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Physiology of Thyroid Hormone Regulation
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B. Active principles of the thyroid gland are
thyroxine (T4) and triiodothyronine (T3)
T4
DIT
T3
MIT
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Synthesis and Metabolism
Thyroid hormone biosynthesis is exceptionally
inefficient
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Synthesis and Metabolism
Hashimotos Thyroiditis
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Major steps in synthesis involve 1. Uptake
of iodide - sodium iodide a. Iodide in
circulation (0.2 to 0.4 µg/dl) is concentrated 20
to 50-fold by gland b. I- transport is
stimulated by TSH and controlled by auto
regulation (decreased stores stimulate,
increased stores inhibit) c. I- transport is
blocked by antithyroid drugs thiocyanate and
perchlorate 2. Oxidation and Iodination
(Organification) a. Oxidation of I- is effected
by H202 and a peroxidase- catalase reaction b.
Enzyme is concentrated at membranes for
iodination of monoiodotyrosine (MIT) and
diiodotyrosine (DIT) residues in thyroglobulin
prior to its storage in thyroid follicle.
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• 3. Formation of T4 and T3 from iodotyrosine
  (coupling reaction)
• a. DIT DIT T4 (intramolecular coupling)
• MIT DIT T3
• These reactions may be catalyzed by the same
  peroxidase
• b. Amount of T4 and T3 formed depends on
  relative quantities of DIT and MIT I2
  deficiency favors T3 synthesis
• c. Synthesis and Storage in colloid space
• 4. Secretion of T3 and T4
• Thyroglobulin is taken up by endocytosis
  and transported in colloid droplets to lysosomes
  for proteolysis.
• 5. Conversion of T4 to T3 via 5-deiodinase in
  peripheral tissues T3 is more potent

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C. Transport in the circulation 1. T4 and T3
carried by thyroxine-binding globulin (TBG
Proloid) affinity for T4 is greater 2. T4 is
also transported by transthyretin (formerly
prealbumin) 3. Free hormones are
biologically active a. 0.03 of plasma T4 b.
0.2 to 0.5 of plasma T3
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D. Receptors members of the nuclear receptor
superfamily 1. Located in the nucleus of
numerous tissues transcription factors 2.
TRa, TRb 3. Nongenomic actions
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E. Actions of T3 and T4 important
determinants of genetically coded developmental
programs (Goodman Gilman) 1. Growth and
development a. Many effects are mediated through
regulation of protein synthesis

• b. Cretinism
• i. Due to iodine deficiency (endemic cretinism)
  or to abnormal thyroid development or defect in
  synthesis of thyroid hormone (sporadic cretinism)
• Impaired growth, mental retardation, short
  extremities, listlessness, large tongue, puffy
  face
• c. Maternal hypothyroidism ? suboptimal fetal
  development

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• 2. Stimulation of cardiovascular system
• a. Thyroid hormones increase sensitivity to
  b-adrenergic receptor-mediated actions
• Heart rate and cardiac output are increased in
  hyperthyroidism ventricular hypertrophy may
  occur
• Calorigenic effect ? heat and energy production,
  ? O2 consumption.
• d. Cholesterol metabolism ? conversion to bile
  acids

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F. Degradation and Excretion 1. Both T4 and T3 -
conjugated in liver to glucuronic and sulfuric
acids through the phenolic group, then excreted
in the bile. 2. T4 half-life is 6-7 days (but
3-4 days in hyperthyroidism, 9- 10 days in
myxedema) 3. T3 - half-life is 1-2 days.
G. Clinical Uses 1. Replacement therapy in
hypothyroidism 2. Obesity (not advised!) 3. TSH
suppression (nontoxic goiter, cancer)
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II. Regulation A. Thyrotropin (TSH) - pituitary
product 1. Synthesis and secretion of this
protein (mw 28,000) are augmented by a
hypothalamic product (TRH) and are
feedback-inhibited by thyroid
hormones 2. Mechanism of action a. Binds to a
G protein-coupled receptor b. Increases hormone
synthesis and secretion, and increases
vascularity of thyroid gland c. Prolonged
stimulation produces hypertrophy and
hyperplasia of thyroid cells. 3. Clinical use -
diagnostic test for thyroid function with
thyroid 123I uptake and scan
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• B. Thyrotropin Releasing Hormone (TRH) -
  hypothalamic product
• Tripeptide (mw 362), structure is pyroglutamic
  acid- histidine-proline amide
• Stimulates TSH secretion and synthesis
• Clinical use - Formerly, provocative test for
  release of TSH, but no longer available in the
  U.S.

