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Lecture Notes (Chapter 77) Thyroid Metabolic Hormones

Objective 77.1 Identify the hormones secreted by the thyroid gland, the thyroid gland utilization
of iodide, and the fate of ingested iodides.

Thyroid Gland

 Composed of many follicles ( 100 to 300 μm in diameter ) filled with colloid.

 The colloid is mainly composed of glycoprotein called thyroglobulin, which contains

thyroid hormones (TH).

 The anterior pituitary gland releases thyroid-stimulating hormone (TSH)  control

secretion of thyroid gland  two thyroid hormones are released
 Thyroxine (T4 )  93%, increase metabolic rate of body.
 Triiodothyronine (T3)  7%, same effects as T4, but stronger, shorter
effect time.

 Lack of TH  Decrease of metabolic rate to 40 - 50% below normal.

 Excessive TH  Increase of metabolic rate to 60 - 100% above normal.
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Utilization of Iodine

 Iodine ( 1mg/week ) in the form of iodides is required to produce normal quantities of

thyroid hormones.

 The iodides ingested orally are absorbed from gastrointestine tract into blood.

 The thyroid cell membrane has pump to actively transport the iodides from the blood into
thyroid cell (called iodide trapping). This makes the concentration of iodide inside of
thyroid cell 30 times higher than that in blood.

 20% of the iodides in blood are taken by thyroid gland and the rest of them are quickly
excreted by kidney.

 With the help of enzyme peroxidase the iodide ion is firstly oxidized to iodine ( I0 ).
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Objective 77.2 Identify thyroglobulin, its functional role, and the chemistry of T4 and T3
formation.

Thyroglobulin and Chemistry of Thyroid Hormones Formation

 A large glycoprotein molecule called thyroglobulin (contains TH) can be synthesized by

Golgi apparatus in the thyroid cell. Thyroxine (T4 ) and triiodothyronine (T3 ) are formed
and remain part of thyroglobulin molecule by iodinase.
 Each thyroglobulin contains 70 tyrosine amino acids.
 If the peroxidase system is blocked the formation of TH will be ceased.

 The thyroglobulin that contains TH will secrete into follicular colloid (follicles) to be
stored.

 The stored TH is normally sufficient to supply for the body for 2 to 3 months. Therefore,
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if the synthesis of TH ceases, the effects of deficiency will not be observed for several
months.

Trapping mechanism:

- Thyroglobulin goes into venules then into circulation

- To cross into cell: phagocytosis of cells by pseudopods  membrane closes in on
thyroglobulin to be absorbed into cell
- Once inside cell: TH released from thyroglobulin by action of proteinase
- Other components reabsorbed by follicle cell after  if cannot recycle extra components
= hypothyroidism
-
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Objective 77.3 Identify the characteristics of T4 and T3 release from thyroglobulin and their
transport to tissues.

Release of Thyroxine and Triiodothyronine from Thyroid Gland

 The surface of the thyroid cell send out pseudopod extensions that close around small
portions of colloid

 Lysosomes in the cell fuse with these vesicles to form digestive enzymes from lysosomes
mixed with colloid.

 The proteinases ( one of the enzymes ) digest the thyroglobulin molecules and release
thyroxine and triiodothyronine from thyroglobulin.

 T4 and T3 diffuse through thyroid cell into blood.

 Iodines become available again for recycling in gland cell to produce additional TH. Lack
of deiodinase enzyme will cause iodine deficiency because of the failure of this recycling
process.

 93% of TH released from gland is thyroxine and 7% of TH is triiodothyronine. In few

days most of the thyroxine is slowly deiodinated to become triiodothyronine ( removal of
one iodines from T4 ). Therefore, the hormone finally used by the tissues is mainly T3.

