Iodothyronine deiodinase

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Type I thyroxine 5'-deiodinase
Identifiers
EC no. 1.21.99.4
CAS no. 70712-46-8
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Type II thyroxine 5-deiodinase
Identifiers
EC no. 1.21.99.3
CAS no. 74506-30-2
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Type III thyroxine 5-deiodinase
4TR3.png
Mouse iodothyronine deiodinase 3 catalytic core rendered from PDB entry 4TR3 [1]
Identifiers
EC no. 1.97.1.11
CAS no. 74506-30-2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
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Gene Ontology AmiGO / QuickGO
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PMC articles
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NCBI proteins

Iodothyronine deiodinases (EC 1.21.99.4 and EC 1.21.99.3) are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine (T4), the precursor of 3,5,3'-triiodothyronine (T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor, influences the expression of genes in practically every vertebrate cell. [2] [3] Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of an otherwise rare amino acid selenocysteine. [4] [5] [6]

Contents

These enzymes are not to be confused with the iodotyrosine deiodinases that are also deiodinases, but not members of the iodothyronine family. The iodotyrosine deiodinases (unlike the iodothyronine deiodinases) do not use selenocysteine or selenium. The iodotyrosine enzymes work on iodinated single tyrosine residue molecules to scavenge iodine, and do not use as substrates the double-tyrosine residue molecules of the various iodothyronines.

Activation and inactivation

In tissues, deiodinases can either activate or inactivate thyroid hormones:

The major part of thyroxine deiodination occurs within the cells.

Deiodinase 2 activity can be regulated by ubiquitination:

D-propranolol inhibits thyroxine deiodinase, thereby blocking the conversion of T4 to T3, providing some though minimal therapeutic effect.[ citation needed ]

Reactions

Reactions catalyzed by specific deiodinase isoforms Iodothyronine deiodinase.png
Reactions catalyzed by specific deiodinase isoforms
Iodothyronine deiodinase activity and regulation Iodothyronine deiodinase.jpg
Iodothyronine deiodinase activity and regulation

Structure

The three deiodinase enzymes share certain structural features in common although their sequence identity is lower than 50%. Each enzyme weighs between 29 and 33kDa. [7] Deiodinases are dimeric integral membrane proteins with single transmembrane segments and large globular heads (see below). [9] They share a TRX fold that contains the active site including the rare selenocysteine amino acid and two histidine residues. [7] [10] Selenocysteine is coded by a UGA codon, which generally signifies termination of a peptide through a stop codon. In point mutation experiments with Deiodinase 1 changing UGA to the stop codon TAA resulted in a complete loss of function, while changing UGA to cysteine (TGT) caused the enzyme to operate at around 10% normal efficiency. [11] In order for UGA to be read as a selenocysteine amino acid instead of a stop codon, it is necessary that a downstream stem loop sequence, the selenocysteine insertion sequence (SECIS), be present to bind with SECIS binding protein-2 (SBP-2), which binds with elongation factor EFsec. [7] The translation of selenocysteine is not efficient, [12] even though it is important to the functioning of the enzyme. Deiodinase 2 is localized to the ER membrane while Deiodinase 1 and 3 are found in the plasma membrane. [7]

The related catalytic domains of Deiodinases 1-3 feature a thioredoxine-related peroxiredoxin fold. [13] The enzymes catalyze a reductive elimination of iodine, thereby oxidizing themselves similar to Prx, followed by a reductive recycling of the enzyme.

Types

Type I iodothyronine deiodinase
Identifiers
SymbolDIO1
Alt. symbolsTXDI1
NCBI gene 1733
HGNC 2883
OMIM 147892
RefSeq NM_000792
UniProt P49895
Other data
EC number 1.21.99.3
Locus Chr. 1 p32-p33
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Structures Swiss-model
Domains InterPro
Type II iodothyronine deiodinase
Identifiers
Symbol DIO2
Alt. symbolsTXDI2, SelY
NCBI gene 1734
HGNC 2884
OMIM 601413
RefSeq NM_000793
UniProt Q92813
Other data
EC number 1.21.99.4
Locus Chr. 14 q24.2-24.3
Search for
Structures Swiss-model
Domains InterPro
Type III iodothyronine deiodinase
Identifiers
SymbolDIO3
Alt. symbolsTXDI3
NCBI gene 1735
HGNC 2885
OMIM 601038
PDB 4TR3
RefSeq NM_001362
UniProt P55073
Other data
EC number 1.97.1.11
Locus Chr. 14 q32
Search for
Structures Swiss-model
Domains InterPro

