The Deiodinase Trio and Thyroid Hormone Signaling

Bianco, Antonio C.; Conceição, Rodrigo Rodrigues da

doi:10.1007/978-1-4939-7902-8_8

Cited by 70 publications

(53 citation statements)

References 119 publications

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“…A century of thyroxine research has led to the commonly held opinion in the thyroid hormone community that 3,3 ′ ,5,5 ′tetraiodo-L-thyronine (L-Thyroxine, L-T4), which is solely produced by the thyroid gland, serves as a prohormone while T3 (3,3 ′ 5-triiodo-L-thyronine), in part secreted by the thyroid gland, is mainly generated in various extra-thyroidal tissues by either type 1 or type 2 deiodinase (DIO1, DIO2) selenoenzymes (1)(2)(3). T3 exerts the majority of known thyroid hormone (TH) effects at the tissue and cellular level, including hypothalamic and pituitary negative feedback regulation of the hypothalamuspituitary-thyroid-periphery (HPTP) axis (4)(5)(6).…”

Section: Introduction Endogenous Thyroid Hormones and Their Metabolitesmentioning

confidence: 99%

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

et al. 2020

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Structural formula of the "Janus-faced" THM 3,5-diiodo-L-thyronine (left), which has the same 3,5-iodine substitution pattern as its putative precursors L-T4 and L-T3 at the tyrosyl-ring, but lacks the iodine substitution in 3 ′-position of the phenolic ring which is essential for binding classical T3-receptors and conveying canonical and non-canonical thyromimetic effects. The roman god Janus symbolized "duality" and "jani" were ceremonial gateways in ancient Rome typically used for symbolically auspicious entrances or exits. Janus-face (right) source: This image comes from the 4th edition of Meyers Konversationslexikon (1885-90). The copyrights have expired and this image is in the public domain. Wikimedia, Meyers_b9_s0153_b1.png. HYPOTHESES AND THEORY a. 3,5-T2 is an endogenous metabolite of thyroid hormones T4 and T3 b. 3,5-T2 might represent the precursor of 3-iodothyronamine c. 3,5-T2 acts like T3 via canonical activation of T3 receptors albeit with lower potency d. 3,5-T2 exerts actions distinct from those of thyromimetically active T3 i) via mitochondrial targets ii) by its intrahepatic accumulation iii) by its intracrine mode of action e. 3,5-T2 formation and action might be altered in patients on T4 replacement therapy and causes adverse effects if abused.

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Section: Introduction Endogenous Thyroid Hormones and Their Metabolitesmentioning

confidence: 99%

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

et al. 2020

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“…DIO2 is primarily responsible for T3 production peripherally. DIO3 inactivates T4 and T3, turning them into rT3 and diiodothyronine, which are not usually measured in clinical settings [18, 19]. The increased levothyroxine requirements could be explained by an increased deactivation of T4 by DIO3, which would lead to increased concentrations of rT3 in plasma.…”

Section: Discussionmentioning

confidence: 99%

Mifepristone Increases Thyroid Hormone Requirements in Patients With Central Hypothyroidism: A Multicenter Study

Guarda

Findling

Yuen

et al. 2019

Journal of the Endocrine Society

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Purpose Mifepristone is a glucocorticoid and progesterone receptor blocker that can be used for patients with hyperglycemia and Cushing syndrome in whom surgery failed to achieve remission or who were ineligible for surgery. We report a case series of patients with Cushing disease (CD) and central hypothyroidism that presented with increased levothyroxine requirements during mifepristone therapy. Methods Retrospective longitudinal case series of patients with CD and central hypothyroidism treated with mifepristone in a retrospective database at four pituitary centers in the United States. Results Five patients with CD were found, all women, median age 50 (interquartile range 47 to 64.5). They received mifepristone because no adequate response or intolerance to other drugs was observed. Mifepristone initiation was associated with a decrease in free thyroxine levels, mandating a dose increase of a median 1.83 (1.71 to 3.5) times the initial dose of levothyroxine to achieve normal levels. Weight loss was seen in four of five patients, ranging from 3.2 to 42.6 kg in up to 54 months of follow-up. Conclusions Although the mechanism behind the decrease in thyroid hormone level is unknown, intestinal malabsorption, decreased residual thyroid function and increased inactivation of T4 via deiodinases are all potential causes. Whereas therapies for hypercortisolism aim to decrease features of hypercortisolemia such as weight gain and depression, hypothyroidism can hamper these goals. This case series raises awareness on the importance of assessment of thyroid status in patients receiving mifepristone to optimize clinical outcomes.

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“…rT3 is rapidly cleared by further deiodination to 3,3-T2 by DIO1, expressed predominantly in the liver and kidney, and also possibly DIO2 which is widely expressed in other tissues. 2 The contribution of each deiodinase to rT3 clearance is yet to be fully established and varies with overall thyroid hormone status. 2,3 The serum concentration of rT3 is typically 1/10 of that of T3 (approximately 17 ng/mL vs. 140 ng/mL), but in some situations may exceed that of T3.…”

Section: Physiologymentioning

confidence: 99%

Clinical and laboratory aspects of 3,3′,5′-triiodothyronine (reverse T3)

Halsall

Oddy

2020

Ann Clin Biochem

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Reverse T3 (3,3â,5â-triiodothyronine or rT3) is the third most abundant iodothyronine circulating in human blood and is produced by the inner ring de-iodination of the pro-hormone thyroxine (T4). Unlike the more abundant and active metabolite T3, the measurement of serum rT3 is yet to find a routine clinical application. As rT3 binds weakly to the T3 thyroid nuclear hormone receptors it is thought to represent an inactive end-product of thyroid hormone metabolism, diverting T4 away from T3 production. The analysis of serum rT3 has, up until recently, been measured by competitive radioimmunoassay, but these methods have been superseded by mass-spectrometric methods which are less susceptible to interference from other more abundant iodothyronines. Serum rT3 concentration is increased as part of the non-thyroidal illness syndrome, and by administration of common medications such as amiodarone which inhibit the metabolism of rT3. Serum rT3 concentration is also affected by genetic conditions that affect the iodothyronine deiodinases, as well as thyroid transporters and transport proteins. Analysis of rT3 can provide a useful diagnostic fingerprint for these conditions. rT3 has been shown to bind extra-nuclear iodothyronine receptors with a potential role in cell proliferation however the clinical relevance of these findings awaits further study.

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The Deiodinase Trio and Thyroid Hormone Signaling

Cited by 70 publications

References 119 publications

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

Mifepristone Increases Thyroid Hormone Requirements in Patients With Central Hypothyroidism: A Multicenter Study

Clinical and laboratory aspects of 3,3′,5′-triiodothyronine (reverse T3)

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