CHAPTER NO 77:

THYROID METABOLIC HORMONES;

SYNTHESIS AND SECRETION OF THE THYROID METABOLIC HORMONES:T3 IS MORE

POTENT THAN T4 BUT IT IS FOR MUCH SHORTER PERIOD IN BLOOD THAN T4.

PHYSIOLOGIC ANATOMY OF THYROID GLAND FROM HISTO

IODINE IS REQUIRED FOR THYROXINE FORMATION:

50mg/year is required of iodine

Iodide pump- the sodium iodide symporter (iodide trapping):

The basal membrane of the thyroid cell has the specific ability to pump the iodide actively
to the interior of the cell. This pumping is achieved by the action of a sodium-iodide
symporter, which co-transports one iodide ion along with two sodium ions across the
basolateral (plasma) membrane into the cell. The energy for transporting iodide against a
concentration gradient comes from the sodium-potassium adenosine triphosphatase
(Na+-K+ ATPase) pump, which pumps sodium out of the cell.

This process of concentrating the iodide in the cell is called iodide trapping. In a normal
gland, the iodide pump concentrates the iodide to about 30 times its concentration in the
blood. This rate of trapping is influenced by the concentration of the TSH, Iodide is
transported out of the thyroid cells across the apical membrane into the follicle by a
chlorideiodide ion counter-transporter molecule called pendrin.

Oxidation of the iodide ion:

conversion of iodide ions to an oxidized form of iodine, either nascent iodine (I0) or I3 −,
which is then capable of combining directly with the amino acid tyrosine. This oxidation of
iodine is promoted by the enzyme peroxidase and its accompanying hydrogen peroxide.
Iodination of the tyrosine and TH formation – organification of thyroglobulin:

The binding of iodine with the thyroglobulin molecule is called organification of the
thyroglobulin, thyroglobulin is released from the Golgi apparatus or as it is secreted
through the apical cell membrane into the follicle, iodine binds with about one sixth of the
tyrosine amino acids within the thyroglobulin molecule.

Tyrosine is first iodized to monoiodotyrosine and then to diiodotyrosine, more of the

iodotyrosine residues become coupled with one another. The major hormonal product of
the coupling reaction is the molecule thyroxine (T4), which is formed when two molecules
of diiodotyrosine are joined together; the thyroxine then remains part of the thyroglobulin
molecule. Or one molecule of monoiodotyrosine couples with one molecule of
diiodotyrosine to form triiodothyronine (T3), which represents about one-fifteenth of the
final hormones. Small amounts of reverse T3 (RT3) are formed by coupling of
diiodotyrosine with monoiodotyrosine, but RT3 does not appear to be of functional
significance in humans.

Storage of thyroglobulin in the colloid of the follicle, where they are attached to the
thyroglobulin, the amount stored is sufficient for 2-3 months hence when synthesis of
thyroid hormone ceases, the physiological effects of deficiency are not observed for
several months.

RELEASE OF THE THYROXINE AND T3 FROM THE THYROID GLAND:

thyroxine and triiodothyronine are cleaved from the thyroglobulin molecule, and then these
free hormones are released. This process occurs as follows: The apical surface of thyroid
cells sends out pseudopod extensions that close around small portions of the colloid to
form pinocytic vesicles that enter the apex of the thyroid cell. Then lysosomes in the cell
cytoplasm immediately fuse with these vesicles to form digestive vesicles containing
digestive enzymes from the lysosomes mixed with the colloid. Multiple proteases among
the enzymes digest the thyroglobulin molecules and release thyroxine and triiodothyronine
in free form, which then diffuse through the base of the thyroid cell into the surrounding
capillaries.

