Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial
Ruben H. Willemsen
Department of Pediatrics, Division of Endocrinology, Erasmus MC Sophia, Rotterdam, the Netherlands,
Search for more papers by this authorNicolette J. T. Arends
Department of Pediatrics, Division of Endocrinology, Erasmus MC Sophia, Rotterdam, the Netherlands,
Search for more papers by this authorWillie M. Bakker-van Waarde
Beatrix Children's Hospital, Groningen, the Netherlands,
Search for more papers by this authorMaarten Jansen
Wilhelmina Children's Hospital, Utrecht, the Netherlands,
Search for more papers by this authorEdgar G. A. H. Van Mil
Free University Medical Center, Amsterdam, the Netherlands,
Search for more papers by this authorRoelof J. Odink
Catharina Hospital, Eindhoven, the Netherlands,
Search for more papers by this authorMaarten Reeser
Juliana Children's Hospital, The Hague, the Netherlands,
Search for more papers by this authorCiska Rongen-Westerlaken
Canisius Wilhelmina Hospital, Nijmegen, the Netherlands,
Search for more papers by this authorWilhelmina H. Stokvis-Brantsma
Leiden University Medical Center, Leiden, the Netherlands
Search for more papers by this authorJohan J. J. Waelkens
Catharina Hospital, Eindhoven, the Netherlands,
Search for more papers by this authorAnita C. S. Hokken-Koelega
Department of Pediatrics, Division of Endocrinology, Erasmus MC Sophia, Rotterdam, the Netherlands,
Search for more papers by this authorRuben H. Willemsen
Department of Pediatrics, Division of Endocrinology, Erasmus MC Sophia, Rotterdam, the Netherlands,
Search for more papers by this authorNicolette J. T. Arends
Department of Pediatrics, Division of Endocrinology, Erasmus MC Sophia, Rotterdam, the Netherlands,
Search for more papers by this authorWillie M. Bakker-van Waarde
Beatrix Children's Hospital, Groningen, the Netherlands,
Search for more papers by this authorMaarten Jansen
Wilhelmina Children's Hospital, Utrecht, the Netherlands,
Search for more papers by this authorEdgar G. A. H. Van Mil
Free University Medical Center, Amsterdam, the Netherlands,
Search for more papers by this authorRoelof J. Odink
Catharina Hospital, Eindhoven, the Netherlands,
Search for more papers by this authorMaarten Reeser
Juliana Children's Hospital, The Hague, the Netherlands,
Search for more papers by this authorCiska Rongen-Westerlaken
Canisius Wilhelmina Hospital, Nijmegen, the Netherlands,
Search for more papers by this authorWilhelmina H. Stokvis-Brantsma
Leiden University Medical Center, Leiden, the Netherlands
Search for more papers by this authorJohan J. J. Waelkens
Catharina Hospital, Eindhoven, the Netherlands,
Search for more papers by this authorAnita C. S. Hokken-Koelega
Department of Pediatrics, Division of Endocrinology, Erasmus MC Sophia, Rotterdam, the Netherlands,
Search for more papers by this authorSummary
Context Alterations in the GH-IGF-I axis in short small-for-gestational-age (SGA) children might be associated with abnormalities in bone mineral density (BMD) and body composition. In addition, birth weight has been inversely associated with diabetes and cardiovascular disease in adult life. Data on detailed body composition in short SGA children and long-term effects of GH treatment are very scarce.
Objective To investigate effects of long-term GH treatment on body composition and BMD by dual energy X-ray absorptiometry (DXA) in short SGA children.
Design Longitudinal 6-year GH study with a randomized controlled part for 3 years.
Results At baseline, fat percentage standard deviation score (SDS) and lumbar spine BMD SDS corrected for height (BMADLS SDS) were significantly lower than zero. Lean body mass (LBM) SDS adjusted for age was also reduced, but LBM adjusted for height (LBM SDSheight) was not decreased. GH treatment induced a decrease in fat percentage SDS and an increase in BMADLS SDS. LBM SDSheight remained similar in GH-treated children, but deteriorated in untreated controls. When these untreated controls subsequently started GH treatment, their LBM SDSheight rapidly normalized to values comparable with zero.
