Height prognosis of children with true precocious puberty and growth hormone deficiency: Effect of combination therapy with gonadotropin releasing hormone agonist and growth hormone Jos6 F. C a r a , MD, Mary L. Kreiter, MD, a n d Robert L. Rosenfield, MD From the Section of Pediatric Endocrinology, Department of Pediatrics, PritzkerSchool of Medicine, University of Chicago, Chicago, Illinois We e v a l u a t e d height prognosis and therapeutic e f f i c a c y of long-term, combination therapy with g o n a d o t r o p i n r e l e a s i n g - h o r m o n e agonist and growth horm o n e (GH) in five children (three girls) with coexistent precocious puberty and GH deficiency. Their clinical characteristics and growth response were compared with those of 12 girls with idiopathic true precocious puberty and eight prepubertal GH-deficient children (one girl). Precocious GH-deficient subjects were older than the precocious GH-sufficient children (9.5 • 1.8 years vs 6.5 • 1.3 years; mean • SD), but b o n e ages were c o m p a r a b l e (12 • 3.7 years vs 10 _ 0.9 years); their c h r o n o l o g i c a g e was similar to that of the prepubertal GHdeficient children (9.6 • 2.1 years), but b o n e a g e was significantly more a d v a n c e d (6.9 • 2.3 years). The mean height velocity of the prepubertal GH-deficient children (3.8 • 1.5 cm/yr) was lower than that of the precocious GH-deficient subjects (6.7 _+ 1.6 cm/yr) and the precocious GH-sufficient children (9.5 • 2.9 cm/yr). Baseline adult height prediction z scores were significantly lower in the precocious GH-deficient children ( - 3 . 7 • 1.0) than in either the precocious GH-sufficient children ( - 2 . 2 • 1.0) or the prepubertal GHdeficient subjects ( - 1 . 5 _ 0.8). During therapy with g o n a d o t r o p i n releasinghormone agonist, growth rates slowed to an a v e r a g e of 3.7 cm/yr in the precocious GH-deficient children but increased after the addition of GH to 7.4 cm during the first year of c o m b i n a t i o n therapy. After 2 to 3 years of c o m b i n a t i o n therapy, height predictions increased an a v e r a g e of 10 cm, c o m p a r e d with an increase of 2.8 cm in the precocious GH-sufficient group treated with g o n a d o t ropin r e l e a s i n g - h o r m o n e agonist alone. We c o n c l u d e that c o m b i n a t i o n treatment with g o n a d o t r o p i n r e l e a s i n g - h o r m o n e agonist and GH improves the height prognosis of children with coexistent true precocious puberty and GH deficiency, but falls short of a c h i e v i n g normal adult height potential. (J PEDIATR 1992;120:709-15)
Supported in part by U.S. Public Health Service grants Nos. HD06308, DK-20595, and RR-00055. Presented in part at the 60th Annual Meeting of the Society for Pediatric Research, New Orleans, La., May 2, 1991.
Submitted for publication Aug. 29, 1991; accepted Dec. 16, 1991. Reprint requests: Jos6 F. Cara, MD, University of Chicago, 5841 S. Maryland Ave., Box No. 118, Chicago, IL 60637. 9/20/35702
709
7 10
Cara,Kreiter, and Rosenfield
GH GnRH
Growth hormone Gonadotropin releasing hormone
True precocious puberty depends on an increase in the secretion of pituitary gonadotropins, which stimulate the gonadal production of sex steroids, and is associated with an increase in the plasma concentrations of growth hormone and insulin-like growth factor I. 1"4 As a result, height velocity is markedly increased; because the rate of skeletal maturation is often increased discordantly, however, epiphyseal closure occurs prematurely and adult height is frequently compromised, resulting in short stature in adulthood. 5-7 Treatment with gonadotropin releasinghormone agonist inhibits the pituitary-gonadal axis, resuiting in suppression of pituitary gonadotropin a n d o f gonadal sex steroid secretion, s12 As a result, the rates of pubertal development and skeletal maturation are arrested, with a consequent improvement in predicted adult height.l~ We and others have noted the coexistence of true precocious puberty and GH deficiency in children with central nervous system injury,13-15 most of whom have intracranial malignancies and received high-dose cranial irradiation for their disease. These subjects have higher than expected growth rates and bone ages, given their GH deficiency state. 16 As a result, the diagnosis of GH deficiency is often overlooked and treatment unnecessarily delayed. 14, 15 We undertook this study to examine the adult height prognoses of children with coexistent precocious puberty and GH deficiency, to compare their adult height prognoses with those of children with true precocious puberty or GH deficiency alone, and to assess the impact of combination treatment with GnRH agonist and GH on the growth rates and predicted adult heights of these children. METHODS