Some of the thyroglobulin in the colloid enters the thyroid cell by endocytosis after binding
to megalin, a protein located on the lumen membrane of the cells. The megalin-
thyroglobulin complex is then carried across the cell by transcytosis to the basolateral
membrane, where a portion of the megalin remains bound to thyroglobulin and is released
into the capillary blood. About three-quarters of the iodinated tyrosine in the thyroglobulin
never become thyroid hormones but remain monoiodotyrosine and diiodotyrosine. During
the digestion of the thyroglobulin molecule to cause release of thyroxine and
triiodothyronine, these iodinated tyrosines also are freed from the thyroglobulin
molecules. However, they are not secreted into the blood. Instead, their iodine is cleaved
from them by a deiodinase enzyme that makes virtually all this iodine available again for
recycling within the gland.

Daily rate of secretion of T3/T4 35 μg of triiodothyronine per day.

TRANSPORT OF T3/T4 BY PROTEINS: mainly with thyroxine binding globulin and much less
so with thyroxine-binding prealbumin and albumin.

THYROXINE AND T3 ARE RELEASED SLOWLY TO TISSUE because of high affinity of the
plasma binding proteins for the thyroid hormones, these substances—in particular,
thyroxine—are released to the tissue cells slowly. Upon entering the tissue cells, both
thyroxine and triiodothyronine again bind with intracellular proteins, with the thyroxine
binding more strongly than the triiodothyronine.

THYROID HORMONE HAVE SLOW ONSET AND LONG DURATION OF ACTION: long patent
period is caused by their binding with proteins both in the plasma and in the tissue cells,
followed by their slow release.

PHYSIOLOGICAL FUCTION OF THE THYROID HORMONES;

THYROID HORMONES INCREASE TRANSCRIPTION OF MANY GENES:

• Most of the t4 secreted is converted into t3: Intracellular thyroid hormone receptors
have a high affinity for triiodothyronine. Consequently, more than 90% of the thyroid
hormone that binds with the receptors is triiodothyronine.
• Thyroid hormones activate nuclear transporter: Thyroid hormone receptors are
either attached to the DNA genetic strands or located in proximity to them. The
thyroid hormone receptor usually forms a heterodimer with retinoid X receptor
 (RXR) at specific thyroid hormone response elements on the DNA. After binding with
thyroid hormone, the receptors become activated and initiate the transcription
process. Large numbers of different types of messenger RNA are then formed,
followed within another few minutes or hours by RNA translation on the
cytoplasmic ribosomes to form hundreds of new intracellular proteins.

