Glen Gross
Thyroid hormone physiology and pharmacology
3/5/2014
Thyroid Anatomy
A.
Follicular cells, involved in thyroid hormone synthesis.
B.
Thyroid follicle – contains colloid which is a proteinaceous containing
thyroglobulin, a glycoprotein necessary for the synthesis of thyroid hormones
(T3 and T4).
C.
Parafollicular “C” cells – produce calcitonin., important for calcium regulation
D.
Unique characteristics include
1. Requires trace element, iodine.
2. Stores thyroid hormone as a thyroglobulin complex.
Thyroid hormonal axis:
Regulation and control
TRH:
1. thryotoprin releasing hormone
a. comes from the hypothalamus
b. acts on the anterior pituitary
c. is the dominant signal for release of TSH
TSH:
1. thyroid stimulating hormone:
a. comes from the anterior pituitary
b. acts on the thyroid cuasing it to release  T3 and T4
Thyroid hormones:
1. T3: triiodthyronine
2. T4: thyroxine
Other negative regulators:
1. acts to decrease TRH release from the hypothalamus:
a. somatostatin
b. dopamine
c. high levels of glucocorticoids (adrenal cortex)
Thyroid Hormone Axis:
Hormone properties, receptors, and target cell signal transduction
Thyrotropin Releasing Hormone: TRH
1. initial form:
a. peptide preprohormone
2. mature form:
a. tripeptide
3. action:
a. stimulates release of TSH from thyrotrophs of the anterior pituitary
The role of TRH:
1. controls energy homeostasis, feeding behavior, thermogenesis and autonomic
regulation
a. does this by controlling the circulating levels of thyroid hormones
Thyrotropin Releasing Hormone:
1. binds to the transmembrane TRH receptors:
a. present on thyrotrophs of the anterior pituitary gland
2. promotes release of  TSH
i. PLC  IP3  increase in Ca2+  release of TSH
Thyroid Stimulating Hormone: TSH:
1. a glycoprotein that consists of:
a. alpha chains
b. beta chains
2. the alpha chain:
a. are homologous to other pituitary hormones (LH, FSH and hCG)
3. the beta chain:
a. is very specific to TSH and confers sepcifiity of hormonal action
b. binds to TSH receptors
TSH:TSH receptor signal transduction:
1. receptors for TSH:
a. located on the plasma membrane of the thyroid follicular cells
b. are G-protein coupled receptors
i. increase cAMP
2. TSH:TSH receptor binding:
a. stimulates thyroid hormone synthesis and release
Net result of Thyroid Hormone Synthesis:
1. Tyrosine is converted to:
a. T3
i. has 2 tyrosine + 3 idoine
b. T4
i. has 2 tyrosine + 4 iodine
The Seven Steps of Thyroid Hormone Synthesis:
1. dietary Iodide is transported into the thyroid follicular cell
2. oxidation of Iodide  Iodine
a. requires thyroid peroxidase
3. Iodine is added to tyrosines that are attached to the thyroglobulin protein
backbone:
a. make Monoiodothyronine (MIT) and Diiododthyronine (DIT)
4. Conjugation of MIT and DIT:
a. makes T3 and T4
i. requires thyroid peroxidase
5. endocytosis of conjugates T3 and T4
6. proteolysis of the conjugates:
a. forms mature T3 and T4
7. movement of T3 and T4 out of the cell
Thyroid peroxidase:
1. is involved in steps requiring:
a. oxidation
b. conjugation
Comparisons of T3 and T4:
1. T3:
a. is more active than T4
b. has a shorted circulating half life (1 day) than T4
2. T4:
a. less active than T3
b. has a longer circulating half life (6 days) than T3
3. both T3 and T4:
a. bind the thyroid hormone receptors
b. however, most T4 is converted into T3
Thyroid Hormone Axis:
Carrier proteins
Thyroid Hormone Carrier Proteins:
1. thyroxine binding globulin:
a. binds 75% of T4 and 75% of T3
b. has one binding site for one thyroid hormone molecule
2. transthyretin:
a. binds 20% of T4 and 5% of T3
b. has two binding sites for two thyroid hormones
3. albumin:
a. binds 5% of T4 and 20% of T3
b. several binding sites for several thyroid hormones
Carrier proteins and Thyroid hormones:
1. almost all T3 and T4 are bound to proteins in the circulation
2. conditions where serum protein levels increase:
a. pregnancy
b. estrogen treatment
3. conditions where serum proteins levels decrease:
a. androgens
b. hyperthyroidism
c. malnutrition
d. nephritic syndrome
4. net effect:
a. total hormone (bound+free) levels may fluctuate
Thyroid Hormone Axis:
Metabolism