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C. Hypothyroidism (myxedema when
severe) 1. Caused by loss of regulatory factor
from pituitary (secondary) or disease of
thyroid (primary, e.g. Hashimotos
thyroiditis) 2. Signs and symptoms related to
decreased heat production, decreased
sympathetic nervous system activity 3. Treatment
replacement levothyroxine is usually
preferred Caution In older individuals, thyroid
replacement should be gradual because an
arrhythmia or a myocardial infarction may be
precipitated by abrupt full replacement.
Osteoporosis may also be a consequence of long
term therapy
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D. Hyperthyroidism 1. Due to excess circulating
T3 and T4 2. May be caused by antibodies of the
IgG type (thyroid stimulating antibody)
which activate TSH receptors (Graves
disease) 3. Signs and symptoms related to
excessive production of heat, increased motor
activity, and increased activity of the
sympathetic nervous system - thyrotoxicosis
(e.g. hypertension, tachycardia, nervousness,
muscle weakness)
Hamburger Thyrotoxicosis
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Tiki - suspected of having hyperthyroidism
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III. Antithyroid Agents A. Four
types 1. Synthesis inhibitors (e.g.
propylthiouracil) 2. Iodide uptake blockers
(e.g. perchlorate) 3. Inhibitors of hormone
release (iodide) 4. Gland ablation (131I
surgery) B. Thioamide Drugs (thiourylenes) 1. S
tructure
Propylthiouracil
Methimazole
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Propylthiouracil
2. Mechanism of action a. Inhibits
organification of tyrosine residues in
thyroglubulin b. Inhibits coupling of MIT and
DIT to form T3 and T4 c. Propylthiouracil
inhibits conversion of T4 to T3 (thus might be
useful to treat thyroid storm or thyrotoxic
crisis) 3. Pharmacokinetics a. Rapid
absorption b. Plasma half-life is short i. 2
hours for propylthiouracil ii. 4-6 hours for
methimazole c. Concentrated in thyroid d. Drugs
and metabolites are excreted in urine e. Drugs
cross placenta, and may also appear in milk
?deiodinase
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4. Untoward Reactions a. Agranulocytosis or
aplastic anemia i. Less than 1 in 500, usually
occurs in the first few months of
treatment. ii. Onset is rapid, recovery
frequent if drug is stopped b. Skin rash - may
subside spontaneously - more common 5. Therapeuti
c Uses a. To treat hyperthyroidism until a
spontaneous remission occurs (Graves
disease) b. To control severe hyperthyroidism in
conjunction with ablation therapy with
131I c. To prepare patients for thyroidectomy
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C. Iodide The oldest remedy for thyroid
disorders, acts rapidly, usually within 24
hours 1. Mechanism of action a. Inhibits
iodotyrosine and iodothyronine synthesis b. Inhibi
ts thyroid hormone release c. Causes a rapid
reduction in gland vascularity 2. Uses a. Immediat
e preoperative period prior to thyroidectomy
after longer term treatment with an antithyroid
drug such as propylthiouracil to further shrink
the gland and reduce vascularization
b. Protection from radioactive
fallout c. Prophylaxis of endemic
goiter d. Beneficial effects in treating
hyperthyroidism eventually wear off
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Chernobyl 10 million children and adults were
administered iodide in Poland after the 1986
nuclear accident
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3. Toxicity a. Occasionally individuals have
acute reactions, including angioedema, fever,
arthralgia and eosinophilia b. Iodism
dermatitis, stomatitis and mental
depression D. Radioactive Iodine 1. 131I
half-life 8 days - emits x-rays and ?-particles
(ablation therapy) 123I half-life 13 hours
(scanning) 2. Mechanism of action a. Trapped by
thyroid b. Incorporated into iodotyrosines and
deposited in follicular colloid c. ?-particles
(131I) destroy parenchymal cells, causing
involution of gland
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3. Uses a. 131I in hyperthyroidsm, as an
alternative to surgery, especially in patients
with contraindications for surgery b. In
treatment of follicular thyroid carcinoma c. 123I
to measure iodine uptake by the thyroid as a
diagnostic test for hyper- or hypothyroidism and
response to TSH

• Toxicity and Contraindications
• a. High incidence of hypothyroidism after use
• b. Contraindicated 6-12 months before, and
  during, pregnancy

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• E. Ionic Inhibitors
• 1. Chemistry thiocyanate also perchlorate and
  periodates
• 2. Uses
• a. Rarely used due to toxicity - agranulocytosis
  and aplastic anemia
• b. When other antithyroid drugs are not
  tolerated

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