Physiology for Medical Students

Endocrine 4

Fatima Daoud. MD. PhD.

Thyroid Metabolic
Hormones

CHAPTER 77 , 14th edition

Thyroid gland
**The thyroid gland, located immediately below
the larynx on each side of and anterior to the
trachea.
** is one of the largest of the endocrine glands,
normally weighing 15 to 20 grams in adults. The
Thyroid gland
v Thyroid follicles produce
thyroid hormones
v Parafollicular cells or C cells
produce calcitonin
Synthesis and Secretion
of the Thyroid Metabolic
Hormones
**about 93% of the metabolically active hormones secreted by the
thyroid gland is thyroxine and 7% is triiodothyronine. However,
almost all the thyroxine is eventually converted to triiodothyronine
in the tissues, so both are functionally important.
** The functions of these two hormones are qualitatively the same,
but they differ in rapidity and intensity of action.
**Triiodothyronine is about four times as potent as thyroxine, but
it is present in the blood in much smaller quantities and persists for
a much shorter time compared with thyroxine.
ach molecule of thyroglobulin contains about 70
tyrosine amino acids, and they are the major
substrates that combine with iodine to form the
thyroid hormones. Thus, the thyroid hormones
form within the thyroglobulin molecule.
 Synthesis of the Thyroid Hormones
apical membrane
basal membrane

vFormation and secretion

of thyroglobulin. Follicle
(Influenced by TSH).
vIodide trapping
(influenced by TSH).
Blood
vOxidation of the iodide ion
(peroxidase)
**The first stage in the formation of thyroid hormones is transport of iodides from the blood into the thyroid
glandular cells and follicles. The basal membrane of the thyroid cell has the specific ability to pump the iodide
actively to the interior of the cell. This is achieved by the action of a sodium-iodide symporter (NIS), 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 ATPase
pump, which pumps sodium out of the cell, thereby establishing a low intracellular sodium concentration and a
gradient for facilitated diffusion of sodium into the cell. This process of concentrating the iodide in the cell is
called iodide trapping
**Iodide is transported out of the thyroid cells across the apical membrane into
the follicle by a chloride-iodide ion counter-transporter molecule called pendrin.
The thyroid epithelial cells also secrete into the follicle thyroglobulin that
contains tyrosine amino acids to which the iodide ions will bind.
** The rate of iodide trapping by the thyroid is influenced by several factors, the
most important being the concentration of TSH.
*’ The first essential step in the formation of the thyroid hormones is conversion
of the iodide ions to an oxidized form of iodine that is then capable of
combining directly with the amino acid tyrosine. This oxidation of iodine is
promoted by the enzyme peroxidase.
** When the peroxidase system is blocked or when it is hereditarily absent
from the cells, the rate of formation of thyroid hormones falls to zero.
 Synthesis of the Thyroid Hormones
apical membrane
basal membrane

vIodination of tyrosine and

Follicle
formation of the thyroid
hormones—“organification”
of thyroglobulin.
vCoupling DIT, MIT Blood
** The binding of iodine with the thyroglobulin molecule is called
organification of the thyroglobulin.
** Tyrosine is first iodized to monoiodotyrosine and then to
diiodotyrosine. Then, during the next few minutes, hours, and even days,
more and more of the iodotyrosine residues become coupled with one
another.
** The major hormonal product of the coupling reaction is the molecule
thyroxine (T 4 ), 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 (T 3 ),
which represents about one-fifteenth of the final hormones
Storage of Thyroglobulin.

• The thyroid gland is unusual among the endocrine glands in its ability
to store large amounts of hormone.
• Each thyroglobulin molecule contains up to 30 thyroxine molecules
and a few triiodothyronine molecules.
• This supply the body with its normal requirements of thyroid
hormones for 2 to 3 months. Therefore, when synthesis of thyroid
hormone ceases, the physiologic effects of deficiency are not
observed for several months.
Secretion of the Thyroid Hormones

vPinocytosis of
thyroglobulin
vProteases cleavage
vRecycling of MIT, DIT
(Deiodinase)
vSecretion of T3, T4 into
the blood
** 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. Thus, the thyroid hormones are
released into the blood.
**Iodine is cleaved from MIT and DIT by a
deiodinase enzyme that makes virtually all this
iodine available again for recycling within the gland
for forming additional thyroid hormones.
Congenital absence of this deiodinase enzyme may
cause iodine deficiency because of failure of this
recycling process.
Transport of Thyroxine and
Triiodothyronine to Tissues
v Upon entering the blood, more than 99% of the thyroxine and
triiodothyronine combines immediately with plasma proteins (
thyroxine-binding globulin).
vHalf the thyroxine in the blood is released to the tissue cells about
every 6 days. (T3 -- 1 day).
vUpon entering the tissue cells, both thyroxine and triiodothyronine
again bind with intracellular proteins. (again stored).
vAll the thyroxine is eventually converted to triiodothyronine in the
tissues.
Thyroid Hormones Have Slow Onset
and Long Duration of Action.
v long latent period before thyroxine
activity begins (2—3d).
v Activity increases progressively and
reaches a maximum in 10 to 12 days.
vT4 half-life (about 15 days).
vSome of the activity persists for as long
as 6 weeks to 2 months.
vThe actions of T3 occur about four
times as rapidly as those of thyroxine.
** Most of the latency and prolonged period of action of these
hormones are probably caused by their binding with proteins
both in the plasma and in the tissue cells, followed by their
slow release. However, we shall see in subsequent discussions
that part of the latent period also results from the manner in
which these hormones perform their functions in the cells
themselves.
Physiological Functions
of the Thyroid Hormones

