Local impact of thyroid hormone inactivation

Dentice, Monica; Salvatore, Domenico

doi:10.1530/joe-11-0002

Cited by 143Thyroid Disorders and TreatmentsThyroid Cancer Diagnosis and TreatmentGrowth Hormone and Insulin-like Growth Factors

Local impact of thyroid hormone inactivation

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Dentice, Monica, Salvatore, Domenico·2011·Journal of Endocrinology

DOI 10.1530/joe-11-0002

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Abstract

Deiodination is a critical process by which the minimally active thyroxine (T(4)) molecule is converted into the favorite ligand for thyroid hormone (TH) receptors, triiodothyronine (T(3)). The iodothyronine deiodinases type 1, 2, and 3 (D1, D2, and D3) constitute a potent mechanism of TH activation (D1 and D2) or inactivation (D3), which functions by tissue specifically regulating TH bioavailability. D2 and D3 are widely expressed and in a dynamically and tightly coordinated fashion, thereby allowing cells to customize their own TH activity. D3, the major T(3) and T(4) inactivating deiodinase, catalyzes their conversion to 3,3'-diiodothyronine and to reverse T(3) respectively. According to common wisdom, D3 plays a major role in lowering serum TH concentrations during development, as supported by the much wider D3 tissue expression in the embryo structures than in the adult tissues. However, several recent studies show that D3 is reexpressed in adult life in various pathophysiological contexts, which strengthens the concept that cell-specific TH inactivation is a critical mediator in cellular TH metabolism. This review focuses on the progress made in understanding the physiological function and significance of D3. It summarizes the intriguing evidence that D3 plays a pivotal role in defining local TH concentration in the developing fetus and in several conditions in adult life.

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In critical conditions, the conversion of T4 to T3 is reduced while the conversion to rT3 is increased.
“In these critical conditions, where a reduction of the metabolism and a reduced T3 level is physiologically desirable, the conversion of T4 to T3 is reduced, while the conversion to rT3 is increased.”
From Can Reverse T3 Assay Be Employed to Guide T4 vs. T4/T3 Therapy in Hypothyroidism? (2019) · cites this paper as [5]
The “Role of D3 in disease” section reports lower circulating T3, higher rT3, and increased D3 activity in critically ill patients; “Type 3 iodothyronine deiodinase” identifies D3 as converting T4 to rT3. The copy does not establish that T4-to-T3 conversion is reduced in those patients or that reduced metabolism and T3 are physiologically desirable. Page numbers were not provided. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Due to alterations in rates of local deiodination in tissues, thyroid hormone signaling can change irrespective of serum hormonal concentrations.
“Due to alterations in rates of local deiodination in tissues, thyroid hormone signaling can change irrespective of serum hormonal concentrations (3, 5).”
From Can Reverse T3 Assay Be Employed to Guide T4 vs. T4/T3 Therapy in Hypothyroidism? (2019) · cites this paper as [5]

