Body Composition, Fasting Leptin, and Sex Steroid Administration Determine GH Sensitivity in Peripubertal Short Children

R. Coutant
2001 Journal of Clinical Endocrinology and Metabolism  
Serum IGF-I levels in GH-treated subjects demonstrate a wide range of responsiveness to GH. However, the factors influencing GH sensitivity are not well known. The aim of this work was 1) to test whether body composition (determined by dual energy x-ray absorptiometry) or factors related to body composition (fasting blood glucose, FFA, C-peptide, leptin, and insulin sensitivity determined by an insulin tolerance test) influence GH sensitivity; and 2) to study the effect of sex steroid priming
more » ... x steroid priming on GH sensitivity. We measured serum IGF-I at baseline and 24 h after a single administration of GH (2 mg/m 2 ) in 60 healthy prepubertal and early pubertal children (height, ؊2.1 ؎ 1.0 SD score). GH sensitivity, as estimated by the increase in serum IGF-I after GH administration (difference between stimulated and baseline serum IGF-I ‫؍‬ ␦ IGF-I), was also determined after a short-term administration of oral ethinyl E2 in girls and im T in boys. The serum IGF-I concentration was 297 ؎ 114 g/liter at baseline and increased to 429 ؎ 160 g/liter, corresponding to a 46 ؎ 29% increase over the baseline value (P < 0.0001, stimulated vs. baseline serum IGF-I). ␦ IGF-I was not different between gender or pubertal stage. There were positive correlations (P < 0.001) between ␦ IGF-I and adiposity (total body fat, r ‫؍‬ 0.62; trunk fat, r ‫؍‬ 0.62), fasting leptin (r ‫؍‬ 0.64), and C-peptide (r ‫؍‬ 0.54), and a negative correlation with fasting FFA (r ‫؍‬ ؊0.33; P < 0.05) even after adjustment for age, gender, and pubertal stage. These factors remained significant independent predictors of the absolute as well as the percent increase in serum IGF-I in multiple regression analyses. Priming with T and ethinyl E2 had a similar stimulating effect on the serum GH peak in response to the insulin tolerance test. In boys, serum baseline IGF-I increased by 60%, and ␦ IGF-I was similar after vs. before T administration. By contrast, in girls, serum baseline IGF-I was similar, and ␦ IGF-I was 60% less after vs. before ethinyl E2 administration. This study indicates that 1) GH sensitivity is determined by fat mass, serum fasting leptin, C-peptide, and FFA; and 2) oral ethinyl E2 and im T have divergent effects on the IGF-I response to a single administration of GH. (J Clin Endocrinol Metab 86: 5805-5812, 2001) Abbreviations: BMI, Body mass index; GH-BP, GH-binding protein; GHD, GH deficiency; ␦ IGF-I, difference between stimulated and baseline serum IGF-I; IGFBP, IGF-binding protein; IRMA, immunoradiometric assay; ITT, insulin tolerance test. , Ministère de la Santé). to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender. J Clin Endocrinol Metab 81:1575-1581 4. Bengtsson BA, Abs R, Bennmarker H, Monson JP, Feldt-Rasmussen U, Hernberg-Stahl E, Westberg B, Wilton P, Wuster C 1999 The effects of treatment and the individual responsiveness to growth hormone (GH) replacement therapy in 665 GH-deficient adults. KIMS Study Group and the KIMS International Board. J Clin Endocrinol Metab 84:3929 -3935 5. M 1998 Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 83:382-395 6. GH Research Society 2000 Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab 85:3990 -3993 7. Thissen JP, Ketelslegers JM, Underwood LE 1994 Nutritional regulation of the insulin-like growth factors. Endocr