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Volume 6 • Issue 3        improving health . . . connecting people . . . saving lives      Fall 2007

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

Walter Bonfig, M.D.
University Children's Hospital, Ludwig Maximilians University, Division of Pediatric Endocrinology, D-80337 Munich, Germany

This article is a summary of an original paper in the Journal of Clinical Endocrinology and Metabolism, Volume 92, No. 5, May 2007, 1635-1639.

INTRODUCTION

Management of children with congenital adrenal hyperplasia (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 withadvancement of bone age, and reduced final height. 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.

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 are used for evaluation of therapy. Reports on long-term follow-up and final height 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 final height and who have been followed in our clinic since diagnosis of CAH.

RESULTS

In total, 33 patients had been treated with prednisone (two times daily) during infancy and childhood, whereas 92 patients had received hydrocortisone (three times daily) for glucocorticoid substitution only. Patients with salt-wasting

(SW) CAH received fludrocortisone in addition. Relative glucocorticoid potency was considered one for hydrocortisone and four for prednisone, so that we use a low-end estimate of hydrocortisone equivalence in our analysis. Since patients were followed at a single center, we present data on a homogenous group of patients with CAH.

Patients with salt-wasting CAH were diagnosed early at a mean age of 0.3 years [range 0-2.7 years, whereas patients with the simple virilizing form were diagnosed at a mean age of 2.2 years [range 0-6 years]. Once the diagnosis of SWCAH had been established, only two patients had suffered from adrenal crisis.

Mean final height in females (n=77) was 158.7±6.3 cm (-1.0±1.0 SDS): females with salt-wasting CAH were significantly taller (160.3±6.4 cm, -0.8±0.9 SDS) than female patients with the simple virilizing form (157.2±5.9 cm, -1.3±1.0 SDS), p<0.05.

In males (n=48), mean final height was 169.8±6.9 cm (-1.2±1.0 SDS): male patients with salt-wasting CAH reached a mean final height of 170.5±6.6 cm (-1.0 ± 1.0 SDS), and males with simple virilizing CAH a final height of 168.0±7.2 cm (-1.4 ± 0.9 SDS). There was no significant height difference between salt-wasting and simple virilizing CAH males (p>0.05), although metabolic control was worst in SV CAH males, indicated by most advanced bone age at onset of puberty.

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

In the hydrocortisone treated group there were 31 SW CAH females and 26 SV CAH females, and 22 SW CAH males and 13 SV CAH males. In the prednisone treated group 6 females and 8 males were salt-wasters, and 14 females and 5 males had the simple virilizing form of CAH. Hydrocortisone treated patients (Final Height-SDS –0.9±0.9) were significantly taller at final height than patients who were treated with prednisone (Final Height-SDS-1.6±1.0), p<0.01.

Prednisone treated patients did not have better suppression of adrenal androgen secretion. Hydrocortisone equivalent doses were significantly higher in the prednisone treated group at the age of two years (p<0.01) and at the start of puberty (p<0.01). Nevertheless, final height in all 125 patients showed no correlation with the hydrocortisone dose or hydro- cortisone equivalent dose given at two years of age (p>0.05), but final height correlated negatively with the dose given at start of puberty (r=-0.3, p<0.05).

Furthermore, patients treated with less than 20 mg hydrocortisone/m2 at start of puberty were significantly taller than patients who were given more than 20 mg hydrocortisone/ m2, p<0.05, irrespective of treatment with hydrocortisone or prednisone.

Mean height SDS at start of puberty was 0.3±1.4 (females 0.1±1.4 SDS and males 0.5±1.4 SDS), and decreased significantly to –0.5±1.2 SDS at the end of puberty (females –0.7±1.2 SDS and males –0.3±1.2 SDS), p<0.01, indicating an insufficient pubertal growth spurt. Total pubertal growth in females was 12.8±7.1 cm and 17.4±6.9 cm in males, which is significantly less than in the reference population of Prader et al with a mean pubertal growth in females 20.3±6.8 cm and 28.2±8.2 cm in males, p<0.01.

DISCUSSION

In our large cohort of homogeneously 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 sex hormones influence on growth is suppressed, resulting in a less profound growth spurt. Accordingly, hydro-cortisone dose at onset of puberty correlated negatively with final height. A significant difference in the effect on final height was seen in the cortic- osteroid used for treatment of CAH. Use of prednisone resulted in higher hydrocortisone equivalent doses and significantly reduced final height. Since hydrocortisone equivalent doses correspond to the anti-inflammatory, and not to the androgen and growth suppressant effects, the meaning of equivalent doses in the context of CAH remain unclear in some aspects.

As experience shows, hydrocortisone is routinely used for treatment 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 summary, final height 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 final height. Accuracy of treatment should not be monitored only by biochemical assessment, but also by careful follow-up of growth velocity especially during puberty. Thus glucocorticoid doses should be adjusted (below 20 mg hydrocortisone or hydrocortisone equivalent dose per m2 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.

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