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The Concise Guide to PHARMACOLOGY 2013/14: Enzymes
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Metabolic Effects of the Intracellular Regulation of Thyroid Hormone: Old Players, New Concepts
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Deiodinases and the Three Types of Thyroid Hormone Deiodination Reactions
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Selenium: An Element of Life Essential for Thyroid Function
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Effects of manipulating hypothalamic triiodothyronine concentrations on seasonal body weight and torpor cycles in Siberian hamsters
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β-Catenin Regulates Deiodinase Levels and Thyroid Hormone Signaling in Colon Cancer Cells
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Thyroid hormones and mitochondria: With a brief look at derivatives and analogues
Cioffi, F., Senese, R., Lanni, A., & Goglia, F. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.06.006 · Cited by 99 · see citing works
Understanding selenoprotein function and regulation through the use of rodent models
Kasaikina, M. V., Hatfield, D. L., & Gladyshev, V. N. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.02.018 · Cited by 98 · see citing works
The Deiodinase Trio and Thyroid Hormone Signaling
Bianco, A. C., & da Conceição, R. R. (2018) · Methods in Molecular Biology · doi:10.1007/978-1-4939-7902-8_8 · Cited by 96 · see citing works
Type 2 deiodinase at the crossroads of thyroid hormone action
Drigo, R. A. E., & Bianco, A. C. (2011) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2011.05.016 · Cited by 95 · see citing works
Tetrac Can Replace Thyroid Hormone During Brain Development in Mouse Mutants Deficient in the Thyroid Hormone Transporter Mct8
Horn, S., Kersseboom, S., Mayerl, S. E., Müller, J., Groba, C., Trajkovic‐Arsic, M., Ackermann, T., Visser, T. J., & Heuer, H. (2013) · Endocrinology · doi:10.1210/en.2012-1628 · Cited by 84 · see citing works
The impact of thyroid hormone dysfunction on ischemic heart disease
von Hafe, M., Neves, J. S., Vale, C., Borges‐Canha, M., & Leite-Moreira, A. F. (2019) · Endocrine Connections · doi:10.1530/ec-19-0096 · Cited by 83 · see citing works
Repair-Related Activation of Hedgehog Signaling in Stromal Cells Promotes Intrahepatic Hypothyroidism
Bohinc, B. N., Michelotti, G. A., Xie, G., Pang, H., Suzuki, A., Guy, C. D., Piercy, D. L., Krüger, L., Swiderska‐Syn, M., Machado, M. V., et al. (2014) · Endocrinology · doi:10.1210/en.2014-1302 · Cited by 86 · see citing works
Metabolism of Thyroid Hormone
Peeters, R. P., & Visser, T. J. (2012) · Cited by 75 · see citing works
Traversing barriers – How thyroid hormones pass placental, blood-brain and blood-cerebrospinal fluid barriers
Landers, K., & Richard, K. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.01.041 · Cited by 72 · see citing works
The colorful diversity of thyroid hormone metabolites
Köhrle, J. (2019) · European Thyroid Journal · doi:10.1159/000497141 · Cited by 67 · see citing works
Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration
Ma, H., Thapa, A., Morris, L. M., Redmond, T. M., Baehr, W., & Ding, X. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1317041111 · Cited by 68 · see citing works
Type 3 deiodinase and consumptive hypothyroidism: a common mechanism for a rare disease
Luongo, C., Trivisano, L., Alfano, F., & Salvatore, D. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00115 · Cited by 67 · see citing works
Serum polybrominated diphenyl ether concentrations and thyroid function in young children
Jacobson, M. H., Barr, D. B., Marcus, M., MUIR, A. B., Lyles, R. H., Howards, P. P., Pardo, L. A., & Darrow, L. A. (2016) · Environmental Research · doi:10.1016/j.envres.2016.05.022 · Cited by 67 · see citing works
Crossover of the Hypothalamic Pituitary–Adrenal/Interrenal, –Thyroid, and –Gonadal Axes in Testicular Development
