Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2479
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 5 1697-1704
Copyright © 2007 by The Endocrine Society
Efficacy and Safety of Histrelin Subdermal Implant in Children with Central Precocious Puberty: A Multicenter Trial
Erica A. Eugster,
William Clarke,
Gad B. Kletter,
Peter A. Lee,
E. Kirk Neely,
Edward O. Reiter,
Paul Saenger,
Dorothy Shulman,
Lawrence Silverman,
Lisa Flood,
William Gray and
David Tierney
Riley Hospital for Children (E.A.E.), Indiana University School of Medicine, Indianapolis, Indiana 46202; University of Virginia (W.C.), Charlottesville, Virginia 22908; Seattle Childrens Hospital and Medical Center (G.B.K.), Seattle, Washington 98104; Pennsylvania State Children’s Hospital (P.A.L.), Hershey, Pennsylvania 17033; Stanford University Medical Center (E.K.N.), Stanford, California 94305; Baystate Children’s Hospital (E.O.R.), Springfield, Massachusetts 01199; Montefiore Medical Center (P.S.), Bronx, New York 10461; University of South Florida and All Children’s Hospital (D.S.), St. Petersburg, Florida 33701; Goryeb Children’s Hospital Atlantic Health System (L.S.), Morristown, New Jersey 07962; and Valera Pharmaceuticals (L.F., W.G., D.T.), Cranbury, New Jersey 08512
Address all correspondence and requests for reprints to: Erica A. Eugster, M.D., Pediatric Endocrinology, Riley Hospital for Children, Room 5960, 702 Barnhill Drive, Indianapolis, Indiana 46202. E-mail: eeugster{at}iupui.edu.
 |
Abstract
|
|---|
Context: GnRH analog (GnRHa) therapy for central precocious puberty (CPP) typically involves im injections. The histrelin implant is a new treatment that provides a continuous slow release of the GnRHa histrelin.
Objective: The objective of the study was to investigate the safety and efficacy of the subdermal histrelin implant for the treatment of CPP in treatment naive and previously treated children.
Design: This was a phase III, open-label, prospective study of 1-yr duration.
Setting: The study was conducted at nine U.S. medical centers.
Patients: Girls ages 2–8 yr (naive) or 2–10 yr (previously treated) and boys 2–9 yr (naive) or 2–11 yr (previously treated) with clinical evidence of CPP and a pretreatment pubertal response to leuprolide stimulation were eligible.
Intervention: A 50-mg histrelin implant was inserted sc in the inner upper arm.
Main Outcome Measures: Peak LH after GnRHa stimulation testing and estradiol (girls) and testosterone (boys) were the main outcome measures.
Results: Thirty-six subjects (20 naive) were enrolled. By 1 month, peak LH fell from 28.2 ± 19.97 (naive) to 0.8 ± 0.39 mIU/ml (P < 0.0001) and from 2.1 ± 2.15 (previously treated) to 0.5 ± 0.32 mIU/ml (P < 0.0056). Estradiol suppressed from 24.5 ± 22.27 (naive) to 5.9 ± 2.37 pg/ml (P = 0.0016) and remained suppressed in previously treated subjects, as did testosterone. Suppression was maintained throughout the study. No significant adverse events occurred.
Conclusions: The subdermal histrelin implant achieves and maintains excellent suppression of peak LH and sex steroid levels for 1 yr in children with CPP. The treatment is well tolerated. Long-term studies are needed to confirm these results.
|
Introduction
|
|---|
CENTRAL PRECOCIOUS PUBERTY (CPP) refers to premature activation of the hypothalamic-pituitary-gonadal axis (1). It occurs much more commonly in girls, in whom it is usually idiopathic (2). The goals of therapy are to restore a prepubertal state, thereby attenuating the deleterious effects of early sex steroid exposure on physical development, skeletal maturation, and ultimate adult height. Since their development in the 1980s (3), long-acting GnRH analogs (GnRHa) have been the standard of care for the treatment of CPP worldwide. Although several drugs and routes of administration are available (4), the most commonly prescribed GnRHa in the United States is depot leuprolide acetate, which is typically given via im injections at intervals of 1 month (5). Assuming good compliance, GnRHa therapy results in reliable suppression of puberty and favorable long-term outcomes in the areas of adult height, reproductive function, bone mineral density, and body composition (6, 7, 8, 9, 10, 11). Although a 3-monthly administration of depot leuprolide has also been used (12, 13, 14), a direct comparison of different dosing regimens has indicated potential problems with insufficient suppression using this schedule (15). Positive experience with a hydrogel implant containing the potent GnRHa histrelin in men with prostate cancer (16, 17, 18) led to the concept that this device might also be applicable to the treatment of CPP in children. Because there is continuous diffusion of histrelin from the microporous walls of the implant, this delivery system would potentially obviate the need for intermittent injections of a depot GnRHa. A pilot study in 11 girls, all of whom were already being treated with traditional GnRHa therapy, demonstrated promising maintenance of hypothalamic-pituitary-gonadal suppression for up to 1 yr after insertion of the histrelin implant (19). The objective of this study was to further investigate efficacy and safety of the subdermal histrelin implant for the treatment of CPP in naive as well as previously treated patients.