Thyroid hormone metabolism:
1. Deiodinases I and II:
a. convert T4  T3
b. causes hormone activation
2. Deiodinases I and III:
a. convert T4  rT3 (inactive)
b. causes hormone inactivation
Deiodinase Enzymes:
1. function:
a. are important for activation and deactivating thyroid hormones
Deiodinase I:
1. found in:
a. liver
b. kidney
2. function:
a. converts T4  active T3
b. increases the level of T3 within cells and in the circulation
b. also converts T4  rT3 (inactive) for disposal
3. is a drug target for:
a. Thionamide
Deiodinase II:
1. found in:
a. brain
b. pituitary
c. skeletal and cardiac muscle
2. function:
a. coverts T4  T3 to supply intracellular stores
Deiodinase III:
1. found in:
a. brain
b. skin
c. placenta
2. function:
a. convers T4  rT3 (inactive)
b. deactivates the hormones
TSH:
1. function:
a. stimulates the secretion of mature thyroid hormones
2. spectrum of effects include:
a. thyroid peroxidase synthesis
b. thryoglobulin transcription
c. Na-/Iodide transport activity  pumps I- into the follicular cell
Target Cells for Thyroid Hormones:
1. these cells have thyroid hormone receptors:
a. TRH
2. entry into the cell from the circulation:
a. most T3 and T4 are bound to TBG (thyroxine binding globulin)
3. enters the cell:
a. by diffusion
b. carrier medaited transport
4. inside the cell:
a. T4  converted to T3
5. in the nucleus:
a. thyroid hormone binds to the thyroid-response-element (TRE)
b. thyroid hormone also associates with the retionic X receptor (RXR)
6. net result:
a. transcription
Thyroid Hormone Axis:
Thyroid hormone actions
Thyroid Hormone Actions:
1. necessary for:
a. normal metabolism
b. growth
c. development in nearly every tissue in the body
2. main functions:
a. regulation of basal metabolic rate
b. increased heat production
c. increased glucose utilization, uptake and synthesis
d. permissive sympathetic effects, increased heart rate and increased contractility
State Testing of Thyroid levels:
1. many states require thyroid testing for newborns:
a. if hormone replacement therapy is started within a few days of birth, growth and
development will be normal
Thyroid Hormone Axis:
Hyposecretion and Hypersecretion Symptoms
Hypothyroid Effects in Infants:
1. hypothyroid disorder in infants:
a. called Cretinism
2. the effects of low thyroid production in infants:
a. profound mental retardation
b. short stature
c. delay in motor development
d. coarse hair
e. protuberant abdomens
3. maternal hypothyroidism etiology:
a. lack of iodine in maternal diet (rare)
b. mother has Hashimoto’s thyroiditis
i. results in anti-TSH antibodies that block the TSH receptor
c. exposure to radioactive iodine
d. anti-thyroid drugs during pregnancy
Hypothyroid effects in Infants: Cretinism
1. signs in newborns:
a. respiratory difficulty
b. cyanosis
c. poor feeding
d. jaundice
e. hoarse cry
f. umbilical hernia
g. poor bone growth and maturation
2. effects on bone growth:
a. tibial and femoral epiphysis will be shorter than expected
3. screening infants:
a. route in TSH and T4 levels
b. helps prevent permanent mental retardation
4. if hormone replacement is started within a few days of birth:
a. mental and physical development will be normal
5. if supplementation is delayed:
a. physical development will recover
b. mental deficits will be permanent
Physiological Effects of Low Thyroid in Adults:
1. functions of normal thyroid hormone levels:
a. promote oxygen consumption
b. heat production
c. free radical formation
Hypothyroidism in Adults
1. slow course of symptoms:
a. lethargy
b. somnolence
c. slowed intellectual functions, including speech
d. stiffness and aching muscles
e. cold intolerance
f. delayed deep tendon reflex relaxation
g. menorrhagia and no ovulation in women
Hyperthyroidism in Adults:
1. symptoms of hyperthyroidism:
a. increased heart rate
b. rapid contractility of muscles
c. increased sensitivity to catecholamines
i. increased number of beta adrenergic receptors on the heart, skeletal muscle,
adipose and lymphocytes
d. amplify the effects of catecholamines at the post-receptor site
e. increase in oxygen demand
i. increased in EPO and erythropoiesis