Conclusion During long-term GH treatment in short SGA children, fat percentage SDS decreased and BMADLS SDS increased. These effects of GH treatment were most prominent in children who started treatment at a younger age and in those with greater height gain during GH treatment. LBM SDSheight remained around 0 SDS in GH-treated children, but declined to low normal values in untreated controls.
References
- 1 Albertsson-Wikland, K., Wennergren, G., Wennergren, M., Vilbergsson, G. & Rosberg, S. (1993) Longitudinal follow-up of growth in children born small for gestational age. Acta Paediatrica, 82, 438–443.
- 2 Hokken-Koelega, A.C., De Ridder, M.A., Lemmen, R.J., Den Hartog, H., De Muinck Keizer-Schrama, S.M. & Drop, S.L. (1995) Children born small for gestational age: do they catch up? Pediatric Research, 38, 267–271.
- 3 Van Pareren, Y., Mulder, P., Houdijk, M., Jansen, M., Reeser, M. & Hokken-Koelega, A. (2003) Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. Journal of Clinical Endocrinology and Metabolism, 88, 3584–3590.
- 4 Sas, T., De Waal, W., Mulder, P., Houdijk, M., Jansen, M., Reeser, M. & Hokken-Koelega, A. (1999) Growth hormone treatment in children with short stature born small for gestational age: 5-year results of a randomized, double-blind, dose-response trial. Journal of Clinical Endocrinology and Metabolism, 84, 3064–3070.
- 5 De Zegher, F., Albertsson-Wikland, K., Wollmann, H.A., Chatelain, P., Chaussain, J.L., Lofstrom, A., Jonsson, B. & Rosenfeld, R.G. (2000) Growth hormone treatment of short children born small for gestational age: growth responses with continuous and discontinuous regimens over 6 years. Journal of Clinical Endocrinology and Metabolism, 85, 2816–2821.
- 6 Barker, D.J., Hales, C.N., Fall, C.H., Osmond, C., Phipps, K. & Clark, P.M. (1993) Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia, 36, 62–67.
- 7 Fantuzzi, G. & Mazzone, T. (2007) Adipose tissue and atherosclerosis: exploring the connection. Arteriosclerosis, Thrombosis and Vascular Biology, 27, 996–1003.
- 8 Ibanez, L., Ong, K., Dunger, D.B. & De Zegher, F. (2006) Early development of adiposity and insulin resistance after catch-up weight gain in small-for-gestational-age children. Journal of Clinical Endocrinology and Metabolism, 91, 2153–2158.
- 9 Sas, T., Mulder, P. & Hokken-Koelega, A. (2000) Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH) treatment in children with short stature born small for gestational age either with or without GH deficiency. Journal of Clinical Endocrinology and Metabolism, 85, 3786–3792.
- 10 De Waal, W.J., Hokken-Koelega, A.C., Stijnen, T., De Muinck Keizer-Schrama, S.M. & Drop, S.L. (1994) Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF-I and IGF-II levels in prepubertal children with short stature after intrauterine growth retardation. The Dutch Working Group on Growth Hormone. Clinical Endocrinology, 41, 621–630.
- 11 Van Dijk, M., Mulder, P., Houdijk, M., Mulder, J., Noordam, K., Odink, R.J., Rongen-Westerlaken, C., Voorhoeve, P., Waelkens, J., Stokvis-Brantsma, J. & Hokken-Koelega, A. (2006) High serum levels of growth hormone (GH) and IGF-I during high dose growth hormone treatment in short children born small for gestational age. Journal of Clinical Endocrinology and Metabolism, 91, 1390–1396.
- 12 Boot, A.M., Engels, M.A., Boerma, G.J., Krenning, E.P. & De Muinck Keizer-Schrama, S.M. (1997) Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. Journal of Clinical Endocrinology and Metabolism, 82, 2423–2428.
- 13 Leger, J., Garel, C., Fjellestad-Paulsen, A., Hassan, M. & Czernichow, P. (1998) Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal. Journal of Clinical Endocrinology and Metabolism, 83, 3512–3516.
- 14 Boonstra, V.H., Arends, N.J., Stijnen, T., Blum, W.F., Akkerman, O. & Hokken-Koelega, A.C. (2005) Food intake of children with short stature born small for gestational age before and during a randomized GH trial. Hormone Research, 65, 23–30.
