THYROID HORMONES

Production, Regulation, and Action

of Thyroid Hormones
Gross and Microscopic Anatomy of the Thyroid
Gland
Production of Thyroid Hormones
Transport and Activities of T3 and T4
Regulation of Thyroid Hormone Production
and Secretion
Actions of Thyroid Hormones
Hyper- and Hypothyroidism
 Histology of the Thyroid Gland
The thyroid gland contains numerous follicles,
composed of epithelial follicle cells and colloid.
Also, between follicles are clear parafollicular cells,
which produce calcitonin (see coming lecture on
calcium balance).
 The Thyroid Gland Histology
Gland is composed of hollow spheres, called colloid follicles.
Squamous epithelial cells, cuboidal cells (follicle cells)

Colloid fills the follicle cavities

I
Follicle cells produce thyroglobulin ---- TH
Thyroid Follicles
 Thyroid Hormones
There are two biologically active thyroid
hormones:
- tetraiodothyronine (T4; usually called thyroxine)
- triiodothyronine (T3)
Derived from modification of tyrosine.
 Thyroid Hormone Synthesis
Iodine sequestered in the thyroid gland by a Na-I pump,
whose activity is controlled by TSH

thyroid thyroid
peroxidase peroxidase
tetraiodothyronine
tyrosine diiodothyronine
(thyroxine, T4)

de-iodination
T4 by tissue T3
 Differences between T4 and T3
The thyroid secretes about 80 microg of T4, but only 5
microg of T3 per day.
However, T3 has a much greater biological activity
(about 10 X) than T4.
An additional 25 microg/day of T3 is produced by
peripheral monodeiodination of T4 (stay tuned.).

thyroid

T4 T3
I-
Why is Iodine Important in Thyroid Hormone
Production?

Thyroid hormones are unique biological molecules in

that they incorporate iodine in their structure.
Thus, adequate iodine intake (diet, water) is required
for normal thyroid hormone production.
Major sources of iodine:
- iodized salt
- iodated bread
- dairy products
- shellfish
Minimum requirement: 75 micrograms/day
US intake: 200 - 500 micrograms/day
 Iodine Metabolism

Dietary iodine is absorbed in the GI tract, then taken

up by the thyroid gland (or removed from the body
by the kidneys).
The transport of iodide into follicular cells is
dependent upon a Na+/I- cotransport system.
Iodide taken up by the thyroid gland is oxidized by
peroxide in the lumen of the follicle:
peroxidase
I- I+

Oxidized iodine can then be used in production of

thyroid hormones.
 The Next Step: Production of Thyroglobulin

Pituitary produces TSH, which binds to follicle cell

receptors.
The follicle cells of the thyroid produce
thyroglobulin.
Thyroglobulin is a very large glycoprotein.
Thyroglobulin is released into the colloid space,
where its tyrosine residues are iodinated by I+.
This results in tyrosine residues which have one or
two iodines attached (monoiodotyrosine or
diiodotyrosine).
 Transport of Thyroid Hormones

Thyroid hormones are not very soluble in water (but are

lipid-soluble).
Thus, they are found in the circulation associated with
binding proteins:
- Thyroid Hormone-Binding Globulin (~70% of hormone)
- Pre-albumin (transthyretin), (~15%)
- Albumin (~15%)
Less than 1% of thyroid hormone is found free in the
circulation.
Only free and albumin-bound thyroid hormone is
biologically available to tissues.
One Major Advantage of this System

The thyroid gland is capable of storing many

weeks worth of thyroid hormone (coupled to
thyroglobulin).

If no iodine is available for this period, thyroid

hormone secretion will be maintained.
Regulation of Thyroid Hormone Levels

Thyroid hormone synthesis and secretion is

regulated by two main mechanisms:
- an autoregulation mechanism, which
reflects the available levels of iodine
- regulation by the hypothalamus and anterior
pituitary
Regulation of Thyroid Hormone Levels

Thyroid hormone synthesis and secretion is

regulated by two main mechanisms:
- an autoregulation mechanism, which
reflects the available levels of iodine
- regulation by the hypothalamus and anterior
pituitary
 Mechanism of Action of TSH

