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 naïve 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.