Growth Hormone & IGF Research 15 (2005) S26S30 www.elsevier.

com/locate/ghir

A review of the eects of therapy on growth and bone mineralization in children with congenital adrenal hyperplasia
Mary Pat Gallagher *, Lenore S. Levine, Sharon E. Obereld
Division of Pediatric Endocrinology, Columbia University, College of Physicians & Surgeons, 622 West 168th Street, PH 5 East, Room 519, New York, NY 10032, United States

Abstract The medical management of children with congenital adrenal hyperplasia (CAH) can be challenging with regard to optimizing nal height. Insucient glucocorticoid suppression of adrenal hormone production will result in acceleration of bone maturation and premature epiphyseal fusion, while appropriate or excessive glucocorticoid therapy can be accompanied by suppression of the growth axis. The extent of the growth suppression appears to be aected by the type and dose of glucocorticoid. Some studies suggest that such growth suppression can be ameliorated through concomitant use of growth hormone (GH) therapy. Available data published over the last 10 years on height outcomes in CAH patients treated with glucocorticoids will be reviewed. 2005 Elsevier Ltd. All rights reserved.
Keywords: Congenital adrenal hyperplasia; Growth velocity; Bone mineralization; Glucocorticoids; Growth hormone

1. Background Congenital adrenal hyperplasia (CAH) is caused by autosomal recessive disorders of adrenal steroidogenesis, the most common of which is 21-hydroxylase deciency. The growth pattern of children with salt-wasting 21hydroxylase deciency is characterized by poor linear growth in infancy. Inadequate salt supplementation and excessive glucocorticoid therapy have been implicated as possible factors. In contrast, children with simple virilizing 21-hydroxylase deciencies often have a characteristic pattern of rapid linear growth during infancy, with advancement of bone age if the diagnosis is delayed until later in childhood. Later diagnosis has been implicated as a possible factor in the poor height outcome of these patients. Treatment of CAH consists of adequate replacement of glucocorticoid, and mineralocorticoid when approCorresponding author. Tel.: +1 212 305 6559; fax: +1 212 305 4778. E-mail address: mpg15@columbia.edu (M.P. Gallagher). 1096-6374/$ - see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ghir.2005.06.006
*

priate, in order to normalize adrenocorticotropic hormone (ACTH) levels and decrease androgen production. Evaluation of the eects of glucocorticoid on growth velocity in patients with CAH is complex, since inadequate control of the disease results in an increased growth velocity. Androgen excess causes acceleration of bone maturation and premature epiphyseal fusion, which will ultimately impair nal height. However, attempts to fully suppress excess adrenal androgens with glucocorticoid often result in a marked reduction in linear growth velocity. Maintaining a balance between over- and under-suppression presents a therapeutic challenge. 2. Factors inuencing growth in CAH Although it is not completely clear which factors are associated with a poor nal height in patients with 21-hydroxylase deciency, previous studies have implicated midparental target height, the clinical form of the disorder (salt-wasting versus simple virilizing), the age

M.P. Gallagher et al. / Growth Hormone & IGF Research 15 (2005) S26S30

S27

at initiation of treatment, the degree of hormonal control, salt balance during infancy, body mass index (BMI) in infancy and puberty, and the dosage of glucocorticoid during infancy and puberty. The role of each of these factors has been evaluated in a number of studies published over the last decade, often with conicting results [113]. Most studies are retrospective, include mixed populations, have a small sample size, and are unable to precisely assess the eect of glucocorticoid dose. A metaanalysis has shown that both earlier diagnosis and compliance may be associated with improved nal height [4]. Other studies have found no correlation between level of hormonal control and nal height but have observed that earlier diagnosis is associated with improved nal height [1]. However, still others report no correlation between nal height and age at diagnosis [3,5]. In a retrospective analysis of subjects with classical 21-hydroxylase deciency, salt supplementation in the rst year of life, in addition to mineralocorticoid supplementation, correlated positively with nal height in subjects with the salt-wasting form of the disorder. This nding was of particular interest, because the improvement was seen even though this subgroup received higher doses of glucocorticoid during infancy [12]. The critical role of salt supplementation during infancy is supported by another study, in which nal height correlated negatively with the age at which mineralocorticoid supplementation was started [1]. Mineralocorticoid supplementation for all classical patients has been suggested by some authors, who feel that a subclinical mineralocorticoid deciency is present in all patients who have this degree of enzyme deciency [1]. Onset of puberty and the magnitude of the pubertal growth spurt are also factors that have been identied as playing a role in nal height in subjects with CAH. Although some studies report normal pubertal timing with an attenuated growth spurt [6,10,12], a large multinational retrospective analysis revealed an early onset of puberty with a normal pubertal growth spurt [5]. Still others report puberty at a later-than-average age [1,7,9]. Yu and Grant [13] reported that increased BMI correlated with earlier menarche. The dosage of glucocorticoid in later childhood and adolescence may correlate with a decrease in the pubertal growth spurt [6,10,12].

