Thyroid and Parathyroid

Hormones

Endocrine Module – Med 7524

(Biochemistry)
 Learning Competencies

1. Describe the structure of the thyroid and

parathyroid glands
2. Explain the hypothalamo-pituitary-thyroid
axis
3. Discuss the biosynthesis, regulation of
secretion, transport in the blood, metabolism
and the biologic functions of the thyroid,
parathyroid glands and calcitonin
4. Explain the pathophysiological mechanisms
of the different disorders of the glands
5. Discuss calcitonin
Thyroid Gland Parathyroid Gland
 Hypothalamo-thyroid
axis
➢ Tissues become sensitive
to epinephrine

➢ Increase cellular
respiration, O2 use and
metabolism

➢ Heat generation and

thermoregulation

➢ Growth and development

 Thyroid Hormones
⚫ There are two thyroid hormones:
1) T3 - triiodothyronine
2) T4 – tetraiodothyronine (thyroxine)

⚫ Important in regulating general metabolism.

- regulator of basal metabolic rate (BMR)

⚫ They require iodine for biologic activity.

⚫ Synthesis takes place in thyroglobulin.

 Thyroglobulin
⚫ Precursor of T3 and T4.
⚫ Large, iodinated, glycosylated protein.
⚫ Composed of two subunits.
⚫ Contain 114 tyrosine residues which are potential
sites of iodination.
⚫ It is a prohormone synthesized in the basal portion of
the follicular cell & stored in extracellular colloid.
⚫ 70% of iodide exists in the form of inactive
precursors: a) monoiodotyrosine (MIT) and
b) diiodotyrosine (DIT).
⚫ 30% of iodide are in the form of T3 and T4.
⚫ Normal T4:T3 ratio is 7:1.
 Three Phases of Thyroid Hormone
Synthesis
A. Iodine uptake and concentration of iodide

- there are 6 to 7 mg of iodine in the body, 90% of

which are in the thyroid gland
- thyroid tissue:blood ratio = 20:1
- thyroid gland is able to concentrate iodine against a
strong electrochemical gradient
- active transport is coupled to the ATPase dependent
Na-K pump
- involves sodium-iodide transporter, activity of
which is primarily controlled by TSH
 Inhibitors of Iodide Transporter
⚫ Class I - anions that compete with iodide
for its carrier and concentrated by the
thyroid.
e.g. perchlorate, perrhenate & pertechnetate
⚫ Class II - competitive inhibitors of iodide
transport but are not concentrated by the
thyroid.
e.g. thiocyanate

❖ Ouabain, an inhibitor of Na+/K–-ATPase,

which powers NIS transport.
 Oxidation of iodide
⚫ An obligatory step in iodide organification and thyroid
hormone biosynthesis

⚫ Involves a heme-containing thyroperoxidase (TPO)

- tetrameric protein
- requires hydrogen peroxide as an oxidizing agent

⚫ Inhibited by thiourea drugs (antithyroid drugs)

 B. Iodination of tyrosine
(organification of iodide)
⚫ Takes place in luminal thyroglobulin
⚫ Also involves thyroperoxidase
⚫ Formation of MIT (monoiodtyrosine) and
DIT (diiodotyrosine)
⚫ Coupling of iodotyrosyls to form thyronine
hormones:
⚫ DIT + DIT = T4 (thyroxine, tetraiodothyronine)
⚫ DIT + MIT = T3
⚫ Also inhibited by thiourea drugs
 C. Thyroglobulin hydrolysis
⚫ Removal of thyroglobulin from the colloid through
endocytosis and back to follicular cell.
⚫ Hydrolysis of thyroglobulin within phagolysosomes.
⚫ Stimulated by TSH
⚫ Inhibited by potassium iodide
⚫ Release of T4 and T3 into the blood stream bound to
thyroxine-binding globulin (TBG).

⚫ 50 ug of thyroid hormone iodide is secreted/day.

