BIO 5406 Notes, 2/08/05
THYROID GLAND
I. Introduction. [Hadley, pp. 312-313]
A. Located ventral to the trachea, just below the larynx (fig. 13.2).
B. Source of two types of hormones.
1. Thyroid hormones (thyroxine and triiodothyronine).
a. Vital to normal growth and development.
b. Important role in energy metabolism.
2. Calcitonin.
a. Important role in regulation of blood calcium.
II. History. [pg. 312]
A. 1656 -- Thyroid gland first described.
B. 1825 -- Caleb Parry described syndrome of enlarged thyroid gland
(goiter), nervousness, and palpitations of the heart.
C. 1835 -- Robert Graves noted the above syndrome accompanied by
protrusion of the eyeballs (exophthalmos) (Graves disease).
D. 1873 -- William Gull described syndrome of deficient mental function
(cretinism), fatigue, and thickened skin (myxedema).
E. 1876 -- Theodor Kocher was the first to surgically remove the thyroid
to treat goiter.
1. Noted that his patients who had total thyroidectomies later developed
symptoms similar to cretinism and myxedema.
a. If he left a portion of the thyroid behind, symptoms were temporary.
2. Noted that thyroid gland contained a high concentration of iodine.
F. 1883 -- Committee on Myxoedema in London sought to establish a link
between cretinism, myxedema, and thyroidectomy.
1. Performed thyroidectomies on several species of animals.
2. Final report was published in 1888, concluding that several forms of
myxedema and cretinism were all due to "the annihilation of the function
of the thyroid body."
G. 1891 -- George Murray was the first to treat myxedema with thyroid gland
extract.
H. 1895 -- Adolph Magnus-Levy demonstrated that thyroid gland extract
increases oxygen consumption in humans.
I. 1914 -- Edward Kendall crystallized and isolated thyroxine.
J. 1935 -- Thyroid-stimulating hormone separated from other pituitary
hormones.
K. 1952 -- Triiodothyronine (T3) was identified.
L. 1961 -- Calcitonin discovered.
M. 1969 -- Andrew Schally and Roger Guillemin independently discovered
the structure of thyrotropin-releasing hormone (TRH).
III. Embryology. [pg. 313]
A. First endocrine gland to appear (day 24 in human).
B. Derived from endoderm as an outgrowth of the pharynx.
1. Between 1st and 2nd pharyngeal pouches (figure).
C. Producing thyroxine by 11th week.
IV. Histology. [pg. 313]
A. Functional unit = thyroid follicle. [Section of thyroid (low power)]
1. Single layer of cuboidal cells -- thyroid follicular cells.
[Section of thyroid (medium power)]
2. Lumen contains colloid.
B. Parafollicular cells (C or clear cells).
1. Large, light‑staining cells located between follicles.
[Thyroid parafollicular cells]
2. Secrete calcitonin.
V. Biosynthesis of Thyroid Hormones. [pp. 314-316]
A. Two unique features.
1. Requires iodine.
2. Thyroid hormones are stored extracellularly.
B. Synthesis of thyroglobulin (fig. 13.4).
1. Thyroglobulin is a large, globular glycoprotein.
2. Substrate for iodination of tyrosine and synthesis of thyroid
hormones.
3. Synthesized by ribosomes on RER and processed and packaged into
secretory granules by Golgi apparatus.
4. Secreted into lumen of thyroid follicle by exocytosis.
C. Iodine uptake (figure).
1. Dependent on dietary iodine.
2. Active transport of iodide ion (I-) by basal membrane.
a. Co-transport with sodium ‑‑ "iodide pump".
3. Iodine concentration in thyroid follicular cell is about 50x concentration
in blood.
D. Iodination of thyroglobulin.
1. Occurs on microvilli at apical surface.
2. Iodide is activated by an enzymatic process.
3. Activated iodide binds to tyrosine residues on thyroglobulin.
a. Only 2% of a.a. in thyroglobulin are tyrosine.
b. One iodide binds to 3-position ‑‑ monoiodotyrosine (MIT).
c. Second iodide binds to 5-position ‑‑ diiodotyrosine (DIT).
