0021-972X/91/7201-0060$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
Vol. 72, No. 1 Printed in U.S.A.
Effect of Deslorelin Dose in the Treatment of Central Precocious Puberty ORA HIRSCH PESCOVITZ, KEVIN M. BARNES, AND GORDON B. CUTLER, JR. Departments of Pediatrics, Physiology/Biophysics, Indiana University Medical Center (O.H.P.), Indianapolis, Indiana 46202; and the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
ABSTRACT. Central precocious puberty is effectively treated with long-acting LHRH analogs (LHRHas). Although at least six LHRHas have now been used in children, there have been no studies to determine the least effective dose of any of these analogs. We sought to determine the effect of decreasing an efficacious dose of deslorelin (D-Trp6-Pro9-NEt-LHRH) on basal and LHRH-stimulated gonadotropins, estradiol levels, and the rates of linear growth and skeletal maturation in subjects with central precocious puberty. Twenty-nine children with central precocious puberty were enrolled in a double blinded study. All subjects were treated for the initial 3 months with deslorelin at a dose (4 Mg/kg-day, sc) known to suppress gonadotropins, linear growth velocity, and the rate of skeletal maturation. After 3 months, the subjects were randomly assigned to receive one of three daily sc doses of deslorelin: 4 Mg/kg (n = 9), 2 Mg/kg (n = 11), or 1 Mg/kg (n = 9). They were treated at this dose in double blinded fashion for 15 months, after which time they resumed therapy at a dose of 4 Mg/kg -day for an additional year. The children in the three groups did not differ in terms of chronological age, bone age, pretreatment growth rate, or Tanner stage at the onset of therapy. Similarly, there were no differences in the clinical and hormonal responses to the first 3 months of LHRHa therapy (4 Mg/kg-day). During the 15-month period at
the three different doses, the three dose groups could not be distinguished from each other in terms of pubertal stage, linear growth velocity, rate of skeletal maturation, sex steroid levels, mean LH or FSH levels, or peak FSH response to LHRH stimulation or to a dose of deslorelin. In contrast, the peak LH response to LHRH stimulation was highest in children treated with the lowest dose (1 Mg/kg day; P < 0.025, by multiple analysis of variance). In addition, the peak LH response to a dose of deslorelin (the LHRHa test) was higher in children treated with 1 Mg/kg-day than in those treated with 4 Mg/kgday (P < 0.04). In summary, the LHRHa test is a sensitive means for detecting activation of the hypothalamic-pituitary-gonadal axis, and deslorelin at a dose of 1 Mg/kg • day results in less gonadotropin suppression than a dose of 4 Mg/kg -day. Based on these short term data, we hypothesize that deslorelin at a dose of 2 Mg/kgday has efficacy similar to that of the dose of 4 Mg/kg -day. However, since no significant toxicity has been reported at the 4 Mg/kg- day dose and until a longer term study can be performed in larger numbers of children, we continue to recommend that deslorelin be used at the dose of 4 Mg/kg -day because of the more extensive data on treatment outcome that are available at this dose. (J Clin Endocrinol Metab 72: 60-64, 1991)
L
ONG-ACTING LHRH analogs (LHRHas) are currently used as conventional therapy in central precocious puberty. In the decade since their introduction, at least six agonist analogs have been developed and tested in children with central precocious puberty (111). While these reports consistently demonstrate efficacy in the suppression of gonadotropins and sex steroids, the reported impact on linear growth, the rate of skeletal maturation, and final or predicted height is more variable. This variability may be related to the different potencies of the various analog preparations, the different dosing regimens or routes of administration used by various investigators, or differing MCRs of the same drugs in different children. One pharmacokinetic study of the LHRHa buserelin [D-Ser(TBU)6EA-LHRH,
Hoechst, Montreal, Canada] was performed in children using a sensitive RIA for buserelin (7). Using this assay, the researchers concluded that peak serum concentrations of buserelin differed greatly depending upon the route of administration, i.e. sc, intranasal, or iv. Deslorelin (D-Trp6-Pro9-Net-LHRH) was the first LHRHa to be used in the treatment of central precocious puberty (8). In studies published from several centers, it was administered at doses between 4-8 /ug/kg-day (1-3, 6, 8). Because no dose-response studies had been performed in children, we designed a dose study to determine if a dose lower than 4 ^g/kg-day would be equally effective in suppressing gonadotropins, sex steroids, and the rates of linear growth and skeletal maturation in children with central precocious puberty.
