A 41-year-old woman presents to her primary care physician

with weight and hair loss, diarrhea, nervousness, and eye

pressure. She has no medical problems,
but some of her family members have similar symptoms and
require medication. On examination, she is noted to have
exophthalmos, an enlarged nontender goiter, hyperreflexia, and
a tremor when her arms are outstretched.
The patient has a decreased thyroid-stimulating hormone (TSH)
level and an increased free thyroxine (T4) level and is diagnosed
with Graves disease (hyperthyroidism).
◆ What is the mechanism by which high levels of iodine
inhibit thyroid production?
◆ How does propylthiouracil (PTU) inhibit thyroid synthesis?
◆ What affect does pregnancy have on the free thyroid
hormonelevel?
The Thyroid Gland
 Hypothalamus

TRH

Anterior
Pituitary

TSH

Thyroid
Gland

Thyroid Hormone
 Thyrotropin Releasing Hormone

• Synthesized in PVN
• Tripeptide
• Pulsatile release / diurnal rhythm
• Half life ~ 5 minutes
 Thyrotroph
TRH

Vesicles
containing
TSH Also  TSH
IP3 & DAG activation
and
synthesis
Release of Ca2+
TSH via
exocytosis
 Thyroid-stimulating Hormone
• Synthesized in thyrotrophs of AP
• Glycoprotein
• Half-life ~ 30 minutes
At the thyroid gland
TSH

cAMP & PLC

Modulation of many TSH

cellular processes Effects
 What is synthesized?
• Major products are:
• Thyroxine (T4) – 90%
• Triiodothyronine (T3) – 9%
•
• Triiodothryronine has the major
physiological actions –more potent.
•
 Importance of Iodine
• Must form part of diet
• Thyroid gland has specialized system for
getting iodine into the follicle
• This is stimulated by TSH
 Iodine ingested
each day
(500μg)

ECF iodine
(150μg)

Liver
Thyroid Gland (processor)
(8000μg)

Circulating Thyroid
Urine Hormones Bile
(485μg) (600μg) (15μg)
 Thyroid Hormone Synthesis
• Very complex
• Iodination of tyrosine molecules occurs in
follicular lumen
• Tyrosine molecules grouped together in
thyroglobulin
 Thyroglobulin
• Large glycoprotein
• Made in epithelial cells
– Synthesised in ribosomes
– Transport to Golgi Apparatus
– Discharged into follicle lumen
• Contains ~ 70 tyrosine molecules
• Synthesis and storage remains here
 Iodide
pump

I- I- I-
Na+
TPO TG
TG
Iodination TPO
of TG I0 MIT DIT

T4
MIT DIT
T3 & T 4
Conjugation TG
of tyrosines T3
TG taken up by
lysoendosomes

Follicular lumen Follicular cell

[Na] is high

Na+ Free [ I ] is high

I-

I-

Na+

K+

Interstitial Follicular Lumen

Fluid Cell
 Thyroid Stimulating Hormone

• Stimulates thyroglobulin synthesis

• Stimulates I trapping
• Stimulates ALL steps of TH synthesis
• Stimulates endocytosis of colloid
• Causes growth of thyroid gland
At the target tissues
T3 T4 Mechanism of
entry remains
unknown

T3 T4

Thyroid
Modulation of gene Hormone
expression Effects
 Actions of Thyroid Hormone
Whole Body Effects
• In general it stimulates oxygen consumption and
heat generation by the body
• Produces so many enzymes and proteins in the
target cell
INCREASES
BASAL
METABOLIC
RATE
 SR Ca2+ATPase
TH
Increased
Na+-K+ATPase CO
And
1 adrenoreceptors
HR

Cardiac Muscle

BMR vasodilation Blood flow

 Metabolic Effects
• Increases glucose absorption from GIT
• Increases use of glucose, fats and proteins
for energy use (oxidation).
• Increase the effects of other hormones that
themselves increase metabolic rate
• Decreases body weight
 glucose

General cell

Fatty acids glucose Amino Acids

glycerol

Liver

lipolysis Protein
breakdown

Adipose Cells Muscle

 Effects on Growth

• Stimulates growth and maturation of bone

• Stimulates somatomedin production in the
cartilage growth plate
• Regulates teeth development and important
for nail and hair follicle function
• Very important in the growth and
development of the fetus and during early
infancy
 Breakdown of Thyroid
Hormones
• T4 is broken down to T3 mainly in liver and
kidneys (5` - deiodinase)
– 55% is rT3 and so has no metabolic effects.
• The T3 has 10X the affinity for Receptor c.f
T4 and 100x that of rT3 .
 T4 Breakdown

Table 50-1
 Long half-life
• 70% of T3 and T4 bound to Thyroxine-
binding globulin (TBG)
• Rest bound to albumin, lipoproteins and
transthyretin
• Maintains an adequate reserve of thyroid
hormone (mainly T4).
• Prevents loss via excretion in urine.
Hypothalamus

TRH

Thyrotroph

TSH

Thyroid
gland

Thyroid
Hormones
 Hyperthyroidism
(Thyrotoxicosis)
Increased levels of TH in the blood
–Thyroid Enlargement (Grave’s Disease)
–Overactive lump (Plummer’s Disease)
–Toxic multinodular goiter

Symptoms
• Irritability.
• Weight loss
• Heat intolerance/Sweating/fever.
• Fast or irregular heart rate.
• Irregular periods and infertility.
• Heart failure in the elderly
 Grave’s Disease
• Most common (1% of population)
• Autoimmune disease
• Females 3-5x more likely
•
• Due to an antibody (TSH-R-Ab [stim]) that
increases growth and function of the thyroid
Hypothalamus

TRH

Thyrotroph
TSH-R-Ab [stim]
TSH

Thyroid
gland

Thyroid
Hormones
 Symptoms of Grave’s Disease
• Weight loss, hyperactivity, palpitations,
nervousness, excessive sweating
• Thyroid enlargement
• Opthalmopathy
• Pretibial myxedema (rare)
 Goiter
• An enlargement of the thyroid gland
• Due to …
– Iodine deficiency
– Substances that affect iodide uptake by
the thyroid
– Or …Increased TSH release
•
 Hypothyroidism
• Due to low levels of TH in blood
– Hashimoto’s thyroiditis
– Thyroidectomy
– Iodide deficiency
• Secondary
– Insufficient pituitary action
– Resistance of organs to TH
 In newborns
• May be due to
– iodine deficiency
– placental transfer of TSH Ab’s
• Symptoms
– Respiratory problems, jaundice, poor feeding, umbilical
hernia, reduction of bone development
–

In children
•Growth retardation
•Mental retardation
 In adults
• Fatigued, coldness, weight gain, menstrual
problems
• Puffy face, slow reflexes, rough dry skin
•  cardiac output, respiration and GFR,
anemia.