Castañeda-Cortés, D. C., Langlois, V. S., & Fernandino, J. I. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00139 · Cited by 67 · see citing works
The pathophysiological consequences of thyroid hormone transporter deficiencies: Insights from mouse models
Heuer, H., & Visser, T. J. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.04.009 · Cited by 64 · see citing works
Thyroid hormone action in epidermal development and homeostasis and its implications in the pathophysiology of the skin
Mancino, G., Miro, C., Cicco, E. D., & Dentice, M. (2021) · Journal of Endocrinological Investigation · doi:10.1007/s40618-020-01492-2 · Cited by 60 · see citing works
Neuronal Hypoxia Induces Hsp40-Mediated Nuclear Import of Type 3 Deiodinase As an Adaptive Mechanism to Reduce Cellular Metabolism
Jo, S., Kalló, I., Bardóczi, Z., Drigo, R. A. E., Zeöld, A., Liposits, Z., Oliva, A. A., Lemmon, V., Bixby, J. L., Gereben, B., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6514-11.2012 · Cited by 60 · see citing works
Role of the Thyroid System in Myelination and Neural Connectivity
Calzà, L., Fernández, M., & Giardino, L. (2015) · Comprehensive physiology · doi:10.1002/cphy.c140035 · Cited by 66 · see citing works
Thyroid Physiology
Stathatos, N. (2012) · Medical Clinics of North America · doi:10.1016/j.mcna.2012.01.007 · Cited by 57 · see citing works
Cardiac Thyroid Hormone Metabolism and Heart Failure
Janssen, R., Muller, A., & Simonides, W. S. (2017) · European Thyroid Journal · doi:10.1159/000469708 · Cited by 55 · see citing works
An Intimate Relationship between Thyroid Hormone and Skin: Regulation of Gene Expression
Antonini, D., Sibilio, A., Dentice, M., & Missero, C. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00104 · Cited by 53 · see citing works
A novel pathway regulates thyroid hormone availability in rat and human hypothalamic neurosecretory neurons
Kalló, I., Mohácsik, P., Vida, B., Zeöld, A., Bardóczi, Z., Zavacki, A. M., Farkas, E., Kádár, A., Hrabovszky, E., Arrojo e Drigo, R., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037860 · Cited by 52 · see citing works
Type 3 deiodinase and solid tumors: an intriguing pair
Dentice, M., Antonini, D., & Salvatore, D. (2013) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.833189 · Cited by 52 · see citing works
Thyroid hormones and derivatives: endogenous thyroid hormones and their targets
Köhrle, J. (2018) · Methods in Molecular Biology · doi:10.1007/978-1-4939-7902-8_9 · Cited by 47 · see citing works
Wnt Signaling in Thyroid Homeostasis and Carcinogenesis
Ely, K., Bischoff, L. A., & Weiss, V. L. (2018) · Genes · doi:10.3390/genes9040204 · Cited by 46 · see citing works
Clinical health issues, reproductive hormones, and metabolic hormones associated with gut microbiome structure in African and Asian elephants
Keady, M., Prado, N. A., Lim, H. C., Brown, J. L., Paris, S., & Muletz‐Wolz, C. R. (2021) · Animal Microbiome · doi:10.1186/s42523-021-00146-9 · Cited by 41 · see citing works
A prospective study of early-pregnancy thyroid markers, lipid species, and risk of gestational diabetes mellitus
Wang, Y., Sun, F., Wu, P., Huang, Y., Ye, Y., Yang, X., Yuan, J., Liu, Y., Zeng, H., Wen, Y., et al. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab637 · Cited by 43 · see citing works
Thyroid hormone promotes differentiation of colon cancer stem cells
Cicatiello, A. G., Ambrosio, R., & Dentice, M. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.03.017 · Cited by 40 · see citing works
MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma
Romitti, M., Wajner, S. M., Ceolin, L., Ferreira, C. V., Ribeiro, R. V. P., Rohenkohl, H. C., Weber, S. D. S., Lopez, P. L. D. C., Fuziwara, C. S., Kimura, E. T., et al. (2016) · Endocrine Related Cancer · doi:10.1530/erc-15-0162 · Cited by 38 · see citing works
Hypothalamic effects of thyroid hormone
Zhang, Z., Boelen, A., Bisschop, P. H. L. T., Kalsbeek, A., & Fliers, E. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.01.018 · Cited by 37 · see citing works
Leptin enhances the intracellular thyroid hormone activation in skeletal muscle to boost energy balance