CHAPTER 76
Hormones Increase the Transcription
of Large Numbers of Genes

• Thyroid hormone does not have any discrete

target organs. It affects virtually every tissue
in the body.
**The general effect of thyroid hormone is to activate nuclear
transcription of many genes. Therefore, in virtually all cells of the body,
great numbers of protein enzymes, structural proteins, transport
proteins, and other substances are synthesized. The net result is a
generalized increase in functional activity throughout the body.
** Most of the thyroxine secreted by the thyroid is converted to
triiodothyronine.
** more than 90% of the thyroid hormone that binds with the
receptors is triiodothyronine.
** Thyroid hormones also appear to have nongenomic cellular effects
that are independent of their effects on gene transcription
Thyroid Hormones Increase Cellular
Metabolic Activity
vIncrease the number and activity of
mitochondria (increased ATP
production).
vIncrease active transport of ions
through cell membranes Na-K-
ATPase.
v Increase the amount of heat.
The basal metabolic rate can increase to 60% to 100% above
normal when large quantities of thyroid hormones are
secreted.
** basal metabolic rate (BMR), the rate of energy expenditure
under standard or basal conditions (awake, at rest, and
fasting). When BMR increases, cellular metabolism of
carbohydrates, lipids, and proteins increases.
** The rate of utilization of foods for energy is greatly
accelerated.
** Although the rate of protein synthesis is increased, at the
same time the rate of protein catabolism is also increased.
** ** The mental processes are excited, and the activities of
most of the other endocrine glands are increased.
Metabolic Effect of Thyroid Hormones
vStimulation of carbohydrate metabolism
Thyroid hormone stimulates almost all aspects of carbohydrate
metabolism.
vStimulation of fat metabolism
• Essentially all aspects of fat metabolism are also enhanced.
• Decreases fat stores of the body.
• Increases free fatty acid concentration in the plasma.
• Decreases the concentrations of cholesterol, phospholipids, and
triglycerides in the plasma.
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.
Thyroid Hormones Effect on
Growth and the Nervous System
• Thyroid hormone not only stimulates GH secretion
and increases production of IGF-I by the liver
• Promotes the effects of GH and IGF-I on the
synthesis of new structural proteins and on bone
growth.
• Thyroid hormone plays a crucial role in
development of the nervous system in children.
• Thyroid hormone is also essential for normal CNS
activity in adults.
**nervous system: They promote synapse formation, myelin production, and
growth of dendrites.

**Thyroid-deficient children have stunted growth that can be reversed by

thyroid replacement therapy, but excess thyroid hormone does not produce
excessive growth.
** In children with hyperthyroidism, excessive skeletal growth often occurs,
causing the child to become considerably taller at an earlier age. However, the
bones also mature more rapidly and the epiphyses close at an early age, so the
duration of growth and the eventual height of the adult actually may be
shortened.
**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. If the fetus does not
secrete sufficient quantities of thyroid hormone, growth and
maturation of the brain both before birth and afterward are
greatly retarded and the brain remains smaller than normal.
Without specific thyroid therapy within days or weeks after
birth, the child without a thyroid gland will remain mentally
deficient throughout life
Sympathomimetic Effect

• Thyroid hormone increases target-cell

responsiveness to catecholamines.

• Thyroid hormone accomplishes this permissive

action by causing a proliferation of catecholamine
target-cell receptors.
Effect of Thyroid Hormones

vThyroid hormone increases heart rate and force of contraction, thus

increasing cardiac output.
vIncreased respiration.
vIncreased gastrointestinal motility.
vEffect on the function of the muscles ( vigorous, tremor).
vIncreases the rates of secretion of several other endocrine glands,
but it also increases the need of the tissues for the hormones.
(pancreases, ant. pituitry, parathyroid)
** CVS via both its direct effect on the heart, and through its effect
of increasing the heart’s responsiveness to catecholamines.
** 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.
 Actions of Thyroid Hormones
T4
5’/3’-deiodinase
T3

T3

NUCLEAR RECEPTOR
Transcription of DNA
GROWTH METABOLISM
Translation of mRNA
• Growth formation • Glucose absorption
• Bone formation Synthesis of new • Glycogenesis
CNS proteins CARDIOVASCULAR • Glycolysis
• Maturation of BMR • Cardiac Output • Gluconeogenesis
• Lipolysis;
CNS • O2 consumption • Heart Rate lipogenesis
• Heat production • Sweating Protein synthesis;
• BMR degradation
• Ventilation
• Na+-K+ ATPase