Our study included three groups of patients, all of whom have been described previously. 1%14 Group 1, which included children with true precocious puberty and GH deficiency (the precocious GH-deficient group), consisted of three girls and two boys. Four patients in this group had intracranial tumors and received high-dose cranial irradiation for their disease; the other patient had empty-sella syndrome. Group 2, children with true precocious puberty alone (precocious GH-sufficient group), included 12 girls with idiopathic true precocious puberty, all of whom were GH sufficient. Group 3, used for baseline comparisons only., included eight prepubertal GH-deficient subjects (one girl). Informed consent was obtained from all subjects and their parents. All study subjects in groups 1 and 2 had true precocious
The Journal of Pediatrics May 1992
puberty, as defined by characteristic clinical and endocrinologic findings, s The diagnosis of GH deficiency was based on peak GH levels of 1.5 ~g/L, peak GH levels of >6 #g/L, or both throughout nocturnal GH secretory study. 14, is To evaluate the impact of combination therapy with GnRH agonist and GH on the growth rates and predicted adult heights of children with coexistent precocious puberty and GH deficiency, the precocious GH-deficient children (group 1) were treated with GnRH agonist alone for 2 to 6 months, followed by combination therapy with GnRH agonist and GH for 3 years (2 years for one subject). Responses of these children were compared with those of the precocious GH-sufficient children (group 2), all of whom were treated with GnRH agonist alone for 3 years. The GnRH agonist therapy consisted & nafarelin (Synarel) at a dose of 1200 to 1600 #g/day, administered intranasally in two daily doses, or leuprolide (Lupron) at a dose of 40 #g/kg per day given as a single daily subcutaneous injection. Patients whose plasma sex hormOnes were not suppressed to prepubertal levels with this nafarelin or leuprolide regimen were given nafarelin at a dose of 4 Fzg/kg per day or leuprolide at a dose of 80/zg/kg per day, administered subcutaneously. Physical examinations, pubertal staging, blood studies, and bone ages were obtained at regular intervals during therapy. Pubertal staging was performed by the method of Tanner 19 and bone ages were determined from the Greulich and Pyle atlas 2~ by the method of Roche et al. 21 Adult height predictions were estimated according to the method or Bailey and Pinneau. 22 The z scores were obtained by subtracting the normal mean measurement (e.g., height for chronologic age) from each child's individual measurement and dividing this number by the corresponding SD, as deScribed previously.23 Growth and adult height prediction data were analyzed by Student t test and the Wileoxon signed-rank test, as appropriate. Longitudinal growth data were also analyzed by repeated measures analysis of variance for comparisons within groups and between groups. All data are presented as mean _+ SD unless otherwise stated. All p values are two tailed. RESULTS As shown in the Table, the precocious GH-deficient children were older than were subjects with precocious puberty
Volume 120 Number 5
GH and GnRH agonist for sexual precocity with GH deficiency
711
12
t._
,e
10 I
(1
E 8 >,
,/
s
.m
0
/,,,
s
'
s,
w
s
> r
"1-
Pretreatment
GnRHaAIone
GnRHa+GH
Therapy Fig. 1.
E•ect•ftreatment•nheightve••city•fchi•drenwithc•existentprec•ci•uspubertyandGHde•ciency.Barsrep-
resent mean _+ SD height velocity before therapy (Pretreatment), while receiving GnRH-agonist therapy alone (GnRHa Alone), and during the first year of combination GnRH-agonist and GH therapy (GnRH + GH). Broken lines represent individual values for each study subject. Asterisk denotes p
Supported in part by U.S. Public Health Service grants Nos. HD06308, DK-20595, and RR-00055. Presented in part at the 60th Annual Meeting of the Society for Pediatric Research, New Orleans, La., May 2, 1991.