|
Subjects and Methods
|
|---|
Subjects
Girls and boys either treatment naive or previously treated for CPP were recruited by pediatric endocrinologists based at nine U.S. medical centers. Institutional review board approval was obtained at each site. Written informed consent was provided by the parents or legal guardians of each study participant before any procedures were performed. In children 7 yr or older, a signed assent form was also obtained. Eligible subjects were girls aged 2–8 yr (naive) or 2–10 yr (previously treated) and boys aged 2–9 yr (naive) or 2–11 yr (previously treated). All naive children had a pretreatment pubertal LH response to gonadorelin (>7 mIU/ml) or leuprolide (>10 mIU/ml) stimulation testing (20, 21, 22). Additional eligibility criteria included a pretreatment bone age advancement of 2 SD or greater along with breast Tanner staging of at least II in girls and a testicular volume of at least 4 cc in boys. All previously treated patients had been on standard GnRHa therapy for at least 6 months before study entry.
Study design
This was a 1-yr, prospective, open-label trial. At baseline, a 50-mg histrelin subdermal implant was inserted into the inner aspect of the upper arm. The implant is 3.5 cm in length and 3.0 mm in diameter and has a wall thickness of 0.5 mm. Histrelin diffuses from the implant at an average rate of 65 µg/d. At all sites, implantation was performed by a pediatric surgeon using a trocar specially designed for the procedure. The type of anesthesia used was left up to the discretion of those performing the implantation at each site and in some cases was mandated by the institutional review board. Local anesthesia with distraction was used at two sites, conscious sedation was used at four sites, and general anesthesia was used at three sites. In previously treated patients, the implant was placed at the time of the next scheduled im GnRHa dose, and no further injections were administered throughout the study.
Pediatric endocrine clinic visits occurred at baseline, 1 month after implantation, and at 3-month intervals thereafter. A history and physical examination, including determination of calculated annualized growth velocity, was performed at every visit. Laboratory assessments included a GnRHa stimulation test using leuprolide acetate 20 µg/kg iv, followed by blood draws for LH and FSH concentrations at 0, 30, and 60 min. Gonadotropins were measured by immunochemiluminometric assay (Esoterix, Calabasas Hills, CA) with a lower limit of detection of 0.02 mIU/ml. Interassay coefficients of variation at the ranges observed in the study were between 5.2 and 10.7% for LH and between 6.7 and 7.8% for FSH. Suppression was defined a priori as a peak stimulated LH less than 4 mIU/ml and peak FSH less than 2.5 mIU/ml.
Serum estradiol (E2) (girls) and testosterone (boys) concentrations were also obtained at every visit and were assayed using RIA (Esoterix). The threshold of sensitivity was 5 pg/ml for E2 and 3 ng/dl for testosterone. Interassay coefficients of variation at the ranges observed were 12% for E2 and 15% for testosterone. Maintenance of suppression was defined as a testosterone less than 30 ng/dl (0.8 nmol/l) for boys and E2 less than 20 pg/ml (73 pmol/liter) for girls. Bone age radiographs were performed at baseline and 12 months and were centrally read (Lifespan Health Research Center, Kettering, OH). Predicted adult height at baseline and at 12 months was determined for each subject using the Bayley and Pinneau tables in the Greulich and Pyle bone age atlas (23). Transabdominal pelvic ultrasounds for determination of uterine and ovarian volumes in the girls were performed at baseline and at the end of the 1 yr of study at each individual site. Serum histrelin concentrations were measured at every visit by liquid chromatography/tandem mass spectrometry (Bioclin Research Laboratories, Athlone, Ireland) with a limit of quantification of 0.05 ng/ml, and information regarding menses was collected. A small subset of patients (n = 5) underwent additional pharmacokinetic studies on d 1–4 after implantation. At completion of the 1 yr of study, subjects had the option of enrolling in an extension phase, at which time the original implant was removed and replaced with a new one.
