The Histrelin Implant: A Novel Treatment for Central Precocious Puberty

Abstract

ABSTRACT. Objective. Standard treatment of central precocious puberty (CPP) consists of intramuscular or subcutaneous administration of a gonadotropin-releasing hormone (GnRH) agonist (GnRHa) at 3-to 4-week intervals. Although generally effective in suppressing clinical and laboratory parameters of puberty, GnRHa injections are painful, and the need for monthly clinic visits may contribute to poor compliance. Recently, a subcutaneous implant was developed that releases the GnRHa histrelin at an average rate of 65 g/day. The aims of this study were to determine if a histrelin implant would suppress gonadotropin and estradiol (E 2 ) in girls with CPP for 1 year and to compare the suppression to standard treatment.Methods. We studied 11 girls with CPP to determine if the histrelin implant can maintain long-term gonadotropin suppression. Mean age at diagnosis was 6 1 ⁄2 years (range: 2-9 years). GnRH (100 g intravenously) stimulation tests (GnRH-STs) showed peak luteinizing hormone and follicle-stimulating hormone responses of 23 ؎ 28 (mean ؎ SD) and 20 ؎ 25 mIU/mL, respectively. All subjects were initially treated with depot intramuscular GnRHa triptorelin embonate. Implants were inserted subcutaneously under local anesthesia, and depot GnRHa treatment was discontinued. Six girls were followed for 15 months after insertion (group A). For the remaining 5 girls, the implant was removed after 9 months, and a new implant was inserted at the same incision site (group B). GnRH-STs were performed before depot GnRHa treatment, immediately before implant insertion, at the 6-and 9-month visits for each patient and the 12-and 15-month visit for those girls followed for 15 months.Results. In all girls, breast development regressed, growth velocity decreased, and bone-age advancement was slowed. Basal gonadotropins and their responses to GnRH-STs and E 2 levels were suppressed. Peak luteinizing hormone and follicle-stimulating hormone responses to GnRH-STs at preinsertion versus 9 months were 1.30 ؎ 1.34 vs 0.25 ؎ 0.08 and 1.68 ؎ 1.08 vs 1.13 ؎ 0.55 mIU/mL, respectively. Basal and stimulated gonadotropin levels and E 2 level remained suppressed in all 6 patients followed for 15 months after implant insertion. Patients and parents reported less pain and discomfort and less interference with school activity and work with the implant compared with standard monthly injections.Conclusions. ABBREVIATIONS. CPP, central precocious puberty; LH, luteinizing hormone; FSH, follicle-stimulating hormone; E 2 , estradiol; GnRH, gonadotropin-releasing hormone; GnRHa, gonadotropinreleasing hormone agonist(s); GnRH-ST, gonadotropin-releasing hormone stimulation test; CBC, complete blood count; IM, intramuscular(ly); SDS, standard deviation score. P recocious puberty is defined as the onset of secondary sexual characteristics associated with increased linear growth velocity and accelerated bone maturation occurring before the age of 7 to 8 years in girls and 9 years in boys. 1,2 If untreated, precocious puberty results in early epiphyseal closure...

The measurement of urinary gonadotropins for assessment and management of pubertal disorder

“…Although measurement of uGn was described over four decades ago, 17,18 its use in routine clinical management had not been considered until the relatively recent availability of more sensitive assays. 3,4,14 In this study of cases that were undergoing routine evaluation of puberty, the addition of uGn assessment has provided promising information regarding the clinical utility of this test for assessment and management of pubertal disorders. In a previous study aimed at creating reference ranges for healthy children, 5 the lack of matched serum samples was considered to be a weakness and in the current study, the close correlation between uGn excretion and serum gonadotrophins in a range of conditions related to pubertal disorders confirms the reliability of uGn for reflecting serum levels.…”

“…2 Recently, a subcutaneous implant releasing the GnRHa histrelin at an average rate of 65 microg/day was developed, with encouraging results. 3,4 Monitoring of adequate suppression is usually based on an assessment of physical growth and puberty and the frequency of injections is often increased when these clinical parameters suggest inadequate suppression. Although there may be scope for further personalization of therapy, this has been difficult to achieve in the absence of objective and reliable tools that are simple, inexpensive and lend themselves to repeat measurements.…”

Gynecologic Issues in the Pediatric and Adolescent Patient with Cancer

“…First-line treatment with longer-acting injectable GnRHa or subcutaneous implant should be considered due to adequate pubertal suppression with the additional benefit of fewer painful injections and facility visits which may aid with increased compliance and patient comfort [11, 19, 21, 22, 23•]. The 11.25-mg depot leuprolide 3-month injection is used most frequently for this indication in the USA [11,19,21]. In addition, a recent study on the depot triptorelin embonate 22.5-mg 6-month injection has been reported and shows promise for a longer-acting extended injection regimen [23•].…”

Experience with the Histrelin Implant in Pediatric Patients

“…The first report of the use of the histrelin implant in children involved a pilot study of 11 girls with CPP, all of whom had previously been treated with a depot GnRHa preparation [8]. Serial GnRH stimulation tests demonstrated lower gonadotropin levels after insertion of the implant than on the depot GnRHa with continued HPG axis suppression throughout the treatment course.…”