3. Glucocorticoid eects in CAH There is considerable variation among the glucocorticoid regimens used for the treatment of CAH. The literature suggests that the majority of patients attain an adult stature within the normal range with conventional therapy, which now utilizes lower glucocorticoid dosages than in the past. However, in studies where such information is available, nal heights are still signi-

cantly less than midparental target heights [1,2,5,913]. Clearly, there is a subpopulation of patients with CAH with poor height for bone age who would benet from additional intervention to achieve a more normal adult stature. Attempts to improve the nal height in this subset of patients have included combination aromatase inhibitor and antiandrogen therapy [1417], adrenalectomy [18], and GH with gonadotropin-releasing hormone agonist (GnRHa) therapy [14,19]. Furthermore, the optimal biochemical parameter for adjusting glucocorticoid regimens is equally controversial. However, there is general agreement that normalization of 17-alpha-hydroxyprogesterone levels should not be a therapeutic goal, as it is likely to result in oversuppression of adrenal androgen production, with negative consequences for growth and body mass index. A random 17-alpha-hydroxyprogesterone level between 500 and 1000 ng/dL, with an androstenedione level less than 50 ng/dL, has been recommended to avoid oversuppression [20]. Androstenedione levels may be a more reliable indicator of both adrenal androgen production and possible under-suppression [9,12]. Poor linear growth and an increased risk of obesity in adulthood have been reported in association with the higher glucocorticoid doses used to treat CAH during infancy. In one study, subjects receiving lower doses of hydrocortisone in infancy had improved height SDS at 1 year of age; and, moreover, their height at 1 year of age correlated with nal height [1]. The childhood dosage of glucocorticoid used may also play a role in nal height. In a study by Pinto and colleagues, nal height data for 27 subjects with classical and nonclassical CAH showed that the mean hydrocortisone dosage administered between 1 and 10 years of age correlated with height decit in classical but not in nonclassical subjects [10]. Another study found that the mean childhood weight correlated negatively with nal height, independent of glucocorticoid dose [8]. BMI in early childhood and later childhood both correlated with nal height deficit in another study, which found no correlation between BMI and glucocorticoid dose [13]. The issues of whether the increase in BMI was related to increase in body fat or in muscle mass and whether it reects overor under suppression were not addressed in these studies. Only one prospective randomized controlled trial has evaluated the role of glucocorticoid dosage on growth in CAH. In this study, hydrocortisone administered at a daily dosage of 25 mg/m2 was associated with greater growth inhibition than was a daily dosage of 15 mg/m2 [21]. Hydrocortisone has traditionally been used because of its short half-life and presumed lesser eect on the hypothalamicpituitary growth axis. Controversy remains whether hydrocortisone should be administered 2 or 3 times per day and how the total daily dose should be divided [2225]. Satisfactory growth outcomes have been reported using longer-acting preparations such as

S28

M.P. Gallagher et al. / Growth Hormone & IGF Research 15 (2005) S26S30

prednisone [26] and dexamethasone [27]. The elixir preparation is preferred over other forms of dexamethasone to enable precise adjustment of the dose.

