BIOC 313

Chapter 5

Thyroid Hormones
Thyroid
Gland
Objectives

1 2 3 4

Determine the Describe the List the metabolic Describe the

different mechanisms of effects of thyroid function
tyrosine- storage, secretion, tyrosine-derived tests. List the
transport, thyroid main laboratory
derived thyroid degradation and hormones. investigations in
hormones and excretion of order to diagnose
the steps of tyrosine-derived thyroid
their synthesis thyroid dysfunction.
explaining the hormones.
role of iodine.
Thyroid Gland

• The thyroid gland is the

largest endocrine organ
in the body
• Its function is to secrete
adequate amount of
thyroid hormones
• Thyroid hormones
promote normal growth
and development and
regulate energy and
heat production.
 Chemistry of Thyroid Hormones
• Thyroid hormones are derivatives of the amino acid
tyrosine bound covalently to iodine. The two principal
thyroid hormones are:
• Thyroxine (also known as T4 or L-3,5,3',5'-
tetraiodothyronine)
• Triiodothyronine (T3 or L-3,5,3'-triiodothyronine)
Structure of thyroid hormones
 Synthesis and secretion
Thyroxine (T4) and triiodothyronine (T3) are the physiologically active
substances that are manufactured by the thyroid and are iodine containing
compounds.

 Only ¼ or 1/5 of the total iodine in the gland is present in the form of T3 , T4 .

 93 % of metabolically active hormones is secreted by the thyroid gland =

Thyroxine (T4)

 7 % = triiodothyronine (T3)

Triiodothyronine is about 4 times as potent as T4

Importance of Iodine

• Iodine, a trace element, is essential for synthesis of thyroid

hormones.
• Approximately 70–80% of total body iodine content is found in the
thyroid.
• Thyroid gland is the only organ that can oxidize iodine by using
H2O2 and thyroperoxidase and NADPH.
• The uptake of iodine by the thyroid gland occurs against a
concentration gradient and needs energy and controlled by TSH
• If there is a deficiency of dietary iodine, the thyroid will not be able
to make thyroid hormone.
Synthesis and
secretion

• Physiologic anatomy thyroid

gland:
 Composed of large number of
closed follicles.
 Filled with a secretory
substance called colloid.
The colloid contains the protein
thyroglobulin which is the
storage form of thyroxine.
Thyroglobulin (Tg)

• Thyroglobulin, a large dimeric glycoprotein (660 kd) containing 134

tyrosine residues, is the major iodine-containing protein of the
thyroid.
• It serves as a storage form of accessible thyroid hormone for the
circulation.
• A small amount of Tg can be detected in the serum and is, in general,
proportional to the thyroid mass.
• Thyroglobulin serves as a substrate for coupling of monoiodotyrosine
(MIT) and diiodotyrosine (DIT) by the thyroid peroxidase-H2O2 system.
• Thyroglobulin is synthesized by thyroid epithelial cells and moves to
lumen, where it is stored in the extracellular colloid
Thyroid hormone synthesis

 Iodine trapping:
 The absorbed iodide present in the diet is trapped into the
follicular cells by an active-transport mechanism that utilizes
energy derived from Na+ , K+-ATPase.
 Oxidation:
Inside the cells, the iodide is oxidized by thyroidal peroxidase and in
the presence of H2O2.
Thyroid hormone synthesis

Organification:
The active iodine is then involved in the iodination of tyrosine, the
precursor of thyroxine.
This does not occur on the free amino acid but after tyrosine become
a part of the protein thyroglobulin.
Iodination yields MIT and DIT.
Iodinated thyroglobulin is stored in the colloid.

monoiodotyrosine (MIT)
diiodotyrosine (DIT)
Thyroid hormone synthesis

 Coupling:
 MIT + DIT → T3
 DIT + DIT → T4

 Proteolysis:
 The release of T3 and T4 involves proteolytic degradation of
thyroglobulin.
 MIT and DIT are also released in this process, and they are
deiodinated and hence do not leave the cell.
 T3 and T4 are released to the blood stream.
Deiodination of MIT and DIT requires deiodinase and NADPH.
 Secretion of TH

• Thyroid hormones are excised from their

thyroglobulin by digestion in lysosomes of
thyroid epithelial cells.
1- Thyroid epithelial cells ingest colloid
which contain thyroglobulin decorated
with thyroid hormone by endocytosis from
their apical borders.
2- Thyroglobulin is digested by hydrolytic
enzyme, liberating free thyroid hormones.
3- Finally, free thyroid hormones diffuse
out of lysosomes, through the basal
plasma membrane of the cell, and into
blood where they quickly bind to carrier
proteins for transport to target cells.
Control of Thyroid
hormones Synthesis
and Secretion

• Synthesis and release of T3 and T4 are

stimulated by thyroid stimulating hormone
(TSH) released from the pituitary gland.
• TSH is under control of thyrotropin releasing
hormone (TRH) which is a released by
hypothalamus.
• Increased plasma levels of T3 and T4 inhibits
the secretion of TRH from hypothalamus and
TSH from the pituitary gland by feed back
mechanism.
Thyroid hormone transport

