Growth hormone (GH) treatment reduces peripheral thyroid hormone action in girls with Turner syndrome
S. Susperreguy
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorM. B. Miras
Servicio de Endocrinología, Hospital de Niños de la Santísima Trinidad, Córdoba,
Search for more papers by this authorM. M. Montesinos
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorI. D. Mascanfroni
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorL. Muñoz
Servicio de Endocrinología, Hospital de Niños de la Santísima Trinidad, Córdoba,
Search for more papers by this authorG. Sobrero
Servicio de Endocrinología, Hospital de Niños de la Santísima Trinidad, Córdoba,
Search for more papers by this authorL. Silvano
Servicio de Endocrinología, Hospital de Niños de la Santísima Trinidad, Córdoba,
Search for more papers by this authorA. M. Masini-Repiso
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorA. H. Coleoni
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorH. M. Targovnik
Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
Search for more papers by this authorC. G. Pellizas
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorS. Susperreguy
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorM. B. Miras
Servicio de Endocrinología, Hospital de Niños de la Santísima Trinidad, Córdoba,
Search for more papers by this authorM. M. Montesinos
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorI. D. Mascanfroni
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorL. Muñoz
Servicio de Endocrinología, Hospital de Niños de la Santísima Trinidad, Córdoba,
Search for more papers by this authorG. Sobrero
Servicio de Endocrinología, Hospital de Niños de la Santísima Trinidad, Córdoba,
Search for more papers by this authorL. Silvano
Servicio de Endocrinología, Hospital de Niños de la Santísima Trinidad, Córdoba,
Search for more papers by this authorA. M. Masini-Repiso
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorA. H. Coleoni
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorH. M. Targovnik
Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
Search for more papers by this authorC. G. Pellizas
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba,
Search for more papers by this authorSummary
Objective Turner syndrome (TS) is an indication for GH therapy in spite of the modest growth response. Somatic growth depends not only on GH insulin-like growth factor I (IGF-I) axis but also on thyroid hormone (TH) status. We have previously reported that supraphysiological IGF-I levels diminished TH actions in rat tissues by reducing the nuclear TH receptor (TR). GH treatment to TS patients induces high IGF-I levels and therefore a reduction of TH action in tissues may be expected. We aimed at evaluating the effect of GH therapy in TS girls on peripheral TH action.
Design and patients We set up a reverse transcription-polymerase chain reaction (RT-PCR) for TR mRNA estimation in peripheral blood mononuclear cells (PBMC) and compared TR mRNA levels from 10 normal, 10 TS and 10 TS girls under GH therapy (0·33 mg/kg/week for 0·5–2 years).
Measurements After RNA extraction from PBMC, TR and β-actin mRNAs were coamplified by RT-PCR. In addition serum biochemical markers of TH action were measured: thyrotropin (TSH), sex hormone binding globulin (SHBG), osteocalcin (OC), β-crosslaps (β-CL), iodothyronines by electrochemiluminescency and IGF-I by immunoradiometric assay (IRMA) with extraction.
Results TR mRNAs from PBMC were reduced in TS patients under GH treatment. In turn, serum TSH, OC, β-CL and IGF-I were increased while SHBG was reduced by GH treatment in TS patients.
Conclusions GH treatment reduced TR expression in PBMC and biochemical serum markers of TH action. These results suggest that GH treatment in TS patients impair peripheral TH action at tissue level and prompt a role in the reduced growth response to the therapy.
References
- 1 Sybert, V.P. & McCauley, E. (2004) Turner's syndrome. New England Journal of Medicine, 351, 1227–1238.
- 2 Gravholt, C.H. (2004) Epidemiological, endocrine and metabolic features in Turner syndrome. European Journal of Endocrinology, 151, 657–687.
- 3 Dacou-Voutetakis, C., Karavanaki-Karanassiou, K., Petrou, V., Georgopoulos, N., Maniati-Christidi, M. & Mavrou, A. (1998) The growth pattern and final height of girls with Turner syndrome with and without human growth hormone treatment. Pediatrics, 101, 663–668.
- 4 Cave, C.B., Bryant, J. & Milne, R. (2003) Recombinant growth hormone in children and adolescents with Turner syndrome. Cochrane Database System Review CD003887.
- 5 The Canadian Growth Hormone Advisory Committee (2005) Impact of growth hormone supplementation on adult height in Turner syndrome: results of the Canadian randomized controlled trial. Journal of Clinical Endocrinology and Metabolism, 90, 3360–3366.
- 6 Darendeliler, F., Ranke, M.B., Bakker, B., Lindberg, A., Cowell, C.T., Albertsson-Wikland, K., Reiter, E.O. & Price, D.A. (2004) Bone age progression during the first year of GH therapy in pre-pubertal children with idiopathic GH deficiency, Turner syndrome or idiopathic short stature, and in short children born small for gestational age: analysis of data from KIGS (Pfizer International Growth Database). Hormone Research, 63, 40–47.
- 7 Harvey, C.B., O'Shea, P.J., Scott, A.J., Robson, H., Siebler, T., Shalet, S.M., Samarut, J., Chassande, O. & Williams, G.R. (2002) Molecular mechanisms of thyroid hormone effects on bone growth and function. Molecular Genetics and Metabolism, 75, 17–30.
