Lecture 31: Thyroid Gland Pharmacology

Question 1

What is the thyroid gland?

Answer 1

“butterfly” shaped gland at the base of the neck

Question 2

What are the two classes of hormones that the thyroid gland releases?

Answer 2

T3 (triiodothyronine - MOST ACTIVE) and T4 (thyroxine) thyroid hormones

Calcitonin

Question 3

What are the multiple levels of hormonal control of thyroid hormone production?

Answer 3

TRH (Thyrotropin releasing hormone, hypothalamus)

TSH (thyroid stimulating hormone, anterior pituitary)

T3 and T4 exert negative feedback on both upstream glands

Question 4

What are the powerful physiological effects of thyroid hormone?

Answer 4

increased basal metabolic rate

sensitization to catecholamines (increased cardiac output, heart rate, breathing rate)

important role in growth and development

Question 5

What are thyroid hormones made up of?

Answer 5

thyroid hormones are made up of 2 modified tyrosine molecules

the precursor protein (thyroglobulin) is tyrosine rich

the tyrosines are enzymatically iodinated (iodine atoms added to the aromatic ring), 1 or 2 iodines per tyrosine ring

iodinated tyrosines are enzymatically coupled (2 linked rings)

TSH stimulation causes this precursor protein to be endocytosed and processed, followed by release of T4 and T3 (T4 is the predominant form that is released)

Question 6

What is the “apical” side (follicle lumen)?

Answer 6

iodination and coupling of thyroglobulin happen here

Question 7

What is the intracellular?

Answer 7

processing of thyroglobulin after it has been iodinated and coupled

Question 8

What is the “basolateral” side (bloodstream)?

Answer 8

T4 and T3 are released here after being generated from thyroglobulin

Question 9

What the accumulation of iodine in thyroid?

Answer 9

the thyroid gland concentrates iodide from the bloodstream (Na+/I- co-transporter)

iodine is transported into the folic lumen, and eventually added to thyroglobulin tyrosines during the iodination step

Question 10

What is the thyroid hormone receptor?

Answer 10

thyroid hormones “break the rules” from what we have learned so far

the thyroid hormone receptor is an intracellular type receptor - acts as a transcription factor after binding of thyroid hormone

however, T3 and T4 are not very lipid soluble and need to be taken up into cells by a transporter protein (many different types) in order to reach their receptors

Question 11

What is the mechanism of action of thyroid hormone?

Answer 11

at rest, unbound thyroid hormone receptors can associate with response elements (TRE) and recruit co-repressors (weakens gene transcription)

T4 and T3 are taken up via a transmembrane receptor, and T4 is typically de-iodinated to form T3

T3 binding in the nucleus causes recruitment of RXR (retinoic acid receptor) to form a heterodimer with the thyroid hormone receptor

recruitment of co-activators leads to enhanced transcription of target genes

Question 12

What is hypothyroidism?

Answer 12

deficient thyroid function

not enough release of thyroid hormone

Question 13

What are the most common causes of hypothyroidism?

Answer 13

iodine deficiency (dietary)

autoimmunity towards thyroid (Hashimoto’s thyroiditis)

congenital defect

inappropriate hormonal regulation (insufficient TSH or TRH)

Question 14

What are the symptoms of hypothyroidism?

Answer 14

fatigue
weight gain
hypersensitivity to cold
bradycardia

Question 15

What is the diagnosis of thpothyroidism?

Answer 15

measurement of TSH is helpful to know whether hypothyroidism is primary vs. seocndary

Question 16

What is primary hypothyroidism?

Answer 16

cause: defect in thyroid function

features: low T4 and T3, high TSH

Question 17

What is secondary hypothyroidism?

Answer 17

cause: central defect (poor function of anterior pituitary or hypothalamus)

features: low T4 and T3, low TSH

Question 18

What is the treatment of hypothyroidism?

Answer 18

hormone replacement, most commonly with synthetic thyroxine (T4) (levothyroxine) extremely commonly prescribed

Question 19

What is hyperthyroidism?

Answer 19

overactive thyroid function

excessive production of thyroid hormone

Question 20

What are the most common causes of hyperthyroidism?

Answer 20

Graves’ disease (stimulatory auto-antibodies against TSH receptor, these activate the receptor leading to excess thyroid hormone release

hyperplasia of the thyroid leading to excess thyroid hormone release (thyroid adenoma, goiter)

Question 21

What are the symptoms of hyperthyroidism?

Answer 21

sleep difficulty
heat (temperature) intolerance
tachycardia
weight loss
tremor

Question 22

What is the diagnosis of hyperthyroidism?

Answer 22

similar to hypothyroidism, measurement of TSH is helpful to determine underlying cause

also, detection of anti-TSH receptor antibodies

Question 23

What is Graves’ disease?

Answer 23

cause: stimulation of thyroid by anti-TSH receptor antibodies (stimulatory)

features: high T4 and T3, low TSH, detection of anti-TSH receptor antibodies “bulging eyes”, exopthalmos

Question 24

What is thyroid hyperplasia?

Answer 24

cause: thyroid adenoma, goiter

features: high T4 and T3, low TSH

Question 25

What is secondary hyperthyroidism?

Answer 25

uncommon

cause: central defect (excessive production of TSH by anterior pituitary)

features: high T4 and T3, high TSH

Question 26

How are both Graves’ disease and Hashimoto’s thyroiditis are auto-immune diseases?

Answer 26

in Graves’ disease, the antibodies cause stimulation of the TSH receptor

in Hashimoto’s thyroiditis, antibodies recognize other thyroid-specific proteins and lead to damage of the thyroid

Question 27

What is exophthalmos?

Answer 27

“bulging eyes”

primarily due to autoimmune damage of muscle/fibroblasts in the eye

Question 28

What is a goiter?

Answer 28

swelling in the neck

in Graves’ disease this is due to overactivation of thyroid tissue (by stimulatory antibodies)

but goiter may also arise in cases of hypothyroidism (such as iodine deficiency) due to increased TSH levels

Question 29

What is surgery as treatment for hyperthyroidism?

Answer 29

resection of part or all of thyroid, followed by hormone replacement

Question 30

What are the drawbacks to surgery as treatment for hyperthyroidism?

Answer 30

danger of disrupting parathyroid glands (Ca2+ disturbances), needs management for hypothyroidism (and possibly hypoparathyroidism)

Question 31

What is radioactive iodine treatment as treatment for hyperthyroidism?

Answer 31

iodine is concentrated within the thyroid, radiation leads to destruction of the thyroid

Question 32

What are the drawbacks to radioactive iodine treatment as treatment for hyperthyroidism?

Answer 32

should not be used in pregnancy, nursing (irreversible destruction of thyroid in the infant)

Question 33

What is anti-thyroid drugs (methimazole) as treatment for hyperthyroidism?

Answer 33

prevents several steps in T4/T3 synthesis

Question 34

What are the drawbacks to anti-thyroid drugs (methimazole) as treatment for hyperthyroidism?

Answer 34

diverse side effects

Question 35

What is symptomatic treatment with beta-blockers as treatment for hyperthyroidism?

Answer 35

may help with issues such as tachycardia

Question 36

What are the drawbacks to symptomatic treatment with beta-blockers as treatment for hyperthyroidism?

Answer 36

does not influence underlying cause of the disease

Question 37

What are thioamides?

Answer 37

e.g. Methimazole

prevent iodination and coupling steps (mediated by thyroperoxidase enzyme)