PharmacologyTier 1Medical Sciences concept

Growth hormone axis drug mechanisms (pegvisomant, somatostatin analogues)

Core concept

The axis: hypothalamic GHRH (+) and somatostatin (-) -> pituitary somatotroph GH -> hepatic IGF-1
- GH acts through a JAK2-STAT5 cytokine receptor
- IGF-1 gives negative feedback and mediates most peripheral growth effects
- Ghrelin stimulates GH via GHS-R

Drug	Target	Effect
Somatostatin analogues - octreotide, lanreotide, pasireotide	SSTR2 (pasireotide SSTR1,2,3,5)	dec GH secretion from the tumour
Pegvisomant	GH receptor ANTAGONIST (pegylated GH analogue)	Blocks the receptor peripherally -> dec IGF-1; GH level rises
Cabergoline	D2 agonist	dec GH in a minority; best if the tumour co-secretes prolactin
Somatropin	Recombinant GH	Replacement

Pegvisomant binds site 1 of the GH receptor but cannot dimerise it -> no signalling
- Monitor IGF-1, never GH - GH rises because feedback is removed and the assay cross-reacts

Acromegaly management
- Transsphenoidal surgery is first-line for a resectable tumour
- Persistent disease -> somatostatin analogue (first-line medical), then add or switch to pegvisomant or cabergoline; radiotherapy for residual
- Biochemical control target: normal age-matched IGF-1 and random GH <1 mcg/L
Somatostatin analogue adverse effects - diarrhoea, steatorrhoea, abdominal cramps, gallstones/biliary sludge, hyperglycaemia (inhibits insulin as well as GH), sinus bradycardia
- Pasireotide causes markedly more hyperglycaemia (broader receptor coverage, greater insulin suppression)
Pegvisomant - LFT monitoring (transaminitis), lipohypertrophy at injection sites; does not shrink the tumour - monitor with MRI for tumour growth
GH is diabetogenic - both excess (acromegaly) and replacement cause insulin resistance and can precipitate or worsen diabetes
- Successful acromegaly treatment often improves glycaemic control
GH replacement in adult GH deficiency - dose titrated by IGF-1, not weight; adverse effects are fluid retention, arthralgia, carpal tunnel, worsened glucose
- Diagnosis needs dynamic testing (insulin tolerance test or glucagon stimulation) - a random GH is useless
Screening for acromegaly is IGF-1; confirmation is failure of GH to suppress <1 mcg/L on a 75 g OGTT

Acromegaly mortality is driven by cardiovascular disease, sleep apnoea and colorectal cancer - and normalising IGF-1 restores it toward normal
- Screen for OSA, diabetes, hypertension, cardiomyopathy, colonoscopy
Octreotide has uses well beyond acromegaly: variceal bleeding, sulfonylurea-induced hypoglycaemia, carcinoid syndrome, chylothorax, high-output fistula, neuroendocrine tumours (and Ga-68 DOTATATE PET uses the same receptor)
A rising GH on pegvisomant is expected - do not interpret it as treatment failure
Pituitary apoplexy, hypopituitarism and visual field loss are the tumour-related risks; check the visual fields

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