Download Physiologic Effects of Thyroid Hormones

Physiologic Effects of Thyroid Hormones
It is likely that all cells in the body are targets for thyroid hormones. While not strictly
necessary for life, thyroid hormones have profound effects on many "big time" physiologic
processes, such as development, growth and metabolism. Many of the effects of thyroid
hormone have been delineated by study of deficiency and excess states, as discussed briefly
below.
Metabolism: Thyroid hormones stimulate diverse metabolic activities most tissues, leading to
an increase in basal metabolic rate. One consequence of this activity is to increase body heat
production, which seems to result, at least in part, from increased oxygen consumption and
rates of ATP hydrolysis. By way of analogy, the action of thyroid hormones is akin to
blowing on a smouldering fire. A few examples of specific metabolic effects of thyroid
hormones include:
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Lipid metabolism: Increased thyroid hormone levels stimulate fat mobilization,
leading to increased concentrations of fatty acids in plasma. They also enhance
oxidation of fatty acids in many tissues. Finally, plasma concentrations of cholesterol
and triglycerides are inversely correlated with thyroid hormone levels - one diagnostic
indiction of hypothyroidism is increased blood cholesterol concentration.
Carbohydrate metabolism: Thyroid hormones stimulate almost all aspects of
carbohydrate metabolism, including enhancement of insulin-dependent entry of
glucose into cells and increased gluconeogenesis and glycogenolysis to generate free
glucose.
Growth: Thyroid hormones are clearly necessary for normal growth in children and young
animals, as evidenced by the growth-retardation observed in thyroid deficiency. Not
surprisingly, the growth-promoting effect of thyroid hormones is intimately intertwined with
that of growth hormone, a clear indiction that complex physiologic processes like growth
depend upon multiple endocrine controls.
Development: A classical experiment in endocrinology was the demonstration that tadpoles
deprived of thyroid hormone failed to undergo metamorphosis into frogs. Of critical
importance in mammals is the fact that normal levels of thyroid hormone are essential to
the development of the fetal and neonatal brain.
Other Effects: As mentioned above, there do not seem to be organs and tissues that are not
affected by thyroid hormones. A few additional, well-documented effects of thyroid hormones
include:
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Cardiovascular system: Thyroid hormones increases heart rate, cardiac contractility
and cardiac output. They also promote vasodilation, which leads to enhanced blood
flow to many organs.
Central nervous system: Both decreased and increased concentrations of thyroid
hormones lead to alterations in mental state. Too little thyroid hormone, and the
individual tends to feel mentally sluggish, while too much induces anxiety and
nervousness.
Reproductive system: Normal reproductive behavior and physiology is dependent on
having essentially normal levels of thyroid hormone. Hypothyroidism in particular is
commonly associated with infertility.
Circulation
Most of the thyroid hormone circulating in the blood is bound to transport proteins. Only a
very small fraction of the circulating hormone is free (unbound) and biologically active, hence
measuring concentrations of free thyroid hormones is of great diagnostic value.
When thyroid hormone is bound, it is not active, so the amount of free T3/T4 is what is
important. For this reason, measuring total thyroxine in the blood can be misleading.
Type
Percent
bound to thyroxine-binding globulin (TBG)
70%
bound to transthyretin or "thyroxine-binding prealbumin" (TTR or TBPA) 10-15%
paraalbumin
15-20%
unbound T4 (fT4)
0.03%
unbound T3 (fT3)
0.3%
T3 and T4 cross the cell membrane easily as they are lipophilic molecules, and function via a
well-studied set of nuclear receptors in the nucleus of the cell, the thyroid hormone receptors.
T1a and T0a are positively charged and do not cross the membrane; they are believed to
function via the trace amine-associated receptor TAAR1 (TAR1, TA1), a G-protein-coupled
receptor located in the cell membrane.
Another critical diagnostic tool is measurement of the amount of thyroid-stimulating hormone
(TSH) that is present.