In most vertebrates, there are three types of enzymes that can deiodinate thyroid hormones:

TypeLocationFunction
type I (DI)is commonly found in the liver and kidney DI can deiodinate both rings [14]
type II deiodinase (DII) is found in the heart, skeletal muscle, CNS, fat, thyroid, and pituitary [15] DII can only deiodinate the outer ring of the prohormone thyroxine and is the major activating enzyme (the already inactive reverse triiodothyronine is also degraded further by DII)
type III deiodinase (DIII) found in the fetal tissue and the placenta; also present throughout the brain, except in the pituitary [16] DIII can only deiodinate the inner ring of thyroxine or triiodothyronine and is the major inactivating enzyme

Function

Deiodinase 1 both activates T4 to produce T3 and inactivates T4. Besides its increased function in producing extrathyroid T3 in patients with hyperthyroidism, its function is less well understood than D2 or D3 [2] [7] Deiodinase 2, located in the ER membrane, converts T4 into T3 and is a major source of the cytoplasmic T3 pool. [2] Deiodinase 3 prevents T4 activation and inactivates T3. [9] D2 and D3 are important in homeostatic regulation in maintaining T3 levels at the plasma and cellular levels. In hyperthyroidism D2 is down regulated and D3 is upregulated to clear extra T3, while in hypothyroidism D2 is upregulated and D3 is downregulated to increase cytoplasmic T3 levels. [2] [7]

Serum T3 levels remain fairly constant in healthy individuals, but D2 and D3 can regulate tissue specific intracellular levels of T3 to maintain homeostasis since T3 and T4 levels may vary by organ. Deiodinases also provide spatial and temporal developmental control of thyroid hormone levels. D3 levels are highest early in development and decrease over time, while D2 levels are high at moments of significant metamorphic change in tissues. Thus D2 enables production of sufficient T3 at necessary time points while D3 may shield tissue from overexposure to T3. [12]

Also, iodothyronine deiodinases (type 2 y 3; DIO2 and DIO3, respectively) respond to seasonal changes in photoperiod-driven melatonin secretion and govern peri-hypothalamic catabolism of the prohormone thyroxine (T4). In long summer days, the production of hypothalamic T3 increase due to DIO-2-mediated conversion of T4 to the biologically active hormone. This process allows to active anabolic neuroendocrine pathways that maintain reproductive competence and increase body weight. However, during the adaptation to reproductively inhibitory photoperiods, the levels of T3 decrease due to peri-hypothalamic DIO3 expression that catabolizes T4 and T3 into receptor inactive amines. [17] [18]

Deiodinase 2 also plays a significant role in thermogenesis in brown adipose tissue (BAT). In response to sympathetic stimulation, dropping temperature, or overfeeding BAT, D2 increases oxidation of fatty acids and uncouples oxidative phosphorylation via uncoupling protein, causing mitochondrial heat production. D2 increases during cold stress in BAT and increases intracellular T3 levels. In D2 deficient models, shivering is a behavioral adaptation to the cold. However, heat production is much less efficient than uncoupling lipid oxidation. [19] [20]

Disease relevance

In cardiomyopathy the heart reverts to a fetal gene programming due to the overload of the heart. Like during fetal development, thyroid hormone levels are low in the overloaded heart tissue in a local hypothyroid state, with low levels of deiodinase 1 and deiodinase 2. Although deiodinase 3 levels in a normal heart are generally low, in cardiomyopathy deiodinase 3 activity is increased to decrease energy turnover and oxygen consumption. [7]