•
• Non genomic functions of the thyroid hormones: The site of nongenomic thyroid
hormone action appears to be the plasma membrane, cytoplasm, and perhaps
some cell organelles such as mitochondria. Nongenomic actions of thyroid
hormone include regulation of ion channels and oxidative phosphorylation and
appear to involve activation of intracellular secondary messengers such as cyclic
adenosine monophosphate (cAMP) or protein kinase signaling cascades.
• Thyroid hormones increases cellular activity: e rate of protein synthesis is
increased, at the same time the rate of protein catabolism is also increased.
• Thyroid hormone increases the size and surface are of the Mt hence increasing
production of the ATP, to energize cellular functions
• Thyroid hormones increase active transport of ions through CM: mainly increasing
activity of Na+-K+ ATPase. This increased activity in turn increases the rate of
transport of sodium and potassium ions through the cell membranes of some
tissues. Because this process uses energy and increases the amount of heat
produced in the body, it has been suggested that this might be one of the
mechanisms by which thyroid hormone increases the body’s metabolic rate.
• EFFECT OF THYROID HORMONE ON THE GROWTH: HYPOTHYROIDISM; RATE OF
GROWTH RETARD, IN HYPERTHY; EXCESSIVE GROWTH. An important effect of
thyroid hormone is to promote growth and development of the brain during fetal life
and for the first few years of postnatal life
• EFFECTS OF THE THYROID HORMONE ON THE SPECIFIC BODY FUNCTIONS:
1) STIMULATION OF CARBOHYDRATE METABOLISM; rapid glucose uptake by cells,
enhanced glycolysis, enhanced gluconeogenesis, increased rate of absorption
from the gastrointestinal tract, and even increased insulin secretion with its
resultant secondary effects on carbohydrate metabolism.
2) Stimulation of fat metabolism; lipids are mobilized rapidly from the fat tissue,
which decreases fat stores of the body
3) Effect of the plasma and liver fats: Increased thyroid hormone decreases the
concentrations of cholesterol, phospholipids, and triglycerides in the plasma,
even though it increases the free fatty acids.
One of the mechanisms by which thyroid hormone decreases plasma
cholesterol concentration is to increase significantly cholesterol secretion in the
bile and consequent loss in the feces. A possible mechanism for the increased
cholesterol secretion is that thyroid hormone induces increased numbers of
low-density lipoprotein receptors on the liver cells, leading to rapid removal of
low-density lipoproteins from the plasma by the liver and subsequent secretion
of cholesterol in these lipoproteins by the liver cells
4) Increased requirement for vitamins, because the hormone increase the activity
of enzymes and these enzymes have coenzymes that are vitamins.
5) Increased basal metabolic rate
6) Decreased body weight
7) Increased blood flow and cardiac output: . Increased metabolism in the tissues
causes more rapid utilization of oxygen than normal and increased release of
metabolic end products from the tissues. These effects cause vasodilation in
most body tissues, thus increasing blood flow. The rate of blood flow in the skin
especially increases because of the increased need for heat elimination from
the body. As a consequence of the increased blood flow, cardiac output.
8) Increased heart rate: thyroid hormone have direct effect on the excitability of the
heart which increases the heart rate.
9) Increased heart strength; However, when thyroid hormone is increased
markedly, heart muscle strength becomes depressed because of long-term
excessive protein catabolism. Indeed, some severely thyrotoxic patients die of
cardiac decompensation secondary to myocardial failure.
10) Normal arterial pressure
11) Increased respiration due to increased o2 consumption and production of co2.
12) Increased GIT MOTILITY: In addition to increased appetite and food intake,
which has been discussed, thyroid hormone increases secretion of digestive
juices and motility of the gastrointestinal tract. Hyperthyroidism therefore often
results in diarrhea.
13) Excitatory effects on CNS: WHEN LEVEL OF TH IS INCREASED, y psychoneurotic
tendencies, such as anxiety complexes, extreme worry, and paranoia.
14) Effect on the Function of the Muscles. A slight increase in thyroid hormone
usually makes the muscles react with vigor but, with excessive thyroid hormone,
the muscles become weakened because of excess protein catabolism.
Conversely, lack of thyroid hormone causes the muscles to become sluggish,
and they relax slowly after a contraction.
15) Muscle Tremor. One of the most characteristic signs of hyperthyroidism is a fine
muscle tremor. This symptom is not the coarse tremor that occurs in
Parkinson’s disease
16) Effect on Sleep. Because of the exhausting effect of thyroid hormone on the
musculature and on the central nervous system, persons with hyperthyroidism
often have a feeling of constant tiredness,
17) Effect on other endocrine gland: due to increase glucose metabolism increase
the insulin, also increase s many metabolic activities related to bone formation
and, as a consequence, increases the need for parathyroid hormone
18) Effect of TH on sexual function: In men, lack of thyroid hormone is likely to cause
loss of libido; a great excess of the hormone, however, sometimes causes
impotence. In women, lack of thyroid hormone often causes menorrhagia and
polymenorrhea, Hypothyroidism in women, as in men, is likely to result in a
greatly decreased libido.

REGULATION OF TH SECRETION:

TSH FROM THE ANTERIOR PITUITARY: / thyrotropin

increases secretion of thyroxine and triiodothyronine by the thyroid gland. It has the
following specific effects on the thyroid gland:

1. Increased proteolysis of thyroglobulin that has already been stored in the

follicles.

2. Increased activity of the iodide pump, which increases the rate of “iodide
trapping”.

3. Increased iodination of tyrosine to form the thyroid hormones

4. Increased size and increased secretory activity of the thyroid cells

5. Increased number of thyroid cells plus a change from cuboidal to columnar cells.

First two steps with in 30minutes, other 3 with in days and hours.
Cyclic Adenosine Monophosphate Mediates the Stimulatory Effect of TSH, The first event
in this activation is binding of TSH with specific TSH receptors on the basal membrane
surfaces of the thyroid cell. This binding then activates adenylyl cyclase in the membrane,
which increases formation of cAMP inside the cell. Finally, cAMP acts as a second
messenger to activate protein kinase, which causes multiple phosphorylations throughout
the cell. The result is both an immediate increase in secretion of thyroid hormones and
prolonged growth of the thyroid glandular tissue.