- 8 Davis, P.J., Davis, F.B. & Cody, V. (2005) Membrane receptors mediating thyroid hormone action. Trends in Endocrinology and Metabolism, 16, 429–435.
- 9 Yen, P.M., Ando, S., Feng, X., Liu, Y. & Maruvada, P. (2006) Thyroid hormone action at the cellular, genomic and target gene levels. Molecular and Cellular Endocrinology, 246, 121–127.
- 10 Kindblom, J.M., Gothe, S., Forrest, D., Tornell, J., Vennstrom, B. & Ohlsson, C. (2001) GH substitution reverses the growth phenotype but not the defective ossification in thyroid hormone receptor alpha 1−/–beta−/– mice. Journal of Endocrinology, 171, 15–22.
- 11 O'Shea, P.J., Bassett, J.H., Sriskantharajah, S., Ying, H., Cheng, S.Y. & Williams, G.R. (2005) Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta. Molecular Endocrinology, 19, 3045–3059.
- 12 Jorgensen, J.O.L., Moller, J., Laureen, T., Orskov, H., Christiansen, J.S. & Weeke, J. (1994) Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults. Clinical Endocrinology, 41, 609–614.
- 13 Bettendorf, M., Doerr, H.G., Hauffa, B.P., Lindberg, A., Mehls, O., Partsch, C.J., Schwarz, H.P., Stahnke, N. & Ranke, M.B. (2006) Prevalence of autoantibodies associated with thyroid and celiac disease in Ullrich-Turner syndrome in relation to adult height after growth hormone treatment. Journal of Pediatric Endocrinology and Metabolism, 19, 149–154.
- 14 Pellizas, C.G., Coleoni, A.H., Cabanillas, A.M., Masini-Repiso, A.M. & Costamagna, M.E. (1996) Response of triiodothyronine-dependent enzyme activities to insulin-like growth factor I and growth hormone in cultured rat hepatocytes. European Journal of Endocrinology, 134, 215–220.
- 15 Pellizas, C.G., Coleoni, A.H., Costamagna, M.E., Di Fulvio, M. & Masini-Repiso, A.M. (1998) Insulin-like growth factor I reduces thyroid hormone receptors in the rat liver: evidence for a feedback loop regulating the peripheral thyroid hormone action. Journal of Endocrinology, 158, 87–95.
- 16 Pellizas, C.G., Bonaterra, M., De Paul, A.L., Aoki, A., Coleoni, A.H. & Torres, A.I. (2000) Somatotroph response to periodical IGF-I administration to male rats. Acta Histochemica, 102, 439–451.
- 17 Pellizas, C.G., Montesinos, M.M., Masini-Repiso, A.M., Torres, A.I. & Coleoni, A.H. (2002) Differential modulation of liver and pituitary triiodothyronine and 9-cis retinoid acid receptors by insulin-like growth factor I in rats. Thyroid, 12, 1071–1078.
- 18 Nagayama, Y., Yamashita, S., Hirayu, H., Ashizawa, K., Harakawa, S., Inoue, S., Izumi, M. & Nagataki, S. (1988) Expression and regulation of c-erb A mRNA from lymphocytes in patients with thyroid dysfunction. Endocrinologia Japonica, 35, 463–467.
- 19 Meier-Heusler, S., Pernin, A., Liang, H., Goumaz, O., Burger, A.G. & Meier, C.A. (1995) Quantitation of β1 triiodothyronine receptor mRNA in human tissues by competitive reverse transcription polymerase chain reaction. Journal of Endocrinological Investigation, 18, 767–773.
- 20 Feart, C., Pallet, V., Boucheron, C., Higheret, D., Alfos, S., Leteneur, L., Dartigues, J.F. & Higueret, P. (2005a) Aging affects the retinoid acid and the triiodothyronine nuclear receptor mRNA expression in human peripheral blood mononuclear cells. European Journal of Endocrinology, 152, 449–458.
- 21 Feart, C., Vallortigara, J., Higueret, D., Gatta, B., Tabarin, A., Enderlin, V., Higueret, P. & Pallet, V. (2005b) Decreased expression of retinoid nuclear receptor (RARα and RARγ) mRNA determined by real-time quantitative RT-PCR in peripheral blood mononuclear cells of hypothyroid patients. Journal of Molecular Endocrinology, 34, 849–858.
- 22 Regalbuto, C., Alagona, C., Maiorana, R., Di Paola, R., Cianci, M., Alagona, G., Sapienza, S., Vigneri, R. & Pezzino, V. (2006) Acute changes in clinical parameters and thyroid function peripheral markers following L-T4 withdrawal in patients totally thyroidectomized for thyroid cancer. Journal of Endocrinological Investigation, 29, 32–40.
- 23 Seppel, T., Becker, A., Lippert, F. & Schlaghecke, R. (1996) Serum sex hormone-binding globulin and osteocalcin in systemic nonthyroidal illness associated with low thyroid hormone concentrations. Journal of Clinical Endocrinology and Metabolism, 81, 1663–1665.
