Age-dependent response to T4 overtreatment and recovery on systemic and organ level

in Journal of Molecular Endocrinology
Authors:
Helena Kerp Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Search for other papers by Helena Kerp in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-6036-0230
,
Kostja Renko Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Experimentelle Endokrinologie, Berlin, Germany
German Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Berlin, Germany

Search for other papers by Kostja Renko in
Current site
Google Scholar
PubMed Close
,
Georg Sebastian Hönes Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Search for other papers by Georg Sebastian Hönes in
Current site
Google Scholar
PubMed Close
,
Klaudia Brix Department of Life Sciences and Chemistry, Jacobs University Bremen, Bremen, Germany

Search for other papers by Klaudia Brix in
Current site
Google Scholar
PubMed Close
,
Josef Köhrle Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Experimentelle Endokrinologie, Berlin, Germany

Search for other papers by Josef Köhrle in
Current site
Google Scholar
PubMed Close
,
Lars Christian Moeller Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Search for other papers by Lars Christian Moeller in
Current site
Google Scholar
PubMed Close
, and
Dagmar Führer Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Search for other papers by Dagmar Führer in
Current site
Google Scholar
PubMed Close

Correspondence should be addressed to D Führer: dagmar.fuehrer@uk-essen.de
DOI:
https://doi.org/10.1530/JME-21-0109
Volume/Issue:
Volume 67: Issue 4
Article Type:
Research Article
Page Range:
161–172
Online Publication Date:
09 Sep 2021
Copyright:
© Society for Endocrinology 2021
Restricted access
Rent on DeepDyve

Sign up for journal news

Thyroid hormone (TH) metabolism and cellular TH action are influenced by ageing. To investigate the response to thyroxine (T4) overtreatment, a kinetic study was conducted in young and aged mice with chronic hyperthyroidism and hormone withdrawal. Five and 22 months old male mice were treated with T4 or PBS over 5 weeks, followed by observation for up to 12 days. Serial analysis was performed for thyroid function parameters, transcript levels of TH target genes, deiodinase type 1 (DIO1) activity as well as serum lipids at 12, 24, 72, 144, 216, and 288 h after cessation of T4 administration. Higher FT3 concentrations and higher renal DIO1 activities were noted in aged mice 12 h after T4 withdrawal and marked thyroid-stimulating hormone elevation was found in aged mice after 12 days compared to respective controls. A biphasic expression pattern occurred for TH target genes in all organs and a hypothyroid organ state was observed at the end of the study, despite normalization of TH serum concentrations after 72 h. In line with this, mirror-image kinetics were detected for serum cholesterol and triglycerides in aged and young mice. Recovery from TH overtreatment in mice involves short- and medium-term adaption of TH metabolism on systemic and organ levels. Increased renal DIO1 activity may contribute to higher T3 concentrations and prolonged thyrotoxicosis followed by hypothyroidism in an aged-mouse organism. Translation of these findings in the clinical setting seems warranted and may lead to better management of hyperthyroidism and prevention of T4 overtreatment in aged patients.

Supplementary Materials

    • Supplementary Figure 1
    • Supplementary material

Journal of Molecular Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 1495 56 0
PDF Downloads 377 16 0

 

  • Collapse
  • Expand
Online ISSN:
1479-6813
Print ISSN:
0952-5041
Copyright:
© Society for Endocrinology 2021
Page(s):
12
Article Type:
Research Article
Received Date:
15 Jul 2021
Accepted Date:
26 Jul 2021
Print Publication Date:
01 Nov 2021
Online Publication Date:
09 Sep 2021
Keywords:
thyroid hormone action; ageing; thyroid hormone kinetics; gene expression

