neuroendocrinology - feedback mechanism, GH

Question 1

what is a hormone?

Answer 1

A chemical signalling molecule secreted from an endocrine gland which acts on a target organ to exert and effect

Question 2

how is hormone different from a neurotransmitter

Answer 2

hormone has to transported in the blood to the target tissue and can have longest lasting actions (slower signal transmission)
neurotransmitter travel along axon terminals and synaptic clefts to communicate between never cells,

hormones produced by endocrine system, neurotransmitter produced by nervous system

only stimulate postsynaptic neurons

Question 3

can you name the 5 secretory cells of the anterior pituitary gland?

Answer 3

thyrotroph produce TSH -- 5%
gonadotroph produce LH/ FSH -- 10% 
cortIcotroph produce ACTH --15-20%
somatotroph produce GH -- 50%
lactotroph produce prolactin -- 10-25%

Question 4

describe how the post and ant pitutiary devlelop in embryo

Answer 4

ant: upgrowth of pharnyx // non neuronal tissue. forms Rathkes pouch after 4-5 weeks
post: down-growth of 3rd ventricle, neuronal tissue

Problems can lead to kallman syndrome - hypogobadism and lack of smell

Question 5

what is another name given to the posterior pituitary
A pars intermedia
B pars nervosa
C adenohypophysis
C median eminance
E neurohypophysis

Answer 5

OPTION B AND E

posterior pituitary relates to the nervous system

Question 6

what is the role of transcription factors in pituitary development?

Answer 6

they have different spacial and temporal expression which then regulate expression of different secretory cell types seen in the pituitary (specifically the anterior pituitary)
- between the infundibulum and the posterior pituitary
> TF prop-1 and pit-1 expression is key for somatotroph production
> corticotrophs are the only cells that do not derive from a progenitor cell/ has their own separate pathway with distinct TF used

Question 7

where are the cell bodies of the neurosecretory cells located that project into the Posterior Pit and the Anterior Pit?

Answer 7

hormones of the posterior pituitary are released from neurosecretory cells with cell bodies located in supraoptic nucleus (SON) and paraventricular nucleus (PVN)

hormones of the anterior pituitary are released from neurosecretory cells with cell bodies located in -
SON, PVN, arcuate and median preoptic nucleus as well!

Question 8

which cell bodies project to the posterior pituitary? what do they secrete? Whst stimulates them?

Answer 8

SON and PVN project to posterior pituitary.
they secrete ADH which is released upon low blood volume or increased plasma osmolarity , sensed by osmoreceptors to increase water reabsorption by kidney.

oxytocin which helps 1qwith lactation and can help with labour contractions. Suckling is a stimulant and can be sensed by stretch receptors in uterus

Question 9

why is growth hormone secreted in pulses whilst other hormones like TSH and GnRH have regular secretion?

Answer 9

GH is under both positive and negative control (GHRH, ghrelin and somastatin) so this will lead to pulses of secretion

the other hormones are under primary single positive control so there will be regular release of the hormone

Question 10

how do the magnocellular neurons and the parvocellular neurons (of the PVN) differ?
How do they affect the HP - adrenal axis

Answer 10

magnocellular neurons much larger and project into medial eminence and peptides released -> hypophyseal artery -> capillary plexus -> posterior pituitary so ADH is released in circulation

parvocellular neurons are smaller and project to median eminence and then into the primary plexus of the hypophyseal portal system but instead the vasopressin enters the anterior pituitary instead

> action of ADH in anterior pituitary will activate cortiotrophs to secrete ACTH

Question 11

why is levels of TRH hard to detect in circulation

Answer 11

TRH is a 3aa long peptide hormone so has a very short half life so very hard to detect

Question 12

how do the two types of lactotrophs differ?

Answer 12

> both types have a large nucleus
type 1 - have very few secretory granules are larger and seem to be a reservoir that can be utilized to increase prolactin secretion during pregnancy but are otherwise inactive

type 2 - have secretory granules are dense with small secretory granules which are active to secrete prolactin

Question 13

how might injury to the hypophyseal tract/portal system affect prolactin secretion?

Answer 13

may inhibit the release of amine - dopamine. So prolactin secretion will increase as it is no longer under primary single negative control

Question 14

for GH experiemtns, we can take ‘automated serial blood samples’ to track hormone levels. why can’t we just take one sample?

Answer 14

GH is secreted in pulses so we are unable to be certain if our single measurement represents peak or trough levels of GH so serial samples can help to track GH levels over a certain time period.

A single measurement would not be able to determine if that was a peak or low GH level

Question 15

decribe the structure of GH

Answer 15

Human Growth Hormone is a 191 AA protein containing:
• 4 a-helices
• 2 disulfide bridges - help to maintain tertiary structure
• 2 non-identical binding domains - important in receptor activation

Question 16

how does the GH-receptor differ in humans and rodents?
~ GHR/GHBP gene`

DRAW THIS

Answer 16

both transcribed from the GHR gene and have 10 exons
> mice has alternative exon 8a which produces a truncated protein thats secreted called growth hormone binding protein (GHBP)
> human GHBP is produced from the cleavage of GHreceptor at the transmembrane domain to create the GHBP

Question 17

how does GH bind to its receptor?

