Thyroid Gland

From Pharmacology to Clinical

Practice

Lecture 7
Dr. Nesrine Salah El Dine
 Thyroid Glands
 The thyroid gland is located in the neck, close to the first part
of the trachea
Thyroid hormones are produced by the thyroid
gland.

Thyroid gland uses iodine (mostly available

from the diet in foods) to produce thyroid
hormones:
1. Seafood
2. Bread
3. Salt
 Chemistry of Thyroid
Hormones
 Thyroid hormones are derivatives of
the amino acid tyrosine bound
covalently to iodine. The two
principal thyroid hormones are:
 Thyroxine (T4 or L-3,5,3',5'-
tetraiodothyronine)
 Triiodotyronine (T3 or L-3,5,3'-
triiodothyronine)
 T4 Versus T3

T4 T3
Bound Form 99.97% 99.7%
(Inactive)
Free Form 0.03% 0.3%
(Active)
T1/2 7 days 1.5 days
Activity Lower Higher
Source Biosynthesis Biosynthesis +
T4 De-Iodination
(40%)
 Synthesis and Secretion of
Thyroid Hormones
 PRECURSORS for making thyroid hormones:
 Tyrosines

They are provided from a large glycoprotein called thyroglobulin,

synthesized by thyroid epithelial cells and secreted into the lumen
of the follicle (colloid)
Only a small fraction is used to synthesize T4 and T3.

 Iodine, or more accurately iodide (I-), is taken up from blood

by thyroid epithelial cells, which have on their outer plasma
membrane a sodium-iodide symporter or "iodine trap“
 Once inside the cell, iodide is transported into the lumen of the
follicle along with thyroglobulin
 Synthesis and Secretion of
Thyroid Hormones
 Synthesis: Thyroid peroxidase catalyzes two sequential reactions:
 Iodination of tyrosines on thyroglobulin ("organification of
iodide").
 Synthesis of thyroxine or T3 from two iodotyrosines
 Storage & Release
 Storage: Thyroid hormones accumulate in colloid, on
the surface of thyroid epithelial cells tied up in
molecules of thyroglobulin
 Release. Thyroid hormones are excised by digestion
in lysosomes of thyroid epithelial cells
 Control of Thyroid Hormone Synthesis
and Secretion

 Synthesis processes is stimulated by TSH from the

anterior pituitary gland
 Binding of TSH to its receptors on thyroid epithelial
cells stimulates synthesis of:
 iodine transporter
 thyroid peroxidase
 thyroglobulin
 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 enhance oxidation of fatty acids in many tissues
 Plasma concentrations of cholesterol and triglycerides are inversely
correlated with thyroid hormone levels - one diagnostic indication of
hypothyroidism is increased blood cholesterol concentration.
 Physiologic Effects of
Thyroid Hormones
 Carbohydrate metabolism:
 Thyroid hormones stimulate almost all aspects of carbohydrate
metabolism, including increased gluconeogenesis &
glycogenolysis to generate free glucose
 Growth:
 Thyroid hormones are essential for normal growth in children, as
evidenced by the growth-retardation observed in thyroid deficiency
 the growth-promoting effect of thyroid hormones is intimately
linked with that of growth hormone
 Development:
 Normal levels of thyroid hormone are essential to the development
of the fetal and neonatal brain
 Physiologic Effects of
Thyroid Hormones
 Other Effects:
 CVS:

Thyroid hormones increases heart rate, cardiac contractility and

CO & produce vasodilation
 CNS:

Too little thyroid hormone, depresses CNS & the individual tends
to feel mentally sluggish, while too much induces anxiety and
nervousness
 Reproductive system:

 Normal reproductive behavior & physiology is dependent on

having essentially normal levels of thyroid hormone.
Hypothyroidism in particular is commonly associated with
infertility
 HYPOTHYROIDISM
 Deficient thyroid hormone
 Prevalence:
 1.4-2% (females) 0.1-0.2% (males)
 Increase with age up to 6%
 Primary hypothyroidism (most frequent) involves
the thyroid gland
 Secondary hypothyroidism results from pituitary
dysfunction
 Tertiary hypothyroidism: hypothalamic-pituitary
axis hypothyroidism
 Causes of Hypothyroidism
Primary Hypothyroidism Goitrous Hypothyroidism
 Idiopathic atrophy  Hashimoto’s Thyroiditis

