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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2128
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3318-3325
Copyright © 2005 by The Endocrine Society

Treatment with Growth Hormone and Luteinizing Hormone Releasing Hormone Analog Improves Final Adult Height in Children with Congenital Adrenal Hyperplasia

Karen Lin-Su, Maria G. Vogiatzi, Ian Marshall, Madeleine D. Harbison, Maria C. Macapagal, Brian Betensky, Susan Tansil and Maria I. New

Department of Pediatrics (K.L.-S., M.D.H., M.C.M., S.T., M.I.N.), Mount Sinai School of Medicine, New York, New York 10029; Department of Pediatric Endocrinology (M.G.V., B.B.), Weill Medical College of Cornell University, New York, New York 10021; and Department of Pediatric Endocrinology (I.M.), Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901

Address all correspondence and requests for reprints to: Maria I. New, M.D., Mount Sinai Medical Center, 1 Gustave L. Levy Place, Box 1198, New York, New York 10029. E-mail: maria.new{at}mssm.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Final adult height is often compromised in children with congenital adrenal hyperplasia (CAH). This study examines the impact of GH and LHRH analog (LHRHa) on final adult height in patients with CAH due to 21-hydroxylase deficiency. Fourteen patients with CAH (eight males, six females) predicted to be more than 1.0 SD below their midparental target height received GH and LHRHa until final height. Each patient was matched at the start of GH therapy to a CAH patient treated only with glucocorticoids according to type of CAH, sex, and chronological age. Mean age, bone age, height, height prediction, and target height were the same in both groups at the beginning of GH therapy. Mean duration of GH treatment was 4.4 ± 1.5 yr. Mean duration of LHRHa therapy was 4.2 ± 2.0 yr. In the treatment group, final height SD score of –0.4 + 0.8 was significantly greater than both the initial prediction of –1.5 ± 0.9 (P < 0.0001) and the final height SD score of the untreated group of –1.4 ± 1.1 (P = 0.01). Our results indicate that the combination of GH and LHRHa improves final adult height in patients with CAH.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
FINAL ADULT HEIGHT is often significantly compromised in patients with congenital adrenal hyperplasia (CAH) (1, 2, 3), of which the most common form is 21-hydroxylase deficiency (21-OHD). Due to excess androgens that do not require 21-hydroxylase for synthesis (4), affected children often develop accelerated linear growth during childhood accompanied by premature epiphyseal fusion (5), ultimately resulting in reduced adult height compared with their parentally determined target height (6, 7, 8, 9, 10, 11, 12).

Adult short stature is a salient complication of CAH even when patients are appropriately treated with glucocorticoid replacement. Previous studies (7, 8, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22) have demonstrated that the adult height reached by patients with CAH is generally below their target height (calculated on the basis of gender and midparental height) (23, 24) and that the degree of hormonal control does not correlate directly with the degree of short stature. Data from our group and others suggest that patients with CAH are about 10 cm shorter than their parentally based target height (9, 15, 25, 26, 27, 28). Likewise, Yu and Grant (18) found the mean adult height SD scores (SDSs) of women treated for CAH in childhood to be 1.2 SD below that expected for parental heights.

Failure to achieve optimal adult height in patients with CAH may be due to several different factors. First, high levels of adrenal androgens result in rapid somatic growth, which is accompanied by premature fusion of the epiphyses and ultimate short stature. Second, central precocious puberty often develops in patients with CAH due to androgen activation of the hypothalamic-pituitary-gonadal axis, thus exacerbating premature epiphyseal fusion (29, 30). Lastly, the treatment of CAH with glucocorticoids can suppress growth and diminish final height (31, 32, 33). Unfortunately, the necessary treatment with glucorticoid replacement has not allowed for satisfactory adrenal suppression without producing an unacceptable degree of iatrogenic hypercortisolism. Moreover, long-term administration of glucocorticoids, even at replacement doses, has been associated with poor growth (34). Glucocorticoids exert multiple growth-suppressing effects, interfering with endogenous GH secretion, IGF-I bioactivity, as well as bone formation and collagen formation, processes essential for normal growth (28).