TSH binds to a plasma membrane-bound, G protein-

coupled receptor on thyroid follicle cells.
Specifically, it activates a Gs-coupled receptor,
resulting in increased cAMP production and PKA
activation.
Adenylyl
TSH Cyclase

Gsa
ATP cyclic AMP
Follicle cell

Protein kinase
A
 Regulation of TSH Release from
the Anterior Pituitary
TSH release is influenced by hypothalamic TRH, and
by thyroid hormones themselves.
Thyroid hormones exert negative feedback on TSH
release at the level of the anterior pituitary.
- inhibition of TSH synthesis
- decrease in pituitary receptors for TRH
hypothalamus

+ TRH
TRH receptor -
-
pituitary T3/T4
TSH synthesis
Influence of TRH on TSH Release
Thyrotropin-releasing hormone (TRH) is a
hypothalamic releasing factor which travels through
the pituitary portal system to act on anterior pituitary
thyrotroph cells.
TRH acts through G protein-coupled receptors,
activating the IP3 (Ca2+) and DAG (PKC) pathways to
cause increased production and release of TSH.

IP3 calcium
G protein-coupled
receptor
TRH phospholipase C calmodulin

DAG PKC
Thyroid hormones also inhibit TRH synthesis.
Other Factors Regulating Thyroid Hormone
Levels
Diet: a high carbohydrate diet increases T3 levels,
resulting in increased metabolic rate (diet-induced
thermogenesis).
Low carbohydrate diets decrease T3 levels,
resulting in decreased metabolic rate.
Cold Stress: increases T3 levels in other animals,
but not in humans.
Other stresses: increased or decreased?
Any condition that increases body energy
requirements (e.g., pregnancy, prolonged cold)
stimulates hypothalamus TRH TSH (Pit)
 Actions of Thyroid Hormones

Thyroid hormones are essential for normal

growth of tissues, including the nervous system.
Lack of thyroid hormone during development
results in short stature and mental deficits
(cretinism).
Thyroid hormone stimulates basal metabolic rate.
What are the specific actions of thyroid hormone
on body systems?
 Actions of Thyroid Hormone
Required for GH and prolactin production and
secretion
Required for GH action
Increases intestinal glucose reabsorption
(glucose transporter)
Increases mitochondrial oxidative
phosphorylation (ATP production)
Increases activity of adrenal medulla
(sympathetic; glucose production)
Induces enzyme synthesis
Result: stimulation of growth of tissues and
increased metabolic rate. Increased heat
production (calorigenic effect)
 Effects of Thyroid Hormone on Nutrient
Sources
Effects on protein synthesis and degradation:
-increased protein synthesis at low thyroid
hormone levels (low metabolic rate; growth)
-increased protein degradation at high thyroid
hormone levels (high metabolic rate; energy)

Effects on carbohydrates:
-low doses of thyroid hormone increase glycogen
synthesis (low metabolic rate; storage of
energy)
- high doses increase glycogen breakdown (high
metabolic rate; glucose production)
 Negative Feedback Actions of Thyroid
Hormones on TSH Synthesis and Release

TRH synthesis
hypothalamus

+ TRH -

TRH receptor -
T3/T4
-
pituitary
TSH synthesis

TSH binds
Thyroid gland
follicle cell receptors
 Mechanism of Action of T3

T3/T4 acts through the thyroid hormone receptor

- intracellular, in steroid receptor superfamily
- acts as a transcription factor
- receptor binds to TRE on 5 flanking region of
genes as homodimers and/or heterodimers.
- multiple forms (alphas and betas) exist
- one form (alpha-2) is an antagonist at the TRE

hypervariable DBD HBD

 Effects of Thyroid Hormones on the
Respiratory System
Increase resting respiratory rate
Increase minute ventilation
Increase ventilatory response to hypercapnia
and hypoxia
 Effects of Thyroid Hormones on the
Renal System
Increase blood flow
Increase glomerular filtration rate
 Effects of Thyroid Hormones on
Oxygen-Carrying Capacity

Increase RBC mass

Increase oxygen dissociation from
hemoglobin
 Effects of Thyroid Hormones on
Intermediary Metabolism