Statistics
Continuous variables were summarized using descriptive statistics (sample size, mean, SD, median, minimum, and maximum). Discrete variables were summarized by frequency and percentages. When applicable, all statistical tests were conducted against a two-sided alternative hypothesis, using an overall significance level (alpha) of 0.05. All analyses and computations were performed using SAS version 9.1.3 (SAS Institute, Cary, NC) on the Microsoft Windows XP platform (Richmond, CA).
Subject characteristics
Thirty-six subjects (33 girls) aged 7.9 ± 1.7 yr were enrolled in the study. Of these, 20 were naive and 16 were previously treated. Average height z-score at baseline was 1.5 ± 1.4, whereas average body mass index (BMI) z-score was 1.5 ± 0.8. The majority of the girls in both groups were at Tanner stage III for breast development. The three boys, all of whom were previously treated, were aged 6.6, 9.8, and 11.6 yr. Two were at Tanner stage II for genitalia, and one was at Tanner stage III. Naive subjects had an average bone age of 9.9 ± 1.8 yr at study entry, whereas previously treated subjects had an average bone age of 11.7 ± 1.9 yr. Baseline patient characteristics are summarized in Table 1
.
|
Results
|
|---|
Hormonal assessments
Peak stimulated LH concentration in the naive group decreased from 28.2 ± 20 mIU/ml at baseline to 0.8 ± 0.4 mIU/ml (P < 0.0001) by 1 month after implantation. Peak stimulated LH in the previously treated group also decreased from 2.1 ± 2.1 to 0.5 ± 0.3 mIU/ml (P = 0.0056) by 1 month. Two girls in the previously treated group were not suppressed (defined as peak LH < 4 mIU/ml) at baseline but were suppressed by 1 month after implant insertion. As shown in Figs. 1 and 2, suppression was maintained in all subjects throughout the 12 months of study. Peak FSH concentration decreased from 14.5 ± 6.7 mIU/ml at study entry to 1.1 ± 0.5 mIU/ml (P < 0.0001) by 1 month in naive patients and from 2.8 ± 2.1 to 1.5 ± 0.9 mIU/ml (P = 0.0055) in the previously treated group. FSH rose slightly throughout the year to 2.5 ± 1.4 mIU/ml in naive and 2.7 ± 2.4 mIU/ml in nonnaive subjects (Fig. 3), similar to what has been observed during traditional GnRHa therapy (24). In the girls, E2 in the naive patients fell from 24.5 ± 22.3 pg/ml (90 ± 82 pmol/liter) at baseline to 5.8 ± 2.4 pg/ml (21 ± 8.8 pmol/liter) by 1 month (P < 0.0016) and remained suppressed. All previously treated girls had a suppressed E2 at baseline, which was maintained throughout the 1 yr of study (Fig. 4). Likewise, testosterone in the three boys (all previously treated) was suppressed at baseline (10.6 ± 1.2 ng/dl or 0.36 ± 0.04 nmol/liter) and remained so throughout the study (data not shown).
View larger version (6K):
[in this window]
[in a new window]
|
FIG. 3. Average FSH concentrations in naive and previously treated patients. The dotted line indicates suppression, which was defined as less than 2.5 mIU/ml.
|
|
View larger version (5K):
[in this window]
[in a new window]
|
FIG. 4. Average serum estradiol in naive and previously treated patients throughout the study. Suppression is indicated by the dotted line and was defined as less than 20 pg/ml. The threshold of sensitivity was 5 pg/ml (18.8 pmol/liter).
|
|
Radiographic studies
The rate of skeletal maturation during the study was assessed by change in bone age over change in chronological age, which averaged 0.7 ± 0.5 in all 36 subjects at month 12. As shown in Table 2 and Fig. 5, the mean bone age to chronological age ratio was significantly reduced after 12 months of treatment in both the naive (P = 0.0002) and the previously treated (P < 0.0001) groups. Uterine and ovarian volumes in the girls either decreased or remained fairly consistent throughout the study (data not shown).