Prospective treatments for preventing the complication of adult short stature can be targeted at the problems described above. The mainstay of treatment for CAH has long been glucocorticoid replacement, and the suppression of ACTH-driven adrenal androgens should theoretically improve height prognosis; however, as mentioned above, even patients who demonstrate adequate hormonal control frequently do not reach their target height. Central precocious puberty can be effectively suppressed by the administration of an LHRH analog (LHRHa). Because treatment with LHRHa is often accompanied by a concomitant deceleration of growth velocity, however, it is unlikely to have a significant impact on final height by itself. GH is a potential treatment that could counter the growth-suppressing effects of glucocorticoids and LHRHa and thus improve final height. In children with central precocious puberty, the combination of GH and LHRHa has been shown to be effective in improving height prediction and final height (35, 36). Moreover, Allen et al. (37) demonstrated that GH treatment can reverse the growth-suppressing effects of glucorticoids, as evidenced by a doubling of growth velocity in children treated with chronic glucocorticoids.

Our group has previously reported a significant improvement in growth velocity and in height prediction in children with CAH after 2 yr of GH with or without LHRHa (16). This study now reports the effect of GH in combination with LHRHa on final adult height in patients with CAH.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study was a nonrandomized study. All patients who were eligible for the study were offered entry. The treatment group consisted of 14 patients with CAH because of 21-OHD, documented by clinical, hormonal, and DNA evidence. Inclusion criteria were bone age (BA) more than 6 yr, BA greater than 1.0 SD ahead of chronological age (CA), and adult height prediction by the Bayley-Pinneau method (38) of at least 1.0 SD below target height. Exclusion criteria were BA greater than 14 yr for males and 13 yr for females, medical disorder or treatment with medications other than hydrocortisone known to impair growth, or noncompliance with medical treatment for CAH.

Subjects for the comparison group were selected from historical CAH patients never treated with GH or LHRHa and concurrent CAH patients who chose not to enroll in the study, all followed by the same physician. Using a computerized database, possible controls were identified for each treated subject by matching for gender, type of CAH, and CA. If more than one possible match was available, the subject with the most similar BA and target height was selected. The comparison group consisted of 14 patients affected with 21-OHD and with compromised height predictions similar to the treatment group but who did not receive either GH or LHRHa. Eleven of the 14 were historical patients, and three of the 14 were concurrent patients who declined treatment. All subjects in the untreated group were under the care of the same physician as the treatment group and received the same regimen for glucocorticoid replacement.

Study design

The institutional review board approved the study, and informed assent and consent were obtained from the subjects and their parents or guardians. Upon enrollment and every 3 months, each subject was evaluated for height, weight, pubertal status, and adrenal hormones. Height was recorded to the nearest 0.1 cm as the average of three measurements using a Harpenden stadiometer. Midparental target height was calculated according to the method of Tanner et al. (24). BA was determined annually according to the method of Greulich and Pyle (39). Predicted adult height was calculated using BA and height according to the Bayley-Pinneau method (38). Height discrepancy was calculated as predicted height minus target height. Final height discrepancy was calculated as final adult height minus target height. Gain in height was defined as final height minus baseline height prediction.

For the treatment group, pubertal status was assessed hormonally at baseline using a 2-h iv LHRH stimulation test. Central puberty was defined as peak LH/FSH ratio more than 1 after LHRH stimulation (40). If the subject demonstrated central puberty at baseline, treatment with LHRHa was initiated. If the subject was prepubertal at baseline, an LHRH stimulation test was repeated annually or at the first sign of clinical puberty. LHRHa was initiated in all subjects in the treatment group once central puberty was documented. The untreated group was not formally tested for onset of central puberty because they were not treated with an LHRHa. Age at onset of puberty was estimated by presence of testicular volume of 4 cc in males and by onset of breast development (Tanner stage II) in females.