Hypothyroidism is a disease diagnosed by decreased levels of serum thyroxine (T4). Presentation in adults leads to decreased metabolism, increased weight gain, and neuropsychiatric complications. [21] During development, hypothyroidism is considered more severe and leads to neurotoxicity as cretinism or other human cognitive disorders, [22] altered metabolism and underdeveloped organs. Medication and environmental exposures can result in hypothyroidism with changes in deiodinase enzyme activity. The drug iopanoic acid (IOP) decreased cutaneous cell proliferation by inhibition of deiodinase enzyme type 1 or 2 reducing the conversion of T4 to T3. The environmental chemical DE-71, a PBDE pentaBDE brominated flame retardant decreased hepatic deiodinase I transcription and enzyme activity in neonatal rats with hypothyroidism. [23]

Quantifying enzyme activity

In vitro, including cell culture experiments, deiodination activity is determined by incubating cells or homogenates with high amounts of labeled thyroxine (T4) and required cosubstrates. As a measure of deiodination, the production of radioactive iodine and other physiological metabolites, in particular T3 or reverse T3, are determined and expressed (e.g. as fmol/mg protein/minute). [24] [25]

In vivo, deiodination activity is estimated from equilibrium levels of free T3 and free T4. A simple approximation is T3/T4 ratio, [26] a more elaborate approach is calculating sum activity of peripheral deiodinases (SPINA-GD) from free T4, free T3 and parameters for protein binding, dissociation and hormone kinetics. [27] [28] [29] [30] In atypical cases, this last approach can benefit from measurements of TBG, but usually only requires measurement of TSH, fT3 and fT4, and as such has no added laboratory requirements besides the measurement of the same.

See also

Related Research Articles

<span class="mw-page-title-main">Thyroid</span> Endocrine gland in the neck; secretes hormones that influence metabolism

The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the isthmus (pl.: isthmi). The thyroid gland is a butterfly-shaped gland located in the neck below the Adam's apple. Microscopically, the functional unit of the thyroid gland is the spherical thyroid follicle, lined with follicular cells (thyrocytes), and occasional parafollicular cells that surround a lumen containing colloid. The thyroid gland secretes three hormones: the two thyroid hormones – triiodothyronine (T3) and thyroxine (T4) – and a peptide hormone, calcitonin. The thyroid hormones influence the metabolic rate and protein synthesis and growth and development in children. Calcitonin plays a role in calcium homeostasis. Secretion of the two thyroid hormones is regulated by thyroid-stimulating hormone (TSH), which is secreted from the anterior pituitary gland. TSH is regulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus.

<span class="mw-page-title-main">Hypothyroidism</span> Insufficient production of thyroid hormones by the thyroid gland

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, extreme fatigue, muscle aches, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Triiodothyronine</span> Chemical compound

Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

<span class="mw-page-title-main">Levothyroxine</span> Thyroid hormone

Levothyroxine, also known as L-thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken orally (by mouth) or given by intravenous injection. Levothyroxine has a half-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood.

<span class="mw-page-title-main">Propylthiouracil</span> Medication used to treat hyperthyroidism

Propylthiouracil (PTU) is a medication used to treat hyperthyroidism. This includes hyperthyroidism due to Graves' disease and toxic multinodular goiter. In a thyrotoxic crisis it is generally more effective than methimazole. Otherwise it is typically only used when methimazole, surgery, and radioactive iodine is not possible. It is taken by mouth.

<span class="mw-page-title-main">Thyroid disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. TFTs may be requested if a patient is thought to suffer from hyperthyroidism or hypothyroidism, or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy. It is also requested routinely in conditions linked to thyroid disease, such as atrial fibrillation and anxiety disorder.

<span class="mw-page-title-main">Thyroxine 5-deiodinase</span> Protein-coding gene in the species Homo sapiens

Thyroxine 5-deiodinase also known as type III iodothyronine deiodinase (EC number 1.21.99.3) is an enzyme that in humans is encoded by the DIO3 gene. This enzyme catalyses the following chemical reaction

Desiccated thyroid extract (DTE), is thyroid gland that has been dried and powdered for medical use. It is used to treat hypothyroidism., but less preferred than levothyroxine. It is taken by mouth. Maximal effects may take up to three weeks to occur.

