| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Clinical Research Centers |
Department of Pediatrics, Division of Pediatric Endocrinology, Weill Medical College of Cornell University-New York Presbyterian Hospital, New York City, New York 10021
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: minew{at}med.cornell.edu
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
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 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.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The cause of adult short stature in patients with 21-OHD or 11ß-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, 5, 6, 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 hypothalamic-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 |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
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 Bailey-Pinneau 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 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.
|
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 µg/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·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 µg/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 immunoassay (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-3ß (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 |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
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.
|
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·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, 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).
|
|
|
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 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.
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).
|
|
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 |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
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 glucocorticoid 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).
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·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, 20, 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 1a 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.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received October 27, 2000.
Revised December 14, 2000.
Accepted December 29, 2000.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  A Luczay, D Torok, A Ferenczi, J Majnik, J Solyom, and G. Fekete Potential advantage of N363S glucocorticoid receptor polymorphism in 21-hydroxylase deficiency. Eur. J. Endocrinol., June 1, 2006; 154(6): 859 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Lin-Su, M. G. Vogiatzi, I. Marshall, M. D. Harbison, M. C. Macapagal, B. Betensky, S. Tansil, and M. I. New Treatment with Growth Hormone and Luteinizing Hormone Releasing Hormone Analog Improves Final Adult Height in Children with Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3318 - 3325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Speiser and P. C. White Congenital Adrenal Hyperplasia N. Engl. J. Med., August 21, 2003; 349(8): 776 - 788. [Full Text] [PDF]
|
|
|
|
|
|
Joint LWPES/ESPE CAH Working Group Consensus Statement on 21-Hydroxylase Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4048 - 4053. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
