0021-972X/01/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 2001 by The Endocrine Society
Vol. 86, No. 4 Printed in U.S.A.
Growth Hormone Therapy Alone or in Combination with Gonadotropin-Releasing Hormone Analog Therapy to Improve the Height Deficit in Children with Congenital Adrenal Hyperplasia* JOSE BERNARDO Q. QUINTOS, MARIA G. VOGIATZI, MADELEINE D. HARBISON, AND MARIA I. NEW Department of Pediatrics, Division of Pediatric Endocrinology, Weill Medical College of Cornell University-New York Presbyterian Hospital, New York City, New York 10021 ABSTRACT Short stature in the adult patient with congenital adrenal hyperplasia (CAH) is commonly seen, even among patients in excellent adrenal control during childhood and puberty. In this study we examine the effect of GH therapy on height prediction in children with both CAH and compromised height prediction. Leuprolide acetate, a GnRH analog (GnRHa), was given to patients with evidence of early puberty. GH (n ⫽ 12) or the combination of GH and GnRHa (n ⫽ 8) was administered to 20 patients with CAH while they continued therapy with glucocorticoids. Each patient in the treatment group was matched according to age, sex, bone age, puberty, and type of CAH with another CAH patient treated only with glucocorticoid replacement. The match was made at the start of GH treatment. Of the 20 patients, 12 have completed 2 yr of therapy. After 1 yr of GH or combination GH and GnRHa therapy, the mean growth rate increased from 5 ⫾ 1.9 to 7.8 ⫾ 1.6 cm/yr vs. 5.4 ⫾ 1.7 to 5 ⫾ 2 cm/yr in the group not receiving GH (P ⬍ 0.0001). During the
C
ONGENITAL ADRENAL hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) or 11-hydroxylase deficiency (11-OHD) results in short adult stature even if good adrenal hormonal control is maintained throughout childhood and puberty. The adult height may be as low as 2 sd below the mean (1–3). The cause of adult short stature in patients with 21-OHD or 11-OHD is unknown; however, the following factors have been suggested 1) elevated adrenal androgens, which cause advanced epiphyseal maturation and premature epiphyseal fusion; 2) early or precocious puberty, which also leads to premature epiphyseal fusion; and c) overtreatment with glucocorticoids (4 –7). If patients with CAH are treated with doses of glucocorticoids sufficient to suppress precursor hormone to the normal range, an unacceptable degree of hypercortisolism is commonly observed. Glucocorticoid-induced growth suppression is complex, involving several steps in the hypothaReceived October 27, 2000. Revision received December 14, 2000. Accepted December 29, 2000. Address all correspondence and requests for reprints to: Maria I. New, M.D., Weill Medical College of Cornell University/New York Presbyterian Hospital, 525 East 68th Street, M-622, New York, New York 10021. E-mail:
[email protected]. * This work was supported in part by USPHS Grant HD-00072, General Clinical Research Center Grant 06020, and Eli Lilly & Co.
second year of treatment, the mean growth rate was 6 ⫾ 1.6 vs. 4.2 ⫾ 2.1 cm/yr in the group not receiving GH (P ⬍ 0.001). The height SD score for chronological age in the treatment group at the end of 1 and 2 yr of treatment improved significantly more than the nontreatment group (P ⬍ 0.01). A similar improvement in the height SD score for bone age was found in the treatment group after 1 (⫺1.4 ⫾ 0.9 vs. ⫺1.7 ⫾ 0.9; P ⬍ 0.0001) and 2 yr of therapy (⫺0.67 ⫾ 0.68 vs. ⫺1.7 ⫾ 1.2; P ⬍ 0.0004). The mean predicted adult height improved from 159 ⫾ 11 (baseline) to 170 ⫾ 7.5 cm (after 2 yr of therapy) closely approximating target height (173 ⫾ 8 cm). All patients continued the hydrocortisone treatment. In patients with CAH and compromised height prediction, treatment with GH or the combination of GH and GnRHa results in an improvement of growth rate and height prediction and a reduction in height deficit for bone age. (J Clin Endocrinol Metab 86: 1511–1517, 2001)
lamic-pituitary-insulin-like growth factor I (IGF-I) axis, including inhibition of endogenous GH secretion, as well as other well known catabolic effects such as a decrease in intestinal calcium adsorption (8). Children with CAH may develop early central precocious puberty due to bone age advancement, further compromising final height. Treatment with GnRH analog (GnRHa) is effective in arresting central puberty (9, 10), but frequently results in concomitant deceleration of growth rate. This study examines the effect of GH therapy on growth in prepubertal children with CAH. Recombinant GH has been given alone or in combination with GnRHa in pubertal patients in an effort to improve the height deficit of these CAH patients. Glucocorticoid therapy was continued to maintain optimal suppression of adrenal androgen secretion. Subjects and Methods Subjects The study participants (treatment group) consisted of 20 patients with CAH documented by clinical, hormonal, and DNA evidence. Inclusion criteria were 1) age more than 4 yr, 2) bone age more than 2.0 sd advanced for their chronological age, or 3) height prediction by BaileyPinneau at least 2.0 sd below their target height. Patients 18 and 19 were exceptions to the inclusion criteria of a height prediction greater than 2 sd below the mean. Both patients were treated with GH and GnRHa, and had height predictions between 1 and 2 sd below their target height. Their height deficit therefore was 1–2 sd, and both benefited significantly
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compared with controls (Table 1a). Patients 9 and 15 were also treated with GH, although their height predictions were less than 2 sd below the mean. Both patients demonstrated significant deterioration in their height prediction for 2 consecutive yr before enrollment, which prompted treatment with GH. The results proved that treatment was beneficial, and their data are therefore included in this paper. Exclusion criteria were 1) patients with bone age greater than 14 for boys and 13 for girls, 2) medical disorder or treatment with medications other than hydrocortisone known to impair growth, and 3) noncompliance with medical treatment. The control group was a historical group that consisted of 20 CAH patients with similarly compromised height predictions as the treatment group but who did not receive GH or GnRHa. The patients in the control group have been followed for 6 –30 yr in the same clinic, by the same physician, using the same protocol as the treatment group. The treatment group and control group were matched for sex, chronological age (CA), bone age (BA), pubertal status, and type of CAH at the start of GH treatment. The growth parameters were compared.
