central precocious puberty ( cpp ) is   defined as   activation of the hypothalamic - pituitary - gonadal 
 ( hpg ) axis before the   age of 8 years in caucasian girls   and 7.5 years in 
 african   american girls , and before the age of 9 years in boys . gonadotropin releasing hormone analogs ( gnrha ) have been the cornerstone 
 of treatment of cpp for more than 20 years . a depot form of gnrha is traditionally used 
 in the us 
  and is administered as a monthly injection . 
 although known to be safe and effective [ 35 ] , 
 the need for intramuscular injections may be bothersome to patients and 
 adversely affect compliance . a one - year 
 subcutaneous histrelin implant has emerged as an alternative approach for the 
 treatment of cpp . histrelin is a gnrha 
 which is 150 times more potent than endogenous gnrh . the implant is a flexible , non - biodegradable 
 device that contains histrelin acetate and is inserted subcutaneously using a 
 trocar . the microporous walls allow 
 histrelin to diffuse at a rate of approximately 65 mcg / day . a pilot study of 11 girls with cpp showed 
 that the implant effectively suppressed the hpg axis . this was followed by a phase iii prospective 
 trial involving 36 children which demonstrated safety and efficacy of the 
 implant for one year . whether a    second   year of therapy with 
 a new implant would have similar results is unknown . thus , the objective of this study was to 
 determine safety and efficacy of a second year of therapy with a new implant 
 for the treatment of cpp . patients from nine 
 us 
  medical centers who completed the one - year phase iii trial were offered the 
 option to have a second implant placed . informed consent was obtained from parents or 
 legal guardians , and assent from all children greater than 7 years of age . inclusion criteria included patients in whom 
 the decision was made to continue with gnrha therapy . this was a one - year multicenter prospective open label trial . 
 at all sites , a pediatric surgeon removed the first implant and inserted 
 the second during the same procedure , using a standardized trocar device . the type of anesthesia used varied according 
 to site , and included local anesthesia , conscious sedation , 
  or general 
 anesthesia . height and weight were measured at every 
 visit and annualized growth velocity was determined . gnrha stimulation tests were performed at 1 , 
 6 , and 12 months after placement of the second implant . they were performed using a dose of 20 mcg / kg 
 of aqueous leuprolide acetate and measuring lh and fsh at baseline , 30 , and 60 
 minutes after gnrha . gonadotropin levels 
 were measured by immunochemiluminometric assay ( esoterix , calabasas hills , calif , usa ) . < 2.5 miu / ml were considered 
 suppressed ( prepubertal references values ; lh 0.023 , fsh 1.04.2 in girls , 
 0.263.0 in boys ) . estradiol and 
 testosterone were measured by radioimmunoassay ( esoterix ) at baseline only . levels below 20 pg / ml ( 73.42 pmol / l ) for estradiol 
 and 30 ng / dl ( 0.69 nmol / l ) for testosterone were considered suppressed 
 ( prepubertal reference ranges ; estradiol < 15 pg / ml , testosterone 310 ng / dl ) 
 . histrelin levels were measured at 1 , 6 , 
 and 12 months after placement of the second implant . bone age radiographs were obtained annually 
 and were centrally read ( lifespan health research center , kettering , ohio , usa ) .   predicted adult heights were determined using 
 the bayley - pinneau method , using the average rather 
 than accelerated tables . all statistical tests were conducted using the student s paired 
 t - test . all analysis and computations 
 were performed using sas version 9.1.3 ( sas institute , cary , 
 nc , usa ) on the microsoft windows xp 
 platform ( richmond , calif , usa ) . thirty one 
 patients ( 29 girls ) had a second implant placed .   of these , 18 had been nave to gnrha 
 treatment prior to placement of the first implant and 12 had been previously 
 treated . peak lh in 
 response to gnrha stimulation remained suppressed in all subjects throughout 
 the study period ( figure 1 ) . it 
 decreased from 0.92      0.58 miu / ml at 12 months to 0.51      0.33 miu / ml at 24 
 months ( p < .0001 ) in the nave group , and from 0.74      0.50 miu / ml   at 12 
 months to 0.45 0.35 miu / ml at 24 months ( p = .0081 ) in previously treated 
 subjects . peak fsh in response to gnrha 
 stimulation at 24 months was not different than at 12 months and remained 
 suppressed at 2.45      1.12 miu / ml ( nave ) and 2.40      1.11 miu / ml    ( previously 
 treated ) . testosterone levels in the two boys at 24 
 months were 6.8 ng / dl and 13 ng / dl , respectively . histrelin levels were detectable throughout 
 the second year of therapy and are shown in figure 2 . the average bone 
 age to chronological age ratio decreased significantly in all patients from 
 1.29 at the time of the second implant to 1.23 at 24 months ( p < .0001 ) 
 ( figure 3 ) . no difference in growth 
 velocity sds was seen at 24 months compared to 12 months in the nave 
 patients . in contrast , the growth 
 velocity sds decreased from   1.50      2.70 at 12 months to   2.52      2.68 at 24 months in the previously 
 treated patients ( p = .005 ) . one patient 
 in the nave group was started on growth hormone because of significant slowing 
 of growth .   as shown in figure 4 , average 
 predicted adult height increased in both groups of girls at 24 months relative 
 to baseline , resulting in a 5.1 cm increase in the group as a whole after two 
 years of treatment , ( p < .0001 ) . mean 