View this table:
[in this window]
[in a new window]
|
TABLE 2. Ratio of bone age to chronological age in naive and previously treated patients at baseline and 12 months
|
|
View larger version (6K):
[in this window]
[in a new window]
|
FIG. 5. Change in the ratio of bone age (BA) to chronological age (CA) from baseline to 12 months in study participants. The mean is indicated in bold.
|
|
Growth and clinical parameters
Height z-score at 12 months had decreased by –0.2 ± 0.3 (P = 0.0060) in the previously treated group, whereas it did not change significantly in the naive patients. BMI z-scores did not change significantly throughout the study in either group of subjects. Growth velocity SD score at month 12 was 0.6 ± 2.3 (range – 3.2–6.9) in naive patients and –1.8 ± 2.5 (range – 7.2–3.2) in the previously treated patients, indicating average growth rates among all 36 subjects at less than the 50th percentile. There was no difference in predicted adult heights in either group at 12 months, compared with baseline. Clinical evidence of secondary sexual development as assessed by Tanner staging either regressed or remained stable on average in both groups of subjects. One girl who was naive to treatment had experienced menarche 2 months before receiving the implant. She reported one additional episode of menses 10 d after the implant was placed, which resolved within 1 d. Two of the previously treated patients reported mild spotting within 1–2 months of implant insertion, which was never documented by a physician and also resolved within 2–3 d.
Pharmacokinetics
Mean histrelin concentration was highest at month 1 and decreased through month 12, remaining above the limit of quantification at most time points. Continuous sc release was evident because histrelin plasma levels were sustained throughout the study period for all subjects. These results are illustrated in Fig. 6.
Safety
Of the 36 patients, 18 (50%) reported implant site reactions such as bruising or pain. The majority of these were mild and resolved without therapy within 1–2 wk. Several instances of difficulty with the implant removal process were noted, and seven cases in which the implant had been broken as a result were identified. There was one case in which ultrasound localization of the implant was required for removal. There were no cases of implant extrusion in any of the children, and no subject was discontinued from treatment due to an adverse event. There were no clinically significant findings in hematology, clinical laboratory, or urinalysis parameters. Of the 32 patients who were continued on GnRHa therapy at the conclusion of the 1 yr of study, 31 opted to have a second implant placed. LH values in the four subjects in whom it was decided to allow puberty to ensue ranged from 6.7 to 16 mIU/ml at month 13, and histrelin levels were undetectable at this time. Thus, as expected, the hypothalamic-pituitary-gonadal suppression obtained with the histrelin implant appeared to be completely reversible.
|
Discussion
|
|---|
Whereas alternate strategies such as the use of GnRH antagonists (25, 26) may someday find a place in the treatment of precocious puberty, first-line therapy currently consists of GnRHa administration. Although these compounds have a proven track record in terms of efficacy and safety for the treatment of CPP, the requirement for intermittent injections is inherently unpopular in a pediatric population. Thus, the histrelin implant represents a potentially appealing and novel mode of delivery that results in the continuous diffusion of the potent GnRHa histrelin. This study illustrates rapid and sustained hypothalamic-pituitary-gonadal axis suppression after implant insertion in both treatment naive and previously treated subjects for 1 yr. Despite a wide range of body sizes, this single dosage of the implant appeared to be equally effective in all study participants. Treatment with the histrelin implant also significantly attenuated the rate of skeletal maturation during the 1 yr of therapy, although there was no statistically significant change in predicted adult heights. The lack of gain in predicted adult heights is not unexpected, given the relatively short duration of the study.
The comparatively greater potency of histrelin as compared with other GnRHa such as leuprolide (4) is readily apparent from the statistically significant decrease in peak LH concentration from baseline to 1 month that was observed in the previously treated group, who were already clinically and biochemically suppressed at study entry. This raises theoretical concerns regarding the potential for a more delayed recovery of the reproductive axis than is typically seen after discontinuation of traditional GnRHa treatment (27, 28). However, rapid recovery of LH and testosterone have been observed in men after histrelin implant removal after prolonged suppression for up to 3 yr (29). Although more data are needed, anecdotal information from the small number of children in whom GnRHa treatment was discontinued after the 1 yr of study also appears to corroborate these results.