Received May 10,1990. Address requests for reprints to: Dr. Ora Hirsch Pescovitz, Rile Hospital for Children A593, Indiana University Medical Center, 702 Barnhill Drive, Indianapolis, Indiana 46223.
Materials and Methods Twenty-nine children with central precocious puberty were admitted to the Clinical Center of the NIH and enrolled in a 60
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DESLORELIN TREATMENT OF PRECOCIOUS PUBERTY double blinded study. The protocol was approved by the Clinical Research Committee of the NICHHD. Informed consent was obtained from either parent, and informed assent from older children. The children ranged in age from 1.5-9 yr at the time of initial evaluation. All children carried a diagnosis of central precocious puberty based on the presence of secondary sexual characteristics, increased linear growth and skeletal maturation, and a pubertal response to LHRH stimulation (Table 1). The majority of children had idiopathic central precocious puberty (19 of 29). The remaining children had central nervous system lesions consistent with the following diagnoses: hypothalamic hamartoma (4 girls and 2 boys), arachnoid cyst (1 girl), neuroblastoma (1 girl), hydrocephalus (1 girl), and optic glioma (1 boy). All subjects were treated for 3 months with deslorelin at a dose known to suppress gonadotropins and the rate of linear growth and skeletal maturation (4 /zg/kg-day, sc). After 3 months, the subjects were assigned randomly to receive one of three daily sc doses of deslorelin: 4 Mg/kg (n = 9). 2 Mg/kg (n = 11), or 1 Mg/kg (n = 9). Randomization was performed by a pharmacist who had no clinical knowledge of the patients. The children were treated in double blinded fashion for 15 months with one of the above doses, after which time they resumed therapy at the dose of 4 Mg/kg • day for an additional year. Evaluation consisted of serum gonadotropin determinations every 20 min for 4 h during the day (1000-1400 h) and night (2200-0200 h). Plasma estradiol levels (girls only) and testosterone levels (boys only) were the mean of three or four determinations obtained at 6- to 8-h intervals over a 24-h period. LHRH was administered iv at a dose of 100 ng, and serum gonadotropins were determined 30 and 15 min before and 0, 15, 30, 60, 90, 120, and 180 min after treatment. The LHRHa test was defined as the gonadotropin response to the usual daily dose of deslorelin, which was administered between 1900-2100 h. Serum gonadotropins were determined 30 and 15 min before and 0, 15, 30, 45, 60, and 90 min and 2, 3, 4, 5, 6, 7, 8, 10, 12, 15,18, 21, and 24 h after treatment. Plasma LH, FSH, estradiol, and testosterone were measured with modifications of previously described methods (12,13). The LH assay had a detection limit of 0.6 IU/L, an intraassay coefficient of variation (CV) of 2.1%, and an interassay CV of 9.0% at the ED50; the FSH assay had a detection limit of 0.6 IU/L, an intraassay CV of 3.6%, and an interassay CV of 11.2% at the ED50; the estradiol assay had a detection limit of 37 pmol/L, an intraassay CV of 5.7%, TABLE 1. Clinical features of children before therapy
No. of patients Age at onset (yr) Ht (SD units) ABA/ACA" Predicted ht (cm)" Breast (girls)0 Pubic hairc Testis size (ml)d 0
1 Mg/kg-day
2 Mg/kg-day
4 Mg/kg•day
9 (8F/1M) 4.9 ± 0.9 2.5 ± 0.5 2.2 ± 0.2 144.1 ± 2.8 3.7 ± 0.3 2.9 ± 0.2 10.0
11 (10F/1M) 6.4 ± 0.3 2.9 ± 0.4 1.8 ± 0.1 148.9 ± 2.2 3.8 ± 0.3 3.1 ± 0.4 15.0
9 (8F/1M) 5.1 ± 0.8 3.3 ± 0.2 2.2 ± 0.2 149.3 ± 3.1 3.8 ± 0.2 3.0 ± 0.3 15.0
The change in bone age divided by the change in chronological age. By the method of Bayley-Pinneau (24). c Tanner stage (15, 16). d By Prader orchidometer (17). 6
61
and an interassay CV of 13.4% at the ED80; the testosterone assay had a detection limit of 0.30 nmol/L, an intraassay CV of 4.7%, and an interassay CV of 9.7% at the ED50. Both LH and FSH assays had 0.8% cross-reactivity with gonadotropin a-subunit on a weight per volume basis. Height was the mean of 10 stadiometer heights. The growth velocity and bone age calculations for each dose did not include data from the initial 3-month period of deslorelin treatment. At 12 and 18 months, 6 months of growth and bone age data were used to calculate annualized values. At 30 months, 12 months of data were used for the annualized values. A radiograph of the left hand and wrist was obtained for bone age (14). Computed tomography of the head and ultrasound of the adrenal glands and ovaries were performed to exclude lesions. Pubertal examinations were performed using the method of Tanner for breast and pubic hair staging (15, 