Transport of Thyroxine and Triiodothyronine to the Tissues

 Once the T4 and T3 enter in the blood, T4 and T3 (both hydrophobic) combine
immediately with several plasma-binding proteins including:
 Thyroxine-binding globulin ( mainly )
 Thyroxine-binding prealbumin ( less so )
 Albumin ( less so )  #1 protein in blood, helps transport of hydrophobic
compounds

 Half of T3 in blood is released to tissue cells in one day.

 Half of T4 is released in 6 days, because the plasma-binding protein has higher affinity
for T4.  longer half life & more active

 When the T4 and T3 enter tissue cells, they bind with intracellular proteins ( more strongly
bind with T4 ) and will be used by the tissue cell slowly over days or weeks.
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Latency and Duration of Action of Thyroid Hormones

 After injection of a large quantity of thyroxine into a human being, there is a long latent
period of 2 - 3 days ( no effect on metabolic rate ) before the T4 activity is observed.

 Once the T4 activity does begin, it increases progressively and reaches a maximum in 10 -
12 days. Then, it decreases with a half-life of about 15 days ( even as long as 2 months ).

 The action of T3 occurs 4 times as faster as those of T 4. The latent period is 6 - 12 hours
and the maximum cellular activity occur within 2 to 3 days.

 Because the plasma-binding protein has higher affinity for thyroxine, release of T 4 is
slower than that of T3.

Objective 77.4 Identify the actions and underlying mechanisms of the effects of thyroid
hormones on metabolic rates and specific dietary substances.

Function of Thyroid Hormones in the Tissue

 The general effect of thyroid hormone is to cause nuclear transcription of genes for
synthesizing large number of substances in the cells including:
 protein enzymes
 structural proteins
 transport proteins
 other substances

 Before the hormone acting on the genes, almost all the thyroxine is deiodinated to
triiodothyronine, then T3 bind with intracellular thyroid hormone receptors in the nucleus
( 90% for T3 , 10% for T4 ).

 The thyroid hormone receptors are attached to the DNA genetic strands.

 Once attached, the receptors become activated and initiate the transcription process 
Different types of messenger RNA are formed  Many new types of proteins are
formed by RNA translation on cytoplasmic ribosomes.

 Most of actions of thyroid hormone result from the enzymatic and other functions of
these new proteins.
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Objective 76.5 Identify the major physiological effects of thyroid hormone on general body
mechanisms.

Effect of Thyroid Hormones on Metabolic Activities

 Increase basal metabolic rate to 60 - 100% above normal.

 Accelerate the rate of utilization of foods for energy.
 Increase the rate of protein synthesis.
 Increase the rate of protein catabolism.
 Accelerate the growth rate of young people.
 Excite mental process.
 Increase the activity of most of the endocrine glands.

Effect of Thyroid Hormones on Mitochondria

 Increase the number and size of mitochondria.

 Increase the total membrane surface area of mitochondria  increase the formation
rate of ATP to energize cellular function.
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Effect of TH in Increasing Active Transport of Ions Through Cell Membrane

 TH can activate enzymes: Na-ATPase and K-ATPase,  increase the transport rate
of Na and K ions through cell membrane of tissues.

 Increase heat production in the body because

 active transport uses energy from ATP.
 TH also causes most cell membrane to become leaky to Na ions, which activates
the Na pump.

Effect of TH on Growth

 Lack of TH ( hypothyroid ) causes growth rate retarded for growing children.

 Excessive TH ( hyperthyroid ) causes rapid skeletal growth, early bone mature for
children.

Effect of TH on Specific Bodily Mechanisms

 On Carbohydrate Metabolism

 Stimulates all aspects of carbohydrate metabolism because of the increase of metabolic

enzymes. The effects include as follows.
 Increase absorption rate of glucose from gastrointestinal tract.
 Increase uptake rate of glucose by cells.
 Enhance glycolysis ( use of glucose for energy through anaerobic conversion of
glucose to lactic acid ).
 Enhance gluconeogenesis ( formation of glycogen from protein or fat ).
 Increase insulin secretion.

