The thyroid gland produces three hormones -- thyroxine (tetraiodothyronine, T₄), triiodothyronine (T₃), and calcitonin.  Calcitonin is primarily employed in bone homeostasis and will be covered in the next section.  The overall effect of the thyroid hormones T₃ and T₄ include necessary actions that contribute to growth, development, control of body temperature, and energy levels through control of basal metabolic processes.

 Biosynthesis -- Iodine is a vital component of the hormones.  A minimum dietary intake of 75 mcg is required for the daily production of thyroid hormones.  (The USRDA for iodine is 150 mcg.)   Dietary iodide is taken up by the thyroid gland by specialised transport systems in a process called iodide trapping.  Once in the gland, iodide is converted to iodine by thyroidal peroxidase enzymes (which may be inhibited by elevated levels of iodine, as described below).  The iodine is then combined with residues of the amino acid tyrosine to form mono-iodotyrosine (MIT) and di-iodotyrosine (DIT).  With the products becoming incorporated into thyroglobulin, the thyroid storage sites of thyroid hormones.  This process is termed iodide organification.  The MIT and DIT may then combine to form tri- and tetra-iodothyronine (MIT + DIT --> triiodothyronine & DIT + DIT --> tetraiodothyronine).  This occurs in a ratio of approximately 5:1 (5 T₄ : 1 T₃).

Release and Pharmacokinetics -- Upon stimulation by TSH, the thyroid hormones are released by a combination of proteolysis of thyroglobulin, freeing the hormone, and exocytosis (released into the circulation).  Circulating thyroid hormone is highly bound (>99%) to thyroid binding globulin.  (RECALL that œstrogens will increase and androgens decrease circulating levels of TBG.)  Circulating levels of T₄ and T₃ closely match the ratios of the production, with the ratio of 4:1 (T₄:T₃).  The active biological half-life of these hormones are 7 days for T₄ and 1 day for T₃.   Thyroid hormones are then taken up by cells throughout the body where they may exert their effect.  Once in the cell T₄ is metabolised to T₃ or inactive metabolites (this conversion also occurs in the thyroid and plasma, but to a lesser extent) by the enzyme iodinase.

Iodinase exists in different isoforms that are specific for the 5 or 5' position of T₄.  Of the 75 mcg of T₄ produced by the thyroid daily, approximately 33% or 25 mcg are converted to T₃ by the enzyme 5'-iodinase.  Approximately 45% or 35 mcg is converted to reverse T₃ by 5-iodinase.  The remaining 25% or 15 mcg is metabolised by deamination, decarboxylation, or conjugation with either glucuronide or sulphate.  These metabolites as well as reverse T₃ do not have biological activity.  Therefore, the effective thyroid hormone is T₃, available at a daily production value of approximately 30 mcg (25 mcg by conversion of T₄ and 5 mcg produced and secreted by the thyroid gland directly).

Mechanism of Action
Once this conversion has taken place, T₃ may then interact with a specific thyroid hormone receptor, which is nuclear.  The T₃ is taken up by the nucleus of the cell and interacts with the receptor to produce a gene active response, resulting in transcription/translation of DNA/RNA  to increase protein synthesis specific for that cell.  (RECALL that this mechanism is essentially the same as that for steroid hormone receptors, except in this instance, thyroid hormones are not steroidal in structure.)  NOTE that the affinity of T₄ for the receptor is approximately 1/4 that of T₃, so that while T₄ has a longer half-life, it must be converted to T₃ to produce the full effect of thyroid hormones.

Physiologic Effects -- The overall effects of thyroid hormones is to increase metabolic processes.  Many of these effects are physiologically identical to stimulation of the sympathetic nervous system.   It is believed that at least some of the effects of the thyroid hormones are due to increased synthesis of beta-adrenergic receptors, thus increasing the sensitivity of a specific cell to adrenergic stimulation.  A summary of the specific effects are presented in the table below.
 