All subjects in the treatment group received recombinant human GH [somatropin (ribosomal DNA origin)] at a dose of 0.3 mg/kg·wk divided into seven sc doses per week. GH treatment was continued until final height was reached. Final height was defined as a growth velocity less than 1.5 cm/yr over a 6-month period and BA of 15 yr in girls or 17 yr in boys. In six of the treated subjects, GH was provided by Eli Lilly & Co. (Indianapolis, IN). The remaining eight received GH through their medical insurance. All pubertal patients were additionally treated with LHRHa (leuprolide acetate) at a dosage of 300 µg/kg im every 28 d. The cost of LHRHa was covered through the patients’ medical insurance plans. LHRHa was continued until there was no longer any height discrepancy, i.e. height prediction equaled or exceeded target height, as long as the child was at an appropriate CA for puberty. If the height discrepancy was never recovered, then LHRHa was discontinued when the growth velocity fell to less than 3 cm/yr over a 6-month period with a BA of at least 13 yr in girls and 14 yr in boys. Blood for measurement of IGF-I, IGF binding protein 3, thyroid function, and hemoglobin A1c was obtained annually in patients in the treatment group.

All subjects in both groups received glucocorticoid therapy, the dose of which was adjusted as necessary to maintain optimal suppression of adrenal steroids [target 17-hydroxyprogesterone (17-OHP) levels < 1000 ng/dl]. Additionally, mineralocorticoid replacement therapy in the form of fludrocortisone (0.1–0.15 mg daily) was given to all patients classified with salt-wasting CAH, as determined by either a history of salt-wasting crisis or undetectable aldosterone levels. Good adrenal control was defined as more than 75% of 17-OHP levels less than 1000 ng/dl. Fair adrenal control was defined as 25–75% of 17-OHP levels less than 1000 ng/dl. Poor control was defined as less than 25% of 17-OHP levels less than 1000 ng/dl.

Statistical analysis

The primary endpoint variables were growth velocity, final adult height SDS, final height discrepancy, and gain in height. A t test was used to compare the mean raw scores and SDS for the primary end-point variables between the treated and untreated groups. Comparisons using paired Student’s t test were also made within the treatment group between time points, i.e. baseline height prediction compared with final height as well as baseline height discrepancy compared with final height discrepancy. Pearson correlation was used to measure the association between continuous variables. A result was considered statistically significant if P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics

The mean baseline characteristics were similar between the treated and untreated groups (Table 1Go). Males and females were equally enrolled (8:6), and the mean age of enrollment was 9.67 yr (range, 6.3–13.7). Each group had nine classical patients and five nonclassical patients. BA was markedly advanced compared with CA in both groups (mean advancement, 2.8 yr).


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  		TABLE 1. Baseline characteristics of subjects

 
Mean height SDS for CA was above the mean in both groups [treated, 0.73 ± 1.3; untreated, 0.64 ± 1.0, P = not significant (NS)]. Mean height SDS for BA, however, was below the mean in both groups (treated, –1.6 ± 0.8; untreated, –1.5 ± 1.3, P = NS). Mean predicted height SDS was equally poor in both groups (treated, –1.5 ± 0.9; untreated, –1.4 ± 1.1, P = NS) compared with target height SDS, which was equivalent in both groups (treated, 0.01 ± 0.8; untreated, –0.06 cm ± 0.8, P = NS).

Adrenal hormone control

During the treatment period, both groups had similar numbers of subjects in good, fair, or poor control. The treatment group had seven good, five fair, and two poor. The untreated group had five good, seven fair, and two poor. In the treatment group, there was no difference with respect to adrenal control in final height SDS (good, –0.21 + 0.7; fair, –0.68 + 0.5; poor, –0.37 + 2.0, P = NS) or gain in height SDS (good, 1.3 + 0.7; fair, 1.0 + 0.8; poor, 0.7 + 0.7, P = NS).

Duration of GH and LHRHa therapy

The mean age at the start of GH treatment was 9.67 ± 2.00 yr, and the mean age at completion of GH treatment was 14.1 ± 1.71 yr. The mean duration of GH treatment was 4.4 ± 1.5 yr (range, 2.6–7.9). There was not a significant correlation between duration of GH treatment and gain in height. There was, however, a significant negative correlation between age at the start of GH and gain in height (r = –0.55, P = 0.02).

