| Background:Girls diagnosed with central precocious puberty（CPP）or early and fast puberty（EFP）tend to exhibit temporarily rapid acceleration in growth due to increased sex hormone production or exposure,leading to premature closure of the growth plate and a shorter final adult height（FAH）.Rapid progression of the secondary sexual characteristics in children can also cause poor social adaptability,psychological stress,and emotional disorders.CPP/EFP can be treated with GnRHa to halt maturation via suppression of the HPG axis.It is still a doubt that the CPP/EFP girls whether will benefit from the treatment of GnRHa combined with rhGH.However,large-scale studies to evaluate the treatment effects on FAH are still lacking.Objective:1.The aim of this study was to compare the final outcomes of patients treated with GnRHa therapy with and without combined rhGH treatment.2.The aim of this study was to explore the effects of long-term treatment for CPP/EFP on FAH of its main influencing factors.3.The aim of this study was to investigate the best treatment plan for these CPP/EFP girls already having a menstrual cycle.Methods:1.Participants The medical records of 230 girls diagnosed with CPP/EFP from 2000 to 2020 wereretrospectively reviewed at the Pediatric Department of Shandong Provincial Hospital,Cheeloo College of Medicine,Shandong University.2.Study Design163 CPP girls and 67 EFP girls received GnRHa+rhGH treatment（n=144）,GnRHa alone（n=34）,no treatment（n=20）,or rhGH treatment（n=32）.3.Statistical analysis The data are presented as mean±SD,and 95% confidence intervals were used where indicated.The paired t-test was applied to compare data within each group,and the independent t-test was used to make comparisons between the 2 groups.Multiple linear regression analysis was used to determine correlations between multiple parameters and height outcome.A p-value of <0.05 was considered statistically significant.Results:1.Characteristics and auxological data We performed the final evaluations at a mean age of 14.1 ± 0.8 years after a mean treatment duration of 3.33±1.37 years.No significant differences were observed in the baseline data among these three group（p>0.05）.2.Comparison of growth outcomes between GnRHa group and GnRHa+rhGH group FAH in the GnRHa+rhGH group was（162±3.91）cm,significantly higher than the value of FAH in GnRHa group（160±3.02）cm（p=0.034）.The height gain（FAH-PAH）was significantly different among the GnRHa and rhGH treatment,GnRHa alone,and no treatment groups（p<0.05;10.88±3.04,4.91±5.26,and 1.31±0.67 cm,respectively）.The genetic height gain（FAH-Tht）was 4.45±1.87 cm for the GnRHa+rhGH group and1.75±2.87 cm for the GnRHa group,while the control group nearly reached their Tht.3.Correlation between FAH and other auxological factors FAH was significantly and positively correlated with the time of treatment,with PAHSDSTHt and with the target height,whereas the difference between chronological age at the start was negatively correlated with FAH.4.To investigate the best treatment plan for these CPP/EFP girls already having a menstrual cycle.There was no significant difference in FAH between GnRHa+rhGH group and rhGH group,so the same as in height gain（FAH-PAH）and genetic height gain（FAH-Tht）.Conclusion:1.FAH was significantly higher than the initial PAH in girls with CPP who were treated with GnRHa or combined with rhGH.The combined rhGH group had more additional height gain than the GnRHa-alone group.2.Age at baseline,duration of treatment,PAHSDSTHt and THt at start of treatment were correlated with FAH.3.GnRHa treatment was still effective even after 8 years of age in girls with CPP/EFP.4.The combined rhGH group did not achieve more additional height gain than the rhGH-alone group.Background:Adolescence is the last period of linear increase in height.Due to the start of the hypothalamic-pituitary-gonadal axis（HPGA）,there would be a sudden increase in height,about the last 15%~20% of the total height;On the other hand,sex hormones promote sexual development and psychological maturity.Estrogen activates the GHIGF1-growth plate axis to promote growth,but simultaneously estrogen binds with estrogen receptor（ER）and activates cascade reaction,resulting in the proliferation,differentiation,apoptosis and calcification of chondrocytes and the maturation and fusion of epiphysis.The remained growth space is finally shortened so as to the end of growth period.Therefore,how to improve the final adult height of short adolescents with high bone age is of great concern.The main treatment currently is rhGH combined with gonadal hormone-releasing hormone analogs（GnRHa）to delay the growth of bone age and gain more time for height growth.However,GnRHa can inhibit the development process of puberty at the same time,which may cause adverse