Study design The institutional review committee of our hospital approved the study, and informed consent was obtained from the patients and their parents. Upon enrollment in the study, patient’s weight, height, and Tanner status were recorded. BA and serum IGF-I and IGF-binding protein-3 (IGFBP-3) measurements were made. Pubertal status was assessed clinically and hormonally by LH-releasing hormone (LHRH) test (gonadorelin hydrochloride, 100 g/m2, iv). Plasma LH and FSH levels were evaluated at 0, 15, 30, 60, 90, and 120 min after the iv administration of LHRH. A pubertal response was defined as a peak LH value of at least 10 mIU/L. See Table 1a for clinical characteristics of all patients. All patients in the treatment group were treated at the outset with recombinant human GH [somatropin (ribosomal DNA origin)] at a dose of 0.3 mg/kg䡠week, sc, 7 days/week. In 9 of the 20 treated patients, GH was provided by Eli Lilly & Co. (Indianapolis, IN). All pubertal patients were additionally treated with GnRHa (leuprolide acetate) at a dosage of 300 g/kg every 28 days. Patients continued to receive glucocorticoid therapy to maintain optimal suppression of adrenal steroids. Mineralocorticoid replacement therapy was added in salt-wasting patients. Both control and treated patients were evaluated at 3-month intervals for assessment of height, weight, pubertal development, and adrenal steroids. Height was measured three times at each visit with a Harpenden stadiometer. The average of the three measurements was used in data analysis. A LHRH test was performed every 6 months. Pubertal patients had LHRH stimulation testing 3 months after initiation of GnRHa therapy and then repeat testing every 6 months. GnRHa doses were adjusted if follow-up LHRH test was not suppressed. BA was determined annually according to the method of Greulich and Pyle (11) by a single observer, and adult height was predicted according to the Bayley-Pinneau method (12). Target height was calculated according to the method of Tanner et al. (13). Height deficit was calculated in centimeters as the difference in target height and predicted adult height. Blood for measurement of IGF-I and IGFBP-3 concentrations, thyroid function tests, complete blood count, and glycosylated hemoglobin (HgbA1c) was obtained annually from patients in the treatment group. Serum adrenal steroid concentrations were measured every 3 months in the early morning (0830 – 0930 h), approximately 2 h after morning medications, in both treated and control groups. Good control of adrenal secretion was defined as a serum 17-hydroxyprogesterone (17-OHP) value of 300 –1000 ng/dL, poor control as a serum 17-OHP value greater than 1000 ng/dL, and oversuppression as a 17-OHP level less than 300 ng/dL (2). Serum ⌬4-androstenedione concentrations were analyzed similarly based on norms appropriate for the subject’s Tanner stage (mean ⫾ sd). The dose of glucocorticoid was adjusted to maintain the morning serum 17-OHP concentrations between 300 and 1000 ng/dL and serum ⌬4-androstenedione levels within the age-appropriate norms. PRA was measured every 3 months and maintained in the normal range for age.
Hormone assay Serum adrenal steroid concentrations were measured according to previously reported methods (14). Plasma LH and FSH concentrations were determined with a commercial microparticle enzyme immunoas-
say (Abbott Laboratories, North Chicago, IL). The lowest limit of sensitivity was 0.5 mIU/mL (n ⫽ 51 runs in replicates of 10), defined as the concentration at 2 sd from the AxSYM LH calibrator A (0 mIU/mL), and it represents the lowest measurable concentration of LH that can be distinguished from zero. IGF-I was extracted from serum using ethanol HCl, and then serum was assayed by RIA (SmithKline Beecham, Vanuys, CA). IGFBP-3 was assayed using a specific high affinity polyclonal antibody directed against the binding subunit, IGFBP-3 (Endocrine Sciences, Inc., Tarzana, CA).