 Iatrogenic destruction  Drug-induced (iodides, Li+,

(surgery, radioactive I2) amiodarone, interferone-α)

 Cretinism (Congenital  Iodine deficiency

hypothyroidism)  Natural goitrogens (turnips,

cabbage)
 Symptoms of hypothyroidism
 Fatigue  Dry skin
 Depression  Muscle cramps
 Modest weight gain  Increased cholesterol levels
 Cold intolerance  Decreased concentration
 Excessive sleepiness  Vague aches and pains
 Dry, coarse hair  Swelling of the legs
 Constipation
 Symptoms of hypothyroidism

As the disease becomes more severe:

 Puffiness around the eyes

 Slowing of HR and heart failure.

 Life-threatening coma (myxedema coma).

This condition requires hospitalization and immediate treatment

with thyroxin given by injection.

 Properly diagnosed, hypothyroidism can be easily and

completely treated with TH replacement.
 Untreated hypothyroidism can lead to cardiomyopathy and
pleural effusion
 Goal of Therapy
 Reverse signs & symptoms of hypothyroidism
 Normalize TSH
 Normalize free thyroxine
 2-3 weeks thyroxine replacement are needed for
improvement to start
 Optimal thyroxine therapy dosage must be administered
for 6-8 weeks to reach normal hormonal levels followed
by evaluation of thyroid function tests
 After normalization, lab tests are monitored every 3-6
months for the 1st year, then yearly
 Thyroid Function Tests
 Evaluation of TSH and free thyroxine levels (FT4) is the
principal recommended tests
 Total thyroxine (TT4) & tri-iodothyronine (TT3) are less
indicative:
 False elevated TT4 & TT3 are common in euthyroid
pregnant woman
 TT3 is often low in elderly patients & many acute &
chronic nonthyroid illnesses because of suppressed
peripheral conversion of T4 to T3
 Radioactive Iodine Uptake (RAIU), an index of I2
utilization by the gland & indirect measure of hormone
synthesis
 Antithyroid antibodies (autoimmune diseases)
 Serum cholesterol (elevated in hypothyroidism)
 Prolactin (as a widely available test of pituitary
function)
 Testing for anemia
 Thyroid Hormone
Products
 Natural Desiccated THYROID (USP) is derived from
pork, beef or sheep thyroid gland
o It should contain only 0.17-0.23%organic iodine by
weight
o Allergic reactions to animal proteins
o T3 is more rapidly absorbed than T4, and elevated T3
levels can occur after oral intake
o FT4 levels are low, may mislead to administer more
hormone
o Loss of tablet potency after prolonged storage
o Low cost
 Thyroid Hormone
Products
 Levothyroxine (L-Thyroxine) is the
replacement thyroid therapy
 Advantages: stability, uniform potency, low
cost, no foreign allergic protein
o Once/day & drug-free week ends (t1/2:7 days)
 Triiodthyronine: not recommended as first
choice (disadv. similar to natural T3)
 Combination of T4 & small dose of T3 is
preferable to T4 alone
 Thyroid Hormone
Products
 Triiodthyronine disadvantages:
• Short t1/2 requires multiple dosing
• Higher cost & potential for cardiotoxicity
 Triiodthyronine, When used?
 For patients requiring short-term replacement
 In patients with impaired T4-T3 conversion
 LIOTRIX is a combination of synthetic T4 & T3 in a
ratio of 4:1
 Same advantages of T3 preparations
 Stable & potent but more expensive
 Treatment requires life-long therapy.
 The most active thyroid hormone is actually T3. So why do
physicians choose to treat patients with the T4?
 T3 is available and there are certain indications for its use.
 However, for the majority of patients, a form of T4
levothyroxine sodium (Levoxyl) is the preferred treatment.
 It is a more stable form of TH and requires once a day
dosing, whereas T3 is much shorter-acting and needs to be
taken multiple times a day. Synthetic T4 is readily and
steadily converted to T3 naturally in the bloodstream, and
this conversion is appropriately regulated by the body's
tissues.