Long term outcome of gonadotrophin releasing hormone analogue therapy in Sri Lankan children with central precocious puberty

Introduction: Central precocious puberty (CPP) needs treatment to minimise the psychosocial impact and optimize the auxological outcome. Objective: To analyse the growth pattern and outcome of gonadotrophin releasing hormone analogue (GnRHa) therapy in a cohort of children with CPP Method: Heights were serially recorded, skeletal age monitored and height velocities calculated in children with CPP prospectively followed up from presentation to cessation of therapy with GnRHa. The response to treatment was assessed as the height standard deviation scores (SDS), ratio of chronological age to bone age and reduction of height velocity with treatment and the significance was determined using the paired ‘t’ test and ANOVA. Their heights when last seen were compared with their predicted mature heights and target heights which were calculated based on the bone age prior to treatment and the parents’ heights respectively. Results: There were 9 patients (8 girls) with a mean age of 56.4 (19.1) and 124.2 (15.2) months at onset and completion of treatment respectively. There was a significant reduction in the height SDS, bone age acceleration and height velocity with treatment. The heights at final assessment were acceptable for the national average in the majority. Conclusion: There was a significant reduction in the height SDS, bone age acceleration and height velocity in the cohort of children with CPP treated with a GnRHa. ___________________________________________ Professor in Paediatrics, Faculty of Medicine, University of Colombo and Consultant Paediatrician, Lady Ridgeway Hospital, Colombo, Intern Medical Officer, Lady Ridgeway Hospital, Colombo, Professor in Community Medicine, Faculty of Medicine, University of Colombo *Correspondence: shamyadesilva@hotmail.com (Received on 6 June 2014: Accepted after revision on 18 July 2014) (


Introduction
Gonadotrophin releasing hormone dependent precocious puberty or central precocious puberty (CPP) is suspected when secondary sexual characteristics appear before 8 years and 9 years respectively in a girl or boy 1,2,3 .Menarche in a very young girl is a cause of immense psychological distress to the parents and family and is socially unacceptable.A young boy manifesting symptoms and signs of puberty is equally distressing to the parents and their behaviour may be disruptive at school.Untreated CPP will also result in a progressive advancement in skeletal maturation with premature epiphyseal closure, ultimately compromising the final adult height.Therefore, treatment is indicated with a gonadotrophin releasing hormone analogue (GnRHa) to block the pituitarygonadal axis and arrest the progression of puberty.This will result in slowing skeletal maturation thus reducing the growth velocity thereby preserving the growth potential 1,2,3 .This is an analysis of the growth pattern and outcome of long-acting GnRHa therapy in a cohort of children with CPP and the first such report from Sri Lanka.

Objective
To analyse the growth pattern and outcome of GnRHa therapy in a cohort of children with CPP

Method
Data, recorded prospectively, of a cohort of children with CPP presenting to a single ward at the Lady Ridgeway Hospital, Colombo over approximately 12 years, was analysed at the cessation of therapy.CPP was confirmed by biochemical, radiological and ultrasound investigations.The decision to treat was based on published criteria 1 and after discussing same with the parents.All the children had neuro-imaging prior to commencing therapy.Treatment was with a gonadotrophin releasing hormone analogue, Goserellin acetate 3.6mg, given 4 weekly subcutaneously.They were followed up at regular intervals in the ward and the relevant anthropometric data and clinical features were recorded prospectively by the chief investigator.Serial measurements of the standing height were taken using a wall-mounted stadiometer as per published instructions 4 .The skeletal maturation was monitored periodically using the Greulich-Pyle Atlas 5 .
The patients' height standard deviation scores (SDS) prior to treatment and at the time of discontinuing therapy were calculated using the Learning Management Systems (LMS) growth programme version 2.69 (2010) using World Health Organisation (WHO) Child and 5-19 growth reference standards (2006/2007).The initial skeletal maturation and subsequent response to treatment were documented as chronological age/bone age [CA/BA] 6 .The paired 't' test was used to determine the significance of the above findings.The pre-treatment height velocity and velocity during the first and last year of treatment were calculated and were compared using the F test or the analysis of variance (ANOVA).
The pre-treatment predicted mature heights (PMH) were calculated 4 and were compared with the heights at the most recent assessment and with the expected target heights of the children based on their parents' heights.Calculation of the PMH is based on the BA prior to treatment which should be more than 7 years 4 .The BA is unreliable for predicting height gain after treatment has been started 1 .Predicted mature height could not be calculated in one child (Serial no: 4) as her bone age was less than 7 years when treatment was commenced 2,4 .We used the column 'advanced' when the bone age advancement was greater than 1 year 4 to assess the PMH.The target height (TH) or mid-parental height was calculated thus 7 : Girl → mother's height + father's height -13.0cm ⁄ 2 Boy → mother's height + father's height + 13.0cm ⁄2 Target height range was taken as the TH ± 8.5cm 7 .
Discontinuation of therapy was done taking into consideration the wishes of the parents and child, onset of puberty in the peers and age of menarche of the mother and sisters of the girls and at an appropriate age of the child for pubertal onset 1,8 .

