Drug Effects on the Hypothalamo-Pituitary Axis

Question 1

What is the effect of ghrelin on GH release?

Answer 1

Stimulates

Question 2

What is the abnormality in GH insensitivity? What are the biochemical findings?

Answer 2

GH fails to stimulate IGF-1 release

Increased GH, decreased IGF-1

Question 3

What is the abnormality in secondary GH deficiency? What are the biochemical findings?

Answer 3

The pituitary does not produce GH

Decreased GH, decreased IGF-1

Question 4

What is the abnormality in tertiary GH deficiency? What are the biochemical findings?

Answer 4

Most commonly there is no production of GHRH (but can also be absence of ghrelin), due to variety of causes
Decreased GH, decreased IGF-1, decreased GHRH or ghrelin

Question 5

Why can’t GH be given orally?

Answer 5

It has zero bioavailability after oral administration as it is a peptide hormone and is broken down by the liver (first-pass metabolism)

Question 6

How is GH administered?

Answer 6

Daily or multi-daily parenterally via injection

Question 7

What is the effect of GH on T4?

Answer 7

Can reduce T4 levels

Question 8

Does GH have a short or long half-life?

Answer 8

Short; it is a peptide hormone

Question 9

What is the relationship between GHRH and ghrelin?

Answer 9

Synergistic (stimulation of the GHRH receptor elevates cAMP, and stimulation of the ghrelin receptor elevates Ca2+)

Question 10

What is the possible therapeutic application of ghrelin?

Answer 10

Therapy for GH deficiency and eating-related disorders

Question 11

What is the 2 therapeutic applications of IGF-1? What is 1 possible side effect?

Answer 11

For GH-insensitivity (Laron dwarfism) and patients with anti-GH antibodies
May cause hypoglycaemia

Question 12

What are the 3 possible treatment options for GH excess?

Answer 12

Tumour removal (if relevant)
Reduction of GH release via somatostain analogues or DA antagonist
Inhibition of GH action via GH antagonist or GH receptor antagonist

Question 13

What is pegvisomant?

Answer 13

A GH receptor antagonist

Question 14

How can GH-secreting tumours be located?

Answer 14

Treating the patient with a circulating tagged somatostatin analogue, which binds SST2 receptors
SST2 receptors internalise upon activation (like many GPCRs), taking the radioligand with it
The tumour can then be visualised by in vivo receptor scintigraphy

Question 15

What effect does somatostatin have on the pituitary?

Answer 15

Reduces GH release

Can also reduce TSH release

Question 16

What is the problem with using somatostatin as a potential therapy for GH excess? How can these be overcome?

Answer 16

Requires parenteral administration and has a short half-life

Can be overcome by using analogues with “unnatural” AAs (e.g. D-AAs), as these confer resistance to enzymatic cleavage

Question 17

Give 2 examples of somatostatin analogues

Answer 17

Octreotide

Lanreotide

Question 18

How can the effectiveness of somatostatin analogues be increased?

Answer 18

By including a DA agonist (e.g. bromocriptine or cabergoline)

Question 19

How do GH antagonists work?

Answer 19

By replacing the glycine at position 120 in hGH (119 in mice), necessary as it produces a cleft in the hormone which allows for site 2 binding and receptor activation, with a lysine residue (the side chain prevents site 2 binding)

Question 20

What type of receptor is the GH receptor? Describe its structure

Answer 20

Tyrosine kinase-type

Has 2 binding sites; binding site 1 is high affinity, site 2 is lower affinity but leads to receptor activation

Question 21

How can the half-life of GH antagonists be increased? How is this achieved?

Answer 21

Via PEGylation
Increases the size of the molecule to reduce renal filtration
PEG hydrophilicity improves solubility
Decreases accessibility for proteolytic enzymes

Question 22

What is the drawback of PEGylation of GH antagonists?

Answer 22

PEGylation occurs at lysines, which are required for site 1 binding, and so the binding affinity is reduced

Question 23

What is B2036? What advantages and disadvantages does it have compared with PEGylated GH antagonists?

Answer 23

A GH antagonist with 9 mutations
Retains lysine residues so has good affinity
No PEGylation so has a short half-life

Question 24

What is the difference in terms of the actions and daily dosing of carbimazole and propylthiouracil?

Answer 24

Carbimazole inhibits TPO; given once daily

Propylthiouracil inhibits TPO and deiodinase; given 2-4 times daily

Question 25

What are the drawbacks of using thioamines (including propylthiouracil and carbimazole) to treat hyperthyroidism?

Answer 25

May lead to goitre
A large initial dose is required with smaller maintenance doses
May cause agranulocytosis (occurs rapidly so monitoring is not useful unless there is a clinical indication)
Propylthiouracil may cause hepatotoxicity (LFTs should be performed)

Question 26

What is liothyronine? What is it used to treat?

Answer 26

A T3 analogue

Usually used only in severe hypothyroidism and myxoedemic coma

Question 27

What is the difference in half-life between liothyronine and thyroxine?

Answer 27

Liothyronine is less strongly protein-bound and so has a shorter half-life (~1 day)

Question 28

What is the volume of distribution of thyroxine? What is the half-life and how is it dosed?

Answer 28

~10L

Half-life of 7 days; typically 1/7 dose is taken every day as this is easier for patients to remember

Question 29

Why is there sometimes poor compliance in thyroxine therapy?

Answer 29

There is slow accumulation of thyroxine, potentially causing side effects
Onset of action is slow
Dose often needs adjustment

Question 30

What is the relationship between T3 and cortisol?

Answer 30

Cortisol inhibits conversion of T4 to T3

T3 inhibits cortisol production