B 28

Hormones - Thyroid axis

Sujin Bao, Ph.D.

 Learning objectives

1. Chemical nature of thyroid hormones and their receptors

2. Functions of thyroid hormone
3. Synthesis of thyroid hormones
4. Control of thyroid hormone production: hypothalamus, pituitary
gland; ligands, receptors, and second messengers
5. Clinical cases: cretinism; hypothyroidism; hyperthyroidism;
Graves’ disease; Hashimoto’s thyroiditis
 Thyroid hormones

1. Chemistry of thyroid hormones

2. Functions of thyroid hormones
3. Synthesis of thyroid hormones
4. Regulation of thyroid hormones
5. Clinical correlation of thyroid
hormones
 The Thyroid Gland

- It is located in the anterior neck on

trachea just inferior to larynx.
- It contains two lateral lobes and
an isthmus.
- It produces two hormones:
• Thyroid hormone: tyrosine
based with 3 or 4 iodine
molecules
- T4 (thyroxine) and T3
• Calcitonin: 32-amino acid
polypeptide hormone, involved
in calcium and phosphorus
metabolism (see Parathyroid
Hormone lecture) 4
 1. Thyroid hormones
- Derived from tyrosine.
- Lipid soluble; 70% bound to thyroid binding globulins (TBG)
- T4 bound to TBG tighter than T3
- Half life: 6 days (T4) and 1 day (T3)
- Circulating thyroid hormone T4: T3 = 50:1
- Affinity for the nuclear receptor T4: T3 = 1: 10
- Many target tissues can convert T4 to T3 (peripheral activation)

Thyroxine (T4) 3,5,3’-Triiodothyronine (T3)

Thyroid is composed of spherical follicles
- Follicle cells: produce thyroglobulin, the precursor of thyroid
hormone (thyroxine)
- Colloid lumen is rich of thyroglobulin
- Parafollicular “C” cells: produce calcitonin

6
 2. Function of thyroid hormones
It functions via thyroid hormone receptor (TR), a nuclear receptor.
Thyroid Hormones increase the transcription of large numbers of
genes.
 Steroid/thyroid hormone family of nuclear receptors
GR: glucocorticoid receptor
C-erbA: thyroid hormone
receptor 
ER: estrogen receptor

Target genes of thyroid hormone:

- Growth hormone
- Malic enzyme
- Globulin
- Many others
 Effects of thyroid hormones

1) Metabolism - Increases the basal metabolic rate

- The rate at which the body uses oxygen to transform nutrients
(carbohydrates, fats and proteins) into energy
2) Development - Affects many target cells throughout the body;
some effects are
- Protein synthesis
- Bone growth
- Neuronal maturation
- Cell differentiation
 Metabolic effects of thyroid hormone

• Regulates Basal Metabolic Rate (BMR).

• Increases oxygen consumption in most target tissues.
• Permissive actions: TH increases sensitivity of target
tissues to catecholamines, thereby elevating lipolysis,
glycogenolysis, and gluconeogenesis.

catecholamines

dopamine norepinephrine epinephrine

Thyroid Hormone
- increases the Number and activity of mitochondria.
- increases Active Transport of Ions through Cell Membranes.
One of the enzymes that increases its activity in response to
thyroid hormone is Na-K-ATPase.
- stimulates almost all aspects of carbohydrate metabolism
- decreases the fat stores of the body (lipids are mobilized
rapidly from the fat tissue); increases the free fatty acid
concentration in the plasma and greatly accelerates the oxidation
of free fatty acids by the cells.
- decreases the concentrations of cholesterol, phospholipids,
and triglycerides in the plasma
- increases vitamin requirements
 Effects of thyroid hormones on specific bodily mechanisms

- Increased heart rate. Note: with normal arterial pressure.

- Increased heart strength
- Increased blood flow and cardiac output
- Increased respiration
- Decreased body weight
 Effects of thyroid hormones on development

TH is critical for normal development of the skeletal system and

musculature in growing children. Note: TH controls production of
growth hormone, which is essential for skeletal growth.
TH is also essential for normal brain development and regulates
synaptogenesis, neuronal integration, myelination and cell
migration.
Cretinism is the term for the constellation of defects resulting
from untreated neonatal hypothyroidism.
 3. Synthesis of thyroid hormones
- Thyroglobulin is
synthesized in the rough
endoplasmic reticulum and
follows the secretory
pathway to enter the
colloid in the lumen of the
thyroid follicle by
exocytosis.