The mean age at initiation of LHRHa therapy was 9.47 ± 2.0 yr, and the mean age at completion of LHRHa therapy was 13.63 ± 1.2 yr. The mean duration of LHRHa therapy was 4.2 ± 2.0 yr. There was not a significant correlation between gain in height and duration of LHRHa treatment or age at the start of LHRHa. Of the 14 subjects, eight started LHRHa treatment before starting GH. Of those eight subjects, four were on LHRHa for at least 1 yr before starting GH (range, 1.0–3.93 yr) due to central precocious puberty (onset of central puberty before age 8 yr in girls or before age 9 yr in boys) (41) that was diagnosed before initiation of the study. The other four subjects were on LHRHa for less than 1 yr before starting GH (range, 0.25–0.55 yr). These subjects were started on LHRHa for a short period before GH due to earlier availability of the medication but were not on LHRHa long enough for there to have been a substantial impact before GH and were effectively more similar to the subjects who were started on LHRHa and GH simultaneously. There were no statistical differences between the four subjects who received LHRHa for at least 1 yr before GH and the other 10 subjects in terms of baseline height prediction SDS, baseline height discrepancy, initial BA, final height SDS, or gain in height SDS (see Table 2Go).


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  		TABLE 2. Subjects treated with LHRHa for >1 yr prior to GH

 
Onset of puberty

Five of the 14 subjects in the treatment group had central precocious puberty compared with only one of the 14 subjects in the untreated group. However, the groups were still similar with regards to onset of puberty in that the majority of subjects (10 of 14 in each group) had early onset of puberty (before age 10 in girls and age 11 in boys) (41). The mean age at onset of puberty was not statistically different between the two groups (9.15 ± 2.1 yr in the treated group and 9.94 ± 1.3 yr in the untreated group, P = 0.13).

Growth velocity and bone maturation

Growth velocity was significantly higher in the treated group compared with the untreated group in yr 1–4 (using Bonferroni adjustments for multiple comparisons) (Fig. 1Go). The difference in growth velocity was not statistically significant by yr 5 of GH; however, there were only four subjects receiving GH in the 5th yr. Baseline growth velocity was actually significantly higher in the untreated group than the treated group (untreated, 6.5 ± 1.3 cm/yr; treatment, 5.1 ± 1.7 cm/yr, P < 0.05), most likely reflecting the four subjects in the treatment group who received LHRHa therapy for at least 1 yr before the time of enrollment. When the four subjects who received prior LHRHa therapy and their respective matches are removed from analysis for yr 0, there was no significant difference in baseline growth velocity between the groups (untreated, 6.7 ± 1.5 cm/yr; treated, 5.4 ± 1.7 cm/yr, P = NS).



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  		FIG. 1. Growth velocity from study yr 0–5 in untreated and treated subjects. Average growth velocity of normal population for age (mean age of subjects during treatment year) is demonstrated in dashed line. Expressed as mean ± SE. *, Significant difference at P < 0.05 adjusting for the number of comparisons.

 
BA did not differ significantly between the two groups in yr 0–5 (Fig. 2Go).



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  		FIG. 2. BA from yr 0–5 of treatment (P = NS). Expressed as mean ± SE.

 
Final adult height

Final adult height SDS improved significantly in the treatment group compared with the baseline height prediction SDS (–0.4 ± 0.8 vs. –1.5 ± 0.9, P < 0.0001). Mean final adult height SDS of –0.4 ± 0.8 in the treatment group was also significantly better than the mean final adult height SDS of –1.4 ± 1.1 in the untreated group (P = 0.01) (Fig. 3Go). Mean final adult height in the treated group was 171.5 ± 6.1 cm for males (compared with 163.1 ± 5.6 cm in untreated group) and 163.6 ± 3.4 cm for females (compared with 158.4 ± 8.4 cm in untreated group).



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  		FIG. 3. Predicted and final height SDS of control and treated groups. Final height SDS of treated group is significantly greater than baseline predicted height SDS (P < 0.0001). Final height SDS of treated group is also significantly greater than final height SDS of control group (P < 0.01).