4. Possible role of GH in glucocorticoid-treated patients Glucocorticoid administration may aect the growth axis in CAH in several ways. While studies have shown that subjects with CAH have normal responses to provocative GH stimulation testing [28,29], it has been suggested that the pattern of GH release changes with the administration of glucocorticoids [14,22,30]. However, normal IGF-I levels are reported in the majority of studies [12]. In vitro studies of chondrocyte mitosis reveal an incomplete blockade of chondrocyte proliferation in response to IGF-I with the administration of dexamethasone. This suggests that it may be possible to overcome the glucocorticoid-mediated blockade with the administration of growth factors such as IGF-I or even GH [31]. Animal studies have shown that the inhibition of length and weight gain induced by glucocorticoid was reversible in a dose-dependent fashion by GH administration [32]. Studies in human subjects who received glucocorticoid for immunosuppression after renal transplantation, for asthma, and for treatment of JRA have also demonstrated a reduction in glucocorticoid-mediated suppression of growth with the administration of GH [3237]. Bone mineral density (BMD) also has been studied in subjects receiving glucocorticoid for the treatment of CAH. Although many studies have shown no signicant dierences in BMD between patients with CAH and controls as measured by DXA [22,3841], others have found signicantly lower BMD z-scores in all or certain subpopulations of CAH patients [4246]. In another study, total body bone mineral content was found to be lower in male subjects with CAH than in controls [47]. Biochemical markers of bone turnover have also been evaluated in patients with CAH. Bone turnover was lower in patients with CAH than in controls, and osteocalcin levels correlated positively with growth velocity and negatively with BMD [38,40]. Studies conducted in subjects being treated for various disorders have shown that long-term treatment with glucocorticoid induces osteoporosis, with biochemical evidence of decreased bone turnover and bone loss occurring principally within the rst 6 months of treatment [44,48,49]. Glucocorticoids can directly inhibit bone formation by osteoblasts [48]. Bone resorption is also observed, as glucocorticoids cause a decrease in the intestinal absorption and an increase in the renal excretion of calcium. The resulting secondary hyperparathyroidism contributes to the osteopenia prominently observed in the trabecular bone. If bone mineral acquisition is adversely aected by long-term glucocorticoid therapy in patients with

CAH, GH administration may reverse these eects in this population. In adult patients with GH deciency, spinal trabecular BMD was shown to increase after 1 year of GH treatment as measured by quantitative CT [50]. A similar study in GH-decient adults demonstrated an improvement in BMD during the rst 3 years of GH therapy; thereafter, BMD reached a plateau [51]. In children with idiopathic short stature, normalization of BMD and increased bone turnover has been observed after 1 year of GH treatment [52]. In another study of GH-decient children, improvement in BMD with GH therapy was demonstrated [53]. Glucocorticoid excess is also known to increase protein catabolism and decrease lipid oxidation, causing a change in body composition. These changes have been shown to have signicant implications for patients with CAH. In subjects receiving prednisone therapy, growth hormone has been shown to decrease the protein catabolism associated with glucocorticoid administration [54]. Additionally, even in the face of continuing glucocorticoid-induced catabolism, GH can increase protein synthesis, thereby increasing lean body mass [55]. GH is also known to increase lipid oxidation [56], suggesting that its concurrent administration with glucocorticoid would reverse the changes in body composition observed in patients requiring chronic therapy with glucocorticoids. One study has reported an improvement in growth velocity and predicted adult height following combined GH and GnRHa therapy in 12 subjects with CAH when compared to historical controls [19]. We recently completed a study (manuscript in preparation) to assess the eect of GH combined with GnRHa therapy on the growth, body composition, and total body bone mineral content of pubertal patients with CAH. GnRHa therapy was used as an adjunctive therapy in order to extend the period of growth. Our preliminary ndings indicate that this regimen is associated with improvements in predicted adult height as well as body composition in these glucocorticoid-treated pubertal patients with CAH.

5. Summary This review of the literature suggests that patients with CAH could potentially benet from GH administration. This population is at risk for short stature due both to the underlying disorder and to the suppression of the growth axis by glucocorticoids, and GH administration could result in an improvement in nal height. Additionally, these patients may develop complications due to glucocorticoid excess, including obesity and its associated metabolic abnormalities. Therefore, this group of patients is likely to benet from GH administration in terms of improved growth velocity, lean body mass, and possibly bone mineral acquisition.