f. promotes GI motility
i. hyperdefecation
Physiological Effects of Excess Thyroid hormone in Adults:
1. effects on bones:
a. increased turnover
b. net resorption  hypercalcuria
2. effects on muscles:
a. increased protein turnover
b. net loss in skeletal muscle and proximal myopathy
c. increased speed of muscle contraction and relaxation:
4. effects on the liver:
a. increased hepatic gluconeogenesis and glycogenolysis
b. increased intestinal glucose absorption
i. problem for diabetic patients
Physiological Effects of Excess Thyroid Hormone in Adults:
1. effects on cholesterol:
a. increase in LDL receptor number to accelerate LDL clearance
b. total LDL cholesterol levels are usually higher in hypothyroidism patients instead
2. effects on several other hormones:
a. production
b. responsiveness
c. metabolic clearance
3. effects of puberty:
a. starts at an early age
4. effects on sex hormones:
a. conversion of adrogens  estrogens
b. increased sex hormone binding to globulins
c. gynecomastia in men
5. effects on fertility:
a. impairs GnRH
b. altered regulation of ovulation
c. infertility
Thyrotoxicosis:
1. thyroid storm:
a. is a medical emergency
2. definition of thyroid storm:
a. any cause of excessive thyroid hormone concentration
b. is the extreme manifestation of thyrotoxicosis
3. assume that a patient with thyrotoxicosis will develop thyroid storm:
a. treat aggressively for primary symptoms
4. drugs for treating thyroid storm:
a. beta blockers
b. thionamides (anti-thyroid)
c. corticosteroids
i. to cover for the decrease in adrenal function cuased by high thyroid levels
5. mortality rate of thyroid storm:
a. fatal in 20-30%
Thyroid Hormone Axis:
Etiology
Causes of Hypothyrodism:
1. primary hypothyroidism: problem lies in the gland
a. congenital defects
b. gland destruction (surgical, radioacative, external radiation)
c. iodine deficiency
d. autoimmune
i. Hashimoto’s thyroiditis is a chronic lymphocytic process of destruction
ii. antibodies react against proteins in the thyroid gland  cuase destruction
2. secondary and tertiary hypothyroidism: problem lies outside the gland
a. usually due to pituitary deficiencies
b. thyroid hormone resistance syndromes
i. tissue resistance to normal hormone production
c. hypothyroidism in children
i. results in impaired gonadotropin secretion  delays puberty
3. hypothyroidism decreases the stress response of the adrenal gland
Cuases of Hyperthyroidism:
1. results in toxicosis of the target tissues
2. Grave’s Disease:
a. production of immunoglobulins that actually stimulate the thyroid
i. TIS - thyroid stimulating immunoglobulins
b. T cells become sensitive to thyroid antigen  stimulating B cells to produce
antibodies that mimic TSH
c. results in hypersecretion of thyroid hormones
d. IgG can cross the placenta during pregnancy  effects the fetus
Thyroid Hormone Axis:
Goiter
Goiter:
1. an enlarged thyroid gland
2. can occur with hyo-or-hyperthyroidism
Goiter Associated with Hypothyroidism:
1. low iodine levels: (dietary)
a. decrease the circulating levels of T3 and T4
b. there is no negative feedback from sufficient levels of T3 and T4 to prevent the
thyroid gland from enlarging
Goiter Associated with Hyperthyoidism:
1. thyroid stimulating immunoglobulins (TSI):
a. increase the size of the thyroid gland despite feedback inhibtion from sufficient levels
of T3 and T4
Thyroid Hormone Axis
Diagnosis
Diagnostic Tests of Thyroid Function:
1. TSH test:
a. first line test
b. most accurate measure of thyroid activity available
i. even for detecting mild hypothyroidism
c. readings are interpreted as above or below normal
2. T3 and T4 test:
a. shows the level of T3 and T4 in the blood
b. with hyperthyrodism:
i. levels of one or both will be higher
3. Thyroid-stimulating immunoglobulin test (TSI):
a. measures the level of TSI
b. patients with Grave’s Disease:
i. will have the antibody
c. patients with hyperthyroidism caused by other conditions will not have the antibody
Resting Serum TSH and clinical symptoms:
• Euthyroid: 0.5-5 microUnits/mL
• Hypothyroid: > 10 microUnits/mL
• Hyperthyroid: < 0.05 microUnits/mL
Total and Free T4 can be measured.