effects on children’s physical and psychological development.The treatment period is long with high costs.In addition,the inhibition effect of GnRHa is limited for those who have entered middle and late adolescence and had precocious bone age（bone age over 13.5years for males and over 12.5 years for females）.Hence,only rhGH could be used to improve the final adult height which leads to the limited effect.Aromatase,encoded by CYP19A1 gene,is a rate-limiting enzyme in the conversion of androgen to estrogen.Aromatase inhibitors（AI）are a class of compounds that can inhibit aromatase or compete to bind with aromatase active sites.They can block thetransformation of androstenedione and testosterone to estradiol and estrone,and reduce the synthesis of estrogen.AI is now widely used to treat breast cancer,endometriosis and estrogen-related tumors.The third generation of nonsteroidal AI,including anastrozole（LTZ）and letrozole（ANZ）has been used in the treatment of fibrous osteodystrophy syndrome,familial male-limited precocious puberty,congenital adrenal cortex hyperplasia in the field of pediatric endocrine domain because of its reversibility,high efficiency,relatively safe and high estrogen inhibition rate（> 97%）.Recently it has been suggested that AI can be used to treat short stature in adolescent boys to delay the progression of bone age and improve the expected adult height.But there is no long-term follow-up with large samples.As aromatase exists in various cells and tissues such as the ovary,testis,mammary gland,adipose tissue,brain,placenta and bone,the safety of long-term application of AI needs to be further studied.The application of AI in pediatrics is still off-label.This study retrospectively analyzed the treatment outcome of rhGH combined with letrozole for the short adolescent male with high bone age and the result was compared with the monotherapy of rhGH.The efficacy and safety were followed up to evaluate the clinical value of this regimen.Objective:1.To observe the efficacy of recombinant human growth hormone（rhGH）combined with letrozole in the treatment of adolescent boys with short stature,including the gain of the final adult height,the advancement of bone age,height velocity,and changes in IGF-1 level.2.To evaluate the safety of recombinant human growth hormone（rhGH）combined with letrozole in adolescent boys with short stature.Methods:1.Participants106 boys with short stature who had entered puberty were enrolled in our study from2000 to 2020,in the Pediatric Department of Shandong Provincial Hospital,Cheeloo College of Medicine,Shandong University.2.Study DesignBoth groups were given the subcutaneous injection of rhGH at a dose of 0.15-0.20U/（kg·d）every night before going to bed,and the oral dose of letrozole in the combined treatment group was 1.25-2.5mg/d,once a day.The children were followed up every 3 months in the pediatric endocrinology clinic and continued to be followed up after drug withdrawal to a final adult height.3.Data Collection Data at baseline and follow-up at 6,12 and 24 months after letrozole treatment were compared between the two groups.Measurement data were collected at each visit,including height,weight and the stage of secondary sexual characteristics.Moreover,the laboratory indicators were also collected,including serum IGF-1 level,fasting blood glucose（FBG）,glycosylated hemoglobin,uric acid,liver function indicators（ALT,AST）,renal function indicators（BUN,SCR）and thyroid function（FT3,FT4,TSH）.The bone age was evaluated every six months.FAH was an important index.4.Statistical analysis SPSS26.0 software was used for statistical analysis,and the Shapiro-Wilk test was used to determine whether the measurement data were in accordance with the normal distribution.The measurement data in accordance with the normal distribution were represented by mean±standard deviation.Paired t-test was used for comparison indicators before and after treatment.Comparison between two treatment groups was performed by independent sample t-test.Enumeration data are described by the number of cases and percentage（%）.p <0.05 indicated that the difference was statistically significant.Results1.General clinical characteristics of subjects Results of 106 boys were retrospectively analyzed,including 59 in the rhGH+letrozole group and 47 children in the rhGH group.All of the children reached final adult height.The total follow-up time was 2-10 years.The mean duration of rhGH treatment in the two groups was 39.41±2.04 and 32.22±1.84 months respectively,and there was statistical difference between the two groups（p=0.047）.Patients in therhGH+LTZ group were treated with letrozole for 24±6.25 months.There was no statistical difference in baseline data between the two groups.2.Comparison of curative effects after treatment2.1 