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Reduced Final Height Outcome in Congenital Adrenal Hyperplasia under Prednisone Treatment: Deceleration of Growth Velocity during Puberty

University Children’s Hospital, Ludwig Maximilians University, Division of Pediatric Endocrinology, D-80337 Munich, Germany

Address all correspondence and requests for reprints to: Walter Bonfig, M.D., University Children’s Hospital, Department of Endocrinology, Ludwig Maximilians University, Lindwurmstr. 4, D-80337 Munich, Germany. E-mail: wbonfig{at}web.de or walter.bonfig{at}med.uni-muenchen.de.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Normal to decreased final height (FH) has been reported in patients with congenital adrenal hyperplasia (CAH).

Objective: The objective was to determine FH outcome and influences of steroid treatment.

Methods: The effects of glucocorticoid treatment for classical CAH were retrospectively studied in 125 patients (77 females). Growth pattern, FH, and pubertal development were recorded.

Results: Corrected FH was in the lower range of genetic potential [females with simple virilizing (SV)-CAH, –0.6 ± 1.0 SD score (SDS) vs. females with salt-wasting (SW)-CAH, –0.6 ± 0.9 SDS; males with SV-CAH, –1.1 ± 0.9 SDS vs. males with SW-CAH, –0.9 ± 0.9 SDS]. Total pubertal growth was significantly reduced in comparison with a reference population (females with SV-CAH, 11.9 ± 6.5 cm, and females with SW-CAH, 13.8 ± 7.6 cm vs. reference 20.3 ± 6.8 cm, P < 0.01; and males with SV-CAH, 15.4 ± 6.6 cm, and males with SW-CAH, 18.5 ± 6.9 cm vs. reference 28.2 ± 8.2 cm, P < 0.01). Thirty-three patients had been treated with prednisone, which resulted in reduced FH compared with patients (n = 92) treated with hydrocortisone (–1.0 ± 0.9 SDS vs.–0.6 ± 0.9 SDS; P < 0.05). FH correlated negatively with hydrocortisone dose given at the start of puberty (r = –0.3; P < 0.05). Pubertal development started early in boys [9.8 ± 2.3 yr (SV) and 10.6 ± 1.9 yr (SW)] and was timely in girls [9.8 ± 1.9 yr (SV) and 10.3 ± 1.5 yr (SW), menarche at 13.3 ± 1.7 yr (SV) and 13.7 ± 1.5 yr (SV)].

Conclusion: Patients with CAH are able to achieve adequate FH with conventional therapy. Total pubertal growth is significantly decreased, and treatment with prednisone results in decreased FH. In addition to biochemical analysis, treatment should be adjusted to normal growth velocity, especially during puberty.

	Introduction

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CONGENITAL ADRENAL HYPERPLASIA (CAH) is caused by the loss or severe decrease in activity in one of the five steroidogenic enzymes involved in cortisol biosynthesis. In 90–95% of all cases 21-hydroxylase deficiency is found (1). It is caused by mutations in the 21-hydroxylase gene (CYP21), which is located in the human leukocyte antigen gene cluster region on the short arm of chromosome 6 (6p21.3) (2). The disease can be divided into the classical and nonclassical forms. The worldwide incidence of classical 21-hydroxylase deficiency is approximately 1 in 14,000 births (3). Therefore, carrier frequency of this autosomal recessive disease is about 1 in 60. The deficiency of 21-hydroxylase leads to accumulation of 17-hydroxyprogesterone and results in increased production of adrenal androgens and decreased production of glucocorticoids. In addition to impaired cortisol biosynthesis, aldosterone production may be decreased [salt-wasting (SW)-CAH].

In simple virilizing (SV) CAH, there is virilization of external genitalia in newborn females and pseudoprecocious puberty due to overproduction of androgens in both sexes. In SW-CAH, additional severe renal salt loss occurs as a consequence of aldosterone deficiency.

Overproduction of androgens causes virilization, accelerated growth, advanced skeletal maturation, and early epiphyseal fusion.

Management of children with CAH is a challenge with regard to growth outcome. Traditional treatment consists of substitution of cortisol to reduce excessive androgen production and its consequences. Undertreatment with steroids leads to androgen excess with advancement of bone age, and reduced final height (FH). In overtreatment, growth is suppressed by growth-inhibiting effects of steroids. Further side effects of overtreatment are truncal obesity and osteoporosis. Overtreatment is a greater risk when potent longer-acting glucocorticoids such as prednisone or dexamethasone are used. Therefore, there is only a narrow therapeutic window in the traditional treatment of CAH with glucocorticoids. Alternate approaches in the treatment of CAH have been investigated recently, including the use of antiandrogens, aromatase inhibitors, and adrenalectomy (4).