M.P. Gallagher et al. / Growth Hormone & IGF Research 15 (2005) S26S30

S29

References
[1] A. Balsamo, A. Cicognani, L. Baldazzi, et al., CYP21 genotype, adult height, and pubertal development in 55 patients treated for 21-hydroxylase deciency, J. Clin. Endocrinol. Metab. 88 (2003) 56805688. [2] M.S. Cabrera, M.G. Vogiatzi, M.I. New, Long term outcome in adult males with classic congenital adrenal hyperplasia, J. Clin. Endocrinol. Metab. 86 (2001) 30703078. [3] J. DiMartino-Nardi, E. Stoner, A. OConnell, M.I. New, The eect of treatment of nal height in classical congenital adrenal hyperplasia (CAH), Acta Endocrinol. Suppl. (Copenh) 279 (1986) 305314. [4] E.A. Eugster, L.A. Dimeglio, J.C. Wright, G.R. Freidenberg, R. Seshadri, O.H. Pescovitz, Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deciency: a meta-analysis, J. Pediatr. 138 (2001) 2632. [5] H. Frisch, F. Waldhauser, J. Lebl, et al., Congenital adrenal hyperplasia: lessons from a multinational study, Horm. Res. 57 (Suppl. 2) (2002) 95101. [6] Z. Hochberg, J. Schechter, A. Benderly, E. Leiberman, A. Rosler, Growth and pubertal development in patients with congenital adrenal hyperplasia due to 11-beta-hydroxylase deciency, Am. J. Dis. Child. 139 (1985) 771776. [7] G.J. Klingensmith, S.C. Garcia, H.W. Jones, C.J. Migeon, R.M. Blizzard, Glucocorticoid treatment of girls with congenital adrenal hyperplasia: eects on height, sexual maturation, and fertility, J. Pediatr. 90 (1977) 9961004. [8] J. Jaaskelainen, R. Voutilainen, Growth of patients with 21hydroxylase deciency: an analysis of the factors inuencing adult height, Pediatr. Res. 41 (1997) 3033. [9] S. Muirhead, E.A. Sellers, H. Guyda, Indicators of adult height outcome in classical 21-hydroxylase deciency congenital adrenal hyperplasia, J. Pediatr. 141 (2002) 247252. [10] G. Pinto, V. Tardy, C. Trivin, et al., Follow-up of 68 children with congenital adrenal hyperplasia due to 21-hydroxylase deciency: relevance of genotype for management, J. Clin. Endocrinol. Metab. 88 (2003) 26242633. [11] L.D. Premawardhana, I.A. Hughes, G.F. Read, M.F. Scanlon, Longer term outcome in females with congenital adrenal hyperplasia (CAH): the Cardi experience, Clin. Endocrinol. (Oxf) 46 (1997) 327332. [12] H.J. Van der Kamp, B.J. Otten, N. Buitenweg, et al., Longitudinal analysis of growth and puberty in 21-hydroxylase deciency patients, Arch. Dis. Child. 87 (2002) 139144. [13] A.C. Yu, D.B. Grant, Adult height in women with early-treated congenital adrenal hyperplasia (21-hydroxylase type): relation to body mass index in earlier childhood, Acta Paediatr. 84 (1995) 899903. [14] E. Charmandari, S.M. Pincus, D.R. Matthews, A. Johnston, C.G. Brook, P.C. Hindmarsh, Oral hydrocortisone administration in children with classic 21-hydroxylase deciency leads to more synchronous joint GH and cortisol secretion, J. Clin. Endocrinol. Metab. 87 (2002) 22382244. [15] D.P. Merke, M.F. Keil, J.V. Jones, J. Fields, S. Hill, G.B. Cutler Jr., Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia, J. Clin. Endocrinol. Metab. 85 (2000) 11141120. [16] D.P. Merke, G.B. Cutler Jr., New ideas for medical treatment of congenital adrenal hyperplasia, Endocrinol. Metab. Clin. North Am. 30 (2001) 121135. [17] D.P. Merke, S.R. Bornstein, N.A. Avila, G.P. Chrousos, NIH conference. Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deciency, Ann. Intern. Med. 136 (2002) 320334.

