Effectiveness of Growth-Promoting Therapies Comparison Among Growth Hormone, Clonidine, and Levodopa Cecilia Volta, MD; Lucia Ghizzoni, MD; Gaetano Muto, MD; Raffaella Raffaele Virdis, MD; Sergio Bernasconi, MD \s=b\ The
ability of growth hormone, clonidine, and levodopa
to stimulate growth was compared in short and slowly growing children randomly assigned to different treatment regimens for 6 months. There were 10 children in each group, and 10 additional subjects served as controls. Growth hormone improved mean height velocity, height velocity SD score, and height SD score. The mean height velocity and height velocity SD score were significantly increased by
clonidine, while levodopa only enhanced the mean height velocity SD score of the treated children. Moreover, in nine patients (90%) receiving growth hormone, two (20%) receiving clonidine, and one (10%) receiving levodopa, the height velocity was raised by more than 2 cm/y. The increments in height velocity and height SD score were greatest in the growth hormone group. Clonidine induced an increase in height velocity significantly different from that in control children only. In the control group, there was a significant reduction of height SD score with time. (AJDC. 1991;145:168\p=n-\171) 1981, Rudman
et
al1 showed that short-term growth
(GH) treatment was effective in improving height velocity (HV) in a group of short and slowly grow¬ ing children with normal pituitary function. Since then hormone
several other studies2"7 have demonstrated that a high per¬ centage of short normal children show a sustained clinical benefit from GH therapy. However, the important factors in predicting the response to treatment have not yet been
clearly defined.8 Increasing knowledge of the neuroendocrine mecha¬ nisms regulating GH secretion has led to the use of sub¬ stances known to acutely stimulate GH release from the pituitary,
such
as
clonidine9"11 and levodopa,12,13 for the
treatment of short stature.
The results of these studies are
extremely discordant, probably due to the heterogeneity of clinical features and the small number of subjects studied. To evaluate and compare the growth-promoting effects
Accepted for publication August 6,
1990. From the Department of Pediatrics, University of Parma, Italy. Presented in part at the Third Joint Meeting of the European Society for Pediatric Endocrinology and the Lawson Wilkins Pediatric Endocrinology Society, Jerusalem, Israel, October 31, 1989. Reprint requests to Clinica Pediatrica, Universit\l=a`\degli Studi di Parma, Via Gramsci 14, 43100 Parma, Italy (Dr Bernasconi).
Spaggiari, MD;
of GH, clonidine, and levodopa, we analyzed the growth response to long-term administration of these agents in a group of short children with the same auxological features. The results obtained were compared with those in a group of subjects receiving no medication. MATERIALS AND METHODS children Forty (eight girls and 32 boys) with short stature were evaluated at the Growth Clinic of the Department of Pediatrics of the University of Parma, Italy. Inclusion criteria for entry in the study are reported in Table 1. The value of -0.8 for HV SD score (HVSDS) was chosen because it is the lowest value at which prepubertal children can grow at the third percentile.14 Patients were randomly assigned to the following groups: group 1 (n 10), no medication; group 2 (n 10), levodopa (Larodopa, LaRoche Ine, Basel, Switzerland), 60 mg/kg per day by mouth three times per day up to 25 kg, with a constant dosage of 1500 mg/d thereafter, for 6 months; group 3 (n 10), clonidine =
=
=
(Catapresan, Boehringer, Mannheim, Germany), 75 µg/m2 by mouth twice per day, one third in the morning and two thirds in the evening, for 6 months; and group 4 (n 10), GH (Somatomorm, KabiVitrium Ine, Stockholm, Sweden), 13 IU/m2 per week, subdivided in six subcutaneous daily injections, for 6 months. Informed consent was obtained from parents, and the study was approved by the ethical committee of the Department of Pediatrics of the University of Parma. Standard auxological as¬ sessment (height, weight, height velocity, and pubertal staging) was performed at 3-month intervals for 6 months. Kidney, liver, and thyroid function was checked in all children at baseline, and, in the groups under treatment, after 3 and 6 months; in addition, an oral glucose tolerance test and glycosylated hemoglobin eval¬ uation were performed before and after treatment in group 4 only. A roentgenogram of the left hand for bone age evaluation was performed at baseline and at the end of the study period. Height was measured with a wall-mounted Harpender stadiometer; bone age was determined by an experienced examiner using the standards of Greulich and Pyle. The HV before the study was calculated based on measurements taken in the pre¬ ceding year and expressed as the HVSDS corrected for bone age. An increase in HV greater than 2 cm/y was considered significant, because this approximates 2 SDs of the variation that occurs in whole-year HVs in normal prepubertal children.16 Serum GH, levothyroxine, triiodothyronine, thyroid-stimulating hormone, free thyroxine, and free triiodothyronine levels were measured as previously described.13,17 All results are expressed at mean±SD. For statistical analysis, we used the paired f test for comparisons within groups and the Newman-Keuls test for multiple comparisons among indepen¬ dent groups of data; correlations were evaluated by linear re¬ gression analysis.