⚫ Daily iodide requirement is bet. 150 and 200 ug.
⚫ Iodide from MIT and DIT is scavenged by deiodinase.
 Transport of Thyroid hormones
⚫ One-half to two-thirds of T4 and T3 in the body is
extrathyroidal.
⚫ Most circulates in bound form to:
a) thyroxine-binding globulin (TBG) and
b) thyroxine-binding prealbumin (TBPA)

⚫ TBG is the most important

⚫ It has 100 times the affinity of TBPA
⚫ Has the capacity to bind 20 ug/dl of T4 & T3

⚫ Unbound thyroid hormones are responsible for

biologic activity
 Metabolism of Thyroid Hormones
➢ Plasma half-life of T4 is four to five times that of T3
➢ Extrathyroidal deiodination converts T4 to T3 (also
called reverse T3 or rT3)

➢ T3 binds to thyroid receptors with 10 times the

affinity of T4
➢ T3 is the metabolically active form of the hormone

➢ 80% of circulating T4 is converted to T3 in the liver

and kidney.
➢ Propylthiouracil and propranolol decrease the
conversion of T4 to T3
 Physiologic Effects of Thyroid Hormones
⚫ Regulator of development
⚫ Catalyst for oxidative reactions
⚫ Regulator of metabolic rates

⚫ A. Effects of moderate concentrations

⚫ - Anabolic effects, increased RNA synthesis,
⚫ increased amino acid transport and Increased protein
synthesis

⚫ B. Effects of high concentrations

- Negative nitrogen balance, decreased protein
synthesis, increased carbohydrate and lipid turnover and
uncoupling of oxidative phosphorylation
 Mechanism of Action
⚫ Thyroid hormones bind to specific high-affinity
receptors in the target cell nucleus.

⚫ Major effect is enhanced protein synthesis and

positive nitrogen balance.

⚫ They induce or repress proteins by increasing or

decreasing gene transcription.

⚫ T3 enhance transcription of growth hormone gene.

 Thyroid Hormones in Disease States
⚫ Goiter is enlargement of the thyroid gland.

⚫ Simple goiter represents an attempt to

compensate for decreased thyroid hormone
synthesis.
⚫ - elevated TSH is the common denominator
- caused by deficiency of iodine in the diet or
- metabolic defects involving the various steps in
thyroid hormone synthesis

⚫ Simple goiter is treated with exogenous thyroid

hormone
 Hyperthyroidism

➢ Also called thyrotoxicosis

➢ Hypermetabolic condition associated with
elevated levels of T4 and T3.
➢ Caused by excess synthesis and secretion of thyroid
hormone by the thyroid

Signs and symptoms: Nervousness, anxiety, increased

perspiration, heat intolerance, tremor, hyperactivity,
palpitations, weight loss despite increased appetite,
reduction in menstrual flow or oligomenorrhea (in
women and tachycardia or atrial arrhrythmia
 Most common forms of hyperthyroidism

⚫ - Graves’ disease (Basedow’s disease; most

common with 70-80%)
⚫ - Toxic multinodular goiter (Plummer disease; 15-20%)
⚫ - Toxic adenoma (Hurthle cell adenoma; 3-5%)

A. Hurthle cell adenoma

- a rare benign tumor, typically seen in women
between the ages of 70 and 80 years old
- typically such a mass is removed because it is not
easy to predict whether it will transform into the
malignant counterpart,
- a subtype of follicular thyroid cancer called a
Hürthle cell carcinoma.
B. Toxic multinodular goiter (Plummer disease)

➢ second most common cause of hyperthyroidism

➢ most thyroid nodules are harmless, but some
can be cancerous
➢ usually not a life-threatening condition
 C. Graves Disease
⚫ - Also called Basedow’s disease or Graves-Basedow
disease
⚫ - Caused by an antibody-mediated autoimmune
reaction
⚫ - Manifestations:

1. Goiter – a swelling in the neck just below the

adam’s apple
2. Exophthalmos – protuberance of one or both eyes
3. A non-pitting edema describe as “peau d’orange
(resembling the skin of an orange)
4. Fatigue, weight loss & other symptoms of
hyperthyroidism
 Exophthalmos lid retraction (upper)
lid lag (lower)
- both left eye affected
➢ In exophthalmos the immune system attacks the
muscles and fatty tissues around and behind the
eye, making them swollen.
 Hypothyroidism
- Due to insufficient production of thyroid hormone by
the thyroid gland
- Causes:

1. Iodine deficiency – most common cause world-wide

2. Hashimoto’s thyroiditis – autoimmune disease; a
condition in which your immune system attacks
your thyroid gland
3. Radioactive iodine therapy for hyperthyroidism
4. Secondary hypothyroidism – pituitary gland does not
produce enough TSH
5. Tertiary hypothyroidism – hypothalamus lacks
thyrotropin releasing hormone
 Chemistry and Metabolism of the
Parathyroid Hormone
A. Chemistry
- 84 amino acid polypeptide hormone
- biologic activity resides in N-terminal 1- 34 amino
acid residues
- 5th – 34th amino acids responsible for receptor
binding

B. Synthesis: PreproPTH

ProPTH → Parathormone
C. Storage
- Parathormone is stored in secretary granules
for release in response to a reduction in the levels
of ionized calcium.

D. Degradation
- Degraded by cathepsins in the parathyroid
gland and in the Kupffer cells in the liver.

E. Regulation of secretion

Decreased serum Ca → increases PTH secretion

 Mechanism of Action

PTH-receptor complex (+) adenylate cyclase

increased cAMP

increased calcium

phosphorylation of specific proteins by kinases

activation of enzymes
 Biologic Effects
-Maintenance of calcium balance
A. Long-term effect
- stimulate calcitriol synthesis increase
intestinal absorption of calcium

B. Effects on bones
- increased dissolution of bones increase
calcium in the ECF (largest effect)

C. Effects on kidney
- decreased renal excretion of calcium
increase calcium in ECF (rapid effect)
 Biologic effects

D. Effects on phosphate homeostasis

1. Increased removal of PO4 from bones
2. Increased renal excretion of PO4

Net effect – increased calcium and decreased

phosphate in ECF
 Pathophysiology

⚫ A. Hypoparathyroidism
1. Primary – autoimmune destruction
2. Secondary – accidental removal during
thyroid surgery

Biochemical hallmark – decreased calcium and

increased phosphate in the serum

Manifestations – increased neuromuscular

irritability, tetany and muscle cramps
 B. Pseudohypoparathyroidism

⚫ Deficiency of G adenylate cyclase regulatory

protein

⚫ Defective step beyond formation of cAMP

⚫ Biologically active PTH but there is end-organ

resistance
 C. Hyperparathyroidism

A. Causes:
- Parathyroid adenoma
- Parathyroid hyperplasia
- Ectopic production

B. Biochemical hallmark
- Increased serum Ca and decreased PO4
- Increased bone resorption
- Osteoporosis
- Kidney stones
 Calcitonin

➢ a hormone that is produced in humans by the

parafollicular cells (commonly known as C-cells) of
the thyroid gland
➢ peptide with 32 amino acids
➢ lowers blood levels of calcium by inhibiting the
resorption of bone
➢ involved in helping to regulate levels of calcium
and phosphate in the blood, opposing the action of
parathyroid hormone
➢ release is stimulated by increase in calcium levels
in the blood
 References

1. Harper’s Illustrated Biochemistry 30th Edition

by Rodwell, Bender, Botham, Kennelly and Weil
2. Lehninger Principles of Biochemistry 5th Edition
by Nelson and Cox
3. Textbook of Biochemistry With Clinical Correlation
6th Edition by Thomas M. Devlin
4. Lippincott’s Biochemistry 5th Edition
by Champe and Harvey
5. Textbook of Medical Physiology 13th Edition
by Guyton and Hall