Miro, C., Cicatiello, A. G., Nappi, A., Sagliocchi, S., Acampora, L., Restolfer, F., Cuomo, O., de Alteriis, G., Pugliese, G., Torabinejad, S., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.01.025 · Cited by 35 · see citing works
The Concerted Action of Type 2 and Type 3 Deiodinases Regulates the Cell Cycle and Survival of Basal Cell Carcinoma Cells
Miro, C., Ambrosio, R., Stefano, M. A. D., Girolamo, D. D., Cicco, E. D., Cicatiello, A. G., Mancino, G., Porcelli, T., Raia, M., Vecchio, L. D., et al. (2017) · Thyroid · doi:10.1089/thy.2016.0532 · Cited by 34 · see citing works
Thyroid Function in Aging: A Discerning Approach
Duntas, L. H. (2017) · Rejuvenation Research · doi:10.1089/rej.2017.1991 · Cited by 33 · see citing works
Thyroid hormones and their placental deiodination in normal and pre-eclamptic pregnancy
Kurlak, L. O., Mistry, H. D., Kaptein, E., Visser, T. J., & Pipkin, F. B. (2013) · Placenta · doi:10.1016/j.placenta.2013.02.009 · Cited by 32 · see citing works
Thyroid Hormone Signaling in Retinal Development, Survival, and Disease
Yang, F., Ma, H., & Ding, X. (2017) · Vitamins and hormones · doi:10.1016/bs.vh.2017.05.001 · Cited by 32 · see citing works
Maternal and fetal thyroid dysfunction following porcine reproductive and respiratory syndrome virus2 infection
Pasternak, J. A., MacPhee, D. J., & Harding, J. C. S. (2020) · Veterinary Research · doi:10.1186/s13567-020-00772-2 · Cited by 31 · see citing works
A Hearty Dose of Noncoding RNAs: The Imprinted DLK1-DIO3 Locus in Cardiac Development and Disease
Dill, T. L., & Naya, F. J. (2018) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd5030037 · Cited by 31 · see citing works
Deiodinases and Cancer
Nappi, A., Stefano, M. A. D., Dentice, M., & Salvatore, D. (2021) · Endocrinology · doi:10.1210/endocr/bqab016 · Cited by 30 · see citing works
MiRNAs from DLK1-DIO3 Imprinted Locus at 14q32 are Associated with Multiple Sclerosis: Gender-Specific Expression and Regulation of Receptor Tyrosine Kinases Signaling
Baulina, N., Osmak, G. J., Сергеевич, К. И., Popova, E. V., Boyко, A., Кулакова, О. Г., & Favorova, O. O. (2019) · Cells · doi:10.3390/cells8020133 · Cited by 29 · see citing works
Acute exposure to microcystins affects hypothalamic-pituitary axes of male rats
Shi, T., Xu, L.-L., Chen, L., He, J., Wang, Y., Feng, C., Chen, Y., Giesy, J. P., Wang, Y., Wu, Q., et al. (2022) · Environmental Pollution · doi:10.1016/j.envpol.2022.120843 · Cited by 29 · see citing works
Central Hypothyroidism in Children
García, M., Fernández, A., & Moreno, J. C. (2014) · Endocrine development · doi:10.1159/000363157 · Cited by 28 · see citing works
Effects of hypothyroidism on the respiratory system and control of breathing: Human studies and animal models
Schlenker, E. H. (2012) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2012.02.007 · Cited by 28 · see citing works
Thyroid Hormone and the White Matter of the Central Nervous System: From Development to Repair
Calzà, L., Baldassarro, V. A., Fernández, M., Giuliani, A., Lorenzini, L., & Giardino, L. (2017) · Vitamins and hormones · doi:10.1016/bs.vh.2017.04.003 · Cited by 28 · see citing works
Factors and Mechanisms of Thyroid Hormone Activity in the Brain: Possible Role in Recovery and Protection
Sabatino, L., Lapi, D., & Seppia, C. D. (2024) · Biomolecules · doi:10.3390/biom14020198 · Cited by 30 · see citing works
Leptin intake in suckling rats restores altered T3 levels and markers of adipose tissue sympathetic drive and function caused by gestational calorie restriction
Konieczna, J., Palou, M., Sánchez, J., Picó, C., & Palou, A. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.22 · Cited by 24 · see citing works
The Thyroid Hormone Inactivator Enzyme, Type 3 Deiodinase, Is Essential for Coordination of Keratinocyte Growth and Differentiation
Mancino, G., Sibilio, A., Luongo, C., Cicco, E. D., Miro, C., Cicatiello, A. G., Nappi, A., Sagliocchi, S., Ambrosio, R., Stefano, M. A. D., et al. (2020) · Thyroid · doi:10.1089/thy.2019.0557 · Cited by 25 · see citing works