16). Testicular volume was determined using a Prader orchidometer (17). The data are expressed as the mean ± SEM. Initial statistical comparisons among dose levels at 6, 12, and 18 months of deslorelin treatment (corresponding to 3, 9, and 15 months after randomization to one of the three deslorelin dosages) were performed by multiple analysis of variance (MANOVA) for repeated measures. When significant differences were detected by MANOVA for repeated measures, Student's two-tailed t test with the Bonferroni adjustment was used to compare the results between two doses. Results The children in the three groups did not differ in terms of chronological age, bone age, pretreatment growth rate, or Tanner stage at the onset of therapy. Similarly, there were no differences in the clinical and hormonal responses to the first 3 months of LHRHa therapy (4 /*g/ kg-day). Each of the three patient groups had significant decreases in the rates of linear growth and skeletal maturation in the first 3 months of therapy (P < 0.001), but could not be distinguished from each other during the following 27 months of treatment regardless of the dose of LHRHa (Fig. 1). Furthermore, the three dose groups could not be distinguished from each other in terms of pubertal stage (data not shown), sex steroid levels, mean LH and FSH (Fig. 2), or the peak FSH response to LHRH or deslorelin stimulation (Fig. 3). In contrast, the peak LH response to LHRH and deslorelin stimulation was highest in children treated with the lowest dose (1 jug/kg-day; P < 0.04, by MANOVA; Fig. 3). There were no significant differences in the gonadotropin response to LHRH or deslorelin between the children treated with the 2 and the 4 Mg/kgday doses.
Discussion Although at least six long-acting LHRHas are currently available and have been used to treat children with central precocious puberty (1-11), no dose-response studies have been reported with any of these medications.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 15:03 For personal use only. No other uses without permission. . All rights reserved.
62
PESCOVITZ, BARNES, AND CUTLER
JCE & M • 1991 Vol 72 • No 1
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Vol. 72, No. 1 Printed in U.S.A.
Effect of Deslorelin Dose in the Treatment of Central Precocious Puberty ORA HIRSCH PESCOVITZ, KEVIN M. BARNES, AND GORDON B. CUTLER, JR. Departments of Pediatrics, Physiology/Biophysics, Indiana University Medical Center (O.H.P.), Indianapolis, Indiana 46202; and the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
ABSTRACT. Central precocious puberty is effectively treated with long-acting LHRH analogs (LHRHas). Although at least six LHRHas have now been used in children, there have been no studies to determine the least effective dose of any of these analogs. We sought to determine the effect of decreasing an efficacious dose of deslorelin (D-Trp6-Pro9-NEt-LHRH) on basal and LHRH-stimulated gonadotropins, estradiol levels, and the rates of linear growth and skeletal maturation in subjects with central precocious puberty. Twenty-nine children with central precocious puberty were enrolled in a double blinded study. All subjects were treated for the initial 3 months with deslorelin at a dose (4 Mg/kg-day, sc) known to suppress gonadotropins, linear growth velocity, and the rate of skeletal maturation. After 3 months, the subjects were randomly assigned to receive one of three daily sc doses of deslorelin: 4 Mg/kg (n = 9), 2 Mg/kg (n = 11), or 1 Mg/kg (n = 9). They were treated at this dose in double blinded fashion for 15 months, after which time they resumed therapy at a dose of 4 Mg/kg -day for an additional year. The children in the three groups did not differ in terms of chronological age, bone age, pretreatment growth rate, or Tanner stage at the onset of therapy. Similarly, there were no differences in the clinical and hormonal responses to the first 3 months of LHRHa therapy (4 Mg/kg-day). During the 15-month period at
