Results of a Second Year of Therapy with the 12-Month Histrelin Implant for the Treatment of Central Precocious Puberty
© Samar Rahhal et al. 2009
Received: 10 November 2008
Accepted: 11 February 2009
Published: 17 February 2009
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 years received a second implant. Eighteen were naïve to GnRHa therapy at first implantation. Peak LH declined from mIU/mL at 12 months to mIU/mL at 24 months ( < .0001) in naïve subjects, and from mIU/mL at 12 months to mIU/mL at 24 months ( ) in previously treated subjects. Predicted adult height increased by 5.1 cm at 24 months ( ). 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.
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 . Treatment is often initiated with the goal of preserving final adult height. 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 [3–5], 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. Institutional review board approval was obtained at each site. 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.
2.2. Study Design
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. All implants contained 50 mg of histrelin. Clinic visits occurred every 6 months. 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). Stimulated levels of LH < 4 mIU/mL and FSH < 2.5 mIU/mL were considered suppressed (prepubertal references values; LH 0.02–3, FSH 1.0–4.2 in girls, 0.26–3.0 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 3–10 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.
Summary statistics were performed to derive baseline characteristics. Data are expressed as mean ± standard deviation. All statistical tests were conducted using the student's paired -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).
3.1. Subject Characteristics
Patient characteristics at month 12 when the second implant was placed.
3.2. Hormonal Assessments
3.3. Radiographic Studies and Growth Parameters
Nineteen patients (61%) reported minor implant site reactions, (e.g., bruising or pain) immediately after implant replacement. These were self-resolving and of brief duration. One patient developed a keloid. There were no cases of spontaneous implant extrusion or infection. There were some issues related to implant removal. 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 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.
- Lee PA: Normal ages of pubertal events among American males and females. Journal of Adolescent Health Care. 1980, 1 (1): 26-29. 10.1016/S0197-0070(80)80005-2.View ArticlePubMedGoogle Scholar
- Boepple PA, Mansfield MJ, Wierman ME: Use of a potent, long acting agonist of gonadotropin-releasing hormone in the treatment of precocious puberty. Endocrine Reviews. 1986, 7 (1): 24-33. 10.1210/edrv-7-1-24.View ArticlePubMedGoogle Scholar
- Pasquino AM, Pucarelli I, Accardo F, Demiraj V, Segni M, Di Nardo R: Long-term observation of 87 girls with idiopathic central precocious puberty treated with gonadotropin-releasing hormone analogs: impact on adult height, body mass index, bone mineral content, and reproductive function. The Journal of Clinical Endocrinology & Metabolism. 2008, 93 (1): 190-195. 10.1210/jc.2007-1216.View ArticleGoogle Scholar
- Neely EK, Hintz RL, Parker B: Two-year results of treatment with depot leuprolide acetate for central precocious puberty. The Journal of Pediatrics. 1992, 121 (4): 634-640. 10.1016/S0022-3476(05)81162-X.View ArticlePubMedGoogle Scholar
- Parker KL, Baens-Bailon RG, Lee PA: Depot leuprolide acetate dosage for sexual precocity. The Journal of Clinical Endocrinology & Metabolism. 1991, 73 (1): 50-52. 10.1210/jcem-73-1-50.View ArticleGoogle Scholar
- Hirsch HJ, Gillis D, Strich D: The histrelin implant: a novel treatment for central precocious puberty. Pediatrics. 2005, 116 (6): e798-e802. 10.1542/peds.2005-0538.View ArticlePubMedGoogle Scholar
- Eugster EA, Clarke W, Kletter GB: Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. The Journal of Clinical Endocrinology & Metabolism. 2007, 92 (5): 1697-1704. 10.1210/jc.2006-2479.View ArticleGoogle Scholar
- Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of the Hand and Wrist. 1959, Stanford University Press, Stanford, Calif, USA, 2Google Scholar
- Badaru A, Wilson DM, Bachrach LK: Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty. The Journal of Clinical Endocrinology & Metabolism. 2006, 91 (5): 1862-1867. 10.1210/jc.2005-1500.View ArticleGoogle Scholar
- Kunz GJ, Sherman TI, Klein KO: Luteinizing hormone (LH) and estradiol suppression and growth in girls with central precocious puberty: is more suppression better? Are pre-injection LH Levels useful in monitoring treatment?. The Journal of Pediatric Endocrinology & Metabolism. 2007, 20 (11): 1189-1198. 10.1515/JPEM.2007.20.11.1189.View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.