<span class="mw-page-title-main">Hypothalamic–pituitary–thyroid axis</span> Part of the neuroendocrine system

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

<span class="mw-page-title-main">Reverse triiodothyronine</span> Chemical compound

Reverse triiodothyronine (3,3′,5′-triiodothyronine, reverse T3, or rT3) is an isomer of triiodothyronine (3,5,3′ triiodothyronine, T3).

An antithyroid agent is a hormone inhibitor acting upon thyroid hormones.

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences, and impaired assay characteristics in critical illness.

Myxedema coma is an extreme or decompensated form of hypothyroidism and while uncommon, is potentially lethal. A person may have laboratory values identical to a "normal" hypothyroid state, but a stressful event precipitates the myxedema coma state, usually in the elderly. Primary symptoms of myxedema coma are altered mental status and low body temperature. Low blood sugar, low blood pressure, hyponatremia, hypercapnia, hypoxia, slowed heart rate, and hypoventilation may also occur. Myxedema, although included in the name, is not necessarily seen in myxedema coma. Coma is also not necessarily seen in myxedema coma, as patients may be obtunded without being comatose.

<span class="mw-page-title-main">DIO2</span> Protein-coding gene in the species Homo sapiens

Type II iodothyronine deiodinase is an enzyme that in humans is encoded by the DIO2 gene.

<span class="mw-page-title-main">Thyroid hormones</span> Hormones produced by the thyroid gland

Thyroid hormones are any hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, derived from food. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.

<span class="mw-page-title-main">Iopanoic acid</span> Chemical compound

Iopanoic acid is an iodine-containing radiocontrast medium used in cholecystography. Both iopanoic acid and ipodate sodium are potent inhibitors of thyroid hormone release from thyroid gland, as well as of peripheral conversion of thyroxine (T4) to triiodothyronine (T3). These compounds inhibit 5'deiodinase (5'DID-1 and 5'DID-2) enzymes, which catalyse T4-T3 conversion in the thyroid cell, liver, kidney, skeletal muscle, heart, brain, pituitary. This accounts for the dramatic improvement in both subjective and objective symptoms of hyperthyroidism, particularly when they are used as an adjunctive therapy with thioamides (propylthiouracil, carbimazole). They can be used in the treatment of patients with severe thyrotoxicosis (thyroid storm) and significant morbidity (e.g., myocardial infarction, or stroke) for rapid control of elevated plasma triiodothyronine concentrations. The use of iopanoic acid for treatment of thyrotoxicosis has been discontinued in the United States.

<span class="mw-page-title-main">Iodotyrosine deiodinase</span> Protein-coding gene in the species Homo sapiens

Iodotyrosine deiodinase, also known as iodotyrosine dehalogenase 1, is a type of deiodinase enzyme that scavenges iodide by removing it from iodinated tyrosine residues in the thyroid gland. These iodinated tyrosines are produced during thyroid hormone biosynthesis. The iodide that is scavenged by iodotyrosine deiodinase is necessary to again synthesize the thyroid hormones. After synthesis, the thyroid hormones circulate through the body to regulate metabolic rate, protein expression, and body temperature. Iodotyrosine deiodinase is thus necessary to keep levels of both iodide and thyroid hormones in balance.

Deiodinase (monodeiodinase) is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones.