Function
The thyronines act on nearly every cell in the body. They act to increase the basal metabolic
rate, affect protein synthesis, help regulate long bone growth (synergy with growth hormone),
neuronal maturation and increase the body's sensitivity to catecholamines (such as adrenaline)
by permissiveness. 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 thyronamines function via
some unknown mechanism to inhibit neuronal activity; this plays an important role in the
hibernation cycles of mammals and the moulting behaviour of birds. One effect of
administering the thyronamines is a severe drop in body temperature.
Related diseases
Both excess and deficiency of thyroxine can cause disorders.
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Thyrotoxicosis or 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.
Hypothyroidism (an example is Hashimoto's thyroiditis) is the case where there is a
deficiency of thyroxine, triiodiothyronine, or both.
Clinical depression can sometimes be caused by hypothyroidism[1]. Some research[2] has
shown that T3 is found in the junctions of synapses, and regulates the amounts and activity of
serotonin, norepinephrine, and Gamma-aminobutyric acid (GABA) in the brain.
Medical use of thyroid hormones
Both T3 and T4 are used to treat thyroid hormone deficiency (hypothyroidism). They are both
absorbed well by the gut, so can be given orally. Levothyroxine, the most commonly used
synthetic thyroxine form, is a stereoisomer of physiological thyroxine, which is metabolised
more slowly and hence usually only needs once-daily administration. Natural desiccated
thyroid hormones, also under the commercial name Armour Thyroid, is derived from pig
thyroid glands, it is 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
Thyrolar) and pure-T3 medications (Cytomel).
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.
Production of the thyroid hormones
Thyroid hormones (T4 and T3) are produced by the follicular cells of the thyroid gland and are
regulated by TSH made by the thyrotrophs of the anterior pituitary gland. Because the effects
of T4 in vivo are mediated via T3 (T4 is converted to T3 in target tissues; T3 is 3- to 5- fold
more active than T4).
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 TBG), which is cleaved by
enzymes to produce active T4.
Thyroxine is produced by attaching iodine atoms to the ring structures of tyrosine molecules.
Thyroxine (T4) contains four iodine atoms. Triiodothyronine (T3) is identical to T4, but it has
one less iodine atom per molecule.
Iodide is actively absorbed from the bloodstream by a process called iodide trapping. In this
process, sodium is cotransported with iodide from the apical side of the membrane into the
cell and then concentrated in the thyroid follicles to about thirty times its concentration in the
blood. Via a reaction with the enzyme thyroperoxidase, iodine is bound to tyrosine residues in
the thyroglobulin molecules, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT).
Linking two moieties of DIT produces thyroxine. Combining one particle of MIT and one
particle of DIT produces triiodothyronine.
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DIT + MIT → r-T3 (biologically inactive)
MIT + DIT → triiodothyronine (usually referred to as T3)
DIT + DIT → thyroxine (referred to as T4)
Proteases digest iodinated thyroglobulin, releasing the hormones T4 and T3, the biologically
active agents central to metabolic regulation. Thyroxine is supposedly a prohormone and a
reservoir for the most active and main thyroid hormone T3. T4 is converted as required in the
tissues by deiodinases. Deficiency of deiodinase can mimic an iodine deficiency. T3 is more
active than T4 and is the final form of the hormone, though it is present in less quantity than
T4.
Effect of iodine deficiency on thyroid hormone synthesis
If there is a deficiency of dietary iodine, the thyroid will not be able to make thyroid hormone.
The lack of thyroid hormone will lead to decreased negative feedback on the pituitary, leading
to increased production of thyroid stimulating hormone, which causes the thyroid to enlarge
(goiter). 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.
Anti-thyroid drugs
Iodine uptake against a concentration gradient is mediated by a sodium-iodine symporter and
is linked to a sodium-potassium ATPase. Perchlorate and thiocyanate are drugs that can
compete with iodine at this point. Compounds such as goitrin can reduce thyroid hormone
production by interfering with iodine oxidation.[3]
Effects of thyroxine
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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