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=
Table 1.—Inclusion Criteria for
Entry in the Study
Birth weight appropriate for gestational age No evidence of systemic diseases, malnutrition, dysmorphic syndromes, or psychosocial disturbances Tanner stage 1 of pubertal development Height SD score < 2 Whole-year height velocity SD < -0.8 Growth hormone response to pharmacological stimuli >10 µg/L (insulin hypoglycemia, 0.1 U/kg intravenously, or clonidine, 100 µg/m2 by mouth) Normal thyroid function
Table 2.—Auxological Data Before and After the Study Period
Group Growth Control
Levodopa
Clonidine
Hormone
10
10
10
10
9.4±2.1
9.7±1.8
8.9±2.1
10.9±1.7
9.9 ±2.1
10.2 ±1.8
9.4 ±2.1
11.4 ±1.7
6.89±2.1
7.70±2.2
6.51 ±2.1
8.75 ±1.9
7.88 ±1.8
8.21 ±2.4
7.12 ±1.9
9.57 ±1.9
3.7 ±1.2
3.9 ±0.6
3.8 ±1.0*
3.9 ±0.6*
3.5±0.6
4.5 ± 1.3
5.0±1.1*
6.8±1.0*
-
RESULTS At inclusion, mean chronological age, bone age, HV, height SD score (HSDS), and HVSDS corrected for bone age were similar in all groups (Table 2). There were also no differences in mean midparental height (group 1, 160.4. ±4 cm; group 2, 157.5±4 cm; group 3, 157.3±6 cm; and group 4, 157.9±6 cm). Results at the end of the study period are shown in Table 2 and Fig 1 and can be summarized as follows: Group l.-The HV and HVSDS did not significantly change in the 6-month follow-up. However, there was a significant decrease in the HSDS ( 2.3±0.4 vs 2.4±0.4,
P
ability of growth hormone, clonidine, and levodopa
to stimulate growth was compared in short and slowly growing children randomly assigned to different treatment regimens for 6 months. There were 10 children in each group, and 10 additional subjects served as controls. Growth hormone improved mean height velocity, height velocity SD score, and height SD score. The mean height velocity and height velocity SD score were significantly increased by
clonidine, while levodopa only enhanced the mean height velocity SD score of the treated children. Moreover, in nine patients (90%) receiving growth hormone, two (20%) receiving clonidine, and one (10%) receiving levodopa, the height velocity was raised by more than 2 cm/y. The increments in height velocity and height SD score were greatest in the growth hormone group. Clonidine induced an increase in height velocity significantly different from that in control children only. In the control group, there was a significant reduction of height SD score with time. (AJDC. 1991;145:168\p=n-\171) 1981, Rudman
et
al1 showed that short-term growth
(GH) treatment was effective in improving height velocity (HV) in a group of short and slowly grow¬ ing children with normal pituitary function. Since then hormone
several other studies2"7 have demonstrated that a high per¬ centage of short normal children show a sustained clinical benefit from GH therapy. However, the important factors in predicting the response to treatment have not yet been
clearly defined.8 Increasing knowledge of the neuroendocrine mecha¬ nisms regulating GH secretion has led to the use of sub¬ stances known to acutely stimulate GH release from the pituitary,
such
as
clonidine9"11 and levodopa,12,13 for the
treatment of short stature.
The results of these studies are
extremely discordant, probably due to the heterogeneity of clinical features and the small number of subjects studied. To evaluate and compare the growth-promoting effects
Accepted for publication August 6,
1990. From the Department of Pediatrics, University of Parma, Italy. Presented in part at the Third Joint Meeting of the European Society for Pediatric Endocrinology and the Lawson Wilkins Pediatric Endocrinology Society, Jerusalem, Israel, October 31, 1989. Reprint requests to Clinica Pediatrica, Universit\l=a`\degli Studi di Parma, Via Gramsci 14, 43100 Parma, Italy (Dr Bernasconi).
