Thyroid hormones

Hormones produced by the thyroid gland

The thyroid system of the thyroid hormones T₃ and T₄^[1]

Thyroid hormones are any

simple goitre.^[3]

The major form of thyroid hormone in the blood is thyroxine (T₄), whose half-life of around one week

iodothyronamine (T₁a) and thyronamine (T₀a). All three isoforms of the deiodinases are selenium

-containing enzymes, thus dietary selenium is essential for T₃ production.

American chemist Edward Calvin Kendall was responsible for the isolation of thyroxine in 1915.^[7] In 2020, levothyroxine, a manufactured form of thyroxine, was the second most commonly prescribed medication in the United States, with more than 98 million prescriptions.^[8][9] Levothyroxine is on the World Health Organization's List of Essential Medicines.^[10]

Function

The thyroid hormones act on nearly every cell in the body. It acts to increase the

protein synthesis, help regulate long bone growth (synergy with growth hormone) and neural maturation, and increase the body's sensitivity to catecholamines (such as adrenaline) by permissiveness.^[11] The thyroid hormones are essential to proper development and differentiation of all cells of the human body. These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells

use energetic compounds. They also stimulate vitamin metabolism. Numerous physiological and pathological stimuli influence thyroid hormone synthesis.

Thyroid hormone leads to heat generation in humans. However, the

body temperature

.

Medical use

Both T₃ and T₄ are used to treat thyroid hormone deficiency (

Natural desiccated thyroid hormones are derived from pig thyroid glands, and are a "natural" hypothyroid treatment containing 20% T₃ and traces of T₂, T₁ and calcitonin

. Also available are synthetic combinations of T₃/T₄ in different ratios (such as liotrix) and pure-T₃ medications (INN: liothyronine). Levothyroxine Sodium is usually the first course of treatment tried. Some patients feel they do better on desiccated thyroid hormones; however, this is based on anecdotal evidence and clinical trials have not shown any benefit over the biosynthetic forms.^[12] Thyroid tablets are reported to have different effects, which can be attributed to the difference in torsional angles surrounding the reactive site of the molecule.^[13]

Thyronamines have no medical usages yet, though their use has been proposed for controlled induction of hypothermia, which causes the brain to enter a protective cycle, useful in preventing damage during ischemic shock.

Synthetic thyroxine was first successfully produced by

Charles Robert Harington and George Barger

in 1926.

Formulations

Structure of (S)-thyroxine (T₄)

(S)-triiodothyronine (T₃, also called liothyronine

)

Most people are treated with levothyroxine, or a similar synthetic thyroid hormone.[14]^[15][16] Different polymorphs of the compound have different solubilities and potencies.^[17] Additionally, natural thyroid hormone supplements from the dried thyroids of animals are still available.^[16][18][19] Levothyroxine contains T₄ only and is therefore largely ineffective for patients unable to convert T₄ to T₃.^[20] These patients may choose to take natural thyroid hormone, as it contains a mixture of T₄ and T₃,^{[16][21][22][23][24]} or alternatively supplement with a synthetic T₃ treatment.^[25] In these cases, synthetic liothyronine is preferred due to the potential differences between the natural thyroid products. Some studies show that the mixed therapy is beneficial to all patients, but the addition of lyothyronine contains additional side effects and the medication should be evaluated on an individual basis.^[26] Some natural thyroid hormone brands are FDA approved, but some are not.^[27][28][29] Thyroid hormones are generally well tolerated.^[15] Thyroid hormones are usually not dangerous for pregnant women or nursing mothers, but should be given under a doctor's supervision. In fact, if a woman who is hypothyroid is left untreated, her baby is at a higher risk for birth defects. When pregnant, a woman with a low-functioning thyroid will also need to increase her dosage of thyroid hormone.^[15] One exception is that thyroid hormones may aggravate heart conditions, especially in older patients; therefore, doctors may start these patients on a lower dose and work up to a larger one to avoid risk of heart attack.^[16]

Thyroid metabolism

Central

tyrosyl residues in its protein chain (in total containing approximately 120 tyrosyl residues).
- In conjugation, adjacent tyrosyl residues are paired together.
- Thyroglobulin re-enters the follicular cell by endocytosis.
- Proteolysis by various proteases liberates thyroxine and triiodothyronine molecules
- Efflux of thyroxine and triiodothyronine from follicular cells, which appears to be largely through monocarboxylate transporter (MCT) 8 and 10,^[31][32]

and entry into the blood.

Thyroxine (3,5,3′,5′-tetraiodothyronine) is produced by follicular cells of the thyroid gland. It is produced as the precursor thyroglobulin (this is not the same as thyroxine-binding globulin (TBG)), which is cleaved by enzymes to produce active T₄.

The steps in this process are as follows:^[30]

1. The Na⁺/I⁻ symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodide ion. This is a secondary active transporter that utilises the concentration gradient of Na⁺ to move I⁻ against its concentration gradient.
2. I⁻ is moved across the apical membrane into the colloid of the follicle by pendrin.
3. Thyroperoxidase oxidizes two I⁻ to form I₂. Iodide is non-reactive, and only the more reactive iodine is required for the next step.
4. The thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid.
5. Iodinated Thyroglobulin binds megalin for endocytosis back into cell.
6. Thyroid-stimulating hormone (TSH) released from the anterior pituitary (also known as the adenohypophysis) binds the TSH receptor (a G_s protein-coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid.
7. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the T₄ from the iodinated thyroglobulin.
8. The thyroid hormones cross the follicular cell membrane towards the blood vessels by an unknown mechanism.^[30] Text books have stated that diffusion is the main means of transport,^[33] but recent studies indicate that monocarboxylate transporter (MCT) 8 and 10 play major roles in the efflux of the thyroid hormones from the thyroid cells.^[31][32]

