What is acromegaly and what causes it?
Acromegaly is a rare disorder of excess growth hormone (GH), which drives hepatic and tissue production of insulin-like growth factor 1 (IGF-1). IGF-1 is what causes the coarse features, large hands and feet and the cardiovascular, metabolic, rheumatological and neoplastic complications. In a child with open growth plates the same excess causes gigantism; after fusion it causes acromegaly.
The commonest cause is a GH-secreting (somatotroph) adenoma of the anterior pituitary. The most commonly associated mutation is an activating mutation of the alpha subunit of the stimulatory G protein (GNAS), which keeps cAMP signalling switched on. Rarer causes are listed below.
| Category | Examples |
|---|---|
| Pituitary (commonest) | Somatotroph adenoma; mixed GH-prolactin adenomas; rarely GH-cell carcinoma |
| Syndromic | MEN1, McCune-Albright syndrome, Carney complex, familial isolated pituitary adenoma |
| Ectopic GH | Lymphoma, pancreatic islet-cell tumours |
| Excess GHRH | Hypothalamic hamartoma, choristoma, ganglioneuroma; bronchial carcinoid, small-cell lung cancer, rarely phaeochromocytoma |
| Iatrogenic | Excess GH administration |
What are the clinical features of acromegaly?
Acromegaly is slow and insidious; onset is usually in the third or fourth decade, and the mean age at diagnosis is about 40 in men and 45 in women. Features come from three mechanisms: soft-tissue and bone overgrowth, metabolic effects of GH/IGF-1, and tumour mass effect.
| System | Findings |
|---|---|
| Face and head | Coarse features, frontal bossing, prognathism, thick lips, large nose, macroglossia, widely spaced teeth |
| Hands and feet | Acral enlargement, stubby fingers, increasing ring or shoe size, carpal tunnel syndrome |
| Skin | Thick, oily skin, hyperhidrosis, skin tags, acanthosis nigricans, hypertrichosis |
| Musculoskeletal | Hypertrophic arthropathy, dorsal kyphosis, lumbar hyperlordosis, proximal myopathy, genu varum |
| Cardiovascular | Hypertension, acromegalic cardiomyopathy, valvular disease |
| Respiratory | Obstructive sleep apnoea, snoring, deepened voice |
| Metabolic | Impaired glucose tolerance or diabetes, raised triglycerides, low HDL |
| Mass effect | Headache, bitemporal hemianopia, hypopituitarism, galactorrhoea if prolactin is co-secreted |
Cartilage hypertrophy widens joint spaces, while IGF-1 acting through the IGF-1 receptor causes periosteal bone formation, giving jaw thickening, tooth separation and frontal bossing. Overgrowth of the costochondral joints can splay the ribs.
How is acromegaly diagnosed (IGF-1 and OGTT)?
Screening is biochemical, using serum IGF-1, because unlike GH it does not vary with sleep, exercise or time of day. GH is pulsatile with a half-life of only about 14 minutes, so a random GH is not useful. A normal IGF-1 essentially rules acromegaly out; a raised IGF-1 confirms GH excess and the next step is imaging.
- Screen: age- and sex-adjusted IGF-1. Screen patients with the typical phenotype, or with several linked problems (sleep apnoea, hypertension, uncontrolled type 2 diabetes, debilitating arthropathy, carpal tunnel). Screening for isolated sleep apnoea, diabetes or hypertension alone is not recommended.
- Confirm if equivocal: 75 g oral glucose tolerance test (OGTT) with GH measured at baseline and 2 hours. In acromegaly GH fails to suppress: a GH above 1 ng/mL (about 0.4 ng/mL with current ultrasensitive assays) after the glucose load confirms the diagnosis.
- Image: pituitary MRI is the investigation of choice; adenomas are hypointense on T2-weighted images. If no mass is seen, think of an ectopic source: CT chest and abdomen or DOTATE PET, with serum GHRH (usually above 300 ng/mL in extra-pituitary sources).