Statistical analysis The primary end-point variables for this study are the following: height (and sd score) for CA, height (and sd score) for BA, predicted height (and sd score), height deficit, and growth rate. The Wilcoxon sign-rank test was used to compare the mean raw scores and sd scores for the primary end-point variables between time points (i.e. between baseline and yr 1, baseline and yr 2, yr 1 and yr 2) within each treatment and control group. The height sd score for chronological age was obtained by dividing the difference of the patient’s height (x) and the mean height for age (X) by the sd for age (sd score ⫽ x ⫺ X/sd). Height sd score for BA was obtained by dividing the difference of the patient’s height for BA and the mean height for bone age by the sd for bone age. A result was considered statistically significant if P ⬍ 0.01.
Results Baseline characteristics
The mean baseline characteristics of the treatment and control groups were similar (Table 1b). The majority of the patients were male (13 of 20), and the mean age at enrollment was 8.6 yr (range, 4.75–13.7 yr). BA was markedly advanced compared with CA (mean BA advancement, 3.2 yr) in both groups. Height sd scores for CA of both groups were close to 1 sd above the mean (0.82 ⫾ 1.2 treatment group vs. 0.98 ⫾ 1.4 control group, P ⫽ NS). Height sd score for bone age, however, was about 2 sd below the mean (treatment group, ⫺2.1 ⫾ 1.0; control group, ⫺2.0 ⫾ 1.1; P ⫽ NS). The mean predicted adult height (PAH), therefore, was poor in both groups (PAH: treatment group, 159 ⫾ 10.9 cm; control group, 161 ⫾ 9.2 cm; P ⫽ NS; PAH [sd]: treatment group, ⫺2.0 ⫾ 1.2; control group, ⫺1.7 ⫾ 1.3; P ⫽ NS). All patients were treated with glucocorticoids (and mineralocorticoid replacement was used in the salt-wasting patients), and the degree of adrenal hormonal control in both groups was the same throughout the study (P ⫽ NS). The mean hydrocortisone dose was the same in both groups (14 vs. 17 mg/m2䡠day; P ⫽ NS). Of the 20 patients, 12 were prepubertal, and 8 were in puberty at the time of enrollment. Simple virilizing CAH complicated by central precocious puberty was observed in 2 patients, and the remaining 6 patients were in early puberty with compromised height prediction. Thus, at enrollment 8 patients received the regimen of hydrocortisone, GnRHa, and GH, and 12 patients received hydrocortisone and GH alone. None of the prepubertal patients began puberty in the course of the study. Response to GH and GnRHa therapy
Pubertal stage, plasma gonadotropin, and sex steroid levels. Treatment with GnRHa suppressed sexual development. Peak LH and FSH plasma levels after GnRHa treatment were significantly lower after 3 months of therapy [peak LH pre-GnRHa therapy, 13.6 ⫾ 8.3 IU/L; post-GnRHa,
GnRHa⫹GH
GnRHa⫹GH
GnRHa⫹GH
GnRHa⫹GH
GnRHa⫹GH
GnRHa⫹GH
GnRHa⫹GH
GnRHa⫹GH
GH
GH
GH
GH
GH
GH
GH
GH
GH
GH
GH
GH
Treatment Sex
F F F F F F F F M M M M M M M M M M M M M M M M F F F F F F M M M M M M M M M M
Type of CAH
11OHD SV SW SW NC NC NC NC SV SV 11OHD SV SW SW SV SV SW SW SW SW SV SV NC NC SW SW NC NC SW SW SV SV SW SW SV SV NC NC NC NC 157.3 162.5 151.3 163.8 165.0 162.0 156.8 162.0 178.4 174.0 175.8 176.8 181.6 170.1 173.0 161.2 171.4 170.1 180.0 171.4 177.8 175.2 169.5 184.0 167.7 163.8 167.6 172.7 162.5 161.0 174.0 174.0 184.0 167.0 184.0 179.7 177.8 180.0 172.5 176.5
Target ht (cm)
5.2 5.0 6.5 6.9 7.8 7.8 9.6 10.8 4.8 4.8 6.7 6.6 7.0 7.1 7.5 7.0 8.2 7.8 8.3 9.2 8.4 8.8 9.3 9.1 9.8 10.0 10.6 9.9 10.8 10.9 6.3 6.0 10.0 10.0 10.1 10.5 11.0 10.5 13.7 12.8
CA (yr)
a
CA, Chronological age; BA, bone age; a, control. Patient has not yet finished second year of treatment.
1 1a 2 2a 3 3a 4 4a 5 5a 6 6a 7 7a 8 8a 9 9a 10 10a 11 11a 12 12a 13 13a 14 14a 15 15a 16 16a 17 17a 18 18a 19 19a 20 20a
Patient no.