Answer 17

GH has 2 non identical binding domains
site1 has a higher affinity for the receptor so will bind first. This triggers the flex domain of the receptor to fold enabling site2 of GH to bind to the other half of the receptor dimer = trimeric complex formation

Now if we have too much GH then then all the receptor partners will also bond to site 1 so this flex folding and trimeric complex can’t form so actually inhibits the actions of GH

Question 18

explain why as GH concentration increases, the action of GH shows a bell shaped curve

Answer 18

this is beacuse the GH-r has a preference/ high affinitny for site1 of the GH.
so if there is too much GH, then both halfs of the GH-r dimer will bind to the site1 which then prevents the flex domain from folding and presenting site2 of GH to its partner receptor
so then GH action will decrease

Question 19

why does GH have so many effects on the body? (pleiotrophic actions

Answer 19

because GH- receptors are widely distributed in body and present in many tissue
> liver, chondrocytes, adipose, bone, cartilage
- brain, skeletal muscle. kidney

Question 20

how does GH levels compare between male and females

Answer 20

males have very large pulses of GH followed by periods of undetectable GH
females also have pulses of GH secretion but it is never 0

> experiments show that intermediate/pulses of GH is more effective on skeletal growth than continuous which could explain why males are larger than females

Question 21

amongst having enlarged digits and coarse and thick skin, why is visual disturbances a symptom of acromegly?

Answer 21

acromegly is exess GH. this could be caused by a tumour in the pituitary gland.
the pituitary glans which sits below the OPTIC CHIASM so a tumour could interfere with it and result in a visual disturbance

Question 22

what can we use to model GH dysfunction

Answer 22

guinea pigs are a good model of GH deficiency as they naturally do not have a functional growth hormone receptor so are a good model of Laron Syndome (very rare) and are dwarfs!
> treat with IGF-1

Question 23

describe conditions where there is growth hormone excess. How could you treat such conditions?

Answer 23

Acromegly in adults due to a pituitary gland tumour. So symptoms include visual disturbance, coarse facial features, thick skin, enlarged hands and feet

gigantism in children due ti pituitary gland tumour. So there is excess skeletal growth as GH acts on the open growth plates

> treat with somatostatin which will inhibit GH release. Can also use a mutant GH with a faulty site2 binding domain which prevents formation of trimeric complex (remeber the bell shaped curve)

Question 24

describe conditions where there is growth hormone deficiency. How could you treat such conditions?

Answer 24

dwarfism due to a benign tumour Craniopharyngiomas or even thrombosis of pituitary vessels preventing hormone in circulation. Symptoms include a reduced skeletal growth, reduced muscle mass, increased adipocity, increased bone fracture rate

> treat with recombinant Growth hormone // can be expensive and requires a high dosage

Question 25

how does laron syndrome and pygmy dwarfism differ

Answer 25

laron syndrome - rare form of dwarfism due to a mutation in GH-receptor so treat with IGF-1

pygmy dwarfim - dwarfism even in the womb due to mutation of IGF-1 receptor. Common in native tribes in Kalahari desert. Treat with recombinant GH

profound dwarfism - mutation in GHRH- receptor as seen in Sindh dwarves of pakistan. Treat with recombinant GH

Question 26

how does patterns of GH release affect lipolysis?

Answer 26

it seems that pulses of GH is more effective than continuous secretion at creating the lipolytic effect as there is an increase in glycerol release// an indicator of lipolysis

Interestly IGF1 release. Is increased in continuous exposure

Question 27

how does GH affect lipolysis?

Answer 27

GH will increase lipolysis which is the break down of TAG to FFA. Or more correctly it can prevent lipogenesis

1. can inhibit the differentiation of preadipocyte to adipocyte so reduces the number of adipocytes in tissue
2. can act on bone marrow to REVERSE adipogenesis so the size of fat droplets also decreases

Question 28

how does GH affect the growth plate ?

Answer 28

Acts on the resting zone of the Growth plate which have GHR and they begin differtiation

Also the Liver will release IGF1 in repsosen to growth hormone and it can then act on the proliferative zone of the growth plate for the chondrocutes to clonalky expand

Question 29

how does patterns of GH release affect skeletal growth?

Answer 29

it seems that pulses/intermittent of GH is more effective than continuous secretion on skeletal growth as length of fibula and tibia is longer

Question 30

what is the dual effector hypothesis for GH actions

Answer 30

GH acts on both the bone/growth plate to increase longitudinal growth and the liver to increase IGF-1 secretions

Growth plate has GHR on the resting zone and will respond to GH and begin differentiation and proliferative zone cam clonally expand and reponds to IGF1

interestingly IGF-1 removal doesnt affect skeletal growth so praps dual hypothesis is just a therory

Question 31

why would people with excess GH have diabetes/increased risk of?

Answer 31

as GH action is metabolic and can block the action of glucose to conserve it for the CNS
so over time patients with acromegly can develop insulin resistance or poor glucose tolerance// increased risk of hyperglycameia