Adequacy of treatment is best evaluated by monitoring growth rate and skeletal maturation. In addition, urinary and serum analysis of steroid hormones and determination of 17-hydroxyprogesterone in saliva are used for evaluation of therapy (5).

Reports on long-term follow-up and FH outcome in patients with CAH are still sparse and heterogeneous. There is still controversy on certain factors and on critical periods of growth.

We report on 125 patients with CAH who have reached FH and who have been followed in our clinic since diagnosis of CAH.

	Patients and Methods

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At the end of 2003, a total of 157 patients with CAH due to 21-hydroxylase deficiency have reached FH. For 125 patients, additional data concerning development during infancy, childhood, and puberty and administered glucocorticoid doses were available. All patients were diagnosed and followed exclusively at our clinic.

All data were extracted retrospectively from the patients’ charts. The diagnosis of CAH was based on both clinical symptoms and signs, and later on hormonal analysis and comprehensive genotyping (6). At the time of diagnosis, newborn screening for CAH was not yet available.

Sixty-eight patients had SW-CAH (38 females, 30 males), and 57 patients had the SV form (39 females, 18 males). Patients with nonclassical forms of CAH were not included in this study. All patients were continuously cared for in our clinic, with follow-up appointments every 3 months during the first 2 yr of life and every 6 months in childhood and adolescence. In total, 33 patients had been treated with prednisone (twice daily) during infancy and childhood, whereas 92 patients had received hydrocortisone (three times daily) for glucocorticoid substitution only. Patients with SW-CAH received fludrocortisone in addition (treatment goal, plasma renin activity < 18 ng/ml·h until 6 months of age, < 5.5 ng/ml·h above the age of 6 months). Relative glucocorticoid potency was considered one for hydrocortisone and four for prednisone, so that we use a low-end estimate of hydrocortisone equivalency in our analysis.

Adjustment of glucocorticoid dose was made using auxological data (linear growth), skeletal maturity (treatment goal, bone age within 1 yr of chronological age), and hormonal data [treatment goal, serum 17-hydroxyprogesterone < 600 ng/dl and pregnanetriol (urinary steroid analysis) < 150 µg/d in newborns, < 500 µg/d in toddlers, < 1500 µg/d in children, and < 5000 µg/d in adults]. In toddlers and newborns only, catheterized urine collections were used for adjustment of therapy. None of the patients has received GnRH analog treatment to delay the onset of puberty.

Because patients were followed at a single center, we present data on a homogenous group of patients with CAH. Patients more than 18 yr of age were considered to have reached FH. In addition, growth velocity less than 1 cm/yr and fused epiphyses on x-rays were documented at FH. Total pubertal growth was defined as growth from onset of puberty (breast Tanner stage 2 in girls and testes volume greater than 3 ml) until FH. Target height (TH) was calculated as [maternal height + paternal height ± 13 cm]/2. Data on height and weight and glucocorticoid doses were evaluated at 2 yr of age, at the start of puberty (defined as breast Tanner stage 2 in girls, and testicular volume of 3 ml in boys), and at FH.

Height SD scores (SDS) were calculated with a growth calculator using the Prader reference data (7), which is used in southern Germany and the "Alpine" population (Switzerland, Austria, Southern Germany). Body mass index (BMI) was calculated as weight (kilograms)/ height (meters)². BMI-SDS was expressed with data published by Cole et al. (8).

Bone age was assessed by x-ray of the left hand using the Greulich and Pyle method (9).

The relation between achieved adult height and TH [corrected FH (corr FH)] is expressed as FH-SDS – TH-SDS and was calculated individually for each patient. Parental heights were asked and available on all patients. For analysis of pubertal growth, height-SDS at FH – height-SDS at onset of puberty was calculated, with negative values indicating a decreased pubertal growth spurt.

Statistical analyses were performed with the nonparametric Mann-Whitney U test for between-group comparisons (SW vs. SV CAH, females vs. males, hydrocortisone-treated patients vs. prednisone-treated patients). Spearman’s correlation coefficient was calculated to evaluate correlation of different variables (BMI-SDS at 2 yr, hydrocortisone dose at 2 yr and at start of puberty) with FH. Statistical analyses were done with the SPSS 10.0 software (SPSS Inc., Chicago, IL). A P value < 0.05 was considered statistically significant.

