W5 Growth hormone disorders (GSP) Flashcards
Anterior lobe of pituitary gland is ‘more important’ as it controls production of..? (4)
Secretion of..?
- Controls activity of other endocrine glands
- Ovulation and pregnancy
- Sperm production
- Growth
- Thyrotropin / Thyroid Stimulating Hormone (TSH)
- Adrenocorticotropic hormones (ACTH)
- Luteinising Hormone (LH)
- Follicle Stimulating hormone (FSH)
- Growth hormone (GH)
Growth Hormone (GH) / Somatotropin:
Function?
- From somatotroph cells of anterior pituitary
- Pulsatile release
-Released throughout the day
-Peaks in 1st hour of sleep
-Diurnal variation → blood test for GH not reliable
Function (anabolic & metabolic):
* Postnatal longitudinal growth
* Affects bone growth
* Affects metabolism of glucose, protein, lipids, minerals
GH-IGF axis
* GH acts on liver → release somatomedin/ insulin-like growth factor (IGF)
* Primarily IGF-1
Growth hormone disorders:
2 types?
- Deficiency – restricted growth (dwarfism)
- Excess – gigantism, acromegaly
Restricted growth (dwarfism)
2 types?
- Proportionate short stature (PSS)
* general lack of growth in the body, arms, legs
* e.g. primordial dwarfism - Disproportionate short stature (DSS)
* arms and legs are particularly short due to
poor bone growth
* Most common type: achondroplasia
* Genetic mutation : shorter long-bones →
‘disproportionate’ limb-to-torso lengths
Tests for adult GH deficiency
* Insulin tolerance test (ITT)
- “gold standard” test.
- IV insulin given → induce hypoglycaemia → stimulates pituitary →
release GH and ACTH (GH stimulates liver to release glucose) - Requires controlled environment as hypoglycaemia may be life-threatening
-blood samples taken regularly (e.g. 0, 15, 30, 60, 90 mins) to check glucose and GH levels - severe GH deficiency : peak GH is <9 mU/litre (3 ng/ml) in response to insulin-induced hypoglycaemia of <2.2 mmol/L
(fasting blood glucose is 5-7 mmol/L)
Other Tests for adult GH deficiency? (3)
Which is done if ITT is contraindicated?
=Glucagon stimulation test
* SC/IM glucagon given, and serum GH measured.
* Unknown mechanism, possibly independent of
glucose/insulin effects.
* GHRH-arginine test
* IV GHRH then IV arginine, and serum GH measured.
* GHRH stimulates pituitary, arginine supresses somatostatin
* Growth hormone releasing peptide (GHRP-2) test
* Stimulate GH release, via different receptor to GHRH
Tests for adult GH deficiency (cont’d)
Somatropin in children
- Look at both
-born with SGA
-catch-up growth at 4 years old - Dose is tailored to the individual
-23-50 mcg/kg, or 0.7-1.4 mg/m2
-6-7 times/week
-Subcutaneous injection
Somatropin in adults
- Dose is tailored to the individual
- subcutaneous injection.
- initial dose: 0.2–0.3 mg (0.6–0.9 IU) daily.
- adjusted monthly based on serum IGF-1 and adverse effects, until
reach maintenance dose. - median maintenance dose is 0.4 mg (1.2 IU) daily.
- GH requirements may decrease with age
Complications of GH deficiency – how GH therapy helps? (3)
CVD / Cerebrovascular disease
* ↑ intima-media thickness of carotid arteries – improved
* ↓ left ventricular mass, ↓ left ventricular function, ↓ ejection fraction –improved
* ↑ LDL-C, ↑ triglycerides, ↓ HDL-C – ↓ LDL-C, ↑ HDL-C
* ↑ inflammatory markers (e.g. CRP, proinflammatory cytokines, adipokines) improved
* ↑ coronary calcium scores
Osteopenia / Osteoporosis
* ↓ bone mineral density → ↑ fractures – ↑ BMD, unchanged fracture rate
Body composition
* ↑ fat mass (mainly visceral fat) – ↓ fat
* ↓ muscle mass – ↑ muscle mass, possibly ↑ strength, exercise capacity
Common side effects of somatropin (for info)
- Carpal tunnel syndrome
- Fluid retention/ swelling
- Headache
- Joint pain/ myalgia
- Lipoatrophy – advice: rotate subcutaneous injection sites
- Paraesthesia/ pins & needles
Other treatment considerations
- If on testosterone-replacement therapy: lower GH dose
- If on oral oestrogen therapy: higher GH dose
- Dual-energy X-ray absorptiometry (DXA) to check bone mineral density
-Brittle bones due to disease itself, e.g. Turner syndrome
-Working out ‘bone age’ for restricted growth in children
Leg lengthening surgery
- Procedure
- bone is broken and fixed to a frame/rod.