Rapid Responses to Reverse T3 Hormone in Immature Rat Sertoli Cells: Calcium Uptake and Exocytosis Mediated by Integrin
Zanatta, A. P., Zanatta, L. C. B., Gonçalves, R., Zamoner, A., & Silva, F. R. M. B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077176 · Cited by 23 · see citing works
Thyroid hormones and modulation of diastolic function: a promising target for heart failure with preserved ejection fraction
Neves, J. S., Vale, C., von Hafe, M., Borges‐Canha, M., Leite, A. R., Almeida‐Coelho, J., Lourenço, A. P., Falcão‐Pires, I., Carvalho, D. M., & Leite-Moreira, A. F. (2020) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018820958331 · Cited by 24 · see citing works
Alterations in local thyroid hormone signaling in the hippocampus of the SAMP8 mouse at younger ages: Association with delayed myelination and behavioral abnormalities
Sawano, E., Negishi, T., Aoki, T., Murakami, M., & Tashiro, T. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.23161 · Cited by 22 · see citing works
Is Thyroid Hormone Signaling Relevant for Vertebrate Embryogenesis?
Morvan-Dubois, G., Fini, J., & DEMENEIX, B. A. (2013) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-385979-2.00013-7 · Cited by 22 · see citing works
Selenium nutritional status and thyroid dysfunction
de Souza, L. S. L., Campos, R. D. O., Filho, J. D. S. B., de Jesus, J. D. S., Anunciação, S. M., Cassemiro, J. F., Rende, P. R. F., Hecht, F., & Ramos, H. E. (2025) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-4292-2023-0348 · Cited by 21 · see citing works
Downregulation of Caveolin-1 and Upregulation of Deiodinase 3, Associated with Hypoxia-Inducible Factor-1α Increase, Are Involved in the Oxidative Stress of Graves' Orbital Adipocytes
Regemorter, E. V., Joris, V., Regemorter, V. V., Marique, L., Behets, C., Lengelé, B., Boschi, A., Baldeschi, L., Daumerie, C., Many, M., et al. (2020) · Thyroid · doi:10.1089/thy.2020.0238 · Cited by 21 · see citing works
Effects of thyroid hormones in skeletal muscle protein turnover
Nappi, A., Moriello, C., Morgante, M., Fusco, F., Crocetto, F., & Miro, C. (2024) · Journal of Basic and Clinical Physiology and Pharmacology · doi:10.1515/jbcpp-2024-0139 · Cited by 20 · see citing works
Brain hypothyroidism silences the immune response of microglia in Alzheimer’s disease animal model
Kim, D. K., Choi, H., Lee, W., Choi, H., Hong, S. B., Jeong, J., Han, J., Han, J. W., Ryu, H., Kim, J., et al. (2024) · Science Advances · doi:10.1126/sciadv.adi1863 · Cited by 19 · see citing works
Effects of tetramethyl bisphenol F on thyroid and growth hormone-related endocrine systems in zebrafish larvae
Kim, H.-G., & Ji, K. (2022) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2022.113516 · Cited by 19 · see citing works
Role of thyroid hormones in different aspects of nervous system regeneration in vertebrates
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Authors: Dentice, M., & Salvatore, D.
Affiliations: Federico II University Hospital (IT)
Corresponding author: Dentice, Monica
ORCID: Dentice, Monica
Salvatore, Domenico
Venue: Journal of Endocrinology
Publisher: Bioscientifica
Published: 2011-03-11
Volume: 209
Issue: 3
Pages: 273-282
ISSN: 0022-0795 (ISSN-L)
1479-6805
DOI: 10.1530/joe-11-0002
OpenAlex: W2318017892
Cited by: 143
References: 94
Citations by year: 2026: 4 · 2025: 11 · 2024: 9 · 2023: 5 · 2022: 4 · 2021: 11 · 2020: 8 · 2019: 11 · 2018: 11 · 2017: 16 · 2016: 6 · 2015: 8 · 2014: 8 · 2013: 14 · 2012: 13
FWCI: 1.73
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Endocrinology (publishedVersion)
PubMed (publishedVersion)
INFM-OAR (INFN Catania) (submittedVersion, other-oa)
Funders: Associazione Italiana per la Ricerca sul Cancro
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords: thyroid hormone inactivation, triiodothyronine, thyroxine, thyroid hormone receptor, reverse T3, 3,3'-diiodothyronine, fetal thyroid development
MeSH terms: Aging, Animals, Humans, Iodide Peroxidase, Thyroid Hormones, Thyroxine, Triiodothyronine

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