System	Thyroid Action (Hyperthyroidism or thyroxicosis -- enhanced action)	Thyroid Deficiency (Hypothyroidism)
Skin	Warm, Moist, Sweating, Heat Intolerance, Rash	Pale, Cool, Dry, Cold Intolerance
Eyes, Face	Exophthalmus, OEdema, Diploplia	Drooping lids; puffy, non-pitting oedema, large tongue
Cardiovascular	Decrease PR, tachycardia, positive ino- and chrono-tropy, high output failure, arrhythmias, angina	Increase PR, negative ino- and chrono- tropy, bradycardia, low output failure
Respiratory	Dyspnea, decreased vital capacity, increased RR	Pleural effusion, hypoventilation, CO2 retention
Gastrointestinal	Increased appetite, increase bowel movements	Decreased appetite, constipation, ascites
CNS	Nervousness, hyperactivity	Lethargy, slowed mental processes
Musculoskeletal	Weakness, fatigue, Increased reflexes, hypercalcaemia, osteoporosis	Stiffness, fatigue, decreased reflexes
Renal	Polyuria	Oliguria
Hematopoietic	Increase erythropoiesis, anaemia	Decrease erythropoiesis, anaemia
Reproductive	Menstrual irregularity, decrease fertility, increase gonadal hormone production	Hypermenorrhoea, infertility, decreased libido, hypogonadism
Metabolic	Increased basal rate, negative nitrogen balance, hyperglycaemia, decrease LDL, VLDL, increased vitamin requirements, increase hepatic metabolic activity	Decrease basal rate, positive nitrogen balance, hypoglycaemia (with increased insulin sensitivity) increased LDL, VLDL, decreased vitamin requirements and hepatic metabolic activity

Control of Thyroid Function -- There is a powerful feedback mechanism that contributes to thyroid control.  Elevated levels of circulating T₃ and T₄ will produce a negative feedback effect on the hypothalamus/pituitary to reduce TRH and TSH release.  This, in turn, decreases further thyroid hormone synthesis and release.  The converse is also true.

Additionally, elevated levels of iodine will inhibit thyroid gland activity by decreasing iodide organification (inhibition of thyroid peroxidase) and release of T₃ and T₄.

Physiologic state may also contribute to thyroid control.  In a state of starvation, when energy needs to be conserved, thyroid hormones will be down-regulated (decrease in number) and circulating levels of T₄ and T₃ will also decrease.

Most thyroid agonists are simply synthetic thyroid hormones that do not differ from the endogenous hormones.  These agents are well absorbed (80% for T4 and 95% for T₃) and are bound to TBG just as the endogenous hormones.  There are four versions of thyroid hormone currently marketed.

Desiccated Thyroid -- is thyroid gland from animal sources.  This presents the hormone in the same ratio as that provided by the gland.  However, since it is of animal origin the incidence of allergic reaction is high.

Liotrix -- a mixed product T₄ and T₃ in a 4:1 ratio, respectively.  This attempts to duplicate the circulating levels of the thyroid hormones.  However, owing to the differences in bioavailability, the exact plasma concentrations is only an approximation to those endogenous levels.  Additionally, this agent is more costly than other thyroid hormones.

Liothyronine -- is synthetic T₃ only.  This agent is also relatively expensive.  Since T₄ is converted to active T₃ in the peripheral tissues, the only time the use of this agent would be beneficial is in patients who are deficient in 5'-iodinase and are incapable of converting T₄ to T₃.

Thyroxine -- is synthetic T₄.  This formulation is converted to active T₃ by peripheral tissues.  Since it is relatively inexpensive, is well absorbed, and is biologically active in most patients, this is the preferred choice in thyroid hormone replacement therapy.

The actions of thyroid gland may be blocked by 1) decreasing the production/release of thyroid hormones 2) blocking the effect of the hormone either pharmacologically or physiologically 3) destruction of the gland.  Thyroid antagonists that are goitrogens are those agents that reduce T₃ and T₄ such that the feedback loop will increase TSH release, stimulating the thyroid gland to result in glandular hypertrophy or goiter.

 Thionamides -- Propylthiouracil, Methimazole, Carbimazole

Mechanism of Action -- The thionamides inhibit the enzyme thyroid peroxidase, thus blocking the conversion of iodide to iodine and inhibiting iodide organification.  They also inhibit the coupling of iodotyrosines (MIT/DIT to DIT).  Both of these actions will result in reduced production of thyroid hormones.  These agents have a long onset of action (3-4 weeks) that is dependent upon depletion of thyroid hormone stores prior to clinical signs of  reduction of hormone synthesis.

