Physiology of Growth Hormone Secretion

Question 1

Describe GHRH

Answer 1

-Stimulatory factor controlling GH release
-GHRH - peptide synthesised by neurones in the arcuate nucleus, and released from neurosecretory terminals at the median eminence
-Binds to specific G-protein coupled receptor on pituitary somatotrophs.
=Stimulates GH synthesis and release from stored pools

Question 2

Describe somatostatin

Answer 2

• Inhibitory factor controlling GH secretion
• Somatostatin - peptide synthesised by neurosecretory neurones of the periventricular nucleus
• Somatostatin inhibits secretion of GH from somatotrophs and inhibits the secretion of GHRH

Question 3

What other hormones regulate GH?

Answer 3

-Oestrogen
-Thyroid hormone
=Hypothyroidism - poor growth, blunting of GH responses to stimuli & reduced pituitary GH levels
-Glucocorticoids
=Initial stimulatory effect but later suppressive effect (excess in childhood= short stature)
-Catecholamines
=Stimulatory effect
-Ghrelin
=Stimulatory effect

Question 4

When is GH secreted?

Answer 4

• Pulsatile, circadian rhythm
• On average 10 pulses per day
• Peak in slow wave sleep (affected by ‘jet-lag’)
• Not affected by continuous GHRH administration or by inactivating mutations GHRH receptor
• Probably determined by somatostatin pulsatility

Question 5

How is GH secretion sexually dimorphic?

Answer 5

• Women have higher mean GH levels than men during the day

- May reflect sex differences in somatostatin

Question 6

How do GH levels change with age?

Answer 6

• Decline with age
• Is there a role for GH in senescence, particularly altered body composition?
• GH levels are lower in obesity and are restored by massive weight loss

Question 7

What is the relationship between exercise and GH?

Answer 7

• Exercise - stimulant for GH secretion
• Occurs ~ 10-15 mins after start of exercise
• Anaerobic may be better stimulant than aerobic
• May be mediated by Ach, adrenaline, endogenous opioids

Question 8

Describe GH signalling

Answer 8

• One GH molecule binds to 2 GHR molecules leading to dimerisation
• Activation of receptor-associated Janus kinase, followed by STAT phosphorylation
• Translocates to nucleus and acts as a transcription factor
• Insulin-like growth factor-1 (IGF-1) gene activation

Question 9

What are the direct physiological effects of GH?

Answer 9

Adipocytes have GH receptors. GH stimulates them to break down TG & suppresses ability to take up circulating lipids

Question 10

What are the indirect physiological effects of GH?

Answer 10

• Mediated primarily by IGF-1 secreted from the liver etc. in response to GH.
• Most growth promoting effects of GH due to IGF-1

Question 11

Describe IGF-1

Answer 11

• Liver is principle source of circulating IGF-1
• Also produced by most other tissues
• Autocrine/paracrine effect probably responsible for most linear growth in children

Question 12

What are the 3 phases of growth (Karlberg model)?

Answer 12

• Infancy (0-2)
• Childhood (2+)
• Puberty

Question 13

How is timing of growth different depending on sex?

Answer 13

-Timing and amplitude different
=Infancy and childhood growth similar
=Girls tend not to have falling off in growth rate, puberty occurs earlier and to lower extent

Question 14

Describe the infancy period of growth

Answer 14

• Rapid deceleration in growth velocity (first couple of years)
• Largely nutritionally determined

Question 15

Describe the childhood period of growth

Answer 15

• Largely determined by GH secretion
• Growth till 3 years is an additive combination of infancy and childhood components
• So.. good nutrition remains key in first 2-3 years of life

Question 16

Describe puberty

Answer 16

• GH + sex steroids

- Sex steroids are anabolic and have an effect on GH secretion

Question 17

What are the causes of short stature and poor growth in childhood?