- Meanwhile, a sodium-iodide (Na/I) symporter pumps iodide (I) actively

into the cell, which previously has crossed the endothelium.
- This iodide enters the follicular lumen from the cytoplasm by the
transporter pendrin, in a purportedly passive manner.
- In the colloid, iodide (I) is oxidized to iodine (I0) by an enzyme called
thyroid peroxidase.
- Iodine (I0) is very reactive
and iodinates the
thyroglobulin at tyrosyl
residues in its protein
chain (in total containing
approximately 120 tyrosyl
residues).
- In conjugation, adjacent
tyrosyl residues are paired
together.
- The entire complex re-enters the follicular cell by endocytosis.
- Proteolysis by various proteases liberates thyroxine and triiodothyro-
nine molecules, which enter the blood by largely unknown mechanisms.
Roles of thyroid hormone deiodinases
Three deiodinases (D1, D2 & D3) catalyze the generation
and/disposal of bioactive thyroid hormone.
- D1 & D2 “activate” thyroid hormone by removing a single “outer-
ring” iodine atom. Many target tissues can convert T4 to T3.
- D3 “inactivates” thyroid hormone by removing a single “inner-
ring”iodine atom (reverse T3 or rT3, a biologically inactive form)
All family members contain the novel amino acid selenocysteine
(SeC) in their catalytic center.

“Inner-ring” iodine in T4
 4. Regulation of thyroid function

Regulation of thyroid function by thyrotrophs

TSH binds to specific cell surface receptor

TSHR on the thyroid gland (G protein
coupled receptors), which stimulates
adenylate cyclase to produce cAMP.
TSH increases metabolic activity that is
required to synthesize Thyroglobulin (Tg)
and generate peroxide; TSH also
stimulates both I- uptake and iodination of
tyrosine resides on Tg.
 4. Regulation of thyroid function
Regulation of thyroid function by pituitary gland (thyrotrophs)

Thyroid gland:
- expresses the receptor TSHR, a G
protein-coupled receptor; it activates
adenylyl cyclase, leading to an increase in
cAMP, which activates all functional
aspects of the thyroid cell, including
iodine pumping; thyroglobulin synthesis,
iodination, endocytosis and proteolysis; The  subunits of LH,
thyroid peroxidase activity; and hormone FSH, TSH, and hCG are
release. identical (92 amino
acids); the  subunits
Note: hCG can also activate TSHR. vary
 Regulation of thyrotrophs by the hypothalamus
Hypothalamus: TRH
- produces Thyrotropin-releasing hormone
(TRH): derives from -Gln-His-Pro-Gly-. The N-
terminal Gln is converted to pyroglutamic acid (a
cyclic residue). Gly is converted to the -NH2 at
the carboxyl terminus by peptidylglycine-alpha-
amidating monooxygenase, leading to a
tripeptide: pyroGlu-His-Pro-NH2

 TRH
Pituitary gland:
- expresses thyrotropin-releasing
hormone receptor (TRHR), a G protein-
coupled receptor;
- Activation of TRHR by TRH activates
transcription of TSH via the phospholipase C
(PLC) pathway
 TSH
- The gland secretes TSH, a glycoprotein
 Negative feedback regulation of TRH and TSH

Key players for the thyroid:

TRH - Thyroid Releasing Hormone
(hypothalamus)
TSH - Thyroid Stimulating
Hormone (pituitary)
T4/T3 - Thyroid hormones

T3 and T4 negatively regulate

synthesis of TSH and TRH.
Iodine deficiency: decreased T4
leads to an increase in TSH. TSH
causes thyroid hypertrophy and +
goiter.
HM Goodman, BASIC MEDICAL ENDOCRINOLOGY 3rd Ed.
 Negative feedback regulation of TRH and TSH

Thyrotroph
T3 and T4 negatively regulate
synthesis of TSH and TRHR.
T3 decreases:
- TSH mRNA (pituitary)
- TRHR mRNA (pituitary)
- TRH mRNA (hypothalamus)

HM Goodman, BASIC MEDICAL ENDOCRINOLOGY, 3rd Ed.

