Changes of Thyroid Function During Long-term hGH Therapy in GHD Children. A Possible Relationship with Catch-up Growth?

Abstract

Background: Growth hormone (GH) treatment in patients with GH deficiency (GHD) can determine changes in the thyroid function. The clinical significance of these changes remains controversial, and all studies have so far covered rather a short period - usually no longer than one year. Objective: To determine the effect of long-term recombinant hGH treatment in children with idiopathic GHD on the thyroid function. Patients and methods: Nineteen prepubertal children (12 boys and 7 girls, mean age 9.2 ± 3.1 years) with idiopathic GHD were studied and followed for twenty-four months. None of the patients showed multiple pituitary hormone deficiencies. Nineteen healthy children matched for age and sex acted as controls. Results: Patients with GHD showed a significant increase in TT₃ at twelve months and in FT₃ at six and twelve months after starting GH treatment, with a significant decrease at eighteen and twenty-four months. TT₄ level decreased significantly at twelve months and increased significantly at eighteen and twenty-four months. FT₄ also decreased, but only slightly, after twelve months of hGH treatment, and then increased significantly at twenty-four months. TSH levels did not vary significantly during the course of therapy. TT₃/TT₄ and FT₃/FT₄ ratios increased significantly after six and twelve months of therapy and significantly decreased later, approaching pre-therapy values. The SDS of Growth Velocity (SDS-GV) increased remarkably during the first year of therapy and then decreased significantly during the second year, although it remained significantly higher than the pre-therapy values. TT₃ and TT₃/TT₄ ratio displayed a significant correlation with SDS-GV at twelve months of therapy. In a multiple regression analysis with age, bone age, parental height, GH dose, TT_3, TT₃/TT₄, and the SDS of IGF-I, only the TT₃/TT₄ ratio at twelve months of therapy (p < 0.001) was identified as a significant predictor of SDS-GV. Conclusion: Our data confirm that changes in thyroid function are present in GHD children during long-term hGH therapy. These changes probably resulted from the effect of hGH on the peripheral metabolism of thyroid hormones and appear to be transitory, disappearing during the second year of hGH treatment. We speculate on the functional significance of these changes, and in particular, on their role in catch-up growth after hGH therapy.