Submitted for publication Aug. 29, 1991; accepted Dec. 16, 1991. Reprint requests: Jos6 F. Cara, MD, University of Chicago, 5841 S. Maryland Ave., Box No. 118, Chicago, IL 60637. 9/20/35702
709
7 10
Cara,Kreiter, and Rosenfield
GH GnRH
Growth hormone Gonadotropin releasing hormone
True precocious puberty depends on an increase in the secretion of pituitary gonadotropins, which stimulate the gonadal production of sex steroids, and is associated with an increase in the plasma concentrations of growth hormone and insulin-like growth factor I. 1"4 As a result, height velocity is markedly increased; because the rate of skeletal maturation is often increased discordantly, however, epiphyseal closure occurs prematurely and adult height is frequently compromised, resulting in short stature in adulthood. 5-7 Treatment with gonadotropin releasinghormone agonist inhibits the pituitary-gonadal axis, resuiting in suppression of pituitary gonadotropin a n d o f gonadal sex steroid secretion, s12 As a result, the rates of pubertal development and skeletal maturation are arrested, with a consequent improvement in predicted adult height.l~ We and others have noted the coexistence of true precocious puberty and GH deficiency in children with central nervous system injury,13-15 most of whom have intracranial malignancies and received high-dose cranial irradiation for their disease. These subjects have higher than expected growth rates and bone ages, given their GH deficiency state. 16 As a result, the diagnosis of GH deficiency is often overlooked and treatment unnecessarily delayed. 14, 15 We undertook this study to examine the adult height prognoses of children with coexistent precocious puberty and GH deficiency, to compare their adult height prognoses with those of children with true precocious puberty or GH deficiency alone, and to assess the impact of combination treatment with GnRH agonist and GH on the growth rates and predicted adult heights of these children. METHODS
Our study included three groups of patients, all of whom have been described previously. 1%14 Group 1, which included children with true precocious puberty and GH deficiency (the precocious GH-deficient group), consisted of three girls and two boys. Four patients in this group had intracranial tumors and received high-dose cranial irradiation for their disease; the other patient had empty-sella syndrome. Group 2, children with true precocious puberty alone (precocious GH-sufficient group), included 12 girls with idiopathic true precocious puberty, all of whom were GH sufficient. Group 3, used for baseline comparisons only., included eight prepubertal GH-deficient subjects (one girl). Informed consent was obtained from all subjects and their parents. All study subjects in groups 1 and 2 had true precocious
The Journal of Pediatrics May 1992
puberty, as defined by characteristic clinical and endocrinologic findings, s The diagnosis of GH deficiency was based on peak GH levels of 1.5 ~g/L, peak GH levels of >6 #g/L, or both throughout nocturnal GH secretory study. 14, is To evaluate the impact of combination therapy with GnRH agonist and GH on the growth rates and predicted adult heights of children with coexistent precocious puberty and GH deficiency, the precocious GH-deficient children (group 1) were treated with GnRH agonist alone for 2 to 6 months, followed by combination therapy with GnRH agonist and GH for 3 years (2 years for one subject). Responses of these children were compared with those of the precocious GH-sufficient children (group 2), all of whom were treated with GnRH agonist alone for 3 years. The GnRH agonist therapy consisted & nafarelin (Synarel) at a dose of 1200 to 1600 #g/day, administered intranasally in two daily doses, or leuprolide (Lupron) at a dose of 40 #g/kg per day given as a single daily subcutaneous injection. Patients whose plasma sex hormOnes were not suppressed to prepubertal levels with this nafarelin or leuprolide regimen were given nafarelin at a dose of 4 Fzg/kg per day or leuprolide at a dose of 80/zg/kg per day, administered subcutaneously. Physical examinations, pubertal staging, blood studies, and bone ages were obtained at regular intervals during therapy. Pubertal staging was performed by the method of Tanner 19 and bone ages were determined from the Greulich and Pyle atlas 2~ by the method of Roche et al. 21 Adult height predictions were estimated according to the method or Bailey and Pinneau. 22 The z scores were obtained by subtracting the normal mean measurement (e.g., height for chronologic age) from each child's individual measurement and dividing this number by the corresponding SD, as deScribed previously.23 Growth and adult height prediction data were analyzed by Student t test and the Wileoxon signed-rank test, as appropriate. Longitudinal growth data were also analyzed by repeated measures analysis of variance for comparisons within groups and between groups. All data are presented as mean _+ SD unless otherwise stated. All p values are two tailed. RESULTS As shown in the Table, the precocious GH-deficient children were older than were subjects with precocious puberty
Volume 120 Number 5
GH and GnRH agonist for sexual precocity with GH deficiency
711
12
t._
,e
10 I
(1
E 8 >,
,/
s
.m
0
/,,,
s
'
s,
w
s
> r
"1-
Pretreatment
GnRHaAIone
GnRHa+GH
Therapy Fig. 1.
E•ect•ftreatment•nheightve••city•fchi•drenwithc•existentprec•ci•uspubertyandGHde•ciency.Barsrep-
resent mean _+ SD height velocity before therapy (Pretreatment), while receiving GnRH-agonist therapy alone (GnRHa Alone), and during the first year of combination GnRH-agonist and GH therapy (GnRH + GH). Broken lines represent individual values for each study subject. Asterisk denotes p