Pharmacodynamic Effects -- These agents will reduce the effects of thyroid hormones.  Overdose will resemble acute hypothyroidism.

Adverse Effects -- Other side effects of the thionamides include rash with or without fever in 3-12% of patients.  Side effects which are much less frequent but more severe include a lupus like reaction involving joints, liver damage, and agranulocytosis.  There is a cross-sensitivity between the drugs and a person reacting in this manner to one drug will likely exhibit similar effects with another of the class.

Methimazole has a longer half-life requiring only once daily dosing.  However it freely crosses the placenta, potentially causing thyroid deficiency in the fœtus.  Propylthiouracil has a shorter half-life and is usually dosed q6h.  It is more highly bound to plasma proteins that methimazole but does not cross the placental barrier as readily as methimazole.  Carbimazole is currently unavailable in the U.S.A.
 

Anion Inhibitors -- Perchlorate (ClO₄^-), Pertechnotate (TcO₄^-), thiocyanate (SCN^-), and fluoborate (BF₄^-)
These agents competitively inhibit the uptake of iodide at its transport protein.  They may be used in iodide induced hyperthyroidism (see below), but in actuality are rarely employed.  This is due, at least in part, to the toxicity that may be seen with these agents, including aplastic anæmia, methæmoglobinæmia, and uncoupling of oxidative phosphorylation.

Iodides -- Saturated Solution of Potassium Iodide (SSKI, 1 Gm/mL KI), Lugol's Solution (100 mg/mL KI and 50 mg/mL of  I)
Mechanism of Action --Iodides will decrease organification, T₃/T₄ release, size and vascularisation of the thyroid gland, and proteolysis of thyroglobulin.  Patients may show improvement within 2-7 days of initiation of therapy.  This action is based upon the control mechanism of excess iodine alluded to earlier in the section.  NOTE, HOWEVER, that continued administration will ultimately result in increased glandular storage of  iodine.  The patient may then exhibit "escape" from the inhibitory effect of iodine and subsequent rebound in T₃/T₄ release resulting in acute thyroid toxicity.

Iodine Toxicity -- In addition to the thyroid toxicity that may occur, "iodism" manifests as acneiform rash, swollen salivary glands, mucous membrane ulceration, conjunctivitis, rhinorrhœa, fever, metallic taste, bleeding, and anaphylaxis.

Uses -- Iodine is used primarily as short term inhibition of thyroid hormone activity.  It is also given in low doses as an iodine supplement in patients who are hypothyroid with iodine deficiency.

Iodinated Contrast Media -- Idopate, Iopanoic Acid
Although unapproved for this purpose, the iodine-containing diagnostic agents idopate and iopanoic acid may be used for the purposes described above for iodide.  They are typically less toxic than iodide alone.  These agents appear to be particularly effective in treating thyroid storm (described below) when a rapid reduction in thyroid hormone release is desired.

Radioactive Iodine -- ¹³¹I
This agent is used in Grave's disease, thyroid tumour, or other conditions that may warrant ablation of the thyroid gland (alternative therapy would be thyroidectomy).  ¹³¹I destroys thyroid tissue by beta-radiation with an effective half-life of 5 days.  It appears to produce minimal side effects with maximal efficacy.  Dangers of radiational damage (i.e. reproductive toxicity) appear to be minimal to non-existent.

Hashimoto's Thyroiditis -- The primary form of hypothyroidism in the U.S.A. (Worldwide it is more often due to iodine deficient diets).  Hashimoto's is an autoimmune disease that presents as a decrease in thyroid function.  Treatment is usually with thyroid supplements.

Cretinism -- Congenital hypothyroidism or neonatal iodine deficiency that causes poor development of the CNS, resulting in severe mental retardation and learning disability.

Grave's Disease -- The primary form of hyperthyroidism in the U.S.A.  This disease is also an autoimmune disorder.  However, rather than producing antibodies that depress thyroid function, patients with Grave's disease produce antibodies that act as thyroid stimulating immunoglobulins (TSI) which act as TSH, increasing T₃ and T₄ release.

Thyrotoxicosis factitia -- is thyroid toxicity as a consequence of exogenous thyroid hormone overdose.

Thyroid Storm -- Acute, often life-threatening, thyrotoxicosis.