Physiology of Growth Hormone Secretion Flashcards
Describe GHRH
-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
Describe somatostatin
- 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
What other hormones regulate GH?
-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
When is GH secreted?
- 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
How is GH secretion sexually dimorphic?
- Women have higher mean GH levels than men during the day
- May reflect sex differences in somatostatin
How do GH levels change with age?
- 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
What is the relationship between exercise and GH?
- 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
Describe GH signalling
- 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
What are the direct physiological effects of GH?
Adipocytes have GH receptors. GH stimulates them to break down TG & suppresses ability to take up circulating lipids
What are the indirect physiological effects of GH?
- Mediated primarily by IGF-1 secreted from the liver etc. in response to GH.
- Most growth promoting effects of GH due to IGF-1
Describe IGF-1
- 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
What are the 3 phases of growth (Karlberg model)?
- Infancy (0-2)
- Childhood (2+)
- Puberty
How is timing of growth different depending on sex?
-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
Describe the infancy period of growth
- Rapid deceleration in growth velocity (first couple of years)
- Largely nutritionally determined
Describe the childhood period of growth
- 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
Describe puberty
- GH + sex steroids
- Sex steroids are anabolic and have an effect on GH secretion
What are the causes of short stature and poor growth in childhood?
- 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
What are the central causes of short stature and poor growth in childhood?
-Pituitary abnormalities
=GH deficiency
=TSH deficiency
=Gonadotrophin deficiency
-Causes =Genetic =Tumours e.g. craniopharyngioma =Irradiation =Trauma
Describe Childhood GH deficiency
-1:4000 children
-GH treatment
-Other rare conditions:
=IGF-1 receptor abnormalities
=IGF-1 gene mutation
What are the symptoms of adult growth hormone deficiency?
- Decreased energy
- Social isolation
- Depressed mood
- Anxiety
- may reflect multiple endocrine abnormalities (thyroid, glucocorticoids, gonadotrophins)
What are the clinical features of adult hormone deficiency?
- Increased body fat
- Decreased muscle mass
- Decreased bone density, increased risk of fracture
- Impaired cardiac function
- Decreased insulin sensitivity and impaired glucose tolerance
What is the prevalence of adult growth hormone deficiency?
2-3 per 10,000
What are the causes of adult hormone deficiency?
- 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
Describe treatment for adult hormone deficiency
-GH
-Controversial
-Expensive +++
-May improve
=QOL
=Cardiovascular risk
=Lipids
=Exercise tolerance
=Body composition
=Bone health
What are the causes of GH excess?
-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
What are the symptoms of Acromegaly?
- Facial change, acral enlargement and soft-tissue swelling
- Excessive sweating
- Acroparesthesiae
- Tiredness and lethargy
- Headaches
- Amenorrhoea, infertility
- Diabetes
- Goitre
What happens in untreated acromegaly?
- 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
How do we treat acromegaly?
-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
How do we test for GH deficiency?
- Insulin tolerance test ITT (gold standard)= hypoglycaemia stimulus for GH production
- Arginine
- Clonidine
- Glucagon
- Overnight GH sampling (looking at pulsatility)
How do we test for GH excess?
-Give glucose for hyperglycaemia
=GH suppression (not in acromegaly)