Growth rate and final adult high changes before and after treatment Compared with the baseline data,the HV of the two groups were statistically different at 12 and 24 months after combined treatment with letrozole（p<0.05）.The increasing trend of HV in the two groups was similar 12 months after treatment（p=0.658）.The HV in the rhGH+letrozole group was higher than that in the rhGH group at 24 months（p=0.000）.FAH was 173±2.79 cm in the rhGH+LTZ group while 171±4.36 cm in the rhGH group（p=0.036）.2.2 Changes in IGF-1 SDS levels before and after treatment Compared with the baseline data,IGF-1 SDS of the two groups showed statistically significant differences at 12 and 24 months after treatment（p <0.05）.The growth trend of IGF-1SDS in the two groups was similar at each follow-up time point,but there was no statistical difference（p<0.05）.2.3 Changes in bone age before and after treatment The bone age increment（ΔBA/ΔCA）in the rhGH+letrozole group decreased gradually at the first and second years of treatment and the bone age increment was lower than that in the rhGH group.The difference was statistically significant（p<0.05）.3.Comparison of adverse reactions during treatment3.1 Changes in sex hormone levels during treatment The testosterone levels in the rhGH+letrozole group at 6,12 and 24 months after treatment were statistically different from those before treatment（p<0.05）.There was no significant difference in the testosterone level at 24 months compared with that at 6and 12 months（p> 0.05）,suggesting that testosterone level was not continuously increased after combined treatment.The FSH and LH levels in the rhGH+letrozole group at 6,12 and 24 months after treatment were statistically different from those before treatment（p <0.05）.There wasno significant difference in FSH and LH levels at 24 months compared with those at 6months and 12 months（p> 0.05）,suggesting that the levels of FSH and LH were not continuously increased after combined treatment.The E2 levels in the rhGH+letrozole group at 6 months after treatment were statistically different from those before treatment（p<0.05）.There was no significant difference in E2 levels after 12 and 24 months in the rhGH+letrozole group compared with those after 6 months（p> 0.05）,indicating that E2 level did not decrease continuously significantly after combined treatment.3.2 Changes of liver and kidney function indexes during treatment There was no significant difference in uric acid level after 6 months of letrozole treatment compared with that before treatment（p=0.890）.After 12 months and 24 months of letrozole treatment,uric acid levels were all statistically higher than those before treatment（p> 0.05）.During follow-up,AST,ALT,BUN and SCR in the rhGH+LTZ group were all in the normal range.3.3 Changes in glucose metabolism indexes during treatment No diabetes mellitus occurred during the follow-up period.There was no statistical difference in fasting blood glucose and HbAlc between the two groups at each followup time point（p> 0.05）.Compared with the baseline data,there were either no significant differences in fasting blood glucose at each follow-up time point after treatment（p> 0.05）.No significant difference was found in HbAlc at 6 and 12 months after treatment（p> 0.05）,while there was a significant difference at 24 months after treatment（p=0.023）.3.4 Changes in calcium phosphorus metabolism indexes during treatment There was no statistical difference in serum calcium and phosphorus between the two groups at each follow-up time point（p> 0.05）.Compared with the baseline data,there were either no significant differences in serum calcium and phosphorus at each followup time point after treatment（p> 0.05）.3.5 Others During the follow-up treatment,6 children with hypothyroidism were diagnosed.During the treatment,calcium and calcitriol capsules were routinely taken orally,and no fracture was found.In the rhGH+letrozole group,2 children complained of intermittent knee pain,which was relieved after reducing the amount of exercise.Conclusions:1.Both rhGH combined with letrozole and rhGH alone treatment could increase the gain of final adult height.2.Letrozole combined with rhGH therapy could delay the progression of bone age and prolong the treatment period of rhGH.3.AI has a highly efficient and selective inhibiting effect on estrogen,and no serious adverse reactions have been observed at present.However,its safety is still controversial,especially the long-term effects on the reproductive system and bone metabolism.Long-term clinical follow-up observation with large samples is still needed.Whether to add aromatase inhibitor combination therapy to short boys in late adolescence still needs to fully weigh the advantages and disadvantages. |
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