 predicted adult height for the two boys was 165.6 cm at baseline and 163.7 cm 
 at 24 months ( p = .84 ) . bmi percentiles 
 decreased in all patients from 89.9      12.5% at baseline to 88.0      19.6%   at 24 
 months ( p < .001 ) . testicular volume was   36 ml in one 
 boy and 610 ml in the other at 
 24 months , both of which were not different from 12 months . nineteen patients ( 61% ) reported minor 
 implant site reactions , ( e.g. , bruising or pain ) immediately after implant 
 replacement . at 12 months , 8 patients ( 22.2% ) had implant 
 breakage on removal and 2 ( 5.6% ) required ultrasound localization prior to 
 explantation .   at 24 months , 5 patients 
 ( 16.1% ) had implant breakage on removal and 3 cases ( 9.6% ) required ultrasound 
 localization . the treatment for cpp in the us   has 
 traditionally involved intramuscular monthly injections of leuprolide 
 acetate . while a three - month depot 
 leuprolide is available , it has not been adequately studied in children and 
 failed to demonstrate equivalent short - term hpg axis suppression when compared 
 to monthly injections . although experience is limited , the histrelin acetate implant appears to 
 be an exciting novel therapy for cpp that obviates the need for 
 injections . following placement of a new 
 implant at 12 months , hpg axis suppression was maintained in all patients 
 throughout a second year of therapy .   in 
 addition , the rate of skeletal maturation slowed significantly and predicted 
 adult heights improved after 24 months compared to baseline . in terms of 
 safety , the implant was well tolerated overall . implant site reactions were mild , and minor difficulties with implant removal 
 were reported either at 12 or 24 months in ~20% of patients .   these involved implant breakage and the need 
 for ultrasound to localize the implant . while the implants were not found to be broken in situ , some broke on 
 removal and this made the explant process more difficult and in some cases more 
 time consuming . implant breakage may be 
 related to surgical technique and with improved experience , complications may 
 be avoidable . although no adverse events 
 related to anesthesia have been reported in patients treated with the implant , 
 the inherent risks of conscious sedation and general anesthesia in particular 
 should be taken into consideration when these methods are used . the main 
 theoretical concern with the histrelin implant is the potential for adverse 
 effects on growth , body composition , and the reproductive system from the even 
 more profound hpg axis suppression than that seen with traditional 
 therapy . results from this study suggest 
 that a decline in stimulated lh might occur in each successive year of 
 treatment with this device . while this 
 may raise concern regarding growth while on the implant , a recent study 
 actually suggests that increased suppression of the hpg axis in children with 
 cpp may result in improved growth velocity .   in our study , the growth velocity sds did not 
 change significantly in year 2 in the nave group , but it did decline in the 
 previously treated patients . however , 
 this was likely related to the relatively advanced bone ages in this group of 
 children at the time that the second implant was placed .   despite this , an improvement in predicted 
 adult heights was seen in both groups of patients .   also reassuring was the small yet significant 
 decrease in bmi noted at 24 months compared with 12 months . finally , 4 of the 5 patients who did not have 
 a second implant placed at 12 months returned for stimulated lh measurements at 
 13 months . hpg axis recovery was noted 
 in all 4 subjects by that time .   in 
 addition , histrelin levels were undetectable by 13 months . information from patients on therapy for 
 longer than one year will be needed to determine whether timing of hpg axis 
 recovery will be different in children treated with the implant as compared 
 with traditional monthly injections . in conclusion , the histrelin implant 
 appears to be safe , well - tolerated , and effective when a new implant is placed 
 for a second year of therapy . long - term 
 prospective follow - up of treated patients will be essential in order to confirm 
 these results .
background . 
 gonadotropin releasing hormone analogs ( gnrhas ) are standard of care for central precocious puberty ( cpp ) . 
 the histrelin subcutaneous implant is safe and effective in the treatment of cpp for one year . 
 objective . 
 the study evaluates a second year of therapy in children with cpp who received a new implant after one year of treatment . 
 methods . 
 a prospective one - year study following an initial 12-month treatment period was conducted . 
 results . 
 thirty - one patients ( 29 girls ) aged 7.7      1.5 years received a second implant . 
 eighteen were nave to gnrha therapy at first implantation . 
 peak lh declined from 0.92  0.58 miu / ml at 12 months to 0.51  0.33 miu / ml at 24 months ( p < .0001 ) in nave subjects , and from 0.74  0.50 miu / ml at 12 months to 0.45  0.35 miu / ml at 24 months ( p = .0081 ) in previously treated subjects . 
 predicted adult height increased by 5.1 cm at 24 months ( p = .0001 ) . 
 minor implant site reactions occurred in 61% , while minor difficulties with explantation occurred in 32.2% of subjects . 
 conclusion . 
 the histrelin implant demonstrates profound hypothalamic - pituitary - gonadal axis suppression when a new implant is placed for a second year of treatment . 
 prospective follow - up of this therapeutic modality for the treatment of cpp is needed .