10.0 10.2 10.5 11.0 9.7 10.0 10.8 12.0 8.7 9.0 13.2 12.5 10.0 10.0 10.9 10.0 10.8 10.5 12.5 13.0 11.9 11.0 12.9 11.8 11.1 11.0 12.8 13.0 12.5 12.0 12.8 13.0 13.5 13.4 13.2 16.0 13.5 13.0 14.5 13.5
BA (yr)
TABLE 1a. Comparison between treatment and control groups
108.2 118.0 118.0 123.4 130.1 132.2 129.2 148.6 121.0 118.5 137.5 129.0 118.3 120.6 125.1 115.0 129.2 127.2 134.3 132.0 134.1 130.0 132.2 142.5 138.3 138.0 146.0 145.0 146.0 153.1 129.1 141.7 148.1 143.0 154.1 151.0 149.3 147.0 155.3 152.0
Ht (cm)
Pred. ht (cm)
130.6 140.0 137.8 149.9 158.0 160.0 148.0 165.0 165.0 164.5 160.0 155.7 158.3 161.4 163.0 154.0 168.8 167.8 162.0 155.2 168.0 169.0 156.0 178.0 153.0 152.0 154.0 154.0 158.0 170.0 154.0 166.7 169.0 165.0 176.0 154.0 170.6 172.9 164.0 168.5
Baseline
⫺26.7 ⫺22.5 ⫺13.5 ⫺13.9 ⫺7.0 ⫺2.3 ⫺8.8 3.0 ⫺13.8 ⫺9.5 ⫺15.8 ⫺21.0 ⫺23.3 ⫺8.7 ⫺10.0 ⫺7.2 ⫺3.4 ⫺2.3 ⫺18.0 ⫺16.2 ⫺9.8 ⫺6.0 ⫺13.5 ⫺6.0 ⫺14.7 ⫺11.2 ⫺13.6 ⫺18.7 ⫺4.5 9.0 ⫺20.0 ⫺7.3 ⫺14.8 ⫺1.7 ⫺8.0 ⫺25.3 ⫺7.2 ⫺7.1 ⫺8.5 ⫺8.0
Ht deficit (cm)
6.1 6.2 7.3 8.0 8.6 8.8 10.7 11.8 5.7 5.9 7.7 7.6 7.8 8.1 8.5 8.0 9.2 8.9 9.3 10.1 9.4 10.3 10.3 10.2 10.7 11.0 11.6 10.9 11.8 11.8 7.4 7.1 11.0 11.3 10.9 11.0 12.0 11.5 14.6 14.0
CA
10.5 11.0 11.0 11.0 10.7 11.0 12.0 13.0 9.7 9.4 13.3 13.0 11.6 10.0 10.9 10.0 11.5 11.0 13.0 13.5 12.6 12.0 12.9 12.5 12.0 12.0 13.2 14.0 13.0 14.4 12.8 14.0 13.5 14.0 13.1 16.0 14.0 14.0 14.5 15.5
BA
116.9 122.0 127.0 128.4 137.5 137.4 140.2 153.4 129.0 127.3 144.9 131.0 131.5 126.2 131.9 121.0 135.3 131.3 141.8 135.8 143.4 137.5 139.5 150.0 146.6 143.5 152.0 151.9 153.9 157.1 136.0 144.0 157.8 151.0 158.4 151.0 157.4 150.3 160.6 154.5
Ht
Year 1
136.5 138.0 144.0 145.4 161.7 155.6 156.6 162.3 174.0 174.0 167.9 154.0 166.4 168.9 173.0 162.0 172.0 171.1 166.8 155.0 172.0 170.0 164.8 181.5 162.7 155.6 159.0 156.0 162.8 160.0 162.2 159.0 180.0 167.2 185.0 154.0 173.9 166.0 169.4 159.1
Pred. ht
⫺20.8 ⫺24.5 ⫺7 ⫺18.4 ⫺3.4 ⫺6.4 ⫺1.2 0.3 ⫺4.4 0.0 ⫺7.9 ⫺23.0 ⫺15.2 ⫺1.3 0.0 0.8 1.0 0.9 ⫺13.2 ⫺16.4 ⫺5.8 ⫺5.2 ⫺4.7 ⫺2.5 ⫺5.0 ⫺8.2 ⫺8.6 ⫺16.7 0.3 ⫺1.0 ⫺11.8 ⫺15.0 ⫺4.0 0.5 1.0 ⫺25.7 ⫺3.9 ⫺14.0 ⫺3.1 ⫺17.4
Ht deficit
12.5 12.0 12.7 12.8 8.3 8.1 12.0 12.3 12.0 12.0 12.6 12.7 15.6 15.0
10.6 11.5 11.1 11.0
9.5 9.4
8.6 8.8
11.6 12.8
CA
13.5 15.0 13.5 17.0 12.8 14.5 14.5 15.5 14.0 17.0 14.0 14.0 15.0 17.0
13.2 13.5 13.5 13.0
11.5 13.0
13.5 14.0
12.3 13.5
BA
156.5 155.6 158.3 159.4 141.8 152.0 162.8 157.2 164.0 152.0 161.7 159.2 163.4 154.0
154.0 143.5 145.5 155.9
138.7 129.0
150.0 133.0
147.1 158.8
Ht
Year 2
162.0 157.8 162.5 159.5 169.0 163.4 175.0 161.8 181.2 154.0 178.6 175.0 168.8 155.5
179.0 164.0 165.7 180.0
176.0 151.7
171.0 146.9
157.8 163.0
Pred. ht
5.6 ⫺14.9 0.0 ⫺1.4 ⫺5.0 ⫺10.6 ⫺9.0 ⫺4.9 ⫺2.8 ⫺25.7 0.8 ⫺5.0 ⫺3.7 ⫺21.0
a
a
1.2 ⫺11.2 ⫺3.8 ⫺4.0
a
a
a
a
3.5 ⫺9.5
a
a
4.8 ⫺29.9
a
a
1.0 1.0
a
a
a
a
a
a
Ht deficit
EFFECT OF GH AND GnRH THERAPY ON HEIGHT IN CAH 1513