Answer 17

• Nutrition (anorexia as well)
• Chronic disease (e.g. CF, asthma, IBD, coeliac, renal, liver)
• Genetic conditions (Turner syndrome in girls, Trisomy 21, Noonan syndrome, skeletal dysplasias)
• Steroids (oral, topical, inhaled, endogenous)
• Hypothyroidism
• Psychosocial deprivation

Question 18

What are the central causes of short stature and poor growth in childhood?

Answer 18

-Pituitary abnormalities
=GH deficiency
=TSH deficiency
=Gonadotrophin deficiency

-Causes
=Genetic
=Tumours e.g. craniopharyngioma
=Irradiation
=Trauma

Question 19

Describe Childhood GH deficiency

Answer 19

-1:4000 children
-GH treatment
-Other rare conditions:
=IGF-1 receptor abnormalities
=IGF-1 gene mutation

Question 20

What are the symptoms of adult growth hormone deficiency?

Answer 20

• Decreased energy
• Social isolation
• Depressed mood
• Anxiety
• may reflect multiple endocrine abnormalities (thyroid, glucocorticoids, gonadotrophins)

Question 21

What are the clinical features of adult hormone deficiency?

Answer 21

• Increased body fat
• Decreased muscle mass
• Decreased bone density, increased risk of fracture
• Impaired cardiac function
• Decreased insulin sensitivity and impaired glucose tolerance

Question 22

What is the prevalence of adult growth hormone deficiency?

Answer 22

2-3 per 10,000

Question 23

What are the causes of adult hormone deficiency?

Answer 23

• 30% non-functioning pituitary adenoma
• ACTH secreting tumours
• GH-secreting pituitary adenoma
• Surgery
• Craniopharyngioma
• Irradiation
• Trauma
• usually occurs in context of other pituitary hormone abnormalities

Question 24

Describe treatment for adult hormone deficiency

Answer 24

-GH
-Controversial
-Expensive +++
-May improve
=QOL
=Cardiovascular risk
=Lipids
=Exercise tolerance
=Body composition
=Bone health

Question 25

What are the causes of GH excess?

Answer 25

-Tumour of pituitary (99%)
=Before epiphyses have fused: gigantism
=After growing ends of long bones have fused: acromegaly (prevalence 50-60 per million)
-Rare other causes inc. McCune-Albright

Question 26

What are the symptoms of Acromegaly?

Answer 26

• Facial change, acral enlargement and soft-tissue swelling
• Excessive sweating
• Acroparesthesiae
• Tiredness and lethargy
• Headaches
• Amenorrhoea, infertility
• Diabetes
• Goitre

Question 27

What happens in untreated acromegaly?

Answer 27

• Untreated acromegaly - increase in morbidity, overall mortality at least 2x general population.
• Early studies: > 50% of patients dead by 60yrs (diabetes, cardiovascular, respiratory or cerebrovascular disease)
• Improved treatment of disease and complications means patients are surviving longer. May then be susceptible to other complications such as malignancy

Question 28

How do we treat acromegaly?

Answer 28

-Aims: Normalise GH levels, reduce tumour size, preserve anterior pituitary function

-Surgery – transphenoidal if possible (may use medical therapy to shrink tumour first)
-Drugs – if surgery fails
=Somatostatin analogues (octreotide, lantreotide, pasireotide)
=Long-acting GH receptor antagonist – pegvisomant. A modified recombinant GH molecule which prevents GH receptor dimerisation
=Dopamine agonists (if concurrent high prolactin – works in <10%)
-Radiotherapy - if surgery fails and control difficult

Question 29

How do we test for GH deficiency?

Answer 29

• Insulin tolerance test ITT (gold standard)= hypoglycaemia stimulus for GH production
• Arginine
• Clonidine
• Glucagon
• Overnight GH sampling (looking at pulsatility)

Question 30

How do we test for GH excess?

Answer 30

-Give glucose for hyperglycaemia

=GH suppression (not in acromegaly)