ANT PITUITARY SECRETION OF TSH IS REGULATED BY THYROTROPIN RELEASING

HORMONE FROM HYPOTHALAMUS:

thyrotropin-releasing hormone (TRH), which is synthesized by neurons in the

paraventricular nucleus (PVN) of the hypothalamus. The molecular mechanism by which
TRH causes TSH secreting cells of the anterior pituitary to produce TSH is first to bind with
TRH receptors in the pituitary cell membrane. This binding in turn activates the
phospholipase second messenger system inside the pituitary cells to produce large
amounts of phospholipase C, followed by a cascade of other second messengers,
including calcium ions and diacyl glycerol, which eventually leads to TSH release.

Effects of cold ; increases the TRH secretion.

Effect of other neurogenic stimuli on release of TRH and TSH: TRH neurons in the PVN
receive input from leptin responsive neurons in the arcuate nucleus of the hypothalamus
that regulate energy balance—the neuropeptide Y (NPY)/agouti-related protein (AGRP) and
pro-opiomelanocortin (POMC) neurons which were discussed in Chapter 72. Prolonged
fasting reduces plasma leptin levels which, in turn, decreases POMC activity and
increases NPY/AGRP neuronal activity. Decreased levels of leptin may also directly inhibit
TRH neurons. Together these effects reduce expression of TRH, TSH, and thyroid hormone
secretion, contributing to reduced metabolic rate and conservation of energy when food
supplies are scarce.

Various emotional reactions can also affect the output of TRH and TSH and therefore
indirectly affect the secretion of thyroid hormones. Excitement and anxiety— conditions
that greatly stimulate the sympathetic nervous system—cause an acute decrease in
secretion of TSH, perhaps because these states increase the metabolic rate and body heat
and therefore exert an inverse effect on the heat control center.

FEEDBACK EFFECT OF THYROID HORMONE TO DECREASE TSH:

increased thyroid hormone inhibits anterior pituitary secretion of TSH mainly by a direct
effect on the anterior pituitary gland. However, there is also evidence for negative feedback
effects of thyroid hormone to inhibit thyrotropin releasing hormone by the hypothalamus

AMTITHYROID SIBSTANCE SUPPRESS THYROID SECRETION:

The best known antithyroid drugs are thiocyanate, propylthiouracil, and high
concentrations of inorganic iodides.

Thiocyanate Ions Decrease Iodide Trapping. The same active pump that transports iodide
ions into the thyroid cells can also pump thiocyanate ions, perchlorate ions, and nitrate
ions. Administration of thiocyanate in a high enough concentration can cause competitive
inhibition of iodide transport. The decreased availability of iodide in the glandular cells
does not stop the formation of thyroglobulin; it merely prevents the thyroglobulin that is
formed from becoming iodinated and therefore from forming thyroid hormones. This
deficiency of thyroid hormones in turn leads to increased secretion of TSH by the anterior
pituitary gland, which causes overgrowth of the thyroid gland even though the gland still
does not form adequate quantities of thyroid hormones. Leading to goiter formation.

Propylthiouracil Decreases Thyroid Hormone Formation. Propylthiouracil prevents

formation of thyroid hormone from iodides and tyrosine. The mechanism of this action is
partly to block the peroxidase enzyme that is required for iodination of tyrosine and partly
to block the coupling of two iodinated tyrosines, The absence of thyroxine and
triiodothyronine in the thyroglobulin can lead to tremendous feedback enhancement of
TSH secretion by the anterior pituitary gland, thus promoting growth of the glandular tissue
and forming a goiter.