E. Coupling of iodotyrosyl residues (fig. 13.5).
1. Also occurs at apical border.
2. About 10% of residues become coupled.
a. MIT + DIT -----> triiodothyronine.
b. DIT + DIT -----> tetraiodothyronine.
F. Iodinated thyroglobulin is stored in colloid.
VI. Secretion of Thyroid Hormones. [pp. 314-315]
A. Colloid is engulfed by endocytosis (fig. 13.4).
1. Droplets migrate toward basal membrane.
2. Fuse with lysosomes.
B. Releases amino acid residues, including MIT, DIT, T3, and T4.
1. MIT and DIT are broken down and iodide is recycled.
2. T3 and T4 diffuse across basal membrane (mostly T4).
VII. Transport of Thyroid Hormones. [pg. 320]
A. More than 99% bound to plasma proteins.
B. Mostly bound to thyroxine‑binding globulin (TBG).
C. Tight binding contributes to long plasma half‑life.
1. Bound hormone is not available for metabolism.
2. T4 is more tightly bound than T3.
3. T4 has longer half‑life (T4 = 7 days, T3 = 1‑2 days).
D. Only free thyroxine is available for interaction with target cells.
E. Measurement of only total T4 may be misleading (ex. pregnancy).
1. Estrogen stimulates synthesis of TBG.
2. Feedback mechanisms 8 total T4 in pregnancy to compensate for
increased protein binding.
3. Free T4 levels remain normal.
VIII. Mechanism of Thyroid Hormone Action. [pp. 317-319, 322-325]
A. Biologically active form ───> 3,5,3'‑triiodothyronine (T3).
B. T4 is converted to T3 by deiodinase in liver, kidney, and target tissues
(figure).
1. Some T4 is converted to 3,3',5'‑triiodothyronine (reverse T3), which
is biologically inactive.
2. Major product of thyroid glands is T4 (figure).
C. Nuclear receptors.
1. T4 and T3 cross membranes easily due to lipid solubility (fig. 13.10,
figure).
2. T4 is converted to T3 in cytoplasm by deiodinase.
3. T3 binds to receptors on nuclear chromatin.
4. Stimulates transcription of specific mRNA, thus stimulating synthesis
of specific proteins.
D. Permissive action on other hormones.
1. Thyroid hormones is required for actions of other hormones
(ex. growth hormone).
2. Due to increased synthesis of enzymes required for the actions of
other hormones.
E. Mitochondrial receptors -----> 8 oxidative metabolism.
IX. Thyroid Hormone Actions. [pp. 320-323]
A. Required for growth and development.
1. Bone development.
a. Promotes growth hormone secretion.
b. Permissive effect on growth hormone‑sensitive cells.
2. CNS development is critical during first 2 years.
B. Calorigenic action.
1. 8 energy production and O2 consumption in most tissues.
a. 8 basal metabolic rate (BMR).
2. Important in thermoregulation, since oxidative metabolism generates
heat.
C. Reproduction.
1. Permissive action.
2. Hypothyroid mammals have delayed gonadal development.
3. Hypothyroid females have more irregular menstrual cycles.
X. Control of Thyroxine Secretion. [pp. 315-316, 319-320]
A. Controlled variable is thyroxine concentration in blood.
B. Thyrotropin (TSH).
1. Produced by thyrotropes in ant. pituitary.
2. Large glycoprotein (201 aa).
3. Actions.
a. Binds to membrane receptors on thyroid follicular cells.
b. Acts by increasing cAMP in thyroid follicular cells.
c. Induces thyroid hypertrophy (8 in height of follicular cells).
d. 8 Iodide uptake, 8TG synthesis, 8 uptake of iodinated TG ----->
8 T4 secretion.
C. Thyrotropin‑releasing hormone (TRH).
1. Produced by hypothalamic neurons.
2. Tripeptide.
3. Action.
a. Binds to membrane receptors on thyrotrophs.
b. Acts by increasing cAMP in thyrotrophs.
c. Stimulates synthesis and release of thyrotropin.