 
The final height discrepancy compared with baseline height discrepancy was significantly reduced in the treatment group (–2.8 ± 4.3 cm vs. –10.3 ± 4.4 cm, P < 0.0001). The final height discrepancy of –2.8 ± 4.3 cm was also significantly better than the final height discrepancy of –9.6 ± 8.8 cm in the untreated group, P < 0.01) (Fig. 4Go). Gain in height was significantly greater in the treatment group than in the untreated group (7.4 ± 4.9 cm vs. –0.5 ± 6.6 cm, P = 0.001) (Table 3Go). Mean gain in height in the treated group was 6.46 ± 5.4 cm for males and 8.75 ± 4.3 cm for females (P = NS).



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  		FIG. 4. Height discrepancy before and after treatment for untreated and treated groups. Final height discrepancy in treatment group significantly reduced compared with baseline height discrepancy, P < 0.0001. Final height discrepancy in treatment group significantly reduced compared with untreated group, P < 0.01. Expressed as mean ± SE.

 

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  		TABLE 3. Final adult height

 
Classical vs. nonclassical patients

In the treatment group, there were no statistical differences between classical and nonclassical patients in terms of baseline height prediction SDS, baseline height discrepancy, initial BA, final height SDS, or gain in height SDS (Table 4Go).


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  		TABLE 4. Classical patients compared to nonclassical patients in treatment group

 
Adverse events

IGF-I and IGF binding protein 3 levels did not exceed the normal range for BA in any subject in the treatment group. Hemoglobin A1c and thyroid function remained normal in all subjects in the treatment group. Patients receiving GH reported no adverse events, e.g. diabetes, malignancy, slipped capital femoral epiphyses, or pseudotumor cerebri. Most patients receiving LHRHa reported some discomfort at the injection site, but none reported any significant adverse events, e.g. sterile abscess or infection. All of the study participants remained in the study until completion. Compliance with the study medications was monitored by interviews with parents and subjects at each visit and was additionally monitored via returned empty vials in those subjects receiving GH from Eli Lilly & Co. Reported compliance with GH and LHRHa therapy was more than 90% in all subjects.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Since its introduction in 1950 (42), replacement glucocorticoid therapy remains the fundamental treatment for CAH. The growth-suppressing effects of glucocorticoids, however, combined with the customary high androgens in CAH limit the height potential in children affected with CAH. Although they are quite often tall children, most patients with CAH complete their growth prematurely and are ultimately short adults. Historically, GH has been effective in improving growth velocity in children receiving chronic glucocorticoid therapy (43). GH has also been used in conjunction with LHRHa to improve final height in children with central precocious puberty (35, 36). This study is the first to demonstrate a significant improvement in final adult height outcome in CAH children who are treated with the combination of GH and LHRHa.

The combined treatment of GH and LHRHa targets the various problems causing short stature in children with CAH. LHRHa suppresses central puberty to prevent rapid epiphyseal advancement, whereas GH counters the deceleration in growth velocity that is a hallmark of both LHRHa and glucocorticoid therapy. As demonstrated in this study, growth velocity was significantly higher in the treated group than the untreated group for the first 4 yr of therapy. When the four subjects who received LHRHa for at least 1 yr before GH were included in analysis, the baseline growth velocity was significantly higher in the control group than in the treated group. This difference can probably be attributed to the deceleration in growth velocity commonly seen with LHRHa therapy because the difference was no longer seen when those four subjects and their controls were removed from analysis. Growth velocity was still increased in the 5th yr of treatment but was not statistically evident due to the small number of patients still receiving GH. Some of the effect of GH on growth velocity in these subjects may also be due to the high level of adrenal androgens typical of CAH, which can act synergistically with GH to cause growth acceleration.

The mean gain in height after treatment was 7.3 cm (range, 0–16.3 cm). There was only one subject who did not appear to have any impact of treatment because his final adult height was equivalent to his initial height prediction. Even though there was no apparent height gain in this particular subject, at least there was no loss of height compared with the initial height prediction. In contrast, six of the 15 untreated subjects ended with final adult heights that were below their baseline height predictions, with one patient losing as much as 15.1 cm.