- Assess the rest of the pituitary: prolactin (stalk effect or co-secretion), ACTH and morning cortisol, free T4, FSH, LH and testosterone or oestradiol. Also HbA1c, lipids, visual fields if the tumour approaches the chiasm, echocardiogram and a sleep study if indicated.
How are pituitary adenomas classified?
Pituitary adenomas are tumours of the anterior pituitary, most of them indolent and benign. By size they are microadenomas (below 10 mm), macroadenomas (10 mm or more) and giant adenomas (above 40 mm). By function they are functioning (hormone-secreting) or non-functioning. Non-functioning tumours cause symptoms through mass effect.
| Subtype | Approximate frequency | Clinical syndrome |
|---|---|---|
| Prolactinoma | About 50% (commonest) | Amenorrhoea and galactorrhoea in women; erectile dysfunction and gynaecomastia in men |
| Non-functioning | About 30% | Visual loss, headache, hypopituitarism |
| Somatotroph (GH) | About 11% | Acromegaly or gigantism |
| Corticotroph (ACTH) | About 5% | Cushing disease |
| Thyrotroph, gonadotroph | Rare | Central hyperthyroidism (TSH-oma); usually silent gonadotroph tumours |
Prolactinomas are commonest in women of reproductive age, whereas acromegaly is more often diagnosed in men. Incidental microadenomas are very common on imaging: a meta-analysis found an average frequency of 16.7% (14.4% at autopsy, 22.5% on radiology). Pituitary tumours make up about 17% of primary brain tumours in US registry data.
What does a pituitary tumour do by mass effect?
A macroadenoma compresses neighbouring structures. Visual impairment occurs in roughly 40% to 60% of patients with suprasellar extension that compresses the optic chiasm; the pattern is classically bitemporal hemianopia, followed in frequency by homonymous defects. Involvement of the oculomotor nerve causes diplopia, and invasive tumours may affect cranial nerves IV, V and VI (cavernous sinus). Headache is common but non-specific.
Compression of normal gland produces hypopituitarism, with one or more of these deficiencies: gonadotropin deficiency (amenorrhoea, erectile dysfunction), growth hormone deficiency (fatigue, weight gain), TSH deficiency (cold intolerance, constipation) and ACTH deficiency (hypotension, weight loss, nausea).
Related reading: visual pathway lesions for the field defects, and adrenal cortex hormones and disorders for Cushing disease and adrenal insufficiency.
How do you work up a pituitary mass hormonally?
All incidentally found adenomas need a complete biochemical assessment (Endocrine Society): prolactin, TSH, free T4, IGF-1, GH, FSH, oestradiol or testosterone, ACTH, morning cortisol and a basic metabolic panel. Contrast MRI with a pituitary protocol is the gold standard imaging.
| Test | Interpretation and trap |
|---|---|
| Prolactin | Under 200 ng/mL: microadenoma, stalk effect, hypothyroidism, renal failure, pregnancy, drugs (antipsychotics, antidepressants, opiates, antiemetics). Above 200 ng/mL usually a macroprolactinoma. |
| Hook effect | Giant adenoma with only mildly raised prolactin: assay artefact that can give falsely low levels. |
| Macroprolactin | Inactive 'big prolactin' in an asymptomatic patient; detected by polyethylene glycol precipitation to avoid unnecessary treatment. |
| IGF-1 / GH | IGF-1 is the screen; OGTT if equivocal. IGF-1 is falsely low in liver or kidney disease, anorexia and poorly controlled diabetes. |
| Cushing disease | Screen with late-night salivary cortisol, 24-hour urine free cortisol or 1 mg overnight dexamethasone test (cortisol 1.8 micrograms/dL or more suggests hypercortisolism). |
| ACTH source | MRI is normal in about 50% of ACTH-secreting tumours; inferior petrosal sinus sampling distinguishes pituitary from ectopic (central-to-peripheral ratio above 2 at baseline, above 3 after vasopressin). |
| TSH-oma | High free T4 and T3 with inappropriately normal or high TSH. |
How is acromegaly treated?