 On Fat Metabolism
 Increase fat metabolism.
 Mobilize fatty acids from fat tissues  increase free fatty acids
concentration in the plasma.
 Accelerate oxidation of free fatty acids by cells.
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 On Plasma and Liver Fat

 Decrease the quantity of cholesterol, phospholipids and triglyceride in plasma

even though it increases the free fatty acids. ( because TH increases the secretion
rate of cholesterol in the bile and consequent loss of cholesterol in the feces ).
 Lack of TH ( hypothyroidism ) causes excessive deposition of fat in liver.
 Prolonged hypothyroidism cause severe arteriosclerosis ( hardening of arteries ).

 On Vitamin Metabolism

 Vitamins are essential parts of enzymes or coenzymes. TH increases quantities of

enzymes, in turn, increase the need for vitamins.
 Increase of TH can cause a relative vitamin deficiency unless the increased
quantities of vitamins are available.

 On Basal Metabolism Rate

 Increase the basal metabolism rate to 60 to 100% above normal. If there is no TH

produced the basal metabolism rate reduces to half normal.

 On Body Weight

 Decrease body weight when TH is greatly increased ( but the increase of TH also
increase the appetite, it may balance the change of weight )

 On Cardiovascular System
 Increase blood flow and cardiac output because of the rapid utilization of
oxygen for increased metabolism.
 Increase heart rate because of the increase of cardiac output.
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 Increase the strength of the heart beat ( because of increased enzymatic activity ).
 Increase slightly blood volume because of vasodilation which allows increased
quantities of blood to collect in the circulatory system.
 Increase arterial pressure because of the increased blood flow.

 On Respiration

 Increase rate and depth of respiration because of increased rate of metabolism

 increased use of oxygen.

 On Gastrointestine Tract
 Increase secretion rate of digestive juice and motility of gastrointestinal tract.
 Excessive TH causes diarrhea and lack of TH causes constipation.

 On Central Nervous System

 Increase brain activity ( cerebration ).
 Excessive TH ( hyperthyroid ) cause anxiety, extreme worry and paranoia.

 On Muscle Function

 Muscle becomes weakened with excessive TH, because of excessive protein

catabolism.
 Lack of TH causes muscle to become sluggish and slow relaxation after a
contraction.
 Hyperthyroid causes muscle tremor because of increased reactivity of neuronal
synapses in the areas of the spinal cord that control muscle tone.
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Objective 77.6 Identify the regulatory mechanisms controlling thyroid hormone secretion and
the characteristics, mechanisms of secretion, and target actions of thyrotropin.

 The regulatory mechanism for controlling TH secretion is as follows.

 A hypothalamic hormone called thyrotropin-releasing hormone (TRH) is

secreted by nerve endings in the median eminence of the hypothalamus,
 TRH is transported to anterior pituitary through the hypothalamic-hypophysial
portal vessel
 TRH bind with TRH receptors on the pituitary cell membrane,
 Activates phospholipase second messenger system to produce
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phospholipase C and other second messenger products ( Ca ions, diacyl glycerol ),

 Cause thyrotropin secreting cell in the anterior pituitary to produce and release
thyroid-stimulating hormone (TSH) ( called thyrotropin ),
 TSH bind with TSH receptor on basal membrane surface of thyroid cell,
 Cause increased release of T4 and T3 into blood by increasing the following:
 Proteolysis of thyroglobulin
 Activity of iodide pump
 Iodination of tyrosine for forming TH
 Size and number of thyroid cells

 The secretion of TSH from anterior pituitary is controlled by feedback regulation

mechanism as follows.

 The concentration level of TH in the body fluid will feedback directly to anterior
pituitary.
 Increased TH will directly affect anterior pituitary to cause decrease of
secretion of TSH  decrease the release of TH  eventually
to maintain a constant concentration of free TH in the circulatory body
fluids.