Thyroid hormone · growth hormone · growth hormone therapy · catch-up growth

References

• 1 Lanes R. Long-term outcome of growth hormone therapy in children and adolescents.  Treat Endocrinol. 2004;  3 53-66
• 2 Hubina E, Kovacs L, Szabolcs I, Szucs N, Toth M, Racz K, Czirjak S, Gorombey Z, Goth M I. The effect of gender and age on growth hormone replacement in growth hormone-deficient patients.  Horm Metab Res. 2004;  36 247-253
• 3 Pavel M E, Lohmann T, Hahn E G, Hoffmann M. Impact of growth hormone on central nervous activity, vigilance, and tiredness after short-term therapy in growth hormone-deficient adults.  Horm Metab Res. 2003;  35 114-119
• 4 Portes E S, Oliveira J HA, Maccagnan P, Abucham J. Changes in serum thyroid hormones levels and their mechanisms during long-term growth hormone (GH) replacement therapy in GH deficient children.  Clin Endocrinol. 2000;  53 183-189
• 5 Giavoli C, Porretti S, Ferrante E, Cappiello V, Ronchi C L, Travaglini P, Epaminonda P, Arosio M, Beck-Peccoz P. Recombinant hGH replacement therapy and the hypothalamus-pituitary-thyroid axis in children with GH deficiency: when should we be concerned about the occurrence of central hypothyroidism?.  Clin Endocrinol. 2003;  59 806-810
• 6 Rubio G R, Mellinger R C, Zafar M S, Wolf C B. Evaluation of thyroid function during growth hormone therapy.  Metabolism. 1976;  25 15-21
• 7 Cacciari E, Cicognani A, Pirazzoli P, Bernardi F, Zappulla F, Salardi S, Mozzanti L, Biasini A, Valenti E. Effect of long-term GH administration on pituitary-thyroid function in idiopathic hypopituitarism.  Acta Paediatr Scand. 1979;  68 405-409
• 8 Demura R, Yamaguchi H, Wakabayashi I, Demura H, Shizume K. The effect of hGH on hypothalamic-pituitary-thyroid function in patients with pituitary dwarfism.  Acta Endocrinol. 1980;  93 13-19
• 9 Lippe B M, Van Herle A J, La Franchi S H, Uller R P, Lavin N, Kaplan S A. Reversible Hypothyroidism in growth hormone-deficient children treated with human growth hormone.  J Clin Endocrinol Metab. 1975;  40 612-618
• 10 Municchi G, Malozowski S, Nisula B C, Cristiano A, Rose S R. Nocturnal thyrotropin surge in growth hormone-deficient children.  J Pediatr. 1992;  121 214-220
• 11 Pirazzoli P, Cacciari E, Mandini M. Growth and thyroid function in children treated with growth hormone.  J Pediatr. 1992;  121 210-213
• 12 Sato T, Suzuki Y, Taketani T, Ishiguro K, Masuyama T. Enhanced peripheral conversion of thyroxin to triiodothyronine during rhGH therapy in GH-deficient children.  J Clin Endocrinol Metab. 1977;  45 324-329
• 13 Rose S R, Leong G M, Yanowski J A, Blum D, Heavner G, Barnes K M, Chipman J J, Dichek H L, Jacobsen J, Klein K EO, Cutler G B Jr. Thyroid function in non-growth hormone-deficient short children during a placebo-controlled double blind trial of recombinant growth hormone therapy.  J Clin Endocrinol Metab. 1995;  80 320-324
• 14 Jørgensen J O, Pedersen S A, Laurberg P, Weeke J, Skakkebaek N E, Christiansen J S. Effect of growth hormone therapy on thyroid function of growth hormone deficient adults with and without concomitant thyroxin-substituted central hypothyroidism.  J Clin Endocrinol Metab. 1989;  69 1127-1132
• 15 Cobb W E, Reichlin S, Jackson I M. Growth hormone secretion status is a determinant of the thyrotropin response to thyrotropin-releasing hormone in euthyroid patients with hypothalamus-pituitary disease.  J Clin Endocrinol Metab. 1981;  52 324-329
• 16 Grunfeld C, Sherman M B, Cavalieri R R. The acute effects human growth hormone administration on thyroid function in normal men.  J Clin Endocrinol Metab. 1988;  67 1111-1114
• 17 Rezvani I, DiGeorge A M, Dowshen S A, Bourdony C J. Action of human growth hormone (hGH) on extrathyroidal conversion of thyroxin (T4) to triiodothironine (T3) in children with hypopituitarism.  Pediatr Res. 1981;  15 6-9
• 18 Saggese G, Cesaretti G, Di Spigno G, Cinquanta L, Giannessi N, Cioni C, Bracaloni C. Thyroid and thyrotropin functions in subjects with pituitary nanism treated with growth hormone.  Pediatr Med Chir. 1990;  12 483-488
• 19 Porretti S, Giavoli C, Ronchi C, Lombardi G, Zaccaria M, Valle D, Arosio M, Beck-Peccoz P. Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T(4) therapy become mandatory?.  J Clin Endocrinol Metab. 2002;  87 2042-2045
• 20 Wyatt D T, Gesundheit N, Sherman B. Changes in thyroid hormone levels during growth hormone therapy in initially euthyroid patients: lack of need for thyroid supplementation.  J Clin Endocrinol Metab. 1998;  83 3493-3497
• 21 Boersma B, Wit J M. Catch-up growth.  Endocr Rev. 1997;  18 646-661
• 22 Baron J, Klein K O, Colli M J, Yanovski J A, Novosad J A, Bacher J D, Cutler G B jr. Catch-up growth after glucocorticoid excess: a mechanism intrinsic to the growth plate.  Endocrinology. 1994;  135 1367-1371
• 23 Robson H, Siebler T, Shalet S M, Williams G R. Interaction between GH, IGF-I, glucocorticoids, and thyroid hormones during skeletal growth.  Pediatr Res. 2002;  52 137-147
• 24 van der Eerden B C, Karperien M, Wit J M. Systemic and local regulation of the growth plate.  Endocr Rev. 2003;  24 782-801
• 25 Tanner J M, Whitehouse R H. Clinical longitudinal standard for height, weight, height velocity, weight velocity and stages of puberty.  Arch Dis Child. 1976;  51 170-179
• 26 Greulich W W, Pyle S I. Radiographic atlas of skeletal development of hand and wrist (2nd ed. Stanford). Stanford University Press 1959
• 27 Jørgensen J O, Moller J, Laursen T, Orskov H, Christiansen J S, Weeke J. Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxin to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults.  Clin Endocrinol. 1994;  41 609-614
• 28 Massa G, de Zegher F, Vanderschueren-Lodeweyckx M. Effect of growth hormone therapy on thyroid status of girls with Turner’s syndrome.  Clin Endocrinol. 1991;  34 205-209
• 29 Bianco A C, Salvatore D, Gereben B ZS, Berry M Y, Larsen P R. Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases.  Endocr Rev. 2002;  23 38-89
• 30 Miura M, Tanaka K, Komatsu Y, Suda M, Yasoda A, Sakuma Y, Ozasa A, Nakao K. Thyroid hormones promote chondrocyte differentiation in mouse ATDC5 cells and stimulate endochondral ossification in fetal mouse tibias through iodothyronine deiodinases in the growth plate.  J Bone Miner Res. 2002;  17 443-454