[18] J.J. Van Wyk, E.M. Ritzen, The role of bilateral adrenalectomy in the treatment of congenital adrenal hyperplasia, J. Clin. Endocrinol. Metab. 88 (2003) 29932998. [19] J.B. Quintos, M.G. Vogiatzi, M.D. Harbison, M.I. New, Growth hormone therapy alone or in combination with gonadotropinreleasing hormone analog therapy to improve the height decit in children with congenital adrenal hyperplasia, J. Clin. Endocrinol. Metab. 86 (2001) 15111517. [20] C.J. Migeon, A.B. Wisniewski, Congenital adrenal hyperplasia owing to 21-hydroxylase deciency. Growth, development, and therapeutic considerations, Endocrinol. Metab. Clin. North Am. 30 (2001) 193206. [21] I.N. Silva, C.E. Kater, C.F. Cunha, M.B. Viana, Randomised controlled trial of growth eect of hydrocortisone in congenital adrenal hyperplasia, Arch. Dis. Child. 77 (1997) 214218. [22] L. Ghizzoni, G. Mastorakos, A. Vottero, M.A. Magiakou, G.P. Chrousos, S. Bernasconi, Spontaneous cortisol and growth hormone secretion interactions in patients with nonclassic 21hydroxylase deciency (NCCAH) and control children, J. Clin. Endocrinol. Metab. 81 (1996) 482487. [23] R. Smith, R.A. Donald, E.A. Espiner, C. Glatthaar, G. Abbott, M. Scandrett, The eect of dierent treatment regimens on hormonal proles in congenital adrenal hyperplasia, J. Clin. Endocrinol. Metab. 51 (1980) 230236. [24] H. Moeller, Chronopharmacology of hydrocortisone and 9 alphauorhydrocortisone in the treatment for congenital adrenal hyperplasia, Eur. J. Pediatr. 144 (1985) 370373. [25] E. Charmandari, D.R. Matthews, A. Johnston, C.G. Brook, P.C. Hindmarsh, Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deciency: is current replacement therapy satisfactory? J. Clin. Endocrinol. Metab. 86 (2001) 4679 4685. [26] W.B. Zipf, G.E. Bacon, R.P. Kelch, Hormonal and clinical responses to prednisone treatment in adolescents with congenital adrenal hyperplasia, Horm. Res. 12 (1980) 206217. [27] S.A. Rivkees, J.D. Crawford, Dexamethasone treatment of virilizing congenital adrenal hyperplasia: the ability to achieve normal growth, Pediatrics 106 (2000) 767773. [28] M.A. Sperling, F.M. Kenny, J.C. Schutt-Aine, A.L. Drash, Linear growth and growth hormonal responsiveness in treated congenital adrenal hyperplasia, Am. J. Dis. Child. 22 (1971) 408413. [29] R. Rappaport, E. Bouthreuil, C. Marti-Henneberg, A. Basmaciogullari, Linear growth rate, bone maturation and growth hormone secretion in prepubertal children with congenital adrenal hyperplasia, Acta Paediatr. Scand. 62 (1973) 513519. [30] J.W. Finkelstein, R.M. Boyar, H.P. Rowarg, et al., Growth hormone secretion in congenital adrenal hyperplasia, J. Clin. Endocrinol. Metab. 36 (1973) 121124. [31] I.C. Robinson, B. Gabrielsson, G. Klaus, N. Mauras, C. Holmberg, O. Mehls, Glucocorticoids and growth problems, Acta Paediatr. 411 (Suppl.) (1995) 8186. [32] G. Kovacs, R.N. Fine, S. Worgall, et al., Growth hormone prevents steroid-induced growth depression in health and uremia, Kidney Int. 40 (1991) 10321040. [33] A. Tirendi, C. Traggiai, G.S. Conway, R. Stanhope, Growth hormone deciency in salt-losing congenital adrenal hyperplasia, Eur. J. Pediatr. 161 (2002) 556558. [34] G. Touati, A.M. Prieur, J.C. Ruiz, M. Noel, P. Czernichow, Benecial eects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Eects on growth velocity and body composition, J. Clin. Endocrinol. Metab. 83 (1998) 403409. [35] D.B. Allen, Growth suppression by glucocorticoid therapy, Endocrinol. Metab. Clin. North Am. 25 (1996) 699717. [36] D.B. Allen, J.R. Julius, T.J. Breen, K.M. Attie, Treatment of glucocorticoid-induced growth suppression with growth hormone.