 Another possible feedback ( indirectly ) is:

 Increased TH  increased metabolic function  increased
heat production  increased body temperature  affect on
hypothalamus, which is the body temperature controlling centre 
cause decreased release of TRH from hypothalamus  decreased
release of TSH from anterior pituitary  decreased release of TH
from thyroid cells.
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Objective 77.7 Identify the principal causes, symptoms, and consequences of hyperthyroidism.

Diseases of Thyroid

Hyperthyroidism ( Toxic Goiter, Thyrotoxicosis, Grave's Disease )

 In patients with hyperthyroidism the thyroid gland is increased to 2 to 3 times normal

size.
 Number of thyroid cell is increased even several times more than the size increased.
 Secretion rate increased several fold ( 5 - 15 times normal ).

 Principal Causes

(1) Caused by autoimmunity. Presumably, in the history of the person an excessive

amount of thyroid cell antigens has been released from the thyroid cells. This
causes the formation of antibodies against thyroid gland itself.

 The antibody is called thyroid-stimulating immunoglobulin (TSI). It can

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bind with the same membrane receptors for binding TSH  activate
cAMP second messenger system.

 TSI has much prolonged stimulating effect on the thyroid gland ( 12 hours
for TSI in contrast to 1 hour for TSH ).

 The high level of TH secretion caused by TSI will suppress the production
of TSH in anterior pituitary.

(2) Thyroid adenoma ( tumor ) developed in the thyroid tissue can also cause over-
secretion of TH. But the production of TSH will be depressed.

 Symptoms and Consequences of Hyperthyroidism

 High state of excitability

 Intolerance to heat
 Increased sweating
 Mild to extreme weight loss
 Different degrees of diarrhea
 Muscle weakness
 Nervousness
 Exophthalmos ( protrusion of eyeballs )
 Extreme fatigue
 Inability to sleep
 Tremor of hands
 Other psychic disorders
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Objective 77.8 Identify the principal causes, symptoms, and consequences of hypothyroidism

Hypothyroidism

 Principal Causes

(1) In most cases, it also caused by autoimmunity against the thyroid gland. But the
immunity destroyed the gland rather than stimulates it.

 Patient first has thyroid inflammation ( thyroiditis ),  progressive

deterioration  finally, cause fibrosis of gland  secretion of TH is
diminished or stopped.

(2) Insufficient intake of iodine cause development of extremely large thyroid gland ( called
endemic goiters ). Size is increased to 10 - 20 times normal.

 Lack of iodine prevents production of T4 and T3 , but does not stop the production
of thyroglobulin  less or no TH is available to inhibit the production of
TSH by the anterior pituitary  cause pituitary releasing excessive TSH
 thyroid cells secrete large amounts of thyroglobulin into the follicles 
glands grow larger and larger  but the thyroglobulin still contains less or
no T4 and T3  TSH production cannot be suppressed  cause
worse process.

(3) Enlarged thyroid gland can occur in patients who do not have iodine deficiency ( called "
idiopathic nontoxic colloid goiter " ). The exact cause is unknown yet. The possible
explanations are as follows.

 Mild thyroiditis ( inflammed ) causes slight hypothyroidism  increase

secretion of TSH  progressive growth of noninflammed part of gland.

 Abnormality of enzyme system for production of TH such as

 Deficient iodide-trapping mechanism ( not enough iodines pumped in ),

 Deficient peroxidase system  iodides are not oxidized to iodine,

 Deficient coupling of iodinated tyrosine in thyroglobulin molecule 

TH cannot be formed,

 Deficiency of deiodinase enzyme  iodine cannot be recovered from

iodinated tyrosines  deficiency of iodine.

 Symptoms and Consequences of Hypothyroidism

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 Fatigue
 Extreme somnolence
 Extreme muscular sluggishness
 Slow heart rate
 Decreased blood volume and cardiac output
 Increased weight
 Constipation
 Mental sluggishness
 Depressed growth of hair
 Scaling of skin
 Edematous appearance ( myxedema )
 Increase of blood cholesterol  arteriosclerosis