• Total T4 reflects free + protein bound T4.
• Free T4 measurements better reflect physiologic state of thyroid axis.
Exogenous TRH induction of TSH.
Thyroid Hormone Axis
Therapy
Pharmacological Agents used in Diagnosis and Treatment of Thyroid Disorders
1. Hypothyroidism and thyroid replacement preparations:
a. Levothyroxine (T4)
b. Liothyronine (T3)
2. Thioamides used to treat hyperthyroidism and to prepare for surgery:
a. Propylthiouracil (PTU)
b. Methimazole
c. Potassium Iodide (K)
3. Radioactive Iodine:
a. 131(I) is used for thyroid ablation
b. 123(I) is used for thyroid imaging
Levothyroxine (T4) for Hypothyroidism:
1. treatment features:
a. once daily dose
b. narrow therapeutic index
2. drug features:
a. long half life of 7 days
b. reaching steady state takes 6-8 weeks
3. absorption
a. variable and incomplete
b. decreased by:
i.. iron
ii. calcium
iii. Al(OH)
iv. soy
4. dosing:
a. lower dosing in the elderly and those with heart problems
5. side effects of drug-induced hyperthyoidism:
a. palpitations, tachycardia, tremors and anxiety
b. weight loss
c. increased bowel movements
d. in patients with heart disease:
i. angina
ii. MI
e. atrial fibrillation in the elderly
f. bone loss with over supplementation
Liothyronine (T3) for Hypothyroidism:
1. drug features:
a. short half life of 4-6 hours
b. greater potency than Levothyroxine
2. used when:
a. a quick onset of action is needed
Treatment of Hyperthyroidism:
1. drugs:
a. methimazole
b. propylthiouracil (PTU)
2. used for:
a. hyperthyroidism and to prepare for surgery
Methimiazaole and Propylthiouracil:
1. actions:
a. both inhibit thyroid peroxidase
i. blocks oxidation and conjugation reactions for T3 and T4
2. absorption of both:
a. rapid and complete oral absorption
3. accumulate in the thyroid
4. they both need about two weeks to take effect
Methimazaole:
1. duration of action:
a. 24 hours
Propylthiouracil (PTU):
1. duration of action:
a. 12 hours
2. also inhibits Diodinase I:
a. inhibits the conversion of T4  T3 (active)
FDA warnings for Propylthiouracil:
1. PTU has an increased risk of liver injury compared to Methimazaole
2. PTU is considered a 2nd line drug to treat Grave’s Disease:
a. only used when patients are allergic to Methimazaole
3. Methimazaole has a risk of teratogenic effects during pregnancy:
a. causes aplasia cutis
4. PTU should be used in pregnant women instead
Anti-thyroid drugs: Iodide
Iodide:
1. uses:
a. preparation for thyroidectomy
b. treating thyroid storm
c. protection from radioactive iodide
2. mechanism of action:
a. high concentration of iodide effects thyroid hormones by blocking:
i. transport
ii. synthesis of iodotyrosines and iodotyronines
iii. release
3. escape from therapy can occur:
a. suddenly the therapy no longer works
4. side effects of iodide:
a. allergic reactions
b. sore teeth and gums and increased salivation
Antithyorid Drugs: Radioactive 131(I) and 123(I)
1. 131(I):
a. used for destroying the thyroid
b. main disadvantage is too much destruction can occur
c. need to supplement thyroid hormones after treatment
2. 123(I):
a. used for imaging the thyroid
Nine Facts of Thyroid Hormone Physiology and Pharmacology:
1. Thyroid hormone axis involves stimulatory hypothalamic and anterior pituitary
hormones
2. There are two thyroid hormones. T3 is biologically more active. T4 has a longer
half life. T4 is converted to T3 in cells.
3. Thyroid hormones are required for normal development of the brain and for
growth. Thyroid hormones are key homeostatic regulators.
4. Hypersecretion of thyroid hormones causes roadrunner-like symptoms.
5. Hyposecretion of thyroid hormones causes sloth-like sluggishness.
6. Clinical diagnosis of thyroid function includes resting levels of TSH and thyroid
hormones.
7. Levothyroxine is usually used to treat hyposecretion.
8. Radioactive Iodine is widely used to treat autoimmune Grave’s Disease.
9. The Thionamide drugs, Methimazole and Propylthiouracil can be used to
medically treat thyroid hormone hypersecretion. Methimazole and PTU inhibit
Thyroid Peroxidase. PTU also inhibits Iodinase I.