the three different doses, the three dose groups could not be distinguished from each other in terms of pubertal stage, linear growth velocity, rate of skeletal maturation, sex steroid levels, mean LH or FSH levels, or peak FSH response to LHRH stimulation or to a dose of deslorelin. In contrast, the peak LH response to LHRH stimulation was highest in children treated with the lowest dose (1 Mg/kg day; P < 0.025, by multiple analysis of variance). In addition, the peak LH response to a dose of deslorelin (the LHRHa test) was higher in children treated with 1 Mg/kg-day than in those treated with 4 Mg/kgday (P < 0.04). In summary, the LHRHa test is a sensitive means for detecting activation of the hypothalamic-pituitary-gonadal axis, and deslorelin at a dose of 1 Mg/kg • day results in less gonadotropin suppression than a dose of 4 Mg/kg -day. Based on these short term data, we hypothesize that deslorelin at a dose of 2 Mg/kgday has efficacy similar to that of the dose of 4 Mg/kg -day. However, since no significant toxicity has been reported at the 4 Mg/kg- day dose and until a longer term study can be performed in larger numbers of children, we continue to recommend that deslorelin be used at the dose of 4 Mg/kg -day because of the more extensive data on treatment outcome that are available at this dose. (J Clin Endocrinol Metab 72: 60-64, 1991)
L
ONG-ACTING LHRH analogs (LHRHas) are currently used as conventional therapy in central precocious puberty. In the decade since their introduction, at least six agonist analogs have been developed and tested in children with central precocious puberty (111). While these reports consistently demonstrate efficacy in the suppression of gonadotropins and sex steroids, the reported impact on linear growth, the rate of skeletal maturation, and final or predicted height is more variable. This variability may be related to the different potencies of the various analog preparations, the different dosing regimens or routes of administration used by various investigators, or differing MCRs of the same drugs in different children. One pharmacokinetic study of the LHRHa buserelin [D-Ser(TBU)6EA-LHRH,
Hoechst, Montreal, Canada] was performed in children using a sensitive RIA for buserelin (7). Using this assay, the researchers concluded that peak serum concentrations of buserelin differed greatly depending upon the route of administration, i.e. sc, intranasal, or iv. Deslorelin (D-Trp6-Pro9-Net-LHRH) was the first LHRHa to be used in the treatment of central precocious puberty (8). In studies published from several centers, it was administered at doses between 4-8 /ug/kg-day (1-3, 6, 8). Because no dose-response studies had been performed in children, we designed a dose study to determine if a dose lower than 4 ^g/kg-day would be equally effective in suppressing gonadotropins, sex steroids, and the rates of linear growth and skeletal maturation in children with central precocious puberty.
Received May 10,1990. Address requests for reprints to: Dr. Ora Hirsch Pescovitz, Rile Hospital for Children A593, Indiana University Medical Center, 702 Barnhill Drive, Indianapolis, Indiana 46223.
Materials and Methods Twenty-nine children with central precocious puberty were admitted to the Clinical Center of the NIH and enrolled in a 60
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 15:03 For personal use only. No other uses without permission. . All rights reserved.
DESLORELIN TREATMENT OF PRECOCIOUS PUBERTY double blinded study. The protocol was approved by the Clinical Research Committee of the NICHHD. Informed consent was obtained from either parent, and informed assent from older children. The children ranged in age from 1.5-9 yr at the time of initial evaluation. All children carried a diagnosis of central precocious puberty based on the presence of secondary sexual characteristics, increased linear growth and skeletal maturation, and a pubertal response to LHRH stimulation (Table 1). The majority of children had idiopathic central precocious puberty (19 of 29). The remaining children had central nervous system lesions consistent with the following diagnoses: hypothalamic hamartoma (4 girls and 2 boys), arachnoid cyst (1 girl), neuroblastoma (1 girl), hydrocephalus (1 girl), and optic glioma (1 boy). All subjects were treated for 3 months with deslorelin at a dose known to suppress gonadotropins and the rate of linear growth and skeletal maturation (4 /zg/kg-day, sc). After 3 months, the subjects were assigned randomly to receive one of three daily sc doses of deslorelin: 4 Mg/kg (n = 9). 