Efficacy And Long-Term Safety Of GnRHa Administration In Girls With Idiopathic Central Precocious Puberty

Backgroumd and Objective It has been confirmed that the therapeutic effect can be determined by a single test of luteinizing hormone in several hours after injection of GnRHa,in the treatment of idiopathic central precocious puberty with GnRHa.However,the specific time and cut-off level are not completely unified.In some children,the growth rate is too slow(GV<4cm/ year),in the treatment of GnRHa,which still injury the adult height.Studies have found that when this condition occur,they can be treated with a combination of growth hormone,but its effect on the adult height remains controversial.GnRHa is currently a safe drug for precocious puberty.studies have found that the long-term effects of GnRHa on reproductive system function,BMI,PCOS,,bone density and lipid metabolism are affected.However,there is no direct evidence to prove that GnRHa cause these.so the long-term safety of GnRHa is still controversial.We aimed to analyse the validity of single LH sample 1 h after GnRH analogue(GnRHa)administration in the evaluation of gonadotrophin suppression during CPP therapy and to determine a cut-off level for LH indicating adequate suppression.We also aimed to predict the adult height after combined with growth hormone for those girls whose growth rate less than 4cm per year during the treatment with GnRHa.At the same time,the aim of this study was to observe the long-term safety of GnRHa administration in children with ICPP.Methods From January 2010 to April 2017,217 girls received GnRHa to suppress central precocious puberty for 6~24 months in xi?an children's hospital.All of them hadundergone a GnRH stimulation test before therapy.This research including the following three aspects:1.Value of the single luteinizing hormone determination 1 hour after GnRHa treatment in efficacy of GnRHa Administration in girls with Idiopathic Central Precocious Puberty;2.Who had a significant decrease in growth rate(less than 4cm/year)during the treatment with GnRHa,observed whether the changes of growth rate and PAH before and after combined GH treatment is significant;3.Long-term Safety of GnRHa Administration.Research one:57 cases which defined asstimulating-test randomly divided into three groups A,B and C.There were 23,19 and 15 cases in group A,B,and C respectively.The serum LH concentrations of patients in group A were assayed 1 h after the fourth GnRHa injection.The serum LH concentrations of patients in group B were assayed 2 h after the fourth GnRHa injection.Patients in group C underwent a conventional GnRH stimulation test again before the fourth GnRHa injection,and the peak values of LH were recorded.In order to define appropriate level of LH,a clinical score for pubertal suppression were developed by using Tanner staging,skeletal maturation,Size of the mamary gland,the uterus and ovaries,and growth velocity.We analyzed the best correlation between this clinical score and the value of LH of 1 h after the GnRHa treatment.Research two:During the treatment with GnRHa,26 cases had a significant decrease in growth rate(less than 4cm/year).Then these chidlren were treated with GnRHa.Finally,observeing whether the changes of growth rate and PAH before and after combined GH treatment is statistcally significant.Research three:68 children who had been treated in our center for more than 18 months were observed.After stopping GnRHa for more than one year,the development of sex wasobserved,such as time to start sexual development again.The time and regularity of menstruation,and the development of breast.Length of uterus,volume of ovary,occurrence of polycystic ovary syndrome,PCOS,and changes of body mass index(BMI),to analyze the long-term safety of GnRHa treatment.Results All of 57 patients were effectively,showing that the developed mammary gland became softer,smaller or disappearing.The patients with menstruation showed menstrual cessation.Ultrasound showed that the uterus,ovary and follicle volume were smaller;the progression of bone age was obviously suppressed.The peak values of LH were13.43± 5.44 IU/L,12.82 ± 4.66IU/L and 13.21 ± 5.20 IU/L in group A,B and C before treated with GnRHa.It indicated that there was no significant difference among the three groups(p>0.05).In group A,the values of LH measured 1 h after the fourth GnRHa injection were 1.67±0.60IU/L.In group B,the values of LH measured 2 h after the fourth GnRHa injection were 1.25±0.71IU/L.There was no statistic difference between the group A and B(p>0.05).In group C,the peak values of LH obtained at the second GnRH stimulation test were 1.0±0.4IU/L,and there was no significant difference compared with group A and B(p>0.05).the change of 26 cases in bone age/age was measured.The average growth rate before and after treated with growth hormone was 2.54±0.54 cm/year VS 8.20±2.23 cm/year,respectively PAH was 153.35±3.64 cm VS 160.08±3.40 cm.There was a statistically significant difference(t=-12.66,p<0.05).It is suggested that the combination of growth hormone therapy can improve the prediction of adult lifetime height in children with low growth rate during GnRHa treatment.In the course of observing the long term safety of GnRHa,no adverse effects were found in 68 children with GnRHa during the treatment of GnRHa and in the follow-up after withdrawal.From 3 to 6 months after withdrawal,sexual development began to occur again.Menstruation occurred in 12 girls in the early period of menstruation,and menstruation began in 15 months after the onset of menstruation.No polycystic ovary syndrome was found during the treatment every 3 months and every 6 months after withdrawal.Through the observation of body mass index(BMI),it was found that the standard deviation of age specific BMI(BMISD SCA)and bone age index(BMISD SBA)were higher at the beginning of treatment than at the beginning of treatment with GnRHa.The difference between the two groups before and after treatment was statistically significant(t=-6.40,P< 0.05;t=-11.14,P<0.01).The BMISDS of 31 children at adult height was significantly lower than that of BMISD SCA at the end of treatment(t =-3.60,P < 0.01).Conclusion We establish the LH cut-off values for GnRHa therapy as an LH peak below 2.5 U/L after GnRH test or below 3.0 U/L 1h after GnRHa administration.It may replace the GnRH test as a useful and convenient tool in monitoring therapy in female idiopathic central precocious puberty.When the growth rate of GnRHa is too low(GV<4cm/year),the addition of growth hormone has a good effect on the growth rate and prediction of adult height.GnRHa has no obvious long-term adverse effects on ICPP girls,and has good long-term safety.