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TABLE 1b. Auxological characteristics of treatment and control group at baseline Variables
Treatment group
Control group
N M:F CA (yr) BA (yr) Ht (cm) Ht SD score-CA Ht SD score-BA Pubertal status (no. of patients in puberty) Predicted adult ht (cm) Predicted height SD score Target ht (cm) Ht deficit (cm)
20.0 13:7 8.6 ⫾ 2.2 11.8 ⫾ 1.6 134 ⫾ 12.8 0.82 ⫾ 1.2 ⫺2.1 ⫾ 1.0 8/20 159 ⫾ 10.9 ⫺2.0 ⫾ 1.2 171 ⫾ 9 ⫺12 ⫾ 6.1
20 13:7 8.6 ⫾ 2.1 11.8 ⫾ 1.6 135 ⫾ 12.3 0.98 ⫾ 1.4 ⫺1.96 ⫾ 1.1 8/20 161 ⫾ 9.2 ⫺1.7 ⫾ 1.3 170 ⫾ 7 ⫺9 ⫾ 8.4
Values are expressed as the mean ⫾
SD.
CA, Chronological age; BA, bone age.
year (0.27 ⫾ 0.34 vs. 1.1 ⫾ 0.8; P ⬍ 0.01) and second year of therapy (0.6 ⫾ 0.3 vs. 2.3 ⫾ 1.5; P ⬍ 0.01). Growth rate, height sd score for CA, height sd score for BA, predicted adult height, target height, height deficit for the GH alone and GnRHa plus GH patients are presented in Tables 2a and 2b.
FIG. 1. Growth rate (centimeters per yr) between the treatment and control groups.
2.06 ⫾ 1.1 IU/L (P ⬍ 0.05); peak FSH pre-GnRHa, 4.38 ⫾ 1.3 IU/L; post-GnRHa, 1.3 ⫾ 1 IU/L]. Testosterone levels in males were significantly lower (P ⬍ 0.05) than pre-GnRHa levels (115 ⫾ 69 vs. 18 ⫾ 25 ng/dL). Growth rate and bone maturation. The pretreatment growth rate in the total cohort (n ⫽ 20 patients) was the same in both groups (treatment, 5.0 ⫾ 1.9 cm/yr; control, 5.4 ⫾ 1.8 cm/yr; P ⫽ NS; Fig. 1). After 12 months of GH therapy, the mean growth rate improved in the treatment group compared to the control group (7.8 ⫾ 1.6 vs. 5.0 ⫾ 2.0 cm/yr; P ⬍ 0.001). Growth rate, however, then decreased to 6.0 ⫾ 1.6 cm/yr after the second year in the treatment group and 4.2 ⫾ 2.2 cm/yr in the control group (P ⬍ 0.001; Tables 2a and 2b). Height sd score for CA improved in the treatment group compared with the control group after the first year (1.1 ⫾ 1.0 vs. 0.84 ⫾ 1.2; P ⬍ 0.01) and second year (1.1 ⫾ 1.3 vs. 0.7 ⫾ 1.6; P ⬍ 0.01) of therapy. Similar improvement in the height sd score for BA was found in the treatment group compared with the control group after 1 yr (⫺1.4 ⫾ 0.9 vs. ⫺1.7 ⫾ 0.9; P ⬍ 0.0001) and 2 yr of therapy (⫺0.67 ⫾ 0.68 vs. ⫺1.7 ⫾ 1.2; P ⬍ 0.0004). In the prepubertal patients who received GH alone, the degree of BA advancement (0.65 ⫾ 0.5 and 0.85 ⫾ 0.47 yr at 1 and 2 yr, respectively) was not different from the control group (0.5 ⫾ 0.4 and 1.9 ⫾ 0.8 yr; P ⫽ NS). In the pubertal patients who received GnRHa plus GH, there was less BA advancement compared with the controls during the first
