EndocrinologyTier 2Disease (DEADMAN)

Hypothalamic–pituitary axis disorders - acromegaly

Description

Chronic GH excess in the adult -> IGF-1 driven soft tissue, bone and visceral overgrowth
Before epiphyseal fusion -> gigantism (linear growth); after fusion -> acromegaly (appositional and soft tissue growth, no height gain)
Insidious - median 7-10 years from onset to diagnosis; old photographs and ring/shoe size are the most useful history

Feature groups

Mass effect - headache, bitemporal hemianopia, cranial nerve palsy
Somatic - acral enlargement (~86%), maxillofacial change with prognathism, interdental spacing, malocclusion (~74%), macroglossia, frontal bossing, arthralgia (~46%), carpal tunnel, proximal myopathy
Skin - hyperhidrosis (~48%), oily skin, skin tags, acanthosis nigricans
Cardiovascular - hypertension, biventricular hypertrophy, cardiomyopathy, valve disease
Metabolic/endocrine - insulin resistance and diabetes, hypertriglyceridaemia, goitre, hypogonadism
Other - OSA, colonic polyps, organomegaly (thyroid, liver, spleen, kidney, heart)

Prevalence ~5-13/100,000; incidence ~0.3-0.4/100,000/yr
M=F; mean age at diagnosis 40-50y
~5% familial/syndromic - AIP (young, large, aggressive, DA/SRL-resistant), MEN1, MEN4, Carney complex, X-LAG

>90% a benign monoclonal GH-secreting pituitary adenoma (somatotroph)
- >75% are macroadenomas (>10 mm) at diagnosis - lateral into cavernous sinus, dorsal/suprasellar
- ~25% co-secrete prolactin (mammosomatotroph) - explains galactorrhoea and hypogonadism out of proportion to mass
- ~40% carry a somatic GNAS (gsp) activating mutation -> constitutive cAMP; these are smaller, denser-granulated and more SRL-responsive
<2% ectopic - GHRH from bronchial or pancreatic NET, or (rarer) ectopic GH
- Pituitary looks hyperplastic, not adenomatous, and GHRH is high
GH -> hepatic IGF-1 -> systemic growth
- IGF-1 mediates the somatic features; GH itself drives the insulin resistance

Sequence

1. IGF-1 (age- and sex-matched) - the screening test; no need to fast, no diurnal variation
- Falsely low: malnutrition, liver disease, uncontrolled diabetes, oestrogen (oral), hypothyroidism
- Random GH is useless - pulsatile
2. OGTT with GH suppression - 75 g glucose, GH before and at 2 hours
- Failure of GH to suppress to <=1 microg/L is diagnostic
- Modern ultrasensitive assays use a nadir <0.4 microg/L
- False non-suppression: adolescence, pregnancy, uncontrolled diabetes, liver/renal disease, anorexia
- Unequivocally raised IGF-1 with classic features -> OGTT can be omitted
3. Pituitary MRI with contrast
- No mass -> CT chest/abdomen/pelvis + serum GHRH for an ectopic source

Complete the workup

Full pituitary panel - prolactin, cortisol/ACTH, fT4/TSH, LH/FSH, testosterone/oestradiol
Formal visual fields
HbA1c, lipids, BP
Echocardiogram, sleep study
Colonoscopy at diagnosis
Thyroid ultrasound if goitre; DEXA/spine imaging for vertebral fracture

Examination pearls

Coarse features, frontal bossing, prognathism, macroglossia with splayed teeth
Spade-like, doughy, sweaty hands; positive Phalen; proximal myopathy
Skin tags, acanthosis nigricans; hypertension; bitemporal hemianopia
Signs of active disease: increasing skin tags, sweating, headache, glycosuria, hypertension, worsening fields, still-increasing hand/foot size

Goals of therapy

Age-normalised IGF-1, random GH <1 microg/L, tumour control, reversal of comorbidity, normalised mortality

1. Surgery - first line for essentially everyone

Trans-sphenoidal selective adenomectomy by a high-volume pituitary surgeon
Best for microadenomas (remission ~80-90%) and non-invasive macroadenomas (~40-60%)
Also indicated purely for decompression of the optic apparatus
Pre-operative SRL can shrink a large tumour and improve airway/cardiac risk

2. Medical therapy - persistent or recurrent disease

Agent	Mechanism	Control rate
Octreotide / lanreotide LAR	SSTR2/5 ligand	~40-60%
Pasireotide LAR	Broad SSTR1/2/3/5	>60%; also shrinks tumour
Pegvisomant	GH-receptor antagonist - blocks signal peripherally	>90% IGF-1 normalisation
Cabergoline	Dopamine agonist	20-40%; useful in mild disease or prolactin co-secretion
Paltusotine	Oral once-daily non-peptide SST2 agonist	New oral option after surgery

Pegvisomant: GH levels rise on treatment - monitor IGF-1 only, never GH. LFTs; can enlarge the tumour (rare, image periodically)
Pasireotide: worsens glycaemia by suppressing insulin - the trade-off is control vs new diabetes
Combination (SRL + pegvisomant, or SRL + cabergoline) for partial responders
2025-2026 consensus: outcome goals are now clinical and biochemical control together, with escalation driven by which of the two is unmet

3. Radiotherapy - last line

Stereotactic radiosurgery or fractionated EBRT for residual/recurrent disease after surgery and drugs
Effect takes years - up to 10-15 for maximum; continue medical therapy meanwhile
Delayed hypopituitarism in the majority at 5-10y; cranial nerve and cerebrovascular risk

Comorbidity management is separate and mandatory

Treat hypertension, diabetes, OSA, arthropathy in their own right - biochemical remission does not reverse established arthropathy or fixed bone change
Surveillance colonoscopy every 3-10y depending on findings and disease activity
Cardiac assessment; dental/orthodontic review

Monitoring

Post-operative: IGF-1 and random GH at ~12 weeks, then annually if in remission
Repeat MRI only for clinical or biochemical evidence of relapse, or on medical therapy
Reassess full pituitary function after surgery and after radiotherapy (lifelong after RT)

MEN1 (parathyroid, pancreatic NET, pituitary), MEN4 (CDKN1B), Carney complex (PRKAR1A - myxoma, lentigines), McCune-Albright
AIP mutation / familial isolated pituitary adenoma - young, gigantism, aggressive, poorly SRL-responsive
X-LAG (GPR101 duplication) - infantile-onset gigantism
Colonic adenoma and colorectal cancer; thyroid nodules and possible thyroid cancer excess
OSA (>50%), carpal tunnel, hypertension, T2DM
Multinodular goitre; uterine fibroids

Untreated -> ~2-3x mortality, driven by cardiovascular and respiratory disease
- Normalising IGF-1 restores life expectancy close to normal - this is the point of aggressive control
Cardiac: concentric biventricular hypertrophy -> diastolic dysfunction -> overt failure; arrhythmia, hypertension and valve disease in up to 60% at diagnosis
Respiratory: OSA in >50% - macroglossia, soft tissue and nasal polyps; contributes to peri-operative airway difficulty
Skeletal: arthropathy in ~70% - cartilage thickening, periarticular calcification, osteophytes, synovitis -> degenerative OA; scoliosis, kyphosis and vertebral fracture despite normal or high BMD
Gigantism -> delayed sexual maturation and hypogonadism from tumour mass
Reversible with control: soft tissue swelling, sweating, headache, glucose intolerance, OSA
Not reversible: bone change (prognathism, acral bone), established arthropathy, fixed field loss

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