- 24 Massa, G., De Zegher, F. & Vanderschueren-Lodeweyckx, M. (1991) Effect of growth hormone therapy on thyroid status of girls with Turner's syndrome. Clinical Endocrinology, 34, 205–209.
- 25 Schmitt, K., Hausler, G., Blumel, P., Plochl, E., Waldhor, T. & Frisch, H. (1997) The influence of growth hormone monotherapy and growth hormone in combination with oxandrolone or testosterone on thyroid hormone parameters and thyroxine binding globulin in patients with Ullrich–Turner syndrome. European Journal of Pediatrics, 156, 99–103.
- 26 Wyatt, D., Gesundheit, N. & Sherman, B. (1998) Changes in thyroid hormone levels during growth hormone therapy in initially euthyroid patients: lack of need for thyroxine supplementation. Journal of Clinical Endocrinology and Metabolism, 83, 3493–3497.
- 27 Morimura, T., Tsunekawa, K., Kasahara, T., Seki, K., Ogiwara, T., Mori, M. & Murakami, M. (2005) Expression of type 2 iodothyronine deiodinase in human osteoblast is stimulated by thyrotropin. Endocrinology, 146, 2077–2084.
- 28 Ercan-Fang, S., Schwartz, H.L. & Oppenheimer, J.H. (1996) Isoform-specific 3,5,3′-triiodothyronine receptor binding capacity and messenger ribonucleic acid content in rat adenohypophysis: effect of thyroidal state and comparison with extrapituitary tissues. Endocrinology, 137, 3228–3233.
- 29 Gauthier, K., Chassande, O., Plateroti, M., Roux, J.P., Legrand, C., Pain, B., Rousset, B., Weiss, R., Trouillas, J. & Samarut, J. (1999) Different functions for the thyroid hormone receptors TRα and TRβ in the control of thyroid hormone production and post-natal development. EMBO Journal, 18, 623–631.
- 30 Sato, T., Suzuki, Y., Taketani, T., Ishiguro, K. & Masuyama, T. (1977) Enhanced peripheral conversion of thyroxine to triiodothyronine during hGH therapy in GH deficient children. Journal of Clinical Endocrinology and Metabolism, 45, 324–329.
- 31 Kalina-Faska, B., Kalina, M. & Koehler, B. (2002) Assessment of thyrotropin concentrations in children with somatotropin deficiency treated with growth hormone. Endokrynologia, Diabetologia I Choroby Przemiany Materii Wieku Rozwojowego, 8, 17–21.
- 32 MacGillivray, M.H. (1995) Disorders of growth and development. In: P. Felig, J.D. Baxter, L.A. Frohman eds. Endocrinology and Metabolism, 3rd edn. McGraw-Hill, New York, 1619–1673
- 33 Hampl, R., Snajderova, M., Lebl, J., Lisa, L., Dvorakova, M., Hill, M., Sulcova, J. & Starka, L. (2001) Sex hormone-binding globulin as a marker of the effect of hormonal treatment in Turner's syndrome. Endocrine Regulations, 35, 17–24.
- 34 Beck-Peccoz, P. & Chatterjee, K. (1994) The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid, 4, 225–232.
- 35 Haeusler, G., Schmitt, K., Blumel, P., Plochl, E., Waldhor, T.H. & Frisch, H. (1996) Insulin, insulin-like growth factor-binding protein-1, and sex hormone-binding globulin in patients with Turner's syndrome: course over age in untreated patients and effect of therapy with growth hormone alone and in combination with oxandrolone. Journal of Clinical Endocrinology and Metabolism, 81, 536–541.
- 36 Belgorosky, A., Martinez, A., Domene, H., Heinrich, J.J., Bergada, C. & Rivarola, M.A. (1987) High serum sex hormone-binding globulin (SHBG) and low serum nonbound testosterone in boys with idiopathic hypopituitarism: effect of recombinant human growth hormone treatment. Journal of Clinical Endocrinology and Metabolism, 65, 1107–1111.
- 37 Gafny, M., Silbergeld, A., Klinger, B., Wasserman, M. & Laron, Z. (1994) Comparative effects of GH, IGF-I and insulin on serum sex hormone binding globulin. Clinical Endocrinology, 41, 169–175.
- 38 Rosen, H.N., Moses, A.C., Garber, J., Iloputaife, I.D., Ross, D.S., Lee, S.L., Greenspan, S. & L. (2000) Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcified Tissue International, 66, 100–103.
- 39 Baroncelli, G.I., Bertelloni, S., Ceccarelli, C., Cupelli, D. & Saggese, G. (2000) Dynamics of bone turnover in children with GH deficiency treated with GH until final height. European Journal of Endocrinology, 142, 549–556.
- 40 Gravholt, C.H., Naeraa, R.W., Brixen, K., Kastrup, K.W., Mosekilde, L., Jorgensen, J.O. & Christiansen, J.S. (2002) Short-term growth hormone treatment in girls with Turner syndrome decreases fat mass and insulin sensitivity: a randomized, double-blind, placebo-controlled, crossover study. Pediatrics, 110, 889–896.