Download PDF
Horm Metab Res 2015; 47(09): 674-680
DOI: 10.1055/s-0034-1398616
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects

R. Hoermann
1   Department of Nuclear Medicine, Klinikum Luedenscheid, 58515 Luedenscheid, Germany
,
J. E. M. Midgley
2   North Lakes Clinical, Ilkley, UK
,
R. Larisch
1   Department of Nuclear Medicine, Klinikum Luedenscheid, 58515 Luedenscheid, Germany
,
J. W. Dietrich
3   Medical Department I, Endocrinology and Diabetology, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, Germany
› Author Affiliations
Further Information

Publication History

received 01 September 2014

accepted 07 January 2015

Publication Date:
06 March 2015 (online)

Also available at
    Permissions and Reprints

Abstract

The objective of the study was to evaluate the roles of central and peripheral T3 regulation. In a prospective study involving 1 796 patients, the equilibria between FT3 and TSH were compared in untreated and L-T4-treated patients with varying functional states, residual thyroid secretory capacities and magnitudes of TSH stimulation. T3 concentrations were stable over wide variations in TSH levels (from 0.2 to 7 mU/l) and endogenous T4 production in untreated patients, but unbalanced in L-T4-treated athyreotic patients where T3 correlated with exogenous T4 supply. T3 stability was related to TSH-stimulated deiodinase activity by clinical observation, as predicted by theoretical modelling. Deiodinase activity in treated patients was reduced due to both diminished responsiveness to TSH and lack of thyroidal capacity. Deiodinase activity was increased in high thyroid volume, compared to lower volumes in euthyroid patients (<5 ml, p<0.001). While deiodinase differed between euthyroid and subclinically hypothyroid patients in high volume, 26.7 nmol/s (23.6, 29.2), n=214 vs. 28.9 nmol/s (26.7, 31.5), n=20, p=0.02, it was equivalent between the 2 functional groups in low volume, 23.3 nmol/s (21.3, 26.1), n=117 vs. 24.6 nmol/s (22.2, 27.5), n=38, p=0.22. These findings suggest that the thyroid gland and peripheral tissues are integrated in the physiological process of T3 homeostasis in humans via a feed-forward TSH motif, which coordinates peripheral and central regulatory mechanisms. Regulatory and capacity deficiencies collectively impair T3 homeostasis in L-T4-treated patients.