Iodides in High Concentrations Decrease Thyroid Activity and Thyroid Gland Size. , the
normal endocytosis of colloid from the follicles by the thyroid glandular cells is paralyzed
by the high iodide concentrations. Because this is the first step in release of thyroid
hormones from the storage colloid, there is almost immediate shutdown of thyroid
hormone secretion into the blood. Because iodides in high concentrations decrease all
phases of thyroid activity, they slightly decrease the size of the thyroid gland and especially
decrease its blood supply.

DISEASES OF THYROID GLAND:

HYPERTHYROIDISM: hyperplasia of the thyroid gland.

CAUSES: toxic goiter, Thyrotoxicosis, Graves’ Disease):

Graves’ disease, the most common form of hyperthyroidism, is an autoimmune disease in

which antibodies called thyroid-stimulating immunoglobulins (TSIs) form against the TSH
receptor in the thyroid gland. These antibodies bind with the same membrane receptors
that bind TSH and induce continual activation of the cAMP system of the cells, with
resultant development of hyperthyroidism. The TSI antibodies have a prolonged
stimulating effect on the thyroid gland, lasting for as long as 12 hours, in contrast to a little
over 1 hour for TSH. The high level of thyroid hormone secretion caused by TSI in turn
suppresses anterior pituitary TSH formation. Therefore, TSH concentrations are less than
normal.

THYROID ADENOMA; tumor ) that develops in the thyroid tissue and secretes large
quantities of thyroid hormone. This presentation is different from the more usual type of
hyperthyroidism in that it is usually not associated with evidence of any autoimmune
disease.

Symptoms of hyperthyroidism: (1) a high state of excitability, (2) intolerance to heat, (3)
increased sweating, (4) mild to extreme weight loss (sometimes as much as 100 pounds),
(5) varying degrees of diarrhea, (6) muscle weakness, (7) nervousness or other psychic
disorders, (8) extreme fatigue but inability to sleep, and (9) tremor of the hands.

EXOPTHALMOS IN HYPERTHYROIDISM: degree of protrusion of the eyeballs;

AUTOIMMUNE DISEASE; the eyeball protrusion stretches the optic nerve enough to
damage vision. Much more often, the eyes are damaged because the eyelids do not close
completely when the person blinks or is asleep. As a result, the epithelial surfaces of the
eyes become dry and irritated and often infected, resulting in ulceration of the cornea. The
cause of the protruding eyes is edematous swelling of the retro-orbital tissues and
degenerative changes in the extraocular muscles.

DIAGNOSTIC TESTS FOR HYPERTHYROIDISM: direct measurement of the concentration of

“free” thyroxine (and sometimes triiodothyronine) in the plasma, using appropriate
immunoassay procedures. The following tests also are sometimes used: 1. The basal
metabolic rate is usually increased to +30 to +60 in severe hyperthyroidism.
2. The concentration of TSH in the plasma is measured by immunoassay.

3. almost no plasma TSH.

4. The concentration of TSI is measured by immunoassay.

TREATMENT OF THE HPT:

surgical removal of most of the thyroid gland. In general, it is desirable to prepare the
patient for surgical removal of the gland before the operation by administering
propylthiouracil, usually for several weeks, until the basal metabolic rate of the patient has
returned to normal. Then, administration of high concentrations of iodides for 1 to 2 weeks
immediately before operation causes the gland to recede in size and its blood supply to
diminish.

Treatment of the Hyperplastic Thyroid Gland With Radioactive Iodine. Eighty to 90% of an
injected dose of iodide is absorbed by the hyperplastic, toxic thyroid gland within 1 day
after injection. If this injected iodine is radioactive, it can destroy most of the secretory
cells of the thyroid gland. Usually 5 millicuries of radioactive iodine is given to the patient,
whose condition is reassessed several weeks later. If the patient is still in a hyperthyroid
state, additional doses are administered until normal thyroid status is reached.

HYPOTHYROIDISM:
Hypothyroidism, like hyperthyroidism, is often initiated by autoimmunity against the thyroid gland
(Hashimoto’s disease), but in this case the autoimmunity destroys the gland rather than stimulates it. The
thyroid glands of most of these patients first demonstrate autoimmune “thyroiditis,” which means thyroid
inflammation.