S30

M.P. Gallagher et al. / Growth Hormone & IGF Research 15 (2005) S26S30 National Cooperative Growth Study, J. Clin. Endocrinol. Metab. 83 (1998) 28242829. B. Tonsho, D. Haner, O. Mehls, et al., Ecacy and safety of growth hormone treatment in short children with renal allografts: three year experience. Members of the German Study Group for Growth Hormone Treatment in Children with Renal Allografts, Kidney Int. 44 (1993) 199207. R. Girgis, J.S. Winter, The eects of glucocorticoid replacement therapy on growth, bone mineral density, and bone turnover markers in children with congenital adrenal hyperplasia, J. Clin. Endocrinol. Metab. 82 (1997) 39263929. M. Gussinye, A. Carrascosa, N. Potau, M. Enrubia, E. VicensCalvet, L. Ibanez, et al., Bone mineral density in prepubertal and in adolescent and young adult patients with the salt-wasting form of congenital adrenal hyperplasia, Pediatrics 100 (1997) 671674. C.Y. Guo, A.P. Weetman, R. Eastell, Bone turnover and bone mineral density in patients with congenital adrenal hyperplasia, Clin. Endocrinol. (Oxf) 45 (1996) 535541. S. Mora, F. Saggion, G. Russo, et al., Bone density in young patients with congenital adrenal hyperplasia, Bone 18 (1996) 337 340. F.J. Cameron, B. Kaymakci, E.A. Byrt, P.R. Ebeling, G.L. Warne, J.D. Wark, Bone mineral density and body composition in congenital adrenal hyperplasia, J. Clin. Endocrinol. Metab. 80 (1995) 22382243. C. Paganini, G. Radetti, C. Livieri, V. Braga, D. Migliavacca, S. Adami, Height, bone mineral density and bone markers in congenital adrenal hyperplasia, Horm. Res. 54 (2000) 164168. J. Jaaskelainen, R. Voutilainen, Bone mineral density in relation to glucocorticoid substitution therapy in adult patients with 21hydroxylase deciency, Clin. Endocrinol. (Oxf) 45 (1996) 707713. K. Hagenfeldt, R.E. Martin, H. Ringertz, J. Helleday, K. Carlstrom, Bone mass and body composition of adult women with congenital virilizing 21-hydroxylase deciency after glucocorticoid treatment since infancy, Eur. J. Endocrinol. 143 (2000) 667671. P.O. Almeida Freire, S.H. Lemos-Marini, A.T. Maciel-Guerra, et al., Classical congenital adrenal hyperplasia due to 21-hydroxylase deciency: a cross-sectional study of factors involved in bone mineral density, J. Bone Miner. Metab. 21 (2003) 396401. [47] N.M. Stikkelbroeck, B.A. Hof-Grootenboer, A.R. Hermus, B.J. Otten, M.A. Vant Hof, Growth inhibition by glucocorticoid treatment in salt wasting 21-hydroxylase deciency: in early infancy and (pre)puberty, J. Clin. Endocrinol. Metab. 88 (2003) 35253530. [48] V. LoCascio, E. Bonucci, B. Imbimbo, et al., Bone loss in response to long-term glucocorticoid therapy, Bone Miner. 8 (1990) 3951. [49] I.R. Reid, G.E. Chapman, T.R. Fraser, et al., Low serum osteocalcin levels in glucocorticoid-treated asthmatics, J. Clin. Endocrinol. Metab. 62 (1986) 379383. [50] D.J. OHalloran, A. Tsatsoulis, R.W. Whitehouse, S.J. Holmes, J.E. Adams, S.M. Shalet, Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deciency, J. Clin. Endocrinol. Metab. 76 (1993) 13441348. [51] M.J. Valimaki, P.I. Salmela, J. Salmi, et al., Eects of 42 months of GH treatment on bone mineral density and bone turnover in GH-decient adults, Eur. J. Endocrinol. 140 (1999) 545554. [52] R. Lanes, P. Gunczler, J.R. Weisinger, Decreased trabecular bone mineral density in children with idiopathic short stature: normalization of bone density and increased bone turnover after 1 year of growth hormone treatment, J. Pediatr. 135 (2 Pt 1) (1999) 177 181. [53] G. Saggese, G.I. Baroncelli, S. Bertelloni, S. Barsanti, The eect of long-term growth hormone (GH) treatment on bone mineral density in children with GH deciency. Role of GH in the attainment of peak bone mass, J. Clin. Endocrinol. Metab. 81 (1996) 30773083. [54] F.F. Horber, M.W. Haymond, Human growth hormone prevents the protein catabolic side eects of prednisone in humans, J. Clin. Invest. 86 (1990) 265272. [55] W.M. Bennet, M.W. Haymond, Growth hormone and lean tissue catabolism during long-term glucocorticoid treatment, Clin. Endocrinol. (Oxf) 36 (1992) 161164. [56] A.L. Carrel, S.E. Myers, B.Y. Whitman, D.B. Allen, Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in PraderWilli syndrome: a controlled study, J. Pediatr. 134 (1999) 215221.

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]