Increase glucose absorption from the GI

tract
Increase carbohydrate, lipid and protein
turnover
Down-regulate insulin receptors
Increase substrate availability
Effects Thyroid Hormones in Growth
and Tissue Development

Increase growth and maturation of bone

Increase tooth development and eruption
Increase growth and maturation of epidermis,hair
follicles and nails
Increase rate and force of skeletal muscle
contraction
Inhibits synthesis and increases degradation of
mucopolysaccharides in subcutaneous tissue
Effects of Thyroid Hormones on the
Nervous System

Critical for normal CNS neuronal

development
Enhances wakefulness and alertness
Enhances memory and learning capacity
Required for normal emotional tone
Increase speed and amplitude of peripheral
nerve reflexes
Effects of Thyroid Hormones on the
Reproductive System

Required for normal follicular development

and ovulation in the female
Required for the normal maintenance of
pregnancy
Required for normal spermatogenesis in
the male
Thyroid Hormone Excess: Hyperthyroidism

Emotional symptoms (nervousness, irritability),

fatigue, heat intolerance, elevated metabolic rate,
weight loss, tachycardia, goiter, muscle wasting,
apparent bulging of eyes, may develop
congestive heart failure.
Also due to many causes (excessive TSH release,
autoimmune disorders,)
Thyroid Hormone Deficiency: Hypothyroidism

Early onset: delayed/incomplete physical and

mental development
Later onset (youth): Impaired physical growth
Adult onset (myxedema) : gradual changes occur.
Tiredness, lethargy, decreased metabolic rate,
slowing of mental function and motor activity,
cold intolerance, weight gain, goiter, hair loss, dry
skin. Eventually may result in coma.
Many causes (insufficient iodine, lack of thyroid
gland, lack of hormone receptors, lack of TH
binding globulin.)
Causes of Hypothyroidism

1. Dietary deficiency (iodine)

2. Pituitary defect
3. Enzyme deficiency
4. Thyroid autoimmunity
5. Exposure to 131I
How is Hypothyroidism Related to Goiter?

During iodine deficiency, thyroid hormone

production decreases.
This results in increased TSH release (less negative
feedback).
TSH acts on thyroid, increasing blood flow, and
stimulating follicular cells and increasing colloid
production.
Thyroid Hormone Excess: Hyperthyroidism

Emotional symptoms (nervousness, irritability),

fatigue, heat intolerance, elevated metabolic rate,
weight loss, tachycardia, goiter, muscle wasting,
apparent bulging of eyes, may develop
congestive heart failure.
Also due to many causes (excessive TSH release,
autoimmune disorders,)
 Midwest the Goiter Belt
If goiter is due to decreased I, then thyroid
gland enlarges called endemic or colloidal
goiter.
Pituitary gland TSH to stim thyroid gland to
produce TH, but the only result is that the
follicles accumulate more and more unusable
colloid.
Cells eventually die from overactivity and the
gland atrophies.
How is Goiter Related to Hyperthyroidism?

Due to excessive stimulation by TSH

(thyroglobulin production, enlarged follicles).
In this case, excessive stimulation of the
thyroid gland by TSH DOES result in thyroid
hormone secretion, since iodine is available.
35 years old, 15-20 years old,
China Congo-Kinshasa
Thyroid Hormone Excess: Hyperthyroidism

Emotional symptoms (nervousness, irritability),

fatigue, heat intolerance, elevated metabolic rate,
weight loss, tachycardia, goiter, muscle wasting,
apparent bulging of eyes, may develop
congestive heart failure.
Also due to many causes (excessive TSH release,
autoimmune disorders,)
HYPOTHYROIDISM AND HYPERTHYROIDISM
 SIGNS AND SYMPTOMS
Skin: Increased Sweating and heat intolerance, onycholysis,
hyperpigmentation, pruritus and thinning of the hair.

Eyes: Stare and lid lag, exophtalmos if graves disease

Cardiac: Palpitations, exertional dyspnea, anginal-like chest pain,

tachycardia, atrial fibrillation, CHF

GI: Weight loss, diarrhea

Neuro-psych: Anxiety, restlessness, irritability, emotional lability,

psychosis, agitation, and depression

Metabolic/Endocrine: Hyperglycemia, low serum total and high-

density lipoprotein (HDL) cholesterol