• Thyroid hormones are hydrophobic, and the vast majority of hormone

circulates bound to serum proteins with only a small free fraction of T 4
(0.02%) and T3 (0.30%).
• The free hormone is the only metabolically active fraction of the total
hormone concentration.
• The predominant thyroid hormone binding serum protein is thyroxine-
binding globulin (TBG), which carries approximately 70% of serum T4 and
the majority of T3.
• Transthyretin (previously called T4-binding prealbumin) binds
approximately 20% of T4.
• The remaining serum T4 and T3 are bound to albumin.
Thyroid • Thyroid hormones enter cells
through membrane transporter
hormone proteins.

receptors and • Once inside the nucleus, the

hormone binds its receptor, and the
mechanism hormone-receptor complex
interacts with specific sequences of
of action DNA in the promoters of responsive
genes.
• The hormone-receptor complex
binds to DNA to modulate gene
expression, either by stimulating or
inhibiting transcription of specific
genes
Thyroid Hormone Metabolism

• The thyroidal secretion is primarily the prohormone T4, which is

metabolically inactive and must be converted to the active
hormone T3 by removal of the 5´ phenolic (outer) ring iodine by 5´-
deiodinase.
• Approximately 20% of circulating T3 is derived from thyroidal
secretion and 80% from peripheral conversion of T4.
• T4 can also be converted to reverse T3 (rT3), which is metabolically
inactive.
Physiologic Effects of Thyroid
Hormones

• Metabolism: Thyroid hormones stimulate diverse metabolic activities in

most tissues, leading to an increase in basal metabolic rate.
- Lipid metabolism: Increased thyroid hormone levels stimulate fat
mobilization, leading to increased concentrations of fatty acids in plasma.
They also enhance oxidation of fatty acids in many tissues. Serum
cholesterol level is increased in hypothyroidism and decreased in
hyperthyroidism
- Carbohydrate metabolism: Thyroid hormones stimulate almost
all aspects of carbohydrate metabolism, including enhancement of insulin-
dependent entry of glucose into cells and increased gluconeogenesis and
glycogenolysis to generate free glucose.
- TH increases Ca+2 absorption and bone formation
Physiologic Effects of Thyroid
Hormones

• Growth: Thyroid hormones are necessary for normal growth in

children and young animals, as evidenced by the growth-retardation
observed in thyroid deficiency.
• Development: Normal levels of thyroid hormone are essential to the
development of the fetal and neonatal brain.
• Effect on cardiovascular system: Thyroid hormones increases heart
rate, cardiac contractility and cardiac output.
• Effect on reproductive system: Normal reproductive behavior is
dependent on having essentially normal levels of thyroid hormone.
• Effect on energy metabolism: TH increases oxygen consumption and
production of energy.
Thyroid function tests

• In the last few years, the development of more sensitive laboratory

techniques for the evaluation of thyroid tests has improved the
physician's ability to diagnose thyroid diseases. The following list
includes the most common and useful tests:
• Evaluation of the pituitary-thyroid axis: TSH
• Circulating levels of thyroid hormones:
• Total T4
• Total T3
• Free T4: The free T4 test measures the T4 that's not bound on proteins
in the blood, eliminating the protein interference problems. For that
reason, it can be a more useful test than total T4. Free T4 is often
measured along with TSH to help manage hypothyroidism
• Free T3.
Types of thyroid dysfunction

1- Hypothyroidism
- Primary hypothyroidism: caused by decreased production of T4
and T3 due to thyroid dysfunction (From thyroid destruction)

- Secondary (central) hypothyroidism: caused by decreased

thyroidal stimulation by TSH; may be caused by pituitary TSH
secretion.

2- Hyperthyroidism:
Sustained increases in thyroid hormone biosynthesis and secretion
by the thyroid gland
 I- Hyperthyroidism: ↑T3 & ↑T4:
A] 1ry Hyperthyroidism [↓TSH]:
Grave’s disease.
 Toxic multinodular Goiter
[Plummer’s disease].

Thyroid Solitary thyroid nodules (thyroid

adenoma, or carcinoma)
Disorders Acute & subacute Thyroiditis.
 Over intake of thyroid hormones.
B] 2ry Hyperthyroidism [↑TSH]:
TSH secreting (pituitary adenoma
or carcinoma).
 II- Hypothyroidism: ↓T3 & ↓T4:
A] Primary hypothyroidism [↑TSH]:
Chronic Thyroiditis [Hashimoto
thyroiditis].
Drug induced [Iodine, Antithyroid
drugs].
Endemic goiter: iodine deficiency.
Thyroid Congenital [Cretinism]: thyroid
hormones insufficiency during
Disorders intrauterine fetal life results in
cretinism. This disease shows
abnormal physical development and
mental retardation.
B] 2ry Hypothyroidism [↓TSH]:
Pituitary or Hypothalamic disease
[3ry].

Bioc 313