 5. Clinical correlation – thyroid diseases
1) Primary hypothyroidism
Symptom: - tiredness, poor ability
to tolerate cold, and weight gain.
- somnolence
Causes: The two most common
causes are autoimmune thyroiditis
(Hashimoto's thyroiditis) and
previous treatment for
hyperthyroidism (total or subtotal
thyroidectomy or radioablation
therapy).
Treatment
- Replacement: thyroxine

www.hsc.missouri.edu/~daveg/thyroid/thy_dis.html
1) Primary hypothyroidism

Hashimoto’s thyroiditis: an autoimmune disease in which the thyroid

gland is attacked by a variety of cell- and antibody-mediated immune
processes, causing primary hypothyroidism. It was the first disease to
be recognized as an autoimmune disease.
Symptoms:
- fatigue, weight gain, pale or puffy face, feeling cold, joint and muscle
pain, constipation, dry and thinning hair, heavy menstrual flow or
irregular periods, depression, panic disorder, a slowed heart rate, and
problems getting pregnant and maintaining pregnancy.
Diagnosis: detecting elevated levels of anti-thyroid peroxidase
antibodies (TPOAb) in the serum.
2) Congenital hypothyroidism
Symptoms
- excessive sleeping, reduced interest in
nursing, poor muscle tone, exaggerated
jaundice, and low body temperature
- delay in growth and intellectual development
- Goiter: gradual enlargement of the thyroid
gland
Causes
- mutations in genes involved in thyroxine
synthesis lead to defects in development of the
thyroid gland and metabolism.
Treatment
- Replacement: thyroxine

www.hsc.missouri.edu/~daveg/thyroid/thy_dis.html
Cretinism: a group of conditions characterized by severely stunted
physical and mental growth due to untreated congenital deficiency
of thyroid hormone (congenital hypothyroidism) usually due to
maternal hypothyroidism.
Causes:
- Iodine deficiency: the most common cause
- Thyrotropin (TSH) resistance
- Iodine trapping defect
- Organification defect: the incorporation of iodine into
thyroglobulin, catalyzed by thyroid peroxidase
- Thyroglobulin deficiency
- Iodotyrosine deiodinase deficiency
- Thyroid stimulating hormone (TSH) deficiency
Treatment
- Replacement: thyroxine
3) Hyperthyroidism
Symptom: resembling an overdose of epinephrine. These include fast
heart beat and symptoms of palpitations, nervous system tremor such
as of the hands; weight loss.
Causes: a) pituitary tumor that produces higher TSH; b) an autoimmune
condition called Graves' disease. The body's immune system creates
an antibody that causes the gland to make an excessive amount of
thyroid hormone. c) Thyroiditis is inflammation of the thyroid. A virus or
problem with the immune system causes the gland to swell, leaking
thyroid hormone into the bloodstream. d) excessive iodine. e) thyroid
medications (e.g., hCG).

Note: too much hCG can also cause hyperthyroidism in pregnant women
because hCG and TSH share the same -subunit. hCG can activate TSH
receptor in the thyroid gland.
3) Hyperthyroidism
Graves' disease:
Symptoms: hyperthyroidism; eyes that bulge
out, or “protrude” (or exophthalmos).
Cause: due to an antibody, called thyroid
stimulating immunoglobulin (TSI). TSIs
recognize and bind to the thyrotropin receptor
(TSH receptor) which stimulates the secretion Exophthalmos in
of T4 and T3, leading to excess thyroid Graves’ disease
hormone.
Diagnosis: use blood tests and radioiodine
uptake to confirm the diagnosis.
- Blood tests: Raised T3 and T4, but low TSH,
and presence of TSI antibody
- Radioiodine uptake: increased in the thyroid
www.hsc.missouri.edu/~daveg/thyroid/thy_dis.html
 THYROID DISEASES

Treatment:
Propylthiouracil (PTU) is a
medication used to treat
hyperthyroidism. This includes
hyperthyroidism due to Graves'
disease and toxic multinodular
goiter.
Mechanism: Propylthiouracil (PTU)

PTU inhibits the enzyme

thyroperoxidase, which normally
acts in thyroid hormone
synthesis by oxidizing the anion
iodide (I−) to iodine (I0)
 Summary of changes in hormones in thyroid diseases

T4 TSH TRH
Primary hypothyroidism   
Pituitary hypothyroidism
(secondary)   
Pituitary hyperthyroidism
(secondary)   
Graves’ disease
(autoimmune)   