Results
There were 9 patients (8 girls) who had completed therapy.The age at onset of treatment ranged from 19 months (1yr 7m) to 81 months (6yr 9m) with a mean (SD) of 56.4 (19.07) months.They were 88 to 142 months (7yr 4m to 11yr 10m) at the completion of therapy with the duration of treatment being 44 to 101 months (3yr 8m to 8yr 5m) with a mean of 68 months (5yr 8m) as shown in Table 1.Seven patients were within the target height range when last seen and 2 of them had exceeded the target height (Serial numbers 6 and 7).The 2 patients who had not reached the TH range (Serial numbers 1 and 5) had achieved the PMH -Table 6.

Discussion
Treatment is indicated for CPP as the physical and psychosocial consequences, if untreated, are devastating for the child and family.Treatment improves auxological outcome and causes regression of puberty and reversal of secondary sexual characteristics 3,10 , thus lessening the psychosocial impact of CPP.A satisfactory auxological outcome with treatment has been reported as a reduction in the height SDS and height velocity, and slowing of skeletal maturation thereby improving the final adult height 6,[10][11][12][13] .The commonest outcome of therapy appears to be an improvement in the final height compared to the PMH which is within the TH range but less than the TH 14,15 .. Considering the auxological outcome of our patients, we demonstrated a significant reduction in the height SDS (Table 2 → t=7.93, df=8, p<0.0001) at completion of treatment with the height velocity reducing significantly with time (F=9.489,p<0.0001).The skeletal maturation had also reduced significantly at the final assessment compared to pretreatment skeletal maturation (Table 3 → t= 5.232, df=8, p<0.0001).
Our patients when last seen were aged 10 years 10 months to 15 years 6 months.The timing after menarche at last review was between 1 month and 4 years 1 month (Table 5).Therefore we have only documented the height at last review and not the final adult height (which is defined as a height increment of <0.5cm/year or a bone age ≥16 years in girls and ≥18 years in boys 14 ).The heights when last seen were within the target height range in 7 patients while 2 children (Serial numbers 6 and 7) had reached the TH and 3 had exceeded the PMH (Serial numbers 1, 6 and 7) -Table 6.All the girls were ≤152cm when last seen.But as there is the potential to gain approximately 5.0 to 7.5 cm after onset of menarche 16 , there is still a possibility that their final height would improve.This would be appropriate for the average adult heights for Sri Lankan men and women of 163.6 (6.9) cm and 151.4 (6.4) cm respectively 17 .
The maximum final height has been achieved in patients stopping therapy at a BA of 12.0 to 12.5 years 1,13 .The BA in our patients ranged from 9 years 4 months (112m) to 13 year 6 months (162m) at final assessment with a mean of approximately 11 year 6 months (138.44m± 18.94).Our sample (being an analysis of children followed up in one ward) was too small to decide on the optimum time of stopping treatment based on the BA to gain the maximum height.
Although the height achieved at the end of treatment seems acceptable based on the PMH and TH range of our patients, the criteria regarding timing of stopping treatment probably needs to be examined afresh in our children.The mean (SD) height velocity during the last year of therapy was 3.92 (1.09) cm/year.Although the reduction of height velocity with treatment over the years was significant, the velocity during the last year of treatment was probably inadequate.Therefore, the velocity in relation to BA and CA should be evaluated more closely to give more potential for height gain after stopping therapy.
The mean time to onset of menarche after cessation of treatment in our patients was 17.6 months (approximately 1yr 6m) which is comparable to previous reports 3,18,19 .The time of stopping treatment 1,8,19 should thus be individualized and, apart from the psycho-social indications, based on the TH, PMH, skeletal maturation and the trend of change of height velocity over time and our experience of time to menarche after cessation of therapy.

Conclusion
There was a significant reduction in the height SDS, bone age acceleration and height velocity in the cohort of children with CPP treated with a GnRHa.

Table 1 : Description of patients of the study sample (n=9) Serial number and gender Age at onset of treatment (months) Age at completion of treatment (months)
reduction in the height SDS with therapy (p<0.0001).Bone age prior to stopping treatment ranged from 112 to 162 months (9yr 4m to 13yr 6m) with a mean of 138.44 months (approximately 11yr 6m).

Table 3
gives the outcome of skeletal maturation which confirms a significant reduction in BA acceleration.Table4is an analysis of the height velocities over time with treatment showing a significant progressive reduction with therapy.