Predicted and target heights. Predicted adult height improved significantly in the treatment group by 6.7 ⫾ 2.4 cm (P ⬍ 0.0001) and 8.8 ⫾ 3.3 cm (P ⬍ 0.0004) during the first and second years of treatment (Fig. 2). Predicted adult height in the control group remained unchanged (baseline, 161 ⫾ 9.2 cm; yr 1, 160 ⫾ 9.9 cm; yr 2, 161 ⫾ 9.3 cm). Predicted height sd score significantly improved at yr 1 (P ⬍ 0.0003) and yr 2 (P ⬍ 0.0004) in the treatment group (⫺1.18 ⫾ 1.2 and ⫺0.26 ⫾ 0.69, respectively). The height deficit sd score significantly improved at yr 1 (P ⬍ 0.007) and yr 2 (P ⬍ 0.01) of therapy (⫺1.38 ⫾ 0.71 and ⫺0.65 ⫾ 0.54; Fig. 3). Improvement in predicted adult height was not significantly different between both subgroups (GH alone, GnRHa and GH). Laboratory and adverse events
Mean IGF-I (303 ⫾ 151 ng/mL), IGFBP-3 (4.3 ⫾ 1.09 mg/ L), and HgbA1c (4.9 ⫾ 0.1%) levels before GH therapy were within the normal range for CAs and BAs. There was not a statistically significant change in IGFBP-3 and HgbA1c levels after 1 and 2 yr of treatment within the treatment group. The treatment group, however, had a statistically significant increase in IGF-I levels (mean IGF-I level, 421 ⫾ 171 ng/mL; P ⬍ 0.05) after the first year of treatment. IGF-I levels after the second year did not reach statistical significance (477 ⫾ 210 ng/mL), which was due to the small sample size and large sd. HgbA1c was 5.1 ⫾ 0.1% at the end of the second year of therapy in the treatment group. The patients receiving GH or GnRHa and GH therapy reported no adverse events (e.g. diabetes, malignancy, slipped capital femoral epiphyses, and pseudotumor cerebri), and to date no participant in the treatment group has withdrawn from the study. Discussion
The treatment of CAH with glucocorticoids has remained the same since they were introduced in 1950 (15). Despite adequate treatment, final height has been suboptimal for most patients (1, 2). The present study demonstrates that treatment with GH alone or in combination with a GnRH
EFFECT OF GH AND GnRH THERAPY ON HEIGHT IN CAH
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TABLE 2a. Auxological data before and during treatment (GH alone) Treatment Group Variables
CA (yr) BA (yr) Growth rate (cm/yr) Ht SD score-CA Ht SD score-BA Predicted adult ht (cm) Predicted ht SD score Ht deficit (cm) Ht deficit SD score Target Ht (cm)
Baseline (n ⫽ 12)
7.4 ⫾ 1.5 11 ⫾ 1.3 5.1 ⫾ 1.9 0.6 ⫾ 1.2 ⫺2.7⫾ 0.9 156 ⫾ 12 ⫺2.5 ⫾ 1.1 ⫺13.5 ⫾ 6.8 ⫺2.4 ⫾ 0.9 170 ⫾ 10
Control Group
Yr 1 (n ⫽ 12)
Yr 2 (n ⫽ 5)
Baseline (n ⫽ 12)
Yr 1 (n ⫽ 12)
Yr 2 (n ⫽ 5)
8.4 ⫾ 1.5 11.6 ⫾ 1.1 8.2 ⫾ 1.4a 1.1 ⫾ 1.1a ⫺1.9 ⫾ 0.7a 162 ⫾ 12a ⫺1.7 ⫾ 1.0a ⫺6.9 ⫾ 6.5a ⫺1.6 ⫾ 0.7a 170 ⫾ 10
10 ⫾ 1.2 12.8 ⫾ 0.8 7.4 ⫾ 1.2 1.3 ⫾ 1.5a ⫺1.0 ⫾ 0.4a 170 ⫾ 8.4a ⫺0.6 ⫾ 0.7a ⫺0.5 ⫾ 3.6a ⫺0.6 ⫾ 0.4a 171 ⫾ 8.3
7.5 ⫾ 1.7 10.9 ⫾ 12.2 5 ⫾ 1.8 0.7 ⫾ 1.0 ⫺2.3 ⫾ 1.0 160 ⫾ 10 ⫺1.9 ⫾ 1.4 ⫺9.4 ⫾ 7.7 ⫺2.0 ⫾ 0.8 168 ⫾ 7.3
8.6 ⫾ 1.7 11.5 ⫾ 1.3 4.8 ⫾ 1.4 0.5 ⫾ 0.9 ⫺1.9 ⫾ 1.0 160 ⫾ 12 ⫺1.7 ⫾ 1.5 ⫺9.4 ⫾ 10 ⫺1.6 ⫾ 0.9 169 ⫾ 7.3
10.7 ⫾ 1.6 13.4 ⫾ 0.4 4.3 ⫾ 1.5 0.2 ⫾ 0.9 ⫺1.9 ⫾ 1.5 161 ⫾ 13 ⫺2.0 ⫾ 2.0 ⫺10.7 ⫾ 11 ⫺2.1 ⫾ 0.9 172 ⫾ 10