Despite the notable improvement in final height outcome, the mean final height of the treated group was still 3 cm below the midparental target height. One explanation might be that adrenal control was not optimal in all subjects. In fact, less than half (seven of 15) were considered to be in good control. Nevertheless, surprisingly there was no evidence that adrenal control played a role in final height or in degree of height gain. On the other hand, perhaps there is an imperfect correlation between adrenal control reflected by 17-OHP levels and the androgen levels that are ultimately responsible for BA advancement. It is also possible that earlier initiation of GH would have had a greater impact on final height outcome, as suggested by the significant negative correlation found between age at the start of GH and gain in height.

Severity of disease (classical vs. nonclassical) did not appear to be a factor in response to treatment. There was no difference in baseline characteristics, gain in height, or final height between the two groups. Despite having milder disease, the nonclassical patients had similarly compromised height predictions as the classical patients at the start of treatment, presumably due to fact that only the more severely affected nonclassical patients fulfilled the study’s inclusion criteria in the first place. Moreover, nonclassical patients generally are not identified in the neonatal period and, therefore, do not have the benefit of being treated with glucocorticoid replacement from birth as do classical patients. This delay in treatment in nonclassical patients may explain their similar risk to classical patients for advanced BA and compromised height prediction.

Because the primary treatment goal of this study was to reduce the height discrepancy present at baseline, the timing of LHRHa discontinuation in this study was aimed at maximizing the benefit of GH by delaying epiphyseal fusion. LHRHa therapy was discontinued when there was no longer a height discrepancy (predicted height matched target height) assuming that they were at a socially acceptable age to enter puberty and were psychologically ready. Although one could argue that prolonged pubertal suppression during adolescence may not be warranted and could be potentially psychologically harmful, in this particular subject population, the majority of the subjects (10 of 14) had early onset of central puberty, and all of the subjects had advanced BAs. The mean duration of LHRHa therapy was only 4.2 yr, and the mean age at which LHRHa therapy was discontinued was 13.63 yr, which is in the normal age range for puberty to begin. On the other hand, the rationale for adding LHRHa therapy to GH was to delay epiphyseal fusion, but we were not able to demonstrate a statistically significant difference in BA between the treated and untreated groups. Future studies looking at GH alone compared with GH combined with LHRHa may help to clarify the role of LHRHa in children with CAH who enter central puberty within the normal age range.

This study’s distinction stems from the unique opportunity of the same investigator to follow both treated and untreated subjects longitudinally with otherwise equivalent treatment regimens. Moreover, the two groups were well-matched according to numerous parameters, hopefully minimizing confounding factors that may have influenced the results. As in our previously published manuscript reporting improvement in growth velocity and predicted height (16), the comparison group was largely comprised of historical patients because the majority of patients who were offered treatment accepted treatment. Although it is possible that unidentified differences between the historical patients and the treated subjects might have influenced the study results, both groups received equivalent glucocorticoid/mineralocorticoid treatment by the same physician and were well-matched according to parameters that were felt to be relevant to the study. Likewise, because three of the untreated subjects were patients who declined treatment, it is possible that there was some degree of selection bias that somehow influenced the results. Irrespective of any differences that might exist between the treatment and comparison groups, however, this study more importantly demonstrated a significant improvement within the treatment group between baseline height prediction and final outcome.

The findings presented in this study indicate that GH in combination with LHRHa is an effective therapy for improving adult height in CAH. The promising results from this study pave the way for other potential treatment strategies because there are still a multitude of factors that play a role in growth and final height in patients with CAH that have not been completely elucidated. The variability in outcome underscores the importance of continuing investigation into the optimal treatment for improving stature in patients with CAH.


   Footnotes
 
This work was supported in part by United States Public Health Service Grant HD-00072, by General Clinical Research Center Grant 06020, and by Eli Lilly & Co.

First Published Online March 29, 2005

Abbreviations: BA, Bone age; CA, chronological age; CAH, congenital adrenal hyperplasia; LHRHa, LHRH analog; NS, not significant; 21-OHD, 21-hydroxylase deficiency; 17-OHP, 17-hydroxyprogesterone; SDS, SD score.

Received October 29, 2004.

Accepted March 17, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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