	Results

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Patients with SW-CAH were diagnosed early at a mean age of 0.3 yr (range, 0–2.7 yr; median, 0 yr), whereas patients with the SV form were diagnosed at a mean age of 2.2 yr (range, 0–6 yr; median, 2 yr). Once the diagnosis of SW-CAH had been established, only two patients had suffered from adrenal crisis.

Auxological data (Table 1)

Mean FH in females (n = 77) was 158.7 ± 6.3 cm (–1.0 ± 1.0 SDS); females with SW-CAH were significantly taller (160.3 ± 6.4 cm, –0.8 ± 0.9 SDS) than female patients with the SV form (157.2 ± 5.9 cm, –1.3 ± 1.0 SDS; P < 0.05).

TH-SDS was –0.4 ± 0.8 in females and –0.2 ± 0.6 in males, respectively. This means that parents of the patients with CAH were slightly shorter on average than adults in the normal population. Therefore, corr FH (FH-SDS – TH-SDS) was –0.6 ± 0.9 in females with SW-CAH and –0.6 ± 1.0 in females with SV-CAH (P > 0.05). The corr FH was –0.9 ± 0.9 in males with SW-CAH and –1.1 ± 0.9 SDS in males with SV-CAH (P > 0.05).

A total of 92 patients had been treated with hydrocortisone during infancy and childhood, and 33 patients had received prednisone exclusively during this period (Table 2).

View larger version (7K): [in this window] [in a new window]   FIG. 1. Significant correlation between corr FH-SDS and hydrocortisone or hydrocortisone equivalent dose at start of puberty (n = 125 patients).

Pubertal development (Table 4)

Puberty started regularly at the age of 10.1 ± 1.7 yr in girls [SW girls, 10.3 ± 1.5 yr, and SV girls, 9.8 ± 1.9 yr, compared with the reference population by Largo and Prader (10.9 ± 1.2 yr)], and rather early at the age of 10.3 ± 2.1 yr in boys [SW boys, 10.6 ± 1.9 yr, and SV boys, 9.8 ± 2.3 yr, compared with the reference data by Largo and Prader (11.8 ± 0.9 yr)]. Pubic hair Tanner stage 2 was observed early at 8.7 ± 2.7 yr in girls (SW-CAH, 9.4 ± 2.5, and SV-CAH, 8.0 ± 2.7) and also early in boys at the age of 8.9 ± 3.4 yr (SW-CAH, 10.1 ± 2.5, and SV-CAH, 7.0 ± 3.6 yr).

Menarche occurred at 13.5 ± 1.6 yr, with no significant difference between SW- and SV-CAH (P > 0.05). The age at menarche is comparable to that of the reference population by Largo and Prader (10).

The start of puberty in boys, defined as testicular volume greater than 3 ml, was significantly earlier in boys with SV-CAH than in boys with SW-CAH (9.8 ± 2.3 yr vs. 10.6 ± 1.9 yr; P < 0.05) and also earlier in all male patients than in the reference group by Largo and Prader (11).

BMI was found to be above average in CAH patients irrespective of the sex. At the onset of puberty, males had a mean BMI-SDS of 1.1 ± 0.9, which decreased to 0.9 ± 0.9 when FH was reached. In females there was no change of mean BMI-SDS, with 0.6 ± 1.1 at the start of puberty and 0.6 ± 1.3 at FH.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In our large cohort of homgeneously treated patients with CAH, we found that with regard to growth potential, puberty is an extremely critical period in the treatment of CAH. Total pubertal growth was significantly decreased in both forms of classical CAH, irrespective of the sex. An explanation for the decreased pubertal growth spurt could be a too tight control of the disease at the onset of puberty, so that the influence of the sex hormones on growth is suppressed, resulting in a less profound growth spurt. In addition, therapeutic doses of glucocorticoids increase hypothalamic somatostatin tone (12), resulting in inhibition of GH secretion, which normally peaks during puberty. Accordingly, hydrocortisone dose at the onset of puberty correlated negatively with FH. The pubertal growth was not poor due to prepubertal undertreatment with an advanced bone age at the onset of puberty (except for males with SV-CAH), because bone age was within 1 yr of chronological age in more than two thirds of the patients at that time. Acceleration of bone age in males with SV-CAH used to be caused by delayed diagnosis, but it is no longer a problem because newborn screening is available now. In a multinational study on growth patterns of patients with CAH, Frisch et al. (13) found a maximum growth velocity in the lower normal range. In their analysis of 41 CAH patients, Manoli et al. (14) confirmed that the height gain during puberty is one of the most potent predictors of FH, besides the type of CAH, mean hydrocortisone dose in the first 2 yr, and the mean BMI-SDS in early childhood and after puberty. Growth velocity was also found to be poor during pubertal years of 54 patients with CAH in a multicenter study by Muirhead et al. (15) and in former studies by Stikkelbroeck et al. (16) and Van der Kamp et al. (17). In contrast, in a multicenter study by Hargitai et al. (18), peak height velocity was normal in patients with CAH. In conclusion, maintenance of normal growth velocity is a very important variable in the assessment of control of CAH, especially during the first 6 months of life and during puberty, when growth velocity is fastest.