  • Abuid J & Larsen PR 1974 Triiodothyronine and thyroxine in hyperthyroidism. Comparison of the acute changes during therapy with antithyroid agents. Journal of Clinical Investigation 54 201–20 8. (https://doi.org/10.1172/JCI107744)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Asvold BO, Vatten LJ, Bjoro T, Bauer DC, Bremner A, Cappola AR, Ceresini G, Denelzen WP, Ferrucci L & Franco OH et al. 2015 Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts. JAMA Internal Medicine 175 1037–10 47. (https://doi.org/10.1001/jamainternmed.2015.0930)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Barbesino G 2019 Thyroid function changes in the elderly and their relationship to cardiovascular health: a mini-review. Gerontology 65 1–8. (https://doi.org/10.1159/000490911)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Boelen A, Kwakkel J & Fliers E 2011 Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocrine Reviews 32 670–6 93. (https://doi.org/10.1210/er.2011-0007)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW & Shipley GL et al. 2009 The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clinical Chemistry 55 611–6 22. (https://doi.org/10.1373/clinchem.2008.112797)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Carlwe M, Schaffer T & Sjoberg S 2013 Short-term withdrawal of levothyroxine, induced increase of thyroid-stimulating hormone and an increase ratio of triiodothyronine to thyroxine. European Endocrinology 9 37–39. (https://doi.org/10.17925/EE.2013.09.01.37)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Damiano F, Rochira A, Gnoni A & Siculella L 2017 Action of thyroid hormones, T3 and T2, on hepatic fatty acids: differences in metabolic effects and molecular mechanisms. International Journal of Molecular Sciences 18 744. (https://doi.org/10.3390/ijms18040744)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Donda A, Reymond MJ, Zurich MG & Lemarchand-Beraud T 1987 Influence of sex and age on T3 receptors and T3 concentration in the pituitary gland of the rat: consequences on TSH secretion. Molecular and Cellular Endocrinology 54 29–34. (https://doi.org/10.1016/0303-7207(8790136-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Donda A, Reymond MJ & Lemarchand-Beraud T 1989 Influence of age on the control of thyrotropin secretion by thyrotropin-releasing hormone in the male rat. Neuroendocrinology 49 389–3 94. (https://doi.org/10.1159/000125143)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Duntas LH 2018 Thyroid function in aging: a discerning approach. Rejuvenation Research 21 22–28. (https://doi.org/10.1089/rej.2017.1991)

  • Duntas LH & Brenta G 2018 A renewed focus on the association between thyroid hormones and lipid metabolism. Frontiers in Endocrinology 9 511. (https://doi.org/10.3389/fendo.2018.00511)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Engels K, Rakov H, Zwanziger D, Hones GS, Rehders M, Brix K, Kohrle J, Moller LC & Fuhrer D 2016 Efficacy of protocols for induction of chronic hyperthyroidism in male and female mice. Endocrine 54 47–54. (https://doi.org/10.1007/s12020-016-1020-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Engels K, Rakov H, Hones GS, Brix K, Kohrle J, Zwanziger D, Moeller LC & Fuhrer D 2019 Aging alters phenotypic traits of thyroid dysfunction in male mice with divergent effects on complex systems but preserved thyroid hormone action in target organs. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 74 1162–1169. (https://doi.org/10.1093/gerona/glz040)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Forini F, Nicolini G, Kusmic C, D'aurizio R, Mercatanti A, Iervasi G & Pitto L 2020 T3 critically affects the Mhrt/Brg1 axis to regulate the cardiac MHC switch: role of an epigenetic cross-talk. Cells 9 2155. (https://doi.org/10.3390/cells9102155)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Grossman A, Weiss A, Koren-Morag N, Shimon I, Beloosesky Y & Meyerovitch J 2016 Subclinical thyroid disease and mortality in the elderly: a retrospective cohort study. American Journal of Medicine 129 423–4 30. (https://doi.org/10.1016/j.amjmed.2015.11.027)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Han P, Li W, Lin CH, Yang J, Shang C, Nuernberg ST, Jin KK, Xu W, Lin CY & Lin CJ et al. 2014 A long noncoding RNA protects the heart from pathological hypertrophy. Nature 514 102–106. (https://doi.org/10.1038/nature13596)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Herrmann B, Harder L, Oelkrug R, Chen J, Gachkar S, Nock S, Resch J, Korkowski M, Heuer H & Mittag J 2020 Central hypothyroidism impairs heart rate stability and prevents thyroid hormone-induced cardiac hypertrophy and pyrexia. Thyroid 30 1205–1216. (https://doi.org/10.1089/thy.2019.0705)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hoefig CS, Harder L, Oelkrug R, Meusel M, Vennstrom B, Brabant G & Mittag J 2016 Thermoregulatory and cardiovascular consequences of a transient thyrotoxicosis and recovery in male mice. Endocrinology 157 2957–29 67. (https://doi.org/10.1210/en.2016-1095)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA & Braverman LE 2002 Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): national health and nutrition examination survey (NHANES III). Journal of Clinical Endocrinology and Metabolism 87 489–4 99. (https://doi.org/10.1210/jcem.87.2.8182)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jabbar A, Pingitore A, Pearce SH, Zaman A, Iervasi G & Razvi S 2017 Thyroid hormones and cardiovascular disease. Nature Reviews: Cardiology 14 39–55. (https://doi.org/10.1038/nrcardio.2016.174)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Janssen R, Zuidwijk M, Muller A, Mulders J, Oudejans CB & Simonides WS 2013 Cardiac expression of deiodinase type 3 (Dio3) following myocardial infarction is associated with the induction of a pluripotency microRNA signature from the Dlk1-Dio3 genomic region. Endocrinology 154 1973–197 8. (https://doi.org/10.1210/en.2012-2017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP & Rosenthal MS et al. 2014 Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid 24 1670–1 751. (https://doi.org/10.1089/thy.2014.0028)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kerp H, Gassen J & Fuhrer D 2020 Age and sex influence thyroid hormone effects in target tissues with organ-specific responses. Experimental and Clinical Endocrinology and Diabetes 128 469–472. (https://doi.org/10.1055/a-1083-6272)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ohba K, Leow MK, Singh BK, Sinha RA, Lesmana R, Liao XH, Ghosh S, Refetoff S, Sng JC & Yen PM 2016 Desensitization and incomplete recovery of hepatic target genes after chronic thyroid hormone treatment and withdrawal in male adult mice. Endocrinology 157 1660–16 72. (https://doi.org/10.1210/en.2015-1848)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pearce SH, Razvi S, Yadegarfar ME, Martin-Ruiz C, Kingston A, Collerton J, Visser TJ, Kirkwood TB & Jagger C 2016 Serum thyroid function, mortality and disability in advanced old age: the newcastle 85+ study. Journal of Clinical Endocrinology and Metabolism 101 4385–4394. (https://doi.org/10.1210/jc.2016-1935)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Persani L 1998 Hypothalamic thyrotropin-releasing hormone and thyrotropin biological activity. Thyroid 8 941–94 6. (https://doi.org/10.1089/thy.1998.8.941)