The aims are to normalise GH and IGF-1, relieve tumour mass effect, manage comorbidities and improve mortality. Transsphenoidal surgery is first-line, ideally by a surgeon who does at least 50 pituitary cases a year. Cure rates with normalisation of IGF-1 are about 80% to 90% for microadenomas and 40% to 60% for macroadenomas. Smaller size, lower pre-operative GH/IGF-1 and no cavernous sinus invasion predict cure.
| Drug class | Examples | Key points |
|---|---|---|
| Somatostatin analogues | Octreotide, lanreotide, pasireotide | Mainstay of medical therapy; suppress GH and IGF-1 and shrink tumour. Adverse effects: diarrhoea, cramps, gallstones/biliary sludge, hyperglycaemia (more with pasireotide, 50% to 70%) |
| GH-receptor antagonist | Pegvisomant | Blocks the GH receptor; only IGF-1 is used to monitor (GH may rise); does not shrink the tumour; check liver function tests; improves insulin sensitivity |
| Dopamine agonists | Cabergoline, bromocriptine | Less effective; for mild disease or as an add-on; cabergoline more potent. Adequate response in about 40% with cabergoline |
- Medical therapy is for patients who decline surgery, are unfit, have unresectable tumours or persistent disease after surgery; octreotide before surgery may improve remission rates (needs larger studies).
- Radiotherapy (conventional fractionated, or stereotactic radiosurgery) is the third line; the effect takes years, and hypopituitarism needs monitoring. Radiosurgery needs the tumour to be several millimetres from the optic chiasm.
- Combination: adding pegvisomant to a somatostatin analogue normalised IGF-1 in 95% of patients in one study; monitor liver enzymes.
- Craniotomy is reserved for large suprasellar extension (and other uncommon anatomical reasons).
How are the other pituitary adenomas treated?
| Adenoma | First-line | Notes |
|---|---|---|
| Prolactinoma | Dopamine agonist (cabergoline, bromocriptine) | Cabergoline normalises prolactin and shrinks the tumour in more than 90%. Adverse effects: postural hypotension, valvulopathy, compulsive behaviour. Surgery for resistance, intolerance, or tumours over 1 cm in a woman wanting pregnancy. Can stop after 2 years if MRI shows no visible tumour, with annual prolactin. |
| GH-secreting | Transsphenoidal surgery | Then somatostatin analogues, pegvisomant or cabergoline; radiotherapy as adjunct. |
| ACTH-secreting (Cushing disease) | Transsphenoidal surgery | Cure 70% to 90%; remission is cortisol below 2 micrograms/dL; temporary glucocorticoid cover (up to 12 months). Medical: metyrapone, osilodrostat, levoketoconazole, pasireotide, mifepristone. Bilateral adrenalectomy then risks Nelson syndrome (25% to 40%). |
| TSH-secreting | Transsphenoidal surgery | Cure in 50% to 90%; control thyrotoxicosis first (methimazole or somatostatin analogue) to avoid thyroid storm. |
| Non-functioning | Surgery if visual deficit, optic chiasm compression, apoplexy with visual loss, endocrine loss or growth | Otherwise MRI surveillance; radiotherapy for residual or recurrent tumour. |
After transsphenoidal surgery, monitor urine output and sodium immediately: patients may develop SIADH or, conversely, diabetes insipidus needing desmopressin. Adrenal function must be monitored and covered. Imaging is done at least 3 months post-operatively because packing takes that long to resorb.
What are the common exam traps for this topic?
- IGF-1 is the screening test; random GH is not. OGTT is the confirmatory (suppression) test; GH above 1 ng/mL after 75 g glucose confirms.
- Macroadenoma at least 10 mm, microadenoma below 10 mm, giant above 40 mm.
- Prolactinoma is the commonest pituitary tumour and is treated medically, unlike the others.
- Pegvisomant: monitor IGF-1 not GH; no effect on tumour size.
- Pasireotide causes the most hyperglycaemia of the somatostatin analogues.
- Bitemporal hemianopia = chiasmal compression; headache and visual loss with sudden onset = apoplexy