Thyroid Hormones (THs)

Thyroid Hormones (THs)
• The thyroid gland facilitates normal growth and 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.
• Excess secretion of THs (hyperthyroidism) is, then tachycardia & cardiac
arrhythmias, body wasting, nervousness, tremor & excess heat production can occur.

Note: The thyroid gland also secretes the hormone 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, it is
synthesized by the anterior pituitary. TSH generation is governed by the TRH.

• TSH action is mediated by cAMP which stimulates iodide (I–) uptake.
Oxidation to iodine (I2) by a peroxidase is followed by iodination of tyrosines on thyroglobulin (Abs to 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.
• The hormones are released following proteolytic cleavage of the
thyroglobulin.

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 in
the plasma.

Mechanism of action
• Both T4 & T3 must dissociate from thyroxine-binding plasma proteins
prior to entry into cells, either by diffusion or by active transport.
• In the cell, T4 is enzymatically deiodinated to T3, which enters the nucleus
& attaches to & activates specific receptors, this will promotes the formation of RNA & subsequent protein synthesis, which is responsible for T4 effects.

Pharmacokinetics
• Both T4 & T3 are absorbed after oral administration.
• Food, Ca preparations & AL-containing antacids can decrease the
absorption of T4 (but not of T3).
• T4 is converted to T3 by one of two distinct deiodinases (depending on the
tissue).
• The hormones are metabolized through the microsomal P450 system, thus
drugs that induce this system, eg. 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.
• 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)
• Excessive amounts of THs in the circulation are associated
with a number of disease states, including Graves disease, toxic adenoma, and goiter.
• TSH levels are reduced (due to negative feedback).
• It is treated by the decrease of synthesis and/or release of additional
hormone by, removing part or all of the thyroid gland, by inhibiting synthesis of the hormones, or by blocking release of the hormones.

1. Removal of part or all of the thyroid:
• Either surgically or by destruction of the gland by using radioactive iodine
(131I), which is selectively taken up by the thyroid follicular cells.
• Younger patients are treated with the isotope without prior pretreatment
with methimazole, whereas the opposite is the case in elderly patients.
• Most patients become hypothyroid and require treatment with
levothyroxine.

2. Inhibition of TH synthesis:
• The thioamides, propylthiouracil (PTU) & methimazole, are
concentrated in the thyroid, they inhibit both the oxidative processes essential for iodination of tyrosyl groups & the condensation (coupling) of iodotyrosines to form T3 & T4.
• PTU can also block the conversion of T4 to T3.

Note: Since the synthesis rather than the release of hormones is affected, the onset of these agents is slow, often requiring 3–4 weeks before stores of T4 are depleted.



• The 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 per day. Methimazole is administered
as a single daily dose.
• Relapse may occur.
• Adverse effects are rare; they include agranulocytosis, rash & edema.

Thyroid storm
• Presents with extreme symptoms of hyperthyroidism.
• Treated as hyperthyroidism, except that the drugs are given in higher
doses & more frequently.
• ? -blockers lacking sympathomimetic activity, eg. propranolol, are
effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism.
• IV administration is effective in treating thyroid storm.
• Diltiazem (calcium channel blocker) is an alternative to ? -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).

4. Blockade of hormone release:
• A pharmacologic dose of iodide inhibits the iodination of tyrosines (“acute
Wolff- Chaikoff 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 & include sore mouth & throat,
swelling of the tongue or larynx, rashes, ulcerations of mucous membranes, & a metallic taste in the mouth.