D. Somatostatin (14 aa).
1. Inhibits TSH secretion.
2. Release is stimulated by T3 and T4.
3. Also inhibits growth hormone secretion.
X. Thyroid Disorders. [pp. 316-317, 325-328]
A. Nontoxic goiter (figure).
1. Dependent on dietary iodine.
2. Richest dietary source ‑ seafood.
3. Where dietary iodine is lacking, thyroid hypertrophies to extract more
iodine from blood (figure).
4. Endemic goiter in many mountainous regions and Great Lakes region.
a. Akron, Ohio ‑‑ use of iodine to prevent goiter in 1910's.
b. Prevention -- iodized salt.
B. Hypothyroidism.
1. Insufficient thyroid hormone secretion.
2. Symptoms (table 13.2).
a. Slowed physiologic function.
1. Fatigue and lethargy.
2. Slowed speech and mental function.
3. 9 BMR.
b. Skin is cold, dry scaly, face expressionless.
1. If very severe, mucus builds up under skin ‑‑ myxedema.
c. Menstrual irregularities.
d. Obesity and hypercholesterolemia.
1. Thyroxine stimulates cholesterol metabolism and mobilization of fat.
e. In child ‑‑ retarded growth and delayed puberty.
f. In newborn.
1. Retarded mental and physical development ‑‑ cretinism.
2. Mental retardation can be prevented but not reversed.
3. Primary hypothyroidism (fig. 13.12, table 13.3).
a. Defect in thyroid gland.
b. Most common -----> chronic autoimmune thyroiditis.
1. Follicular cell destruction by immune system.
c. May be associated with goiter (fig. 13.11).
d. T3 and T4 levels ----->
e. TSH levels ----->
4. Secondary hypothyroidism.
a. TSH deficiency.
b. May be pituitary or hypothalamic origin.
1. Often associated with other hypopituitary disorders.
c. T3 and T4 levels ----->
d. TSH levels ----->
5. Treatment.
a. Thyroid hormone replacement therapy.
b. Synthetic preparations (ex. levothyroxine).
C. Hyperthyroidism.
1. Excessive thyroid hormone secretion.
2. Symptoms (table 13.2).
a. Increased rate of physiologic function.
1. Insomnia and anxiety.
2. Excessive heat production.
3. Skin is warm, moist, flushed.
4. 8 BMR.
5. Unexplained weight loss.
6. Rapid, prominent heartbeat.
b. Severe ‑‑ thyroid storm.
3. Graves disease ‑‑ diffuse toxic goiter (fig. 13.12, table 13.3).
a. Stimulation of thyroid follicular cells by antibodies to TSH
receptors (thyroid-stimulating antibody).
b. Not under feedback control.
c. Exophthalmos ‑‑ protrusion of eyeballs.
4. Treatment.
a. Antithyroid drugs (ex. propylthiouracil).
1. Block synthesis of T3 and T4.
b. Surgical removal of thyroid gland (thyroidectomy).
c. Radioactive iodine (ex. I-131).
1. Selectively irradiates thyroid (ß‑rays) (figure).
2. One or two oral doses.
XI. Comparative Aspects. [pp. 331-334]
A. Thyroid gland differs in shape in various vertebrate species (figure).
B. All vertebrates produce T3 and T4.
C. Primary roles.
1. Thermoregulation.
a. Thyroxine secretion is higher during winter in most mammals.
b. Thyroxine secretion is decreased during hibernation in ground
squirrels and black bears.
2. Molting and hair growth.
a. Stimulates molting in salamanders, lizards, birds.
b. Stimulates hair growth in mammals.
3. Metamorphosis.
a. Stimulates metamorphosis in frogs.
4. Reproduction.
a. Gonadal maturation.
b. T4 levels are elevated during spawning migration in salmon.