Spaggiari, MD;
of GH, clonidine, and levodopa, we analyzed the growth response to long-term administration of these agents in a group of short children with the same auxological features. The results obtained were compared with those in a group of subjects receiving no medication. MATERIALS AND METHODS children Forty (eight girls and 32 boys) with short stature were evaluated at the Growth Clinic of the Department of Pediatrics of the University of Parma, Italy. Inclusion criteria for entry in the study are reported in Table 1. The value of -0.8 for HV SD score (HVSDS) was chosen because it is the lowest value at which prepubertal children can grow at the third percentile.14 Patients were randomly assigned to the following groups: group 1 (n 10), no medication; group 2 (n 10), levodopa (Larodopa, LaRoche Ine, Basel, Switzerland), 60 mg/kg per day by mouth three times per day up to 25 kg, with a constant dosage of 1500 mg/d thereafter, for 6 months; group 3 (n 10), clonidine =
=
=
(Catapresan, Boehringer, Mannheim, Germany), 75 µg/m2 by mouth twice per day, one third in the morning and two thirds in the evening, for 6 months; and group 4 (n 10), GH (Somatomorm, KabiVitrium Ine, Stockholm, Sweden), 13 IU/m2 per week, subdivided in six subcutaneous daily injections, for 6 months. Informed consent was obtained from parents, and the study was approved by the ethical committee of the Department of Pediatrics of the University of Parma. Standard auxological as¬ sessment (height, weight, height velocity, and pubertal staging) was performed at 3-month intervals for 6 months. Kidney, liver, and thyroid function was checked in all children at baseline, and, in the groups under treatment, after 3 and 6 months; in addition, an oral glucose tolerance test and glycosylated hemoglobin eval¬ uation were performed before and after treatment in group 4 only. A roentgenogram of the left hand for bone age evaluation was performed at baseline and at the end of the study period. Height was measured with a wall-mounted Harpender stadiometer; bone age was determined by an experienced examiner using the standards of Greulich and Pyle. The HV before the study was calculated based on measurements taken in the pre¬ ceding year and expressed as the HVSDS corrected for bone age. An increase in HV greater than 2 cm/y was considered significant, because this approximates 2 SDs of the variation that occurs in whole-year HVs in normal prepubertal children.16 Serum GH, levothyroxine, triiodothyronine, thyroid-stimulating hormone, free thyroxine, and free triiodothyronine levels were measured as previously described.13,17 All results are expressed at mean±SD. For statistical analysis, we used the paired f test for comparisons within groups and the Newman-Keuls test for multiple comparisons among indepen¬ dent groups of data; correlations were evaluated by linear re¬ gression analysis.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 05/28/2015
=
Table 1.—Inclusion Criteria for
Entry in the Study
Birth weight appropriate for gestational age No evidence of systemic diseases, malnutrition, dysmorphic syndromes, or psychosocial disturbances Tanner stage 1 of pubertal development Height SD score < 2 Whole-year height velocity SD < -0.8 Growth hormone response to pharmacological stimuli >10 µg/L (insulin hypoglycemia, 0.1 U/kg intravenously, or clonidine, 100 µg/m2 by mouth) Normal thyroid function
Table 2.—Auxological Data Before and After the Study Period
Group Growth Control
Levodopa
Clonidine
Hormone
10
10
10
10
9.4±2.1
9.7±1.8
8.9±2.1
10.9±1.7
9.9 ±2.1
10.2 ±1.8
9.4 ±2.1
11.4 ±1.7
6.89±2.1
7.70±2.2
6.51 ±2.1
8.75 ±1.9
7.88 ±1.8
8.21 ±2.4
7.12 ±1.9
9.57 ±1.9
3.7 ±1.2
3.9 ±0.6
3.8 ±1.0*
3.9 ±0.6*
3.5±0.6
4.5 ± 1.3
5.0±1.1*
6.8±1.0*
-
RESULTS At inclusion, mean chronological age, bone age, HV, height SD score (HSDS), and HVSDS corrected for bone age were similar in all groups (Table 2). There were also no differences in mean midparental height (group 1, 160.4. ±4 cm; group 2, 157.5±4 cm; group 3, 157.3±6 cm; and group 4, 157.9±6 cm). Results at the end of the study period are shown in Table 2 and Fig 1 and can be summarized as follows: Group l.-The HV and HVSDS did not significantly change in the 6-month follow-up. However, there was a significant decrease in the HSDS ( 2.3±0.4 vs 2.4±0.4,
P
