The Histrelin Implant: A Novel Treatment for Central Precocious Puberty Harry J. Hirsch, MD*‡; David Gillis, MD§; David Strich, MD࿣; Boris Chertin, MD¶; Amicur Farkas, MD¶; Tzina Lindenberg, MA‡; Hadassa Gelber, BSc‡; and Irving M. Spitz, MD, DSc, FRCP‡ ؎ ABSTRACT. Objective. Standard treatment of central were 1.30 ؎ 1.34 vs 0.25 ؎ 0.08 and 1.68 ؎ 1.08 vs 1.13 precocious puberty (CPP) consists of intramuscular or 0.55 mIU/mL, respectively. Basal and stimulated gonad- subcutaneous administration of a gonadotropin-releas- otropin levels and E2 level remained suppressed in all 6 ing hormone (GnRH) agonist (GnRHa) at 3- to 4-week patients followed for 15 months after implant insertion. intervals. Although generally effective in suppressing Patients and parents reported less pain and discomfort clinical and laboratory parameters of puberty, GnRHa and less interference with school activity and work with injections are painful, and the need for monthly clinic the implant compared with standard monthly injections. visits may contribute to poor compliance. Recently, a Conclusions. The histrelin implant consistently sup- subcutaneous implant was developed that releases the presses clinical and laboratory parameters of puberty for GnRHa histrelin at an average rate of 65 ␮g/day. The 1 year and is a promising new technique for treating CPP aims of this study were to determine if a histrelin im- without the pain and inconvenience of monthly plant would suppress gonadotropin and estradiol (E2)in injections. Pediatrics 2005;116:e798–e802. URL: www. girls with CPP for 1 year and to compare the suppression pediatrics.org/cgi/doi/10.1542/peds.2005-0538; precocious to standard treatment. puberty, gonadotropins, estradiol, GnRH agonists, histre- Methods. We studied 11 girls with CPP to determine lin. if the histrelin implant can maintain long-term gonado- tropin suppression. Mean age at diagnosis was 61⁄2 years (range: 2–9 years). GnRH (100 ␮g intravenously) stimu- ABBREVIATIONS. CPP, central precocious puberty; LH, luteiniz- lation tests (GnRH-STs) showed peak luteinizing hor- ing hormone; FSH, follicle-stimulating hormone; E2, estradiol; mone and follicle-stimulating hormone responses of 23 GnRH, gonadotropin-releasing hormone; GnRHa, gonadotropin- mean ؎ SD) and 20 ؎ 25 mIU/mL, respectively. All releasing hormone agonist(s); GnRH-ST, gonadotropin-releasing) 28 ؎ hormone stimulation test; CBC, complete blood count; IM, intra- subjects were initially treated with depot intramuscular muscular(ly); SDS, standard deviation score. GnRHa triptorelin embonate. Implants were inserted subcutaneously under local anesthesia, and depot GnRHa treatment was discontinued. Six girls were fol- recocious puberty is defined as the onset of lowed for 15 months after insertion (group A). For the secondary sexual characteristics associated remaining 5 girls, the implant was removed after 9 with increased linear growth velocity and ac- months, and a new implant was inserted at the same P celerated bone maturation occurring before the age incision site (group B). GnRH-STs were performed be- 1,2 fore depot GnRHa treatment, immediately before im- of 7 to 8 years in girls and 9 years in boys. If plant insertion, at the 6- and 9-month visits for each untreated, precocious puberty results in early epiph- patient and the 12- and 15-month visit for those girls yseal closure and short final height.3 The most com- followed for 15 months. mon cause in girls is idiopathic central precocious Results. In all girls, breast development regressed, puberty (CPP) caused by the early onset of luteiniz- growth velocity decreased, and bone-age advancement ing hormone (LH), follicle-stimulating hormone was slowed. Basal gonadotropins and their responses to 4 (FSH), and estradiol (E2) secretion. GnRH-STs and E2 levels were suppressed. Peak lutein- Standard treatment of CPP consists of depot par- izing hormone and follicle-stimulating hormone re- enteral preparations of gonadotropin-releasing hor- sponses to GnRH-STs at preinsertion versus 9 months mone agonists (GnRHa), usually at 4-week inter- vals.5 GnRHa are generally effective in retarding From the *Pediatric Day Hospital, ¶Department of Urology, and ‡Institute progression of secondary sexual characteristics, pre- of Hormone Research, Shaare Zedek Medical Center and the Faculty of venting menses, slowing bone-age advancement, Health Sciences, Ben Gurion University of the Negev, Jerusalem, Israel; and improving final height. Injections are painful, §Department of Pediatrics and Pediatric Endocrinology Clinic, Hadassah however, and the need for monthly clinic visits may University Hospital, Ein-Kerem, Jerusalem, Israel; and ࿣Specialty Pediatric Clinics, Endocrinology and Diabetes, Clalit Health Service, Jerusalem, Is- contribute to poor compliance. 