age was 9.3 ±0.8 years;the mean difference between bone age and chronological age was 22.5 ±5.4 month;mean value of body weight standard deviation score is 1.4 ± 0.4;mean value of height standard deviation score is 1.6 ± 0.6;average growth rate of 6 months is 3.7 ± 0.7 cm/6 months;average body mass index is 18.7 ± 2.9 kg/m2;the peak level of luteinizing hormone was 5.7 ± 2.8 IU/L,LH peak/FSH peak is 1.8 ± 1.2.In the initial luteinizing hormone-releasing hormone stimulation test,237 patients had a peak level of luteinizing hormone greater than or equal to 5 IU/L and an LH peak/FSH peak greater than or equal to 0.6,which was diagnosed as central precocious puberty.And the remaining 145 patients were negative.Compared with the control group with negative results,advanced bone age,chronological age,BA-CA difference,body weight standard deviation,body mass index,growth rate and growth rate ratio were significantly higher in central precocious puberty group.However,there was no significant difference in the height standard deviation score between the two groups.In addition,the concentration of luteinizing hormone,follicle stimulating hormone,estradiol,and insulin-like growth factor-1 in the blood of the group of patients with central precocious puberty was higher than that of the control group.No significant differences were observed in the levels of carcinoembryonic antigen,human chorionic gonadotropin,alpha-fetoprotein and neuro-specific enolase in the blood between the two groups.Subsequent 145 subjects who were negative in the initial LHRH stimulation test underwent a subsequent LHRH stimulation test.Of these 145 subjects,42 were diagnosed with central precocious puberty in subsequent LHRH stimulation trials and 103 girls had negative results.Compared with the negative follow-up group,the bone age of the group with central precocious puberty was more advanced,the chronological age was smaller,the difference of BA-CA was significantly increased,the growth rate was faster,and the growth rate ratio was increased.However,there was no significant difference in body weight standard deviation score,height standard deviation score,and body mass index between the two groups.For the various indicators in the blood,higher concentrations of luteinizing hormone and follicle stimulating hormone were detected in the group of patients with central precocious puberty.However,the levels of estradiol,IGF-1,carcinoembryonic antigen,human chorionic gonadotropin,alpha-fetoprotein,and neuro-specific enolase did not change between the two groups.We analyze the relevant parameters by establishing a binary logistic regression model.The results showed that in the initial LHRH stimulation test,the body weight standard deviation score,body mass index,estradiol and IGF-1 concentration were not related to the LHRH stimulation test results.BA-CA differences,growth rate ratios,basic follicle stimulating hormone concentrations and luteinizing hormone concentrations in the blood were associated with LHRH stimulation test results.Using a linear regression model,we found that the BA-CA difference was positively correlated with the peak level of luteinizing hormone,with correlation coefficients R2 of 0.78 and 0.65 respectively.ConclusionsAccording to the results of statistical analysis,advanced bone age is the most effective predictor indicator for luteinizing hormone-releasing hormone stimulation test results.CHAPTER Ⅱ.Differential analysis of nutrient intake、diabetic andlipid profiles in girls between healthy and premature thelarcheBackgroundAccording to surveys from all over the world,the age of breast development has shown an obvious trend in recent years.Premature thelarche usually manifests in girls below the age of 8,as isolated breast development without accelerated growth,developments of pubic and axillary hair advanced,menarche,or bone maturation.It is usually observed during the first two years of the life cycle.Breast hypertrophy is usually bilateral and in a less proportion of patients unilateral,while the enlargement is not excessive without obvious changes in developments of areolae and/or nipples.Typically,the breast development does not proceed past Tanner stage Ⅲ,and in unilateral cases it does not proceed past Tanner stage Ⅱ.The mechanism of its onset is largely unknown.Although premature thelarche is usually benign and normally a self-limited ailment,but nearly 15%of cases rapidly progress to precocious puberty(PP).Therefore,the clinical features,bone age,basal and stimulating gonadotropin concentrations of premature thelarche cases should be carefully evaluated.Premature thelarche is a benign disease affecting young girls.A variety of factors have been reported to be associated with this disease,but the specific molecular mechanisms of premature thelarche are not well understood.The current study aimed to investigate the correlation of several nutrition and metabolic factors with onset of premature thelarche,such as nutrient intake,diabetic parameters and serum lipid profiles.The results could provide a potential group of collective factors to more accurately predict the onset of premature thelarche.At the same time,28 cases of patients with idiopathic central