Key words

TSH - triiodothyronine - feedback control - deiodinase - homeostasis
 

  • References

  • 1 Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, Zeold A, Bianco AC. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008; 29: 898-938
    CrossrefPubMedGoogle Scholar
  • 2 Williams GR, Bassett JHD. Local control of thyroid hormone action: role of type 2 deiodinase: Deiodinases: the balance of thyroid hormone. J Endocrinol 2011; 209: 261-272
    CrossrefPubMedGoogle Scholar
  • 3 Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R. Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. Am J Physiol Endocrinol Metab 1990; 258: E715-E726
    PubMedGoogle Scholar
  • 4 Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 2002; 23: 38-89
    CrossrefPubMedGoogle Scholar
  • 5 Schneider MJ, Fiering SN, Pallud SE, Parlow AF, StGermain DL, Galton VA. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol 2001; 15: 2137-2148
    CrossrefPubMedGoogle Scholar
  • 6 Wagner MS, Wajner SM, Dora JM, Maia AL. Regulation of Dio2 gene expression by thyroid hormones in normal and type 1 deiodinase-deficient C3H mice. J Endocrinol 2007; 193: 435-444
    CrossrefPubMedGoogle Scholar
  • 7 Galton AV, de Waard E, Parlow AF, St Germain DL, Hernández A. Life without the iodothyronine deiodinases. Endocrinology 2014; 155: 4081-4087
    CrossrefPubMedGoogle Scholar
  • 8 Salvatore D. Deiodinases: keeping the thyroid hormone supply in balance. J Endocrinol 2011; 209: 259-260
    CrossrefPubMedGoogle Scholar
  • 9 Abdalla SM, Bianco AC. Defending plasma T3 is a biological priority. Clin Endocrinol (Oxf) 2014; 81: 633-641
    CrossrefPubMedGoogle Scholar
  • 10 Hoermann R, Midgley JEM, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, Larisch R. Homeostatic equilibria beetween free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clin Endocrinol (Oxf) 2014; 81: 907-915
    CrossrefPubMedGoogle Scholar
  • 11 Dietrich JW, Landgrafe G, Fotiadou EH. TSH and thyrotropic agonists: key actors in thyroid homeostasis. J Thyr Res 2012; 1-29
    PubMedGoogle Scholar
  • 12 Dietrich JW, Boehm BO. Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybernet Syst 2006; 269-274
    PubMedGoogle Scholar
  • 13 Midgley JEM, Hoermann R, Larisch R, Dietrich JW. Physiological states and functional relation between thyrotropin and free thyroxine in thyroid health and disease: in vivo and in silico data suggest a hierarchical model. J Clin Pathol 2013; 66: 335-342
    CrossrefPubMedGoogle Scholar
  • 14 R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, ISBN 3-900051-07-0. 2014. Retrieved from www.R-project.org (accessed 30 April 2014)
    PubMedGoogle Scholar
  • 15 Fellows I. Deducer: A data analysis GUI for R. J Stat Softw 2012; 49: 1-15
    PubMedGoogle Scholar
  • 16 Ishii H, Inada M, Tanaka K. Induction of outer and inner ring monodeiodinases in human thyroid gland by thyrotropin. J Endocrinol 1983; 57: 500-505
    PubMedGoogle Scholar
  • 17 Wu SY. Thyrotropin-mediated induction of thyroidal iodothyronine monodeiodinases in the dog. Endocrinology 1983; 112: 417-424
    CrossrefPubMedGoogle Scholar
  • 18 Murakami M, Kamiya Y, Morimura T, Araki O, Imamura M, Ogiwara T, Mizuma H, Mori M. Thyrotropin receptors in brown adipose tissue: thyrotropin stimulates type II iodothyronine deiodinase and uncoupling protein-1 in brown adipocytes. Am J Physiol 1990; 258: 1195-1201
    PubMedGoogle Scholar
  • 19 Toyoda N, Nishikawa M, Mori Y, Gondou A, Ogawa Y, Yonemoto T, Yoshimura M, Masaki H, Inada M. Thyrotropin and triiodothyronine regulate iodothyronine 5′-deiodinase messenger ribonucleic acid levels in FRTL-5 rat thyroid cells. Endocrinology 1992; 131: 389-394
    PubMedGoogle Scholar
  • 20 Beech SG, Walker SW, Arthur JR, Lee D, Beckett GJ. Differential control of type-I iodothyronine deiodinase expression by the activation of the cyclic AMP and phosphoinositol signalling pathways in cultured human thyrocytes. J Mol Endocrinol 1995; 14: 171-177
    CrossrefPubMedGoogle Scholar
  • 21 Koenig RJ. Regulation of type 1 iodothyronine deiodinase in health and disease. Thyroid 2005; 15: 835-840
    CrossrefPubMedGoogle Scholar
  • 22 Morimura T, Tsunekawa K, Kasahara T, Seki K, Ogiwara T, Mori M, Murakami M. Expression of Type 2 iodothyronine deiodinase in human osteoblast is stimulated by thyrotropin. Endocrinology 2005; 146: 2077-2084
    CrossrefPubMedGoogle Scholar
  • 23 Maia AL, Goemann IM, Meyer ELS, Wajner SM. Type 1 iodothyronine deiodinase in human physiology and disease: Deiodinases: the balance of thyroid hormone. J Endocrinol 2011; 209: 283-297
    CrossrefPubMedGoogle Scholar
  • 24 Toyoda N, Nishikawa M. Graves’ immunoglobulin G stimulates iodothyronine 5′ deiodinating activity in FRTL-5 rat thyroid cells. J Endocrinol 1990; 70: 1506-1511
    PubMedGoogle Scholar
  • 25 Vassart G, Dumont JE. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 1992; 13: 596-611
    CrossrefPubMedGoogle Scholar
  • 26 de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim S-W, Harney JW, Larsen PR, Bianco AC. The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest 2001; 108: 1379-1385
    CrossrefPubMedGoogle Scholar
  • 27 Bianco AC, Maia AL, da Silva WS, Christoffolete MA. Adaptive activation of thyroid hormone and energy expenditure. Biosci Rep 2005; 25: 191-208
    CrossrefPubMedGoogle Scholar
  • 28 Pereira VS, Marassi MP, Rosenthal D, Vaisman M, Correa da Costa VM. Positive correlation between type 1 and 2 iodothyronine deiodinases activities in human goiters. Endocrine 2011; 41: 532-538
    PubMedGoogle Scholar
  • 29 Midgley JEM. Direct and indirect free thyroxine assay methods: theory and practice. Clin Chem 2001; 47: 1353-1363
    PubMedGoogle Scholar
  • 30 Fonseca TL, Correa-Medina M, Campos MPO, Wittmann G, Werneck-de-Castro JP, Arrojo e Drigo R, Mora-Garzon M, Ueta CB, Caicedo A, Fekete C, Gereben B, Lechan RM, Bianco AC. Coordination of hypothalamic and pituitary T3 production regulates TSH expression. J Clin Invest 2013; 123: 1492-1500
    CrossrefPubMedGoogle Scholar
  • 31 Escobar-Morreale HF, Obregón MJ, Escobar del Rey F, Morereale de Escobar G. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest 1995; 96: 2828-2838
    CrossrefPubMedGoogle Scholar
  • 32 Escobar-Morreale HF, del Rey FE, Obregón MJ, Morereale de Escobar G. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology 1996; 137: 2490-2502
    CrossrefPubMedGoogle Scholar
  • 33 Boelen A, Kwakkel J, Fliers E. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocr Rev 2011; 32: 670-693
    CrossrefPubMedGoogle Scholar
  • 34 Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2006; 91: 2592-2599
    CrossrefPubMedGoogle Scholar
  • 35 Biondi B, Wartofsky L. Treatment with thyroid hormone. Endocr Rev 2014; 35: 433-512
    CrossrefPubMedGoogle Scholar