References

  1. ↑ Schweizer U, Schlicker C, Braun D, Köhrle J, Steegborn C (July 2014). "Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism". Proceedings of the National Academy of Sciences of the United States of America. 111 (29): 10526–31. Bibcode:2014PNAS..11110526S. doi: 10.1073/pnas.1323873111 . PMC   4115520 . PMID   25002520.
  2. 1 2 3 4 Bianco AC, Kim BW (October 2006). "Deiodinases: implications of the local control of thyroid hormone action". The Journal of Clinical Investigation. 116 (10): 2571–9. doi:10.1172/JCI29812. PMC   1578599 . PMID   17016550.
  3. ↑ Wu Y, Koenig RJ (August 2000). "Gene regulation by thyroid hormone". Trends in Endocrinology and Metabolism. 11 (6): 207–11. doi:10.1016/s1043-2760(00)00263-0. PMID   10878749. S2CID   44602986.
  4. ↑ Köhrle J (January 2000). "The selenoenzyme family of deiodinase isozymes controls local thyroid hormone availability". Reviews in Endocrine & Metabolic Disorders. 1 (1–2): 49–58. doi:10.1023/A:1010012419869. PMID   11704992. S2CID   42616219.
  5. ↑ Köhrle J (May 1999). "Local activation and inactivation of thyroid hormones: the deiodinase family". Molecular and Cellular Endocrinology. 151 (1–2): 103–19. doi:10.1016/S0303-7207(99)00040-4. PMID   10411325. S2CID   11333443.
  6. ↑ Köhrle J (December 2000). "The deiodinase family: selenoenzymes regulating thyroid hormone availability and action". Cellular and Molecular Life Sciences. 57 (13–14): 1853–63. doi:10.1007/PL00000667. PMC   11147027 . PMID   11215512. S2CID   40148034.
  7. 1 2 3 4 5 6 7 8 9 10 Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, et al. (December 2008). "Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling". Endocrine Reviews. 29 (7): 898–938. doi:10.1210/er.2008-0019. PMC   2647704 . PMID   18815314.
  8. ↑ Dentice M, Bandyopadhyay A, Gereben B, Callebaut I, Christoffolete MA, Kim BW, et al. (July 2005). "The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate". Nature Cell Biology. 7 (7): 698–705. doi:10.1038/ncb1272. PMC   1761694 . PMID   15965468.
  9. 1 2 Bianco AC. "Thyroid hormone action starts and ends by deiodination". Bianco Lab & The University of Miami. Retrieved 2011-05-08.
  10. ↑ Valverde C, Croteau W, Lafleur GJ, Orozco A, Germain DL (February 1997). "Cloning and expression of a 5'-iodothyronine deiodinase from the liver of Fundulus heteroclitus". Endocrinology. 138 (2): 642–8. doi: 10.1210/endo.138.2.4904 . PMID   9002998.
  11. ↑ Berry MJ, Banu L, Larsen PR (January 1991). "Type I iodothyronine deiodinase is a selenocysteine-containing enzyme". Nature. 349 (6308): 438–40. Bibcode:1991Natur.349..438B. doi:10.1038/349438a0. PMID   1825132. S2CID   4338963.
  12. 1 2 St Germain DL, Galton VA (August 1997). "The deiodinase family of selenoproteins". Thyroid. 7 (4): 655–68. doi:10.1089/thy.1997.7.655. PMID   9292958.
  13. ↑ Schweizer U, Schlicker C, Braun D, Köhrle J, Steegborn C (July 2014). "Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism". Proceedings of the National Academy of Sciences of the United States of America. 111 (29): 10526–31. Bibcode:2014PNAS..11110526S. doi: 10.1073/pnas.1323873111 . PMC   4115520 . PMID   25002520.
  14. ↑ Moreno M, Berry MJ, Horst C, Thoma R, Goglia F, Harney JW, et al. (May 1994). "Activation and inactivation of thyroid hormone by type I iodothyronine deiodinase". FEBS Letters. 344 (2–3): 143–6. doi: 10.1016/0014-5793(94)00365-3 . PMID   8187873.
  15. ↑ Holtorf K (2012). "Deiodinases". National Academy of Hypothyroidism.
  16. ↑ Kaplan MM (March 1984). "The role of thyroid hormone deiodination in the regulation of hypothalamo-pituitary function". Neuroendocrinology. 38 (3): 254–60. doi:10.1159/000123900. PMID   6371572.