  • Pfaffl MW 2001 A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Research 29 e45. (https://doi.org/10.1093/nar/29.9.e45)

  • Pohlenz J, Maqueem A, Cua K, Weiss RE, Van Sande J & Refetoff S 1999 Improved radioimmunoassay for measurement of mouse thyrotropin in serum: strain differences in thyrotropin concentration and thyrotroph sensitivity to thyroid hormone. Thyroid 9 1265–12 71. (https://doi.org/10.1089/thy.1999.9.1265)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rakov H, Engels K, Hones GS, Strucksberg KH, Moeller LC, Kohrle J, Zwanziger D & Fuhrer D 2016 Sex-specific phenotypes of hyperthyroidism and hypothyroidism in mice. Biology of Sex Differences 7 36. (https://doi.org/10.1186/s13293-016-0089-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rakov H, De Angelis M, Renko K, Hones GS, Zwanziger D, Moeller LC, Schramm KW & Fuhrer D 2019 Aging is associated with low thyroid state and organ-specific sensitivity to thyroxine. Thyroid 29 1723–1733. (https://doi.org/10.1089/thy.2018.0377)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Razvi S, Jabbar A, Pingitore A, Danzi S, Biondi B, Klein I, Peeters R, Zaman A & Iervasi G 2018 Thyroid hormones and cardiovascular function and diseases. Journal of the American College of Cardiology 71 1781–1796. (https://doi.org/10.1016/j.jacc.2018.02.045)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Renko K, Hoefig CS, Hiller F, Schomburg L & Kohrle J 2012 Identification of iopanoic acid as substrate of type 1 deiodinase by a novel nonradioactive iodide-release assay. Endocrinology 153 2506–25 13. (https://doi.org/10.1210/en.2011-1863)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Reymond F, Denereaz N & Lemarchand-Beraud T 1992 Thyrotropin action is impaired in the thyroid gland of old rats. Acta Endocrinologica 126 55–63. (https://doi.org/10.1530/acta.0.1260055)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA & Stan MN et al. 2016 American thyroid association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 26 1343–1421. (https://doi.org/10.1089/thy.2016.0229)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schneider MJ, Fiering SN, Thai B, Wu SY, St Germain E, Parlow AF, St Germain DL & Galton VA 2006 Targeted disruption of the type 1 selenodeiodinase gene (Dio1) results in marked changes in thyroid hormone economy in mice. Endocrinology 147 580–58 9. (https://doi.org/10.1210/en.2005-0739)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schomburg L, Riese C, Renko K & Schweizer U 2007 Effect of age on sexually dimorphic selenoprotein expression in mice. Biological Chemistry 388 1035–10 41. (https://doi.org/10.1515/BC.2007.128)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sinha RA, Bruinstroop E, Singh BK & Yen PM 2019 Nonalcoholic fatty liver disease and hypercholesterolemia: roles of thyroid hormones, metabolites, and agonists. Thyroid 29 1173–1191. (https://doi.org/10.1089/thy.2018.0664)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, Sattar N, Aubert CE, Aujesky D & Bauer DC et al. 2017 Thyroid hormone therapy for older adults with subclinical hypothyroidism. New England Journal of Medicine 376 2534–2544. (https://doi.org/10.1056/NEJMoa1603825)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Streckfuss F, Hamann I, Schomburg L, Michaelis M, Sapin R, Klein MO, Kohrle J & Schweizer U 2005 Hepatic deiodinase activity is dispensable for the maintenance of normal circulating thyroid hormone levels in mice. Biochemical and Biophysical Research Communications 337 739–7 45. (https://doi.org/10.1016/j.bbrc.2005.09.102)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Studer H, Forster R, Conti A, Kohler H, Haeberli A & Engler H 1978 Transformation of normal follicles into thyrotropin-refractory “cold” follicles in the aging mouse thyroid gland. Endocrinology 102 1576–15 86. (https://doi.org/10.1210/endo-102-5-1576)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tamura S & Fujita H 1981 Fine structural aspects on the cold follicles in the aged mouse thyroid. Archivum Histologicum Japonicum: Nihon Soshikigaku Kiroku 44 177–1 88. (https://doi.org/10.1679/aohc1950.44.177)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Taylor PN, Razvi S, Muller I, Wass J, Dayan CM, Chatterjee K & Boelaert K 2019 Liothyronine cost and prescriptions in England. Lancet: Diabetes and Endocrinology 7 11–12. (https://doi.org/10.1016/S2213-8587(1830334-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vadiveloo T, Donnan PT, Murphy MJ & Leese GP 2013 Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the thyroid epidemiology, audit, and research study (TEARS). Journal of Clinical Endocrinology and Metabolism 98 1147–11 53. (https://doi.org/10.1210/jc.2012-3191)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Van der Geyten S, Byamungu N, Reyns GE, Kuhn ER & Darras VM 2005 Iodothyronine deiodinases and the control of plasma and tissue thyroid hormone levels in hyperthyroid tilapia (Oreochromis niloticus). Journal of Endocrinology 184 467–4 79. (https://doi.org/10.1677/joe.1.05986)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • van der Spek AH, Fliers E & Boelen A 2017 The classic pathways of thyroid hormone metabolism. Molecular and Cellular Endocrinology 458 29–38. (https://doi.org/10.1016/j.mce.2017.01.025)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Visser WE, Bombardieri CR, Zevenbergen C, Barnhoorn S, Ottaviani A, Van der Pluijm I, Brandt R, Kaptein E, Van Heerebeek R & Van Toor H et al. 2016 Tissue-specific suppression of thyroid hormone signaling in various mouse models of aging. PLoS ONE 11 e0149941. (https://doi.org/10.1371/journal.pone.0149941)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Waring AC, Arnold AM, Newman AB, Buzkova P, Hirsch C & Cappola AR 2012 Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. Journal of Clinical Endocrinology and Metabolism 97 3944–39 50. (https://doi.org/10.1210/jc.2012-2481)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wiersinga WM, Duntas L, Fadeyev V, Nygaard B & Vanderpump MP 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. European Thyroid Journal 1 55–71. (https://doi.org/10.1159/000339444)

    • PubMed
    • Search Google Scholar
    • Export Citation