Transport and regulation

Question 1

Why is regulation of hormones necessary?

Answer 1

Effective action at the correct tissue (spatial regulation), at the correct time (temporal regulation)
To avoid unwanted side effects

Question 2

How are peptide hormones transported in the blood?

Answer 2

eg. insulin, TSH, CRH, PTH
Water soluble
Hydrophilic
Dissolve in the plasma

Question 3

How are steroid hormones transported in the blood?

Answer 3

eg. estradiol, progesterone, vitamin D
Not water soluble
Lipophilic
95-99% bound to plasma carrier proteins aka hormone binding proteins

Question 4

How are amino-acid derived hormones transported in the blood?

Answer 4

eg. thyroid hormones, melatonin, adrenaline
Not water soluble
Lipophilic
Hormone binding proteins

Question 5

What do oestradiol and testosterone bind to?

Answer 5

Sex hormone binding globulin

Question 6

What do glucocorticoids bind to?

Answer 6

Corticosteroid binding globulin

Question 7

What does vitamin D bind to?

Answer 7

Vitamin D binding globulin

Question 8

What do thyroid hormones bind to?

Answer 8

Thyroid binding globulin and transthyretin

Question 9

What is the non-selective binding protein?

Answer 9

Albumin

Question 10

What proportion of cortisol, aldosterone and progesterone bind to albumin?

Answer 10

25%
47%
80%

Question 11

What are the roles of hormone binding proteins?

Answer 11

Maintain a constant free hormone level
Maintain a large pool of hormone outside the endocrine gland
Safeguard the body from abrupt hormone fluctuations
Facilitate uniform cellular distribution
Allow site-specific delivery

Question 12

Which hormones bind which receptors?

Answer 12

Peptide - cell surface receptors

Steroid and thyroid - intracellular receptors

Question 13

What is the free hormone hypothesis?

Answer 13

Steroids and thyroid hormones reach their intracellular targets by passive diffusion
Hormones bound to proteins are inactive
There is an equilibrium between the free and protein bound form of the hormone

Question 14

Describe steroid hormone uptake

Answer 14

Existence of cell surface binding sites for hormone binding proteins
Multiple roles: receptor for transmembrane signalling, local sequestration, mediate cellular uptake

Question 15

What is megalin?

Answer 15

A receptor for the uptake of carrier bound vitamin D
Member of LDL receptor family
Expressed on apical surface of absorptive epithelia
Works alongside cubulin
KO = rickets
Shown in vitro to have many ligands
Prevents urinary loss of many hormones
Also binds SHBG (specifically to deliver DHT)
Can be blocked by receptor-associated protein
KO mice = closed vagina cavity and testicular maldescent
Needed for sexual maturation

Question 16

What are the implications of binding globulins?

Answer 16

Not only free hormones are biologically relevant

Drugs that affect BP can impact endocrine function

Question 17

What is vitamin D bound to?

Answer 17

90% to vitamin D BP
10% to albumin
0.1% is free
Albumin binding is weaker but the amount of albumin is 100x that of vitamin D BP
Free vitamin D correlates to bone mineral density

Question 18

Describe polymorphisms in vitamin D BP

Answer 18

SNP change the affinity for vitamin D
Different between black and white
Variants Gc1F and GC1S
Total vitamin D lower in blacks, vitamin D binding protein also lower
Free vitamin D is comparable

Question 19

How are thyroid hormones transported?

Answer 19

Monocarboxylate: MCT8 and MCT10
System L amino acid: LAT1 and LAT2
Organic anion polypeptide: OATP1C1, OATP1A2, OATP1A4
Facilitated diffusion
Different distributions around the body

Question 20

What are the affinities for T3 and T4?

Answer 20

MCT8 for T3

MC10 for T4

Question 21

What is an example of microvillus membrane vesicles?

Answer 21

The placenta (synctiotrophoblasts) express a lot of TH receptors on the apical surface to take TH from the maternal blood

Question 22

Describe mutations in MCT8

Answer 22

Located on X chromosome
Male patients with inherited defective form have altered serum thyroid hormone levels
Low T4 and elevated T3
Causes Allan-Herndon-Dudley syndrome

Question 23

What is Allan-Herndon-Dudley syndrome?

Answer 23

Global neurodevelopment delay
Absence of speech development
Severe axial hypotonia
Muscle hypoplasia
Spastic quadriplegia
50+ families globally
MCT8 is essential in neuron function