Values are expressed as the mean ⫾ SD; CA, Chronological age; BA, bone age; P values are derived from treatment vs. control in yr 1 and treatment vs. control in yr 2 compared with baseline. a P ⬍ 0.01. TABLE 2b. Auxological data before and during treatment (GnRHa ⫹ GH) Treatment Group
Control Group
Variables
Baseline (n ⫽ 8)
Yr 1 (n ⫽ 8)
Yr 2 (n ⫽ 7)
Baseline (n ⫽ 8)
Yr 1 (n ⫽ 8)
Yr 2 (n ⫽ 7)
CA (yr) BA (yr) Growth rate (cm/yr) Ht SD score-CA Ht SD score-BA Predicted adult ht (cm) Predicted adult ht SD score Ht deficit (cm) Ht deficit SD score Target ht (cm)
10.3 ⫾ 2 13 ⫾ 1 5 ⫾ 1.9 1.15 ⫾ 1 ⫺1.4 ⫾ 0.8 162 ⫾ 8.8 ⫺1.4 ⫾ 0.9 ⫺11.4 ⫾ 5.1 ⫺1.65 ⫾ 0.7 174 ⫾ 7.8
11.2 ⫾ 2 13.2 ⫾ 0.8a 7.3 ⫾ 1.7 1.0 ⫾ 1.1a ⫺0.7 ⫾ 0.7a 169 ⫾ 9a ⫺0.4 ⫾ 0.9a ⫺4.5 ⫾ 4.0a ⫺0.9 ⫾ 0.6a 174 ⫾ 7.8
12.2 ⫾ 2.1 13.9 ⫾ 0.7a 5.2 ⫾ 1.4a 1.0 ⫾ 1.2a ⫺0.4 ⫾ 0.6 171 ⫾ 7.5a ⫺0.3 ⫾ 0.8a ⫺3.6 ⫾ 3.4a ⫺0.6 ⫾ 0.6a 174 ⫾ 8
10 ⫾ 1.9 13.1 ⫾ 1.4 6.3 ⫾ 1.3 1.3 ⫾ 1.6 ⫺1.4 ⫾ 0.9 163 ⫾ 8.2 ⫺1.4 ⫾ 1.2 ⫺8.5 ⫾ 9.9 ⫺1.2 ⫾ 1.2 172 ⫾ 7.2
11 ⫾ 1.9 14.2 ⫾ 1.2 5.4 ⫾ 2.8 1.2 ⫾ 1.6 ⫺1.5 ⫾ 0.8 160 ⫾ 4.8 ⫺1.8 ⫾ 0.9 ⫺12 ⫾ 8.8 ⫺1.3 ⫾ 1.2 172 ⫾ 7.2
12.1 ⫾ 2.0 15.7 ⫾ 1.3 4.2 ⫾ 2.6 1.1 ⫾ 2.0 ⫺1.6 ⫾ 1.1 161 ⫾ 7 ⫺1.8 ⫾ 1.2 ⫺12 ⫾ 9 ⫺1.4 ⫾ 1.4 173 ⫾ 7
Values are expressed as the mean ⫾ SD; CA, Chronological age; BA, bone age. P values are derived from treatment vs. control in yr 1 and treatment vs. control in yr 2 compared with baseline. a P ⬍ 0.01.
FIG. 2. Predicted adult height (centimeters) before and during treatment in both the treatment and control groups.
agonist (depot leuprolide acetate) improves the growth rate, height deficit, and height prediction of these patients. The goal of CAH therapy for children involves the delicate balance of suppressing adrenal androgen secretion with glucocorticoid administration while maintaining normal growth. That glucocorticoids can induce growth suppression is well known, even when relatively modest replacement doses of steroids are administered (8). The pathogenesis of the growth retardation related to glu-
FIG. 3. Height deficit (centimeters) before and during treatment in both the treatment and control groups.
cocorticoid administration is multifactorial (8). Glucocorticoids interfere with nitrogen and mineral retention, inhibit bone formation directly and indirectly, inhibit chondrocyte mitosis, impair collagen synthesis and its degradation, inhibit pulsatile GH release, reduce GH receptor expression and signal transduction, and inhibit IGF-I bioactivity (16). In addition to congenital adrenal hyperplasia, growth retardation may occur when corticosteroids are used to treat other chronic conditions of childhood such as asthma, nephrotic syndrome, juvenile rheumatoid arthritis, inflammatory bowel disease, and chronic active hepatitis (17).
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QUINTOS ET AL.