  17. ↑ Bao R, Onishi KG, Tolla E, Ebling FJ, Lewis JE, Anderson RL, et al. (June 2019). "Genome sequencing and transcriptome analyses of the Siberian hamster hypothalamus identify mechanisms for seasonal energy balance". Proceedings of the National Academy of Sciences of the United States of America. 116 (26): 13116–13121. Bibcode:2019PNAS..11613116B. doi: 10.1073/pnas.1902896116 . PMC   6600942 . PMID   31189592.
  18. ↑ Barrett P, Ebling FJ, Schuhler S, Wilson D, Ross AW, Warner A, et al. (August 2007). "Hypothalamic thyroid hormone catabolism acts as a gatekeeper for the seasonal control of body weight and reproduction". Endocrinology. 148 (8): 3608–17. doi: 10.1210/en.2007-0316 . PMID   17478556.
  19. ↑ Bianco AC, Silva JE (January 1987). "Intracellular conversion of thyroxine to triiodothyronine is required for the optimal thermogenic function of brown adipose tissue". The Journal of Clinical Investigation. 79 (1): 295–300. doi:10.1172/JCI112798. PMC   424048 . PMID   3793928.
  20. ↑ de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW, et al. (November 2001). "The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue". The Journal of Clinical Investigation. 108 (9): 1379–85. doi:10.1172/JCI13803. PMC   209445 . PMID   11696583.
  21. ↑ Kirkegaard C, Faber J (January 1998). "The role of thyroid hormones in depression". European Journal of Endocrinology. 138 (1): 1–9. doi: 10.1530/eje.0.1380001 . PMID   9461307.
  22. ↑ Berbel P, Navarro D, Ausó E, Varea E, Rodríguez AE, Ballesta JJ, et al. (June 2010). "Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity". Cerebral Cortex. 20 (6): 1462–75. doi:10.1093/cercor/bhp212. PMC   2871377 . PMID   19812240.
  23. ↑ Szabo DT, Richardson VM, Ross DG, Diliberto JJ, Kodavanti PR, Birnbaum LS (January 2009). "Effects of perinatal PBDE exposure on hepatic phase I, phase II, phase III, and deiodinase 1 gene expression involved in thyroid hormone metabolism in male rat pups". Toxicological Sciences. 107 (1): 27–39. doi:10.1093/toxsci/kfn230. PMC   2638650 . PMID   18978342.
  24. ↑ Steinsapir J, Harney J, Larsen PR (December 1998). "Type 2 iodothyronine deiodinase in rat pituitary tumor cells is inactivated in proteasomes". The Journal of Clinical Investigation. 102 (11): 1895–9. doi:10.1172/JCI4672. PMC   509140 . PMID   9835613.
  25. ↑ Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ, et al. (March 2008). "Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats". The Journal of Clinical Investigation. 118 (3): 975–83. doi:10.1172/JCI32824. PMC   2230657 . PMID   18259611.
  26. ↑ Mortoglou A, Candiloros H (2004). "The serum triiodothyronine to thyroxine (T3/T4) ratio in various thyroid disorders and after Levothyroxine replacement therapy". Hormones. 3 (2): 120–6. doi:10.14310/horm.2002.11120. PMID   16982586.
  27. ↑ Dietrich JW (2002). Der Hypophysen-Schilddrüsen-Regelkreis. Berlin, Germany: Logos-Verlag Berlin. ISBN   978-3-89722-850-4. OCLC   50451543. OL   24586469M. 3897228505.
  28. ↑ Rosolowska-Huszcz D, Kozlowska L, Rydzewski A (August 2005). "Influence of low protein diet on nonthyroidal illness syndrome in chronic renal failure". Endocrine. 27 (3): 283–8. doi:10.1385/ENDO:27:3:283. PMID   16230785. S2CID   25630198.
  29. ↑ Dietrich, JW; Landgrafe-Mende, G; Wiora, E; Chatzitomaris, A; Klein, HH; Midgley, JE; Hoermann, R (2016). "Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research". Frontiers in Endocrinology. 7: 57. doi: 10.3389/fendo.2016.00057 . PMC   4899439 . PMID   27375554.
  30. ↑ Chatzitomaris, A; Hoermann, R; Midgley, JE; Hering, S; Urban, A; Dietrich, B; Abood, A; Klein, HH; Dietrich, JW (2017). "Thyroid Allostasis-Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming". Frontiers in Endocrinology. 8: 163. doi: 10.3389/fendo.2017.00163 . PMC   5517413 . PMID   28775711.

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