In conclusion, the histrelin implant appears to be efficacious, safe, and well tolerated in girls and boys with treatment naive and previously treated CPP when left in place for 1 yr. Risks primarily involve minor implant site reactions, although potential complications from the use of conscious sedation or general anesthesia should be taken into account if these methods are used. Although formal assessments were not performed, continuation rates and unsolicited feedback from parents and patients indicated nearly uniform enthusiasm about this form of treatment, compared with traditional injections. Larger-scale prospective studies examining multiple therapeutic and safety outcome parameters are needed to confirm these promising results.
|
Acknowledgments
|
|---|
We thank the institutional general clinical research centers and all of the study coordinators for their invaluable assistance.
|
Footnotes
|
|---|
This work was supported by Valera Pharmaceuticals.
Disclosure Statement: G.B.K., P.A.L., E.K.N., and D.S. have nothing to declare. E.A.E. consults for AstraZeneca and Genentech and received lecture fees from Eli Lilly and Serono. W.C. consults for Abbott Labs and received lecture fees from Aventis and Smith Medical. E.O.R. consults for Pfizer and AstraZeneca and received lecture fees from Genentech. P.S. consults for Pfizer and AstraZeneca and received lecture fees from Eli Lilly. L.S. consults for Valera Pharmaceuticals. L.F., W.G., and D.T. are employed by Valera Pharmaceuticals.
First Published Online February 27, 2007
Abbreviations: BMI, Body mass index; CPP, central precocious puberty; E2, estradiol; GnRHa, GnRH analog.
Received November 13, 2006.
Accepted February 20, 2007.
|
References
|
|---|
- Phillip M, Lazar L 2005 Precocious puberty: growth and genetics. Horm Res 64(Suppl 2):56–61
- Brauner R 2005 Central precocious puberty in girls: prediction of the aetiology. J Pediatr Endocrinol Metab 18:845–847[Medline]
- Crowley Jr WF, Comite F, Vale W, Rivier J, Loriaux DL, Cutler Jr GB 1981 Therapeutic use of pituitary desensitization with a long-acting LHRH agonist: a potential new treatment for idiopathic precocious puberty. J Clin Endocrinol Metab 52:370–372[Abstract]
- Hardin DS, Pescovitz OH 1991 Central precocious puberty and its treatment with long-acting GnRH analogs. Endocrinologist 1:163–169
- Breyer P, Haider A, Pescovitz OH 1993 Gonadotropin-releasing hormone agonists in the treatment of girls with central precocious puberty. Clin Obstet Gynecol 36:764–772[CrossRef][Medline]
- Tuvemo T 2006 Treatment of central precocious puberty. Expert Opin Investig Drugs 15:495–505[CrossRef][Medline]
- Bertelloni S, Baroncelli GI, Ferdeghini M, Menchini-Fabris F, Saggese G 2000 Final height, gonadal function and bone mineral density of adolescent males with central precocious puberty after therapy with gonadotropin-releasing hormone analogues. Eur J Pediatr 159:369–374[CrossRef][Medline]
- Klein KO, Barnes KM, Jones JV, Feuillan PP, Cutler Jr GB 2001 Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience. J Clin Endocrinol Metab 86:4711–4716[Abstract/Free Full Text]
- Clemons RD, Kappy MS, Stuart TE, Perelman AH, Hoekstra FT 1993 Long-term effectiveness of depot gonadotropin-releasing hormone analogue in the treatment of children with central precocious puberty. Am J Dis Child 147:653–657[Abstract]
- Kreiter M, Burstein S, Rosenfield RL, Moll Jr GW, Cara JF, Yousefzadeh DK, Cuttler L, Levitsky LL 1990 Preserving adult height potential in girls with idiopathic true precocious puberty. J Pediatr 117:364–370[CrossRef][Medline]
- Heger S, Partsch CJ, Sippell WG 1999 Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: final height, body proportions, body composition, bone mineral density, and reproductive function. J Clin Endocrinol Metab [Erratum (2000) 85:657] 84:4583–4590
- Carel JC, Lahlou N, Jaramillo O, Montauban V, Teinturier C, Colle M, Lucas C, Chaussain JL 2002 Treatment of central precocious puberty by subcutaneous injections of leuprorelin 3-month depot (11.25 mg). J Clin Endocrinol Metab 87:4111–4116[Abstract/Free Full Text]