Overall corr FH in our patients with 21-hydroxylase deficiency was within 1 SD of TH, which is in accordance with most recent publications by Frisch et al. (13), Manoli et al. (14), Muirhead et al. (15), Eugster et al. (19), Balsamo et al. (20), and Pinto et al. (21), as with former publications (22, 23, 24, 25, 26, 27). However, others have found reduced FH in patients with CAH (17, 18, 28, 29, 30, 31, 32, 33). In contrast to publications by Balsamo et al. (20) and Pinto et al. (21), we found no differences of FH between the different forms of CAH when FH was corrected for TH.

A significant difference in the effect on FH was seen in the corticosteroid used for treatment of CAH. Use of prednisone resulted in higher hydrocortisone equivalent doses and significantly reduced FH. Because hydrocortisone equivalent doses correspond to the antiinflammatory, and not to the androgen and growth suppressant effects, the meaning of equivalent doses in the context of CAH remains unclear in some aspects. A small study of nine children by Punthakee et al. (34) suggests that prednisolone is up to 15 times more potent than hydrocortisone in the treatment of adrenal insufficiency. But there are no further data available on this topic, so we decided to use the established antiinflammatory-based equivalent doses. As experience shows, hydrocortisone is routinely used for teatment of CAH in infancy, childhood, and puberty in our days. To our knowledge, this is the first study to prove that treatment with prednisone leads to decreased growth in children and adolescents with CAH. We also conclude from our results that an optimal hydrocortisone dose during puberty should not exceed 20 mg/m² body surface area.

In contrast, Rivkees and Crawford (35) observed normal growth in a small cohort of children receiving dexamethasone treatment for CAH, although one has to be careful because these patients have not reached FH yet.

As reported before (29), pubertal development of boys, especially those with the SV form, started early (SV 9.8 yr and SW 10.6 yr; P = not significant) together with an acceleration of bone age in SV-CAH boys. In some of these patients, CAH was detected later in life because newborn screening was not available, which resulted in markedly advanced skeletal age at the time of their diagnosis. In girls, we found rather normal pubertal development, with menarche at a mean age of 13.5 yr (SV 13.3 yr and SW 13.7 yr; P = not significant). Age at menarche around 13.5 yr (range, 12.6–14.5 yr) has also been reported by Hughes and Read (36).

In summary, FH in CAH patients receiving traditional therapy is within the lower range of genetic potential. Total pubertal growth is significantly decreased in this cohort. Treatment with prednisone during childhood results in decreased FH. Accuracy of treatment should be monitored not only by biochemical assessment but also by careful follow-up of growth velocity especially during puberty. Thus, glucocorticoid doses should be adjusted (<20 mg hydrocortisone or hydrocortisone equivalent dose per square meter body surface area) in this rapid phase of growth and GnRH analog or aromatase inhibitor treatment should be considered in patients with advanced skeletal maturation.

	Footnotes

 
Disclosure Summary/Statement: The authors have nothing to disclose.

First Published Online February 13, 2007

Abbreviations: BMI, Body mass index; CAH, congenital adrenal hyperplasia; corr FH, corrected FH; FH, final height; SDS, SD score; SV, simple virilizing; SW, salt-wasting; TH, target height.

Received September 26, 2006.

Accepted February 2, 2007.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bonfig, W. Articles by Schwarz, H. P. Search for Related Content PubMed PubMed Citation Articles by Bonfig, W. Articles by Schwarz, H. P. Pubmed/NCBI databases OMIM Compound via MeSH Substance via MeSH Hazardous Substances DB HYDROCORTISONE PREDNISONE Medline Plus Health Information Steroids Related Collections Adrenal and Hypertension Pediatric Endocrinology