Thyroid Hormones (THs)
•
•
•
Dr. Entisar Al-Mukhtar
Thyroid gland facilitates normal growth & maturation by maintaining a level of
metabolism in the tissues that is optimal for their normal function.
Triiodothyronine (T3; the most active form) & thyroxine (T4) are the major THs.
Thyroid gland is not essential for life, although inadequate secretion of THs
(hypothyroidism) results in bradycardia, poor resistance to cold & mental & physical
slowing (can cause mental retardation and dwarfism in children. Whereas excess
secretion of THs (hyperthyroidism) can cause tachycardia & cardiac arrhythmias,
body wasting, nervousness, tremor & excess heat production.
Note: thyroid gland also secretes calcitonin— a serum calcium-lowering hormone.
Thyroid hormone synthesis and secretion
The thyroid gland is made up of multiple follicles that consist of a single layer of
epithelial cells surrounding a lumen filled with thyroglobulin (storage form of TH).
1. Regulation of synthesis:
• TSH(thyrotropin), is a glycoprotein, structurally related to LH & FSH. TSH generation
is governed by the TRH.
• cAMP mediates TSH action & stimulates iodide (I–) uptake. The peroxidase oxides
I– to iodine (I2) this step followed by iodination of tyrosines on thyroglobulin (Abs
against thyroid peroxidase are diagnostic for Hashimoto thyroiditis).
• Condensation of two diiodotyrosine residues gives rise to T4, whereas condensation
of a monoiodotyrosine residue with a diiodotyrosine residue generates T3, which is
still bound to the protein.
• By proteolytic cleavage of the thyroglobulin THs are released.
2. Regulation of secretion:
• TRH stimulates secretion of TSH by the anterior pituitary.
• High levels of circulating TH cause feedback inhibition of TRH.
Note: pharmacologic doses of dopamine, somatostatin, or glucocorticoids can also
suppress TSH secretion.
• Most of the hormone (T3 and T4) is bound to thyroxine-binding globulin (TBG) in the
plasma.
Mechanism of action
• Both T4 & T3 must dissociate from TBG prior to entry into cells.
• In the cell, by deiodinases T4 is deiodinated to T3, which enters the nucleus &
attaches to & activates specific receptors, promoting the formation of RNA &
subsequent protein synthesis, which is responsible for T4 effects.
Pharmacokinetics
• Both THs are absorbed after oral administration.
• Food, Ca preparations & AL-containing antacids can decrease the absorption of T4
(but not of T3).
• Phenytoin, rifampin & Phenobarbital accelerate metabolism of the THs.
Hypothyroidism
• Usually results from autoimmune destruction of the gland or the peroxidase & is
diagnosed by elevated TSH.
1
•
•
It is treated with levothyroxine (T4), which is given once daily (long half-life). Steady
state is achieved in 6 to 8 weeks.
Toxicity is directly related to T4 levels, results in nervousness, heart palpitations &
tachycardia, intolerance to heat & unexplained weight loss.
Hyperthyroidism (thyrotoxicosis)
• Associated with a number of disease states, including Graves disease, toxic
adenoma, and goiter.
• TSH levels are reduced (due to negative feedback).
• Hyperthyroidism is treated by decrease the synthesis and/or release of additional
hormone either by (1) removing part or all of the thyroid gland (2) inhibiting synthesis
of the hormones (3) blocking release of the hormones.
1. Removal of part or all of the thyroid:
131
• Either surgically or by using radioactive iodine ( I), which is selectively taken up
by the thyroid follicular cells.
• Younger patients are treated with the isotope without prior pretreatment with
methimazole, which should be given to elderly patients.
• Most patients become hypothyroid and require treatment with levothyroxine.
2. Inhibition of TH synthesis:
• Propylthiouracil (PTU) & methimazole are thioamides, they concentrated in the
thyroid & inhibit both oxidative processes (essential for iodination of tyrosyl groups)
& condensation (coupling) of iodotyrosines to form T3 & T4.
• PTU can also block the conversion of T4 to T3.
Note: Since the synthesis rather than release of THs is affected, the onset of
thioamides is slow, often requiring 3–4weeks before stores of T4 are depleted.
•
•
•
•
•
•
Thioamides are well absorbed from the GIT, but they have short half-lives.
Methimazole is about ten times more potent than PTU.
Several doses of PTU are required daily. Whereas methimazole is given as a single
daily dose.
Relapse may occur.
Adverse effects are rare including agranulocytosis, rash & edema.
Because of the potential for liver toxicity or liver failure PTU should be reserved to
methimazole intolerant patients.
Thyroid storm
• Presents with extreme symptoms of hyperthyroidism.
• Treated as hyperthyroidism, except that the drugs are given in higher doses & more
frequently.
• Β-blockers lacking sympathomimetic activity eg. Propranolol are effective in
blunting the widespread sympathetic stimulation.
• IV administration is effective in treating thyroid storm.
• Diltiazem is an alternative to β -blockers in patients with severe HF or asthma.
• Other agents include PTU, iodides, iodinated contrast media (which rapidly inhibits
the conversion of T4 to T3) & glucocorticoids (to protect against shock).
2
4. Blockade of hormone release:
• A pharmacologic dose of iodide inhibits the iodination of tyrosines (“acute WolffChaikoff effect”), but this effect lasts only a few days.
• The more important effect of iodide is the inhibition of THs release from thyroglobulin
(mechanisms not yet understood).
• Today, iodide is rarely used as the sole therapy. However, it is employed to treat
potentially fatal thyrotoxic crisis (thyroid storm) or prior to surgery, (decreases the
vascularity of the thyroid gland).
• Iodide is not useful for long-term therapy, because the thyroid ceases to respond to
the drug after a few weeks.
• Iodide is administered orally.
• Adverse effects are relatively minor including sore mouth & throat, swelling of the
tongue or larynx, rashes, ulcerations of mucous membranes & metallic taste in the
mouth.
3