2 Mg/kg (n = 11), or 1 Mg/kg (n = 9). Randomization was performed by a pharmacist who had no clinical knowledge of the patients. The children were treated in double blinded fashion for 15 months with one of the above doses, after which time they resumed therapy at the dose of 4 Mg/kg • day for an additional year. Evaluation consisted of serum gonadotropin determinations every 20 min for 4 h during the day (1000-1400 h) and night (2200-0200 h). Plasma estradiol levels (girls only) and testosterone levels (boys only) were the mean of three or four determinations obtained at 6- to 8-h intervals over a 24-h period. LHRH was administered iv at a dose of 100 ng, and serum gonadotropins were determined 30 and 15 min before and 0, 15, 30, 60, 90, 120, and 180 min after treatment. The LHRHa test was defined as the gonadotropin response to the usual daily dose of deslorelin, which was administered between 1900-2100 h. Serum gonadotropins were determined 30 and 15 min before and 0, 15, 30, 45, 60, and 90 min and 2, 3, 4, 5, 6, 7, 8, 10, 12, 15,18, 21, and 24 h after treatment. Plasma LH, FSH, estradiol, and testosterone were measured with modifications of previously described methods (12,13). The LH assay had a detection limit of 0.6 IU/L, an intraassay coefficient of variation (CV) of 2.1%, and an interassay CV of 9.0% at the ED50; the FSH assay had a detection limit of 0.6 IU/L, an intraassay CV of 3.6%, and an interassay CV of 11.2% at the ED50; the estradiol assay had a detection limit of 37 pmol/L, an intraassay CV of 5.7%, TABLE 1. Clinical features of children before therapy
No. of patients Age at onset (yr) Ht (SD units) ABA/ACA" Predicted ht (cm)" Breast (girls)0 Pubic hairc Testis size (ml)d 0
1 Mg/kg-day
2 Mg/kg-day
4 Mg/kg•day
9 (8F/1M) 4.9 ± 0.9 2.5 ± 0.5 2.2 ± 0.2 144.1 ± 2.8 3.7 ± 0.3 2.9 ± 0.2 10.0
11 (10F/1M) 6.4 ± 0.3 2.9 ± 0.4 1.8 ± 0.1 148.9 ± 2.2 3.8 ± 0.3 3.1 ± 0.4 15.0
9 (8F/1M) 5.1 ± 0.8 3.3 ± 0.2 2.2 ± 0.2 149.3 ± 3.1 3.8 ± 0.2 3.0 ± 0.3 15.0
The change in bone age divided by the change in chronological age. By the method of Bayley-Pinneau (24). c Tanner stage (15, 16). d By Prader orchidometer (17). 6
61
and an interassay CV of 13.4% at the ED80; the testosterone assay had a detection limit of 0.30 nmol/L, an intraassay CV of 4.7%, and an interassay CV of 9.7% at the ED50. Both LH and FSH assays had 0.8% cross-reactivity with gonadotropin a-subunit on a weight per volume basis. Height was the mean of 10 stadiometer heights. The growth velocity and bone age calculations for each dose did not include data from the initial 3-month period of deslorelin treatment. At 12 and 18 months, 6 months of growth and bone age data were used to calculate annualized values. At 30 months, 12 months of data were used for the annualized values. A radiograph of the left hand and wrist was obtained for bone age (14). Computed tomography of the head and ultrasound of the adrenal glands and ovaries were performed to exclude lesions. Pubertal examinations were performed using the method of Tanner for breast and pubic hair staging (15, 16). Testicular volume was determined using a Prader orchidometer (17). The data are expressed as the mean ± SEM. Initial statistical comparisons among dose levels at 6, 12, and 18 months of deslorelin treatment (corresponding to 3, 9, and 15 months after randomization to one of the three deslorelin dosages) were performed by multiple analysis of variance (MANOVA) for repeated measures. When significant differences were detected by MANOVA for repeated measures, Student's two-tailed t test with the Bonferroni adjustment was used to compare the results between two doses. Results The children in the three groups did not differ in terms of chronological age, bone age, pretreatment growth rate, or Tanner stage at the onset of therapy. Similarly, there were no differences in the clinical and hormonal responses to the first 3 months of LHRHa therapy (4 /*g/ kg-day). Each of the three patient groups had significant decreases in the rates of linear growth and skeletal maturation in the first 3 months of therapy (P < 0.001), but could not be distinguished from each other during the following 27 months of treatment regardless of the dose of LHRHa (Fig. 1). Furthermore, the three dose groups could not be distinguished from each other in terms of pubertal stage (data not shown), sex steroid levels, mean LH and FSH (Fig. 2), or the peak FSH response to LHRH or deslorelin stimulation (Fig. 3). In contrast, the peak LH response to LHRH and deslorelin stimulation was highest in children treated with the lowest dose (1 jug/kg-day; P < 0.04, by MANOVA; Fig. 3). There were no significant differences in the gonadotropin response to LHRH or deslorelin between the children treated with the 2 and the 4 Mg/kgday doses.
Discussion Although at least six long-acting LHRHas are currently available and have been used to treat children with central precocious puberty (1-11), no dose-response studies have been reported with any of these medications.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 15:03 For personal use only. No other uses without permission. . All rights reserved.
62
PESCOVITZ, BARNES, AND CUTLER
JCE & M • 1991 Vol 72 • No 1
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