Growth and Disorders Flashcards
Describe the circulating GH molecules composition
Heterogenous composition of 22kDa and 20kDa. 75% of the pituitary GH secretion is of the 22kDa form. 20kDa has diabetogenic effects
Name some factors affecting GH secretion
The secretion can be increased during exercise, physical stress, trauma, hypovolaemic shock, infusion of single amino acids. Whereas decreased in emotional deprivation or hyperglycaemia. The gonadal steroids appear to be responsible for the rise in GH secretion in puberty.
What are the actions of GH?
This activation occurs by binding to 2 GH receptors causing signaling via JAK/STAT to stimulate epiphyseal growth. Stimulates osteoclast differentiation and activity, as well as osteoblast in the bone to increase bone mass formation (endochondral bone formation). GH acts on adipose to induce acute insulin-like effects, decreasing glucose transport, decreased lipogenesis.
It acts on the muscle to increase AA transport, increase N retention and increase energy expenditure.
What is the insulin like growth factor-1?
This mediates many of the anabolic and mitogenic actions of growth hormones. It can induce cellular change by binding to IGF-1 receptors or insulin receptors. The mitogenic and metabolic effects occur by binding to type I IGF receptors.
How can growth abnormalities be monitored and discovered?
The most basic tool useful to monitor the progression/severity of a growth abnormality is using the height vs weight chart to determine the growth velocity
What are primary growth syndromes? Onset?
Can be chromosomal abnormalities (down syndrome) or osteochondrodysplasia (genetic transmission). Can develop as early as gestational age due to intrauterine growth retardation.
The earlier it occurs the less likely complete recapture will occur. It can be caused by maternal and placental factors or intrinsic foetal factors.
State some primary growth disorders
Russel silver Noonans Cockaynes progeria Prader-willi
What are some causes of secondary growth disorders?
Emotional deprivation has shown to decrease GH secretion
- Chronic disease associated with malabsorption, poor intake, and increased metabolic rate
- e.g. DM, pulmonary disease, renal diseas, CKD, chronic inflammation
- Endocrine disorders have also been shown to induce secondary growth disorders
- e.g. IGF-1 def, GH def, hypothyroidism, rickets
What is constitutional delay in puberty and how is it examined?
Later pubertal growth spurt so short compared to peers - typically a family history associated with it.
Diagnosis: by comparing chronological age to bone age determined from X-ray of and wrist. Show chronological age greater than bone age
How is constitutional delay in puberty dealt with?
Accelarte the onset of puberty by administering testosterone - but can reduce height potenital
What are the characteristics of GH deficiency?
low GH and IGF-1
What causes GH def?
- congenital abnormalities of hypothalamus
- inflammation of brain
- trauma
- GHRH receptor defects
Symptoms of GH def
Short stature Decreased height velocity Delayed bone age Delayed dentition Prolonged jaundice
How is the diagnosis of GH done?
Random GH measurements are not very useful as its secretion occurs in a pulsatile manner. Instead physiological and pharmacological tests are used in diagnosis
What physiological tests are used to diagnose GH def?
Exercise test
- GH secretion should increase following exercise
- 15min of exercise with heart rate of >150.
Sleep studies
- Sample GH secretion in your sleep 15x2 min intervals
- most effective in children
What pharmacological tests are used to diagnose GH def?
Tests include insulin tolerance test, glucagon stimulation test, clonidine stimulation test, arginine stimulation test
Describe the clonidine stimulation test
Patients will be given clonidine orally and samples are taken in 30 min intervals (180min). This is a direct GH stimulation.
- Normal peak of GH > 6.5 ug/L
Describe arginine stimulation test
GH secretion is stimulated by a single amino acid.
- Patient will be given 0.5g/Kg to a maximum of 30g in 100mL saline over 3 min, and samples will be collected every 30min (150min)
- Pre-pubertal teens will require sex steroid priming
What is IGF-I def caused by?
This condition is often caused by GH deficiency, due to GH insensitivity
- Secondary cause include antibodies to GH or GHR
What is GH insensitivity caused by?
- Gh receptor abnormalities
- Post receptor abmnormalities of GH signal transduction
- Primary defects of IGF1 biosynthesis
Treatment of GH def
In children daily growth hormone replacement can be given.
GH insensitivity requires recombinant of IGF-1.
How do adults present GH deficiency?
- increased CVD risk,
- depression & anxiety,
- unfavourable lipid profile,
- sexual dysfunction,
- decreased exercise tolerance and muscle mass,
- increased visceral fat,
- fatigue,
- osteopenia/osteoporosis.
When can you advise hormone treatment in adult GH defs?
NICE recommends replacement in patients with an increase of 9mU/L (3ug/L) or less in ITT or similar test plus impaired quality of life judged by scoring 11 or above in the quality of life assessment of growth hormone deficiency in adults questionnaire (QoL-AGHDA).
What QoL score is necessary to continue replacement therapy in adults?
Needs to improve by 7 after 9months
How are adult patients who were diagnosed with GH def as a child treated?
Stop GH treatment for 2-3 months once growth <2cm/year, and the GH axis is tested again. If there is still def then continue treatment till 25 to optimise peak bone mass
What terms are used to GH excess in adults and children
Gigatism - child
Adults - acromegaly
What are some causes of GH excess?
McCune-albright syndrome, pituitary adenoma, MEN1 or other tumours secreting GH or GHRH
Describe gigantism in associated to epiphyses fusion.
Associated with GE excess before epiphyses fuse
Define height of gigantism
> 3SD above normal height
The diagnosis of gigantism
Measure height on two occasion (6m apart). Examine family history, if abnormal then look if its dispropotional growth (limb proportional).
- disproportional growth occurs in XXY, XYY
If there is disproportional growth the growth velocity is examined. Normal height velocity = constitutional tall stature.
If height velocity is rapid then examine precocious sexual maturity
- Yes= precocious puberty
- NO = GH excess, tumour
What is acromegaly?
GH excess experienced following epiphyses fusing, which does not result in increased height
- Hands, head and feet affected
What are symptoms of acromegaly
Apart from height
- diabetes
- headaches
- paraesthesias
What is the major cause of death in acromegaly?
CVD
- develop cardiomyopathy and increased size of left ventricle, hypertension, arrythmias, ischaemic heart disease
How is GH excess diagnosed? OGTT
A OGTT will be performed
- Hyperglycaemia should suppress GH
- 75g anhydrous glucose in 250-300ml of water to be drunk over 5min
- Take samples for GH & glucose 3o min intervals (2hrs)
- Acromegaly will show no suppression of GH
- GH<1ug/L
- Major variabilities meaning it does not have a high specificity
What other investigation can be done in acromegaly?
If GH does not fit with the clinical picture then IGF1 measurements are necessary.
- Note IGF-1 also has a lot of variability
Treating GH excess?
Most common cause: tumour
- Macroadenomas can be removed surgically
- Surgery, via the transsphenoidal route (nostrils), is typically the first line of treatment for operable tumours
- If not operable then use radiotherapy treatment - can cause degrees of anterior pituitary dysfunction
Medical treatment
- somatostatin analogues to suppress GH secretion
- e.g. octreotide can be injected 2-3 times a day
- e.g. lanreotide slow release prep every 28 days
- These act to normalise IGF-1 and shown to reduce tumour volume
If somatostatin analogues fail to treat GH excess what can be used?
GH receptor antagonist, e.g. pegvisomat given daily to decrease IGF-1 conc