Furthermore, children with CAH frequently manifest significant advancement of BA due to excess adrenal androgen secretion, which leads to both short adult height and increased risk for precocious or early puberty. Early puberty may additionally compromise final adult height. GnRH analog therapy in children with CAH and central precocious puberty results in a deceleration of bone age advancement, but frequently in a parallel decrease in growth velocity as well (10). It is therefore unlikely that GnRH analog therapy alone will result in significant recovery of the height deficit in these children. Although it has been predicted that GH administration would improve the growth retardation in CAH patients, this is the first report of the use of GH alone or in combination with GnRH analog in CAH patients with compromised height prediction. A clinical trial was conducted involving 83 poorly growing glucocorticoid-dependent children who were diagnosed with disorders including juvenile rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, systemic lupus erthematosis, and nephrotic syndrome. Recombinant GH was used in 32 of the patients (18), and it was found that the growth-suppressing effects of glucocorticoids can be counterbalanced by GH at doses commonly prescribed for GH deficiency (0.3 mg/kg䡠week). The mean response was a doubling of the baseline growth rate, and responsiveness to GH was negatively correlated with the glucocorticoid dose. The beneficial effects of 1 yr of GH administration on growth velocity and body composition were also demonstrated in 14 children with juvenile chronic arthritis treated long term with glucocorticoids (17). GH treatment increased plasma IGF-I and IGFBP-3 to above normal levels. All patients showed an increase in growth velocity, and mean growth velocity increased from 1.9 to 5.4 cm/yr. Animal studies likewise (19 –21) showed that GH reversed the growth inhibition caused by glucocorticoid treatment. In our cohort of 20 children, the mean growth rate was improved with GH treatment compared with that in the nontreated group, resulting in an improvement in height sd for CA and improved adult height prediction. The positive effects on height prediction were sustained during both years of the trial, to the extent that the height prediction at the end of the 2 yr was very close to the target height. A possible explanation for the excellent response to GH treatment in CAH patients (in contrast to non-CAH individuals with normal GH levels) may be that the excess adrenal androgen secretion, which is not completely suppressed by glucocorticoid treatment, acts synergistically with GH to cause growth acceleration. A close examination of individual patient data in Table 1 reveals that with the exception of patient 5, treatment with GH or combined GH and GnRHa resulted in a decrease in height deficit in every patient compared with the controls. For patient 5, the decrease in height deficit was equal to that of the control. Note that in patient 4, although it may appear that the final height deficit of control and treated patients are the same, the treated patient at baseline had a much greater height deficit. Another control patient (no. 6a) had a greater height deficit at the outset than did the treated match (patient 6), but over 2 yr of follow-up the treated patient’s height
deficit improved, and the control’s worsened. Control patient 14a also had a greater baseline height deficit than the treated match (patient 14); however, patient 14 was significantly closer to target height than patient 14a after 2 yr of treatment. Statistically significant beneficial effects were found in both prepubertal children (GH therapy) and pubertal children (combination of GH and GnRHa) when the data were analyzed separately. The results of GH therapy in prepubertal children during the second year of the study demonstrate improvement in predicted height, height deficit, and bone age sd score; however, the change in growth rate did not reach statistical significance. These results should be interpreted with caution, because only 5 of the 12 children completed both years of the trial. A larger number of patients treated with GH is needed to confirm the present beneficial findings. Pubertal children treated with a combination of GH and GnRHa manifested a decrease in bone age advancement while maintaining a growth rate similar to that of children during puberty. The above can be translated into an improvement of adult height prediction. The authors also recognizes that BA reading is an imperfect science; therefore, the same physician read all BAs in an effort to standardize the methodology in both groups. The present study is unique in that both treated and untreated patients were followed longitudinally by the same investigator in an identical fashion using the same treatment regimen to control adrenal steroid secretion. In addition, we were able to match each GH-treated child with a subject treated with glucocorticoids only, according to multiple parameters, minimizing a possible bias involved in the selection process of a control group. The findings of this study indicate that GH therapy improves the height deficit and compromised height prediction in children with CAH, certainly by the end of the first year of treatment and probably by the end of the second year. Acknowledgment We express our appreciation to Andrea Putnam for her editorial assistance in the preparation of this manuscript, and Cristina Sison, Ph.D., for her assistance with statistical analysis.
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IOF-Servier Young Investigator Fellowship The International Osteoporosis Foundation is pleased to announce the joint winners of the first IOF-Servier Young Investigator Fellowship: Dr. Freda Wynne of the University College of Cork and Dr. Luigi Gennari of the University of Florence. Call for applications: The next Fellowship will be awarded during the IOF-World Congress on Osteoporosis in Lisbon, May 2002. Financed by an unrestricted grant offered by Servier Research Group, the IOF-Servier Young Investigator Research Fellowship is an award of 40,000 Euros to encourage young scientists under the age of 40 to engage in high-quality research in the field of osteoporosis. Deadline for submission of applications: January 15, 2002. For eligibility criteria and application forms please see the IOF web site at www.osteofound.org or contact the IOF secretarial office (
[email protected]) at: International Osteoporosis Foundation, 71 cours Albert Thomas, 69447 Lyon Cedex 03 France. Phone: 33 4 72 91 41 77.