Rev 15:80 -101 8. Argente J, Caballo N, Barrios V, Pozo J, Munoz MT, Chowen JA, Hernandez M 1997 Multiple endocrine abnormalities of the growth hormone and insulinlike growth factor axis in prepubertal children with exogenous obesity: effect of short-and long-term weight reduction. J Clin Endocrinol Metab 82:2076 -2083 9. Drake WM, Coyte D, Camacho-Hubner C, Jivanji NM, Kaltsas G, Wood DF, Trainer PJ, Grossman AB, Besser GM, Monson JP 1998 Optimizing growth hormone replacement therapy by dose titration in hypopituitary adults. J Clin Endocrinol Metab. 83:3913-3919 10. Burman P, Johansson AG, Siegbahn A, Vessby B, Karlsson FA 1997 Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. J Clin Endocrinol Metab 82:550 -555 11. Marshall WA, Tanner JM 1969 Variations in the pattern of pubertal changes in girls. Arch Dis Child 44:291-303 12. Marshall WA, Tanner JM 1970 Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13-24 13. Sempé M, Pedron G, Roy-Pernot MP 1979 Auxologie, methodes et sequences. Paris: Théraplix Public 14. Rolland-Cachera MF, Cole TJ, Sempe M, Tichet J, Rossignol C, Charraud A 1991 Body mass index variations: centiles from birth to 87 years. Eur J Clin Nutr 45:13-21 15. Veldhuis JD, Metzger DL, Martha PM, Mauras N, Kerrigan JR, Keenan B, Rogol AD, Pincus SM 1997 Estrogen and testosterone, but not a nonaromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex hormone replacement. J Clin Endocrinol Metab 82:3414 -3420 16. Martinez AS, Domené H, Ropelato G, Jasper HG, Pennisi PA, Escobar ME, Heinrich JJ 2000 Estrogen priming effect on growth hormone (GH) provocative test: a useful tool for the diagnosis of GH deficiency. J Clin Endocrinol Metab 85:4168 -4172 17. Bonora E, Moghetti P, Zancanaro C, Cigolini M, Querena M, Cacciatori V, Corgnati A, Muggeo M 1989 Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies. J Clin Endocrinol Metab 68:374 -378 18. Martha PM, Jr, Reiter EO, Davila N, Shaw MA, Holcombe JH, Baumann G 1992 The role of body mass in the response to growth hormone therapy. J Clin Endocrinol Metab 75:1470 -1473 19. Fisker S, Vahl N, Jorgensen JO, Christiansen JS, Orskov H 1997 Abdominal fat determines growth hormone-binding protein levels in healthy non-obese adults. J Clin Endocrinol Metab 82:123-128 20. Amit T, Youdim MB, Hochberg Z 2000 Clinical review 112: Does serum growth hormone (GH) binding protein reflect human GH receptor function? J Clin Endocrinol Metab 85:927-932 21. Juul A, Fisker S, Scheike T, Hertel T, Muller J, Orskov H, Skakkebaek NE 2000 Serum levels of growth hormone binding protein in children with normal and precocious puberty: relation to age, gender, body composition and gonadal steroids. Clin Endocrinol (Oxf) 52:165-172 22. Ranke MB, Lindberg A, Chatelain P, Wilton P, Cutfield W, Albertsson-Wikland K, Price DA 1999 Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with idiopathic GH deficiency. J Clin Endocrinol Metab 84:1174 -1183 23. Bjarnason R, Boguszewski M, Dahlgren J, Gelander L, Kristrom B, Rosberg S, Carlsson B, Albertsson-Wikland K, Carlsson LM 1997 Leptin levels are strongly correlated with those of GH-binding protein in prepubertal children. Eur J Endocrinol 137:68 -73 24. Llopis MA, Granada ML, Cuatrecasas G, Formiguera X, Sanchez-Planell L, Sanmarti A, Alastrue A, Rull M, Corominas A, Foz M 1998 Growth hormonebinding protein directly depends on serum leptin levels in adults with different nutritional status.
doi:10.1210/jc.86.12.5805 pmid:11739442 fatcat:rnjezdhkqbfoffoiayrpar4yem