Thyroiditis causes progressive deterioration and finally fibrosis of the gland, with resultant diminished or
absent secretion of thyroid hormone. Several other types of hypothyroidism also occur that are often
associated with development of enlarged thyroid glands, called thyroid goiter, endemic colloid goiter caused
by dietry iodide deficiency; : Lack of iodine prevents production of both thyroxine and triiodothyronine. As a
result, no hormone is available to inhibit production of TSH by the anterior pituitary, which causes the
pituitary to secrete excessively large quantities of TSH. The TSH then stimulates the thyroid cells to secrete
large amounts of thyroglobulin colloid into the follicles, and the gland grows larger and larger. However,
because of lack of iodine, thyroxine and triiodothyronine production does not occur in the thyroglobulin
molecule and therefore does not cause the normal suppression of TSH production by the anterior pituitary.
The follicles greatly enlarge, and the thyroid gland may increase.

Idiopathic non toxic colloid goiter: occur in people who do not have iodine deficiency, cause: thyroiditis,
thyroiditis causes slight hypothyroidism, which then leads to increased TSH secretion and progressive
growth of the noninflamed portions of the gland. This theory could explain why these glands are usually
nodular, with some portions of the gland growing while other portions are being destroyed by thyroiditis. In
some persons with colloid goiter, the thyroid gland has an abnormality of the enzyme system required for
formation of thyroid hormones. The following abnormalities are often encountered:
1) A deficient iodide-trapping mechanism. 2) A deficient peroxidase system,

3) Deficient coupling of iodinated tyrosines in the thyroglobulin molecule.

4) Deficiency of the deiodinase enzyme, which prevents recovery of iodine from the
iodinated tyrosines.

Physiological Characteristics of Hypothyroidism. Tiredness, musclar sluggishness,

decreased cardiac output and blood volume, increased body weight, frog like husky voice,
myxedema.

Myxedema; edematous appearance throughout the body. bagginess under the eyes and
swelling of the face. In this condition, for reasons that are not fully explained, greatly
increased quantities of hyaluronic acid and chondroitin sulfate bound with protein form
excessive tissue gel in the interstitial spaces, which causes the total quantity of interstitial
fluid to increase. Because of the gel nature of the excess fluid, it is mainly immobile and the edema is the
nonpitting type.

Atherosclerosis in Hypothyroidism. lack of thyroid hormone increases the quantity of blood cholesterol
because of altered fat and cholesterol metabolism and diminished liver excretion of cholesterol in the bile.
The increase in blood cholesterol is often associated with increased atherosclerosis.

Diagnostic tests for hypothyroidism: The free thyroxine in the blood is low. The basal metabolic rate in
myxedema is reduced by 30% to 50%. In addition, the secretion of TSH by the anterior pituitary when a test
dose of TRH is administered is usually greatly increased.;

Treatment: a daily oral ingestion of one or more tablets containing thyroxine.

Cretinism; Cretinism is caused by extreme hypothyroidism during fetal life, infancy, or childhood. This
condition is characterized especially by failure of body growth and by mental retardation

. It results from congenital lack of a thyroid gland (congenital cretinism), because of a genetic defect of the
gland, or from a lack of iodine in the diet (endemic cretinism). A neonate without a thyroid gland may have a
normal appearance and function because she or he was supplied with some (but usually not enough) thyroid
hormone by the mother while in utero. A few weeks after birth, however, the neonate’s movements become
sluggish

Treatment of the neonate with cretinism at any time with adequate iodine or thyroxine usually causes normal
return of physical growth, but unless the cretinism is treated within a few weeks after birth. This state results
from retardation of the growth, branching, and myelination of the neuronal cells of the central nervous
system. the soft tissues are likely to enlarge excessively, giving the child with cretinism an obese, stocky, and
short appearance. Occasionally the tongue becomes so large in relation to the skeletal growth that it
obstructs swallowing and breathing, inducing a characteristic guttural breathing.