Thyroglobulin (Tg) is a 660 

(Coupling of DIT to MIT in the opposite order yields a substance, r-T₃, which is biologically inactive.[44]^{[45][relevant?]}) Hydrolysis (cleavage to individual amino acids) of the modified protein by proteases then liberates T₃ and T₄, as well as the non-coupled tyrosine derivatives MIT and DIT.^[46][47] The hormones T₄ and T₃ are the biologically active agents central to metabolic regulation.^[48]

Peripheral

Thyroxine is believed to be a prohormone and a reservoir for the most active and main thyroid hormone T₃.^[49] T₄ is converted as required in the tissues by iodothyronine deiodinase.^[50] Deficiency of deiodinase can mimic hypothyroidism due to iodine deficiency.^[51] T₃ is more active than T₄,^[52] though it is present in less quantity than T₄.

Initiation of production in fetuses

If there is a deficiency of dietary iodine, the thyroid will not be able to make thyroid hormones.^[55] The lack of thyroid hormones will lead to decreased negative feedback on the pituitary, leading to increased production of thyroid-stimulating hormone, which causes the thyroid to enlarge (the resulting medical condition is called endemic colloid goitre; see goitre).^[56] This has the effect of increasing the thyroid's ability to trap more iodide, compensating for the iodine deficiency and allowing it to produce adequate amounts of thyroid hormone.^[57]

Circulation and transport

Plasma transport

Most of the thyroid hormone circulating in the blood is bound to transport proteins, and only a very small fraction is unbound and biologically active. Therefore, measuring concentrations of free thyroid hormones is important for diagnosis, while measuring total levels can be misleading.

Thyroid hormone in the blood is usually distributed as follows:^{[citation needed]}

Despite being lipophilic, T₃ and T₄ cross the cell membrane via carrier-mediated transport, which is ATP-dependent.^[58]

T₁a and T₀a are positively charged and do not cross the membrane; they are believed to function via the

Another critical diagnostic tool is measurement of the amount of thyroid-stimulating hormone (TSH) that is present.

Membrane transport

Contrary to common belief, thyroid hormones cannot traverse

Little is known about intracellular kinetics of thyroid hormones. However, recently it could be demonstrated that the crystallin CRYM binds 3,5,3′-triiodothyronine in vivo.^[60]

Mechanism of action

The thyroid hormones function via a well-studied set of

More recently genetic evidence has been obtained for a second mechanism of thyroid hormone action involving one of the same nuclear receptors, TRβ, acting rapidly in the cytoplasm through the PI3K.^[64][65] This mechanism is conserved in all mammals but not fish or amphibians, and regulates brain development^[64] and adult metabolism.^[65] The mechanism itself parallels the actions of the nuclear receptor in the nucleus: in the absence of hormone, TRβ binds to PI3K and inhibits its activity, but when hormone binds the complex dissociates, PI3K activity increases, and the hormone bound receptor diffuses into the nucleus.^[64]

Thyroxine, iodine and apoptosis

Thyroxine and iodine stimulate the spectacular

• Increases cardiac output
• Increases heart rate
• Increases
  ventilation rate
• Increases basal metabolic rate
• Potentiates the effects of catecholamines (i.e. increases sympathetic activity)
• Potentiates
  brain development
• Thickens endometrium in females
• Increases catabolism of proteins and carbohydrates^[70]

Measurement

Further information: Thyroid function tests

Triiodothyronine (T₃) and thyroxine (T₄) can be measured as free T₃ and free T₄, which are indicators of their activities in the body.

• Hyperthyroidism (an example is Graves' disease) is the clinical syndrome caused by an excess of circulating free thyroxine, free triiodothyronine, or both. It is a common disorder that affects approximately 2% of women and 0.2% of men. Thyrotoxicosis is often used interchangeably with hyperthyroidism, but there are subtle differences. Although thyrotoxicosis also refers to an increase in circulating thyroid hormones, it can be caused by the intake of thyroxine tablets or by an over-active thyroid, whereas hyperthyroidism refers solely to an over-active thyroid.
• Hypothyroidism (an example is Hashimoto's thyroiditis) is the case where there is a deficiency of thyroxine, triiodothyronine, or both.
• γ-aminobutyric acid (GABA) in the brain
  .
• Hair loss can sometimes be attributed to a malfunction of T₃ and T₄. Normal hair growth cycle may be affected disrupting the hair growth.
• Both thyroid excess and deficiency can cause cardiovascular disorders or make preexisting conditions worse.[76] The link between excess and deficiency of thyroid hormone on conditions like arrhythmias, heart failure, and atherosclerotic vascular diseases, have been established for nearly 200 years.^[77][76]

Preterm births can suffer neurodevelopmental disorders due to lack of maternal thyroid hormones, at a time when their own thyroid is unable to meet their postnatal needs.^[78] Also in normal pregnancies, adequate levels of maternal thyroid hormone are vital in order to ensure thyroid hormone availability for the foetus and its developing brain.^[79] Congenital hypothyroidism occurs in every 1 in 1600–3400 newborns with most being born asymptomatic and developing related symptoms weeks after birth.^[80]

Anti-thyroid drugs

Iodine uptake against a concentration gradient is mediated by a sodium–iodine symporter and is linked to a

• Goitre
• Graves–Basedow disease
• Hashimoto's thyroiditis
• Hormone
• Polar T₃ syndrome
• Thyroid gland
• Thyroid-stimulating hormone
• Thyronamines, metabolites of the thyroid hormones that act at the trace amine-associated receptor TAAR1 (TAR1)

References