- 15 Van Der Sluis, I.M., Boot, A.M., Hop, W.C., De Rijke, Y.B., Krenning, E.P. & De Muinck Keizer-Schrama, S.M. (2002) Long-term effects of growth hormone therapy on bone mineral density, body composition, and serum lipid levels in growth hormone deficient children: a 6-year follow-up study. Hormone Research, 58, 207–214.
- 16 Roemmich, J.N., Huerta, M.G., Sundaresan, S.M. & Rogol, A.D. (2001) Alterations in body composition and fat distribution in growth hormone-deficient prepubertal children during growth hormone therapy. Metabolism, 50, 537–547.
- 17 Cooper, C., Westlake, S., Harvey, N., Javaid, K., Dennison, E. & Hanson, M. (2006) Review: developmental origins of osteoporotic fracture. Osteoporosis International, 17, 337–347.
- 18 Yakar, S., Bouxsein, M.L., Canalis, E., Sun, H., Glatt, V., Gundberg, C., Cohen, P., Hwang, D., Boisclair, Y., Leroith, D. & Rosen, C.J. (2006) The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone. Journal of Endocrinology, 189, 289–299.
- 19 Yakar, S., Rosen, C.J., Beamer, W.G., Ackert-Bicknell, C.L., Wu, Y., Liu, J.L., Ooi, G.T., Setser, J., Frystyk, J., Boisclair, Y.R. & LeRoith, D. (2002) Circulating levels of IGF-1 directly regulate bone growth and density. Journal of Clinical Investigation, 110, 771–781.
- 20 Wang, J., Zhou, J., Cheng, C.M., Kopchick, J.J. & Bondy, C.A. (2004) Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth. Journal of Endocrinology, 180, 247–255.
- 21 Arends, N.J., Boonstra, V.H., Mulder, P.G., Odink, R.J., Stokvis-Brantsma, W.H., Rongen-Westerlaken, C., Mulder, J.C., Delemarre-Van de Waal, H., Reeser, H.M., Jansen, M., Waelkens, J.J. & Hokken-Koelega, A.C. (2003) GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial. Clinical Endocrinology, 59, 779–787.
- 22 Tanner, J.M. & Whitehouse, R.H. (1976) Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Archives of Disease in Childhood, 51, 170–179.
- 23 Kroger, H., Vainio, P., Nieminen, J. & Kotaniemi, A. (1995) Comparison of different models for interpreting bone mineral density measurements using DXA and MRI technology. Bone, 17, 157–159.
- 24 Boot, A.M., Bouquet, J., De Ridder, M.A., Krenning, E.P. & De Muinck Keizer-Schrama, S.M. (1997) Determinants of body composition measured by dual-energy X-ray absorptiometry in Dutch children and adolescents. American Journal of Clinical Nutrition, 66, 232–238.
- 25 Boot, A.M., De Ridder, M.A., Pols, H.A., Krenning, E.P. & De Muinck Keizer-Schrama, S.M. (1997) Bone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity. Journal of Clinical Endocrinology and Metabolism, 82, 57–62.
- 26 Arends, N.J., Boonstra, V.H., Duivenvoorden, H.J., Hofman, P.L., Cutfield, W.S. & Hokken-Koelega, A.C. (2005) Reduced insulin sensitivity and the presence of cardiovascular risk factors in short prepubertal children born small for gestational age (SGA). Clinical Endocrinology, 62, 44–50.
- 27 Juul, A., Scheike, T., Davidsen, M., Gyllenborg, J. & Jorgensen, T. (2002) Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation, 106, 939–944.
- 28 Barker, D.J., Osmond, C., Forsen, T.J., Kajantie, E. & Eriksson, J.G. (2005) Trajectories of growth among children who have coronary events as adults. New England Journal of Medicine, 353, 1802–1809.
- 29 Singhal, A., Wells, J., Cole, T.J., Fewtrell, M. & Lucas, A. (2003) Programming of lean body mass: a link between birth weight, obesity, and cardiovascular disease? American Journal of Clinical Nutrition, 77, 726–730.
- 30 Hofman, P.L., Cutfield, W.S., Robinson, E.M., Bergman, R.N., Menon, R.K., Sperling, M.A. & Gluckman, P.D. (1997) Journal of Clinical Endocrinology and Metabolism, 82, 402–406.
Citing Literature