- Carel JC, Blumberg J, Seymour C, Adamsbaum C, Lahlou N 2006 Three-month sustained-release triptorelin (11.25 mg) in the treatment of central precocious puberty. Eur J Endocrinol 154:119–124[Abstract/Free Full Text]
- Schroeter M, Baus I, Sippell WG, Partsch CJ 2002 long-term suppression of pituitary-gonadal function with three-month depot of leuprorelin acetate in a girl with central precocious puberty. Horm Res 58:292–296[CrossRef][Medline]
- Badaru A, Wilson DM, Bachrach LK, Fechner P, Gandrud LM, Durham E, Wintergerst K, Chi C, Klein KO, Neely EK 2006 Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty. J Clin Endocrinol Metab 91:1862–1867[Abstract/Free Full Text]
- Spitz IM, Chertin B, Lindenberg T, Farkas 1999 A long-acting gonadotropin-releasing hormone implant to maintain medical castration for two years in men with prostate cancer. N Engl J Med 340:1439
- Schlegel PN, Kuzma P, Frick J, Farkas A, Gomahr A, Spitz I, Chertin B, Mack D, Jungwirth A, King P, Nash H, Bardin CW, Moo-Young A 2001 Effective long-term androgen suppression in men with prostate cancer using a hydrogel implant with the GnRH agonist histrelin. Urology 58:578–582[CrossRef][Medline]
- Chertin B, Spitz IM, Lindenberg T, Algur N, Zer T, Kuzma P, Young AJ, Catane R, Farkas A 2000 An implant releasing the gonadotropin hormone-releasing hormone agonist histrelin maintains medical castration for up to 30 months in metastatic prostate cancer. J Urol 163:838–844[CrossRef][Medline]
- Hirsch HJ, Gillis D, Strich D, Chertin B, Farkas A, Lindenberg T, Gelber H, Spitz IM 2005 The histrelin implant: a novel treatment for central precocious puberty. Pediatrics 116:e798–e802
- Pescovitz OH, Comite F, Hench K, Barnes K, McNemar A, Foster C, Kenigsberg D, Loriaux DL, Cutler Jr GB 1986 The NIH experience with precocious puberty: diagnostic subgroups and response to short-term luteinizing hormone releasing hormone analogue therapy. J Pediatr 108:47–54[CrossRef][Medline]
- Ibanez L, Potau N, Zampolli M, Virdis R, Gussinye M, Carrascosa A, Saenger P, Vicens-Calvet E 1994 Use of leuprolide acetate response patterns in the early diagnosis of pubertal disorders: comparison with the gonadotropin-releasing hormone test. J Clin Endocrinol Metab 78:30–35[Abstract]
- Rosenfield RL, Perovic N, Ehrmann DA, Barnes RB 1996 Acute hormonal responses to the gonadotropin releasing hormone agonist leuprolide: dose-response studies and comparison to nafarelin—a clinical research center study. J Clin Endocrinol Metab 81:3408–3411[Abstract]
- Greulich WW, Pyle SI 1959 Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford, CA: Stanford University Press
- Lahlou N, Roger M, Chaussain JL, Feinstein MC, Sultan C, Toublanc JE, Schally AV, Scholler R 1987 Gonadotropin and
-subunit secretion during long term pituitary suppression by D-Trp6-luteinizing hormone-releasing hormone microcapsules as treatment of precocious puberty. J Clin Endocrinol Metab 65:946–953[Abstract] - Schultze-Mosgau A, Griesinger G, Altgassen C, von Otte S, Hornung D, Diedrich K 2005 New developments in the use of peptide gonadotropin-releasing hormone antagonists versus agonists. Expert Opin Investig Drugs 14:1085–1097[CrossRef][Medline]
- Roth C 2002 Therapeutic potential of GnRH antagonists in the treatment of precocious puberty. Expert Opin Investig Drugs 11:1253–1259[CrossRef][Medline]
- Jay N, Mansfield MJ, Blizzard RM, Crowley Jr WF, Schoenfeld D, Rhubin L, Boepple PA 1992 Ovulation and menstrual function of adolescent girls with central precocious puberty after therapy with gonadotropin-releasing hormone agonists. J Clin Endocrinol Metab 75:890–894[Abstract]
- Schroor EJ, van Weissenbruch MM, Delemarre-van de Waal HA 1995 Long-term GnRH-agonist treatment does not postpone central development of the GnRH pule generator in girls with idiopathic precocious puberty. J Clin Endocrinol Metab 80:1696–1701[Abstract/Free Full Text]
- Fridmans A, Chertin B, Koulikov D, Lindenberg T, Gelber H, Leiter C, Farkas A, Spitz IM 2005 Reversibility of androgen deprivation therapy in patients with prostate cancer. J Urol 173:784–789[CrossRef][Medline]
Top
Abstract
Introduction