precocious puberty and 25 cases of premature thelarche were collected.Their nutritional status was measured by BMI,and the correlation between the value of the bone age minus the chronological age、LH peak/FSH peak and BMI was found in patients with precocious puberty.MethodsIn this study,the Greulich and Pyle methods were used for bone age assessment.The body mass index is calculated by the following formula:body weight/(height)2.The well-trained pediatric endocrinologist evaluated the puberty stage of the participants according to the Tanner criteria for the development of girls’ breasts.All participants collected venous blood on an empty stomach at 8am and collected serum centrifugally.The insulin-like growth factor 1(IGF-1),follicle stimulating hormone(FSH),luteinizing hormone(LH),estradiol(E2)、progesterone(P)、testosterone(T)、prolactin(PRL)、adrenocorticotropic hormone(ACTH)、cortisol(COR)、insulin(INS)、C-peptide(C-P)、thyroid-stimulating hormone(TSH)、free triiodothyronine(FT3)、free thyroxine(FT4)were detected by electrochemiluminescence method,fasting blood glucose was detected by hexokinase method,quantitative insulin check index(Quicki)and homeostasis model of assessment of insulin resistance(HOMA-IR)were used to assess insulin resistance.Total cholesterol(TC)was detected by enzyme method.High-density lipoprotein cholesterol(HDL-C)and low-density lipoprotein cholesterol(LDL-C)were detected by direct method.The GPO-POD method was used to detect triglycerides(TG).Families of all participants were issued a recall form to keep records of daily food intake of participants within one month of study initiation.ResultsThis study included 263 girls diagnosed with premature thelarche and 222 healthy girls were recruited as healthy controls.Between the anthropometric characteristics of the two groups,there was no significant difference in chronology age,bone age or BMI,indicating a comparable baseline for the rest of the study(chronology age:the average age of the patients was 5.3 ± 0.7 years,and the average age of the control group was 5.5 ± 0.8 years;bone age:patients The average bone age was 6.1 ± 1.1 years,the average age of the control group was 5.9 ± 1.2 years;body mass index:the average body mass index of the patients was 15.1 ± 2.6 kg/m2,and the average body mass index of the control group was 15.8 ± 2.1 kg/m2.),the p values are all greater than 0.05.For hormone levels in the blood,the results showed that the average level of estradiol in the premature thelarche group was 1.74 ± 0.87 ng/dL,and the healthy control group was 1.65 ± 0.63 ng/dL,but there was no statistical difference(p>0.05).However,the peak levels of luteinizing hormone in the group with premature thelarche were significantly higher than those in the healthy control group(luteinizing hormone peak:patient group:3.38±0.79 U/L,control group:3.04±0.62 U/L,p<0.05).Using the Tanner stage to analyze participants’ breast development,the results showed that 78%of patients were in the Tanner stage Ⅱ and the rest were in the Tanner stage III.On the other hand,all healthy girls are in Phase I of the Tanner stage.The study found that a variety of factors are thought to be associated with early onset of breast development.Therefore,we first analyze the nutritional intake of the patient group and the control group.The results showed that the protein intake and fat intake of the patient group were significantly higher than the control group(p value was 0.0016 and 0.0031,respectively).However,the average daily energy and carbohydrate intake of the two groups were essentially the same(p value was 0.1654 and 0.3699,respectively).The concentration of IGF-1 in the blood of the patient group was significantly higher than that of the control group,p<0.0001.Next,we evaluated the diabetic parameters of the two groups.The FGIR of the patient group was slightly lower than that of the healthy control group,but it was still statistically significant(p = 0.0008).Compared with healthy controls,the other two diabetes criteria,QUICKI and HOMA-IR,were also significantly different in the group with premature thelarche,with p values less than 0.0001.Finally,serum lipid mass spectrometry analysis of all participants showed that the total cholesterol,triglyceride and low-density lipoprotein levels in the group with premature thelarche were significantly higher than those in healthy controls,with p values less than 0.0001.However,compared with the healthy control group,the high-density lipoprotein level in the group with premature thelarche was slightly elevated,but not statistically significant.The correlation between nutritional status and precocious puberty was measured by BMI.The results showed that to some extent,the value of the bone age minus the chronological age was related to BMI(r=0.536,p=0.000)and LH peak/FSH peak was associated with BMI(r=0.435,p=0.004).which was statistically highly positively correlated.ConclusionsThe girls with premature thelarche have a certain correlation with high protein and high fat intake,and have a certain correlation with diabetes related indicators and lipid mass spectrometry.Precocious puberty is positively correlated with body mass index within a certain range. |
PDF Full Text Request