6 rael. Chertin et al observed that insertion of a subcu- Accepted for publication Jun 13, 2005. taneous hydrogel implant containing the potent doi:10.1542/peds.2005-0538 GnRHa histrelin suppresses LH and testosterone in Presented in part at the 86th annual meeting of the Endocrine Society; June 16–19, 2004; New Orleans. metastatic prostate cancer for at least 1 year. The Conflict of interest: Dr Spitz is a consultant for Valera Pharmaceuticals Inc, same investigators then proposed to the manufac- manufacturer of the histrelin implant. turer that they assess a revised implant (that releases Reprint requests to (I.M.S.) Institute of Hormone Research, Shaare Zedek more drug on a daily basis) for children with CPP. If Medical Center, POB 3235, Jerusalem 91031, Israel. E-mail: irving@spitz. com effective, this implant could be more convenient and PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad- less painful than monthly injections. The aims of the emy of Pediatrics. present study were to determine if a histrelin im- e798 PEDIATRICS Vol.Downloaded 116 No. 6 from December www.aappublications.org/news 2005 www.pediatrics.org/cgi/doi/10.1542/peds.2005-0538 by guest on September 27, 2021 plant would suppress gonadotropin and E2 in girls or painful?”; and “To what extent is your child’s current treatment with CPP for 12 months and to compare the suppres- regimen inconvenient or disruptive to school, work, or other activities?” sion to standard treatment. This investigator-initiated study was approved by the human investigation committee of each participating institution. Written METHODS informed consent was obtained from the parents before enroll- Subjects ment. The study was designed and the data were analyzed by the academic investigators. Eleven girls with CPP referred to pediatric endocrinologists (H.J.H., D.G., or D.S.) were studied. Inclusion criteria were age of Ͻ Auxological Data 11 years at initial enrollment, advanced bone age, serum E2 level of Ͼ20 pg/mL (73 pmol/L), and pubertal gonadotropin responses Height was measured with a wall-mounted stadiometer. to a standard GnRH stimulation test (GnRH-ST).7–9 Patients with Growth velocity, calculated by comparing height measurements at gonadotropin-independent precocious puberty, children in whom 6-month intervals, was converted to a standard deviation score treatment would be needed for Ͻ1 year, those with other illnesses (GV Ϫ SDS) by using Tanner’s reference data.12 Bone age was that would interfere with follow-up, and those with a history of determined from radiographs of the left hand and wrist by using noncompliance were excluded. the method of Greulich and Pyle.13 BMI (weight [kg]/height 2 Mean age was 61⁄2 years (range: 2–9 years) at initial diagnosis [meters ]) percentiles were determined by using the Centers for 14 and 81⁄2 years (range: 3.75–11 years) at implant insertion. BMI Disease Control and Prevention 2000 growth charts. exceeded the 50th percentile in 9 girls and exceeded the 95th percentile in 4 girls. Pelvic ultrasound showed no ovarian pathol- Hormonal Assays ogy. Routine laboratory tests (urinalysis, complete blood count LH and FSH were measured by a chemiluminescent micropar- [CBC], biochemical screening, thyroid function) were normal. ticle 2-step immunoassay (Abbott Laboratories, Abbott Park, IL). The lower limits of sensitivity of the LH and FSH assays were 0.07 Prior GnRHa Treatment and 0.05 mIU/mL, respectively. In the low range of gonadotropin Treatment with the GnRHa triptorelin embonate (Decapeptyl; levels, intraassay and interassay variations were 2.1% and 3.4% for Ferring, Kiel, Germany) 3.75 mg given intramuscularly (IM) at 3- LH and 2.8% and 3.6% for FSH. E2 was measured by using a to 4-week intervals was begun in all children before study enroll- radioimmunoassay-coated kit (CIS Bio International-Schering, Gif ment. Ten girls were treated from 1 to 26 months and 1 for 39 sur Yvette, France). The reported lower limit of sensitivity was 1.4 Ͻ months. pg/mL. Serum E2 levels in prepubertal girls are typically 20 11,15 pg/mL (73 pmol/L). At this range of E2 levels, the intraassay Histrelin Implant and interassay variations were 13.3% and 17.6%, respectively. The subdermal implant (length: 30 mm; diameter: 3.5 mm; wall thickness: 0.5 mm) consists of a microporous hydrogel containing Statistics 50 mg of histrelin.10 Histrelin diffuses through the implant wall at The statistical analysis was performed by using the nonpara- an average rate of 65 ␮g/day. This version of the implant releases metric Wilcoxon paired sign-rank test. more histrelin than the one used for prostate cancer.10 Before insertion of the implant, a topical preparation of lido- RESULTS caine and prilocaine (EMLA; AstraZeneca, Wilmington, DE) was applied to the medial aspect of the upper arm, after which the skin No menstrual bleeding occurred during the im- was infiltrated with ϳ5 mL of 2% lidocaine. Pediatric surgeons plant treatment. Mean breast development was Tan- (B.C. and A.F.) performed the implant insertions. In 2 patients, ner stage 3.3 (range: 2–4) at implant insertion and 2.7 mild sedation was achieved by oral midazolam hydrochloride (range: 1–3) at 9 months.