- leg is stretched (distraction) via external
mechanism ~1mm/day. - new bone forms in between the two broken
ends. - Extended length
- Femur < 8cm (3.1in)
- Tibia < 5cm (2in)
Physical rehabilitation
* restore mobility to the joints
* increase strength of the muscles
Complications
* Pain due to surgery and deliberate fracture
* Poor bone formation, lengthening at an
inappropriate rate
* Nerve damage
* Infection on bone and/or surrounding soft
tissue
* Blood clots
Excess of Growth Hormone
- Excess GH → excessive action of
IGF-1 - Gigantism
-Occurs when epiphyseal growth plates
still open in childhood (pre-puberty). - Acromegaly
-Occurs when epiphyseal growth plates
have fused/closed.
Epiphyseal plate ≈ cartilage at ends of long bones
Oestrogen & testosterone during puberty initiates plate closure: cartilage → bone
Acromegaly
- Affects slightly more women than men
- Usually due to pituitary adenoma (non-malignant
tumour) → excess GH release - Mechanical pressure by growing tumour on nearby
nerves
-visual disturbance
-headache - Late onset → high morbidity &
mortality
-associated CV, cerebrovascular,
respiratory disorder
Gigantism
- More ‘dramatic’ than acromegaly
- Affects more men than women (~78%)
-Men diagnosed later (~3.7 years delay in
diagnosis)
-X-linked acrogigantism (X-LAG; duplication of the GPR101 gene on X chromosome) → early onset of rapid growth
-Female puberty is earlier: rapid growth in
females ~11yo, in males ~13 yo. - Aryl hydrocarbon receptor interacting
protein (AIP) gene mutations or deletions
→ predispose to pituitary adenoma
Tests for GH excess
- MRI/CT of brain
-check for tumours
-monitor post-treatment - Glucose tolerance test / Glucose challenge test
-Oral glucose 75-100g given → induce hyperglycaemia → inhibits GH release from pituitary
-Blood samples taken regularly (e.g. 0, 30, 60, 90, 120 mins) to check GH levels
-↑ GH (>10 ng/mL) + clinical picture = diagnosis of acromegaly - Random blood sampling for GH level = useless
-Pulsatile/variation in GH secretion
-Short half-life - IGF-1 and IGF binding protein 3 (IGFBP3)
-Possible as a tool for diagnosis, or to monitor progress of treatment
-Levels affected by age, puberty, starvation, obesity, diabetes mellitus, pregnancy.
Management of GH excess:
- Goal: Normalising GH and IGF-1 levels
- Transsphenoidal surgery
-First line treatment
-Remove pituitary adenoma - Pharmacologic treatment
1. Somatostatin analogues - Octreotide, lanreotide, pasireotide
- Subcutaneous injection
- May shrink tumours
2. Dopamine receptor agonists - Bromocriptine, cabergoline
- Usually not as standalone medical treatment
3. GH-receptor antagonists - Pegvisomant
- Recombinant hGH analogue → binds to GH receptors →
GH action blocked → ↓ IGF- - Radiation
- Not first choice; when surgery failed/contraindicated
- Slow results: years to see normalisation of GH/IGF-1 levels
- Hormone replacement therapy
- If hypopituitarism post treatment → replace other pituitary hormones
- Sex hormone replacement as sex hormones stimulate epiphyses closure
- ↓ sex hormones → delayed closing of epiphyses → ↑ height growth
- Long term monitoring
- GH/IGF-1 levels
- Comorbidities, e.g. heart disease, diabetes, sleep apnoea, possible malignancy
