Thyroid hormone (TH) molecules enter cells via membrane transporters and, depending on the cell type, can be activated, that is thyroxine (T4) to 3,5,3’-tri-iodothyronine (T3) conversion, or inactivated - T3 to 3,3’-diiodo-L-thyronine (T2) or T4 to reverse tri-iodothyronine (rT3) conversion. These reactions are catalyzed by the deiodinases. The biologically active hormone, T3, eventually binds to intracellular TH receptors (TR), TRα and TRβ, and initiate TH signaling, i.e. regulation of target genes and other metabolic pathways. At least three families of transmembrane transporters, MCT, OATP and LAT, facilitate the entry of TH into cells, which follow the gradient of free hormone between the extracellular fluid and the cytoplasm. Inactivation or marked downregulation of TH transporters can dampen TH signaling. At the same time, dynamic modifications in the expression or activity of TRs and transcriptional co-regulators can affect positively or negatively the intensity of TH signaling. However, the deiodinases are the element that provides greatest amplitude in dynamic control of TH signaling. Cells that express the activating deiodinase DIO2 can rapidly enhance TH signaling due to intracellular build-up of T3. In contrast, TH signaling is dampened in cells that express the inactivating deiodinase DIO3. This explains how THs can regulate pathways in development, metabolism and growth, despite rather stable levels in the circulation. As a consequence, TH signaling is unique for each cell (tissue or organ), depending on circulating TH levels and on the exclusive blend of transporters, deiodinases and TRs present in each cell. In this article we explore the key mechanisms underlying customization of TH signaling during development, in health and in disease states.
I will have to try and remember to ask the practice pharmacist, who is overseeing my treatment, if she knows. It might make her think. She is very good in many ways, but as usual wants to get my TSH up within range, never mind how I feel
Werner & Ingbar's Thyroid, a medical textbook, devotes chapter 8 to Genomic and Non Genomic Actions of Thyroid Hormones, T3 and T4, (TH). It explains how the nucleus of each cell contains TH receptors and most of our biologic effects at cellular level are mediated by TH receptors. Further, TH acts at nongenomic sites, such as plasma membrane, cytoplasm, and within our mitochondria.
The thyroid produces both T3 and T4. According to Chapter 7, Intracellular Pathways of Iodothyronine Metabolism, about 20% of each day's supply of T3 is produced by the thyroid, with the other 80% is produced by deiodination of T4. In healthy subjects, the DIO2 pathway is believed to contribute more to plasma T3 than does DIO1.
The presence of T3 hormone stimulates DIO1 expression, while T4 levels modulate DIO2 gene expression through local deactivation or activation of ubiquitination/deubiquitination processes. In skeletal muscles, the brain, pituitary, and brown fat, high T4 causes ubiquitin to attach to the DIO2 protein, degrading it, and reducing DIO2 activity. The reverse process occurs with low T4, permitting tissues that contain D2 to modulate T3 concentrations at the local level. This is how we can drag around the house all day or feel energized as a result of TH action.
Thyroid hormone transporter are the subject of another chapter in Werner & Ingbar, and TH directly modulate transporters and enzymes in the plasma membrane and mitochondria, while interacting with other key metabolic pathways regulating fatty acid synthesis and oxidation (DIO1).
TSH, on the other hand, is the pituitary's signaling hormone to the thyroid gland: "We're running low up here, so please send me more thyroid hormone and be quick about it." The TH travels via the plasma to the brain and soothes the pituitary's feedback loop.
It appears the writers of the article cited above have gained a bit more insight into the granular details of the processes that are already well known. For us, it means only that the inscrutable feedback loops that make treating our disease so problematic are being confirmed to be exquisitely complex and remarkable challenging from a clinical standpoint.
Since someone asked about bone density today, I'll throw in the bits from Werner & Ingbar's segment on bone health. Bone health depends upon bone turnover, which is regulated by TH. Deficiency of TH reduces bone turnover and alters bone mineral density (BMD). Fracture risk seems to be increased with hypothyroidism as there is a net increase in mineralization without a major change in bone volume, although bone mass does increase as a result of the prolonged remodeling cycle in hypothyroidism. Studies of people with subclinical hypothyroidism who were treated with T4 showed increased bone turnover and reduced BMD after patients became euthyroid.
"Studies are difficult to interpret," the author notes. What's the optimal amount of replacement TH for optimal bone remodeling? Nobody wants to say. However, in the chapter on Thyrotoxicosis and skeletal health, the author (a different writer from the above) notes that excessive TH resulted in "worm-eaten" bones in one famous patient. There is an equal risk of fracture from too much hormone as too little. Another reason for doctors to not want to treat hypothyroidism if we're still upright and walking.
This related article, posted by Greygoose some time ago, is good too. Emphasises that TSH measurement is NOT an accurate indication of hypothyroidism.
I tried to get the paper about cognitive decline from long term use of levothyroxine and got a rejection from springer the publishers and to cut a long story short the saidgo to the web without giving a web adress. I also tried ResearchGate (of whom Ive been a long time user) and the had greyed out the "button" you push to request full copy of the paper. I spoke to me UK thyroid special;ist to whom Id sent the abstract who was not impressed with the abstract and said she would try to get a copy but she did not think it worthwile to pay for it. The other place I had tried was the British Library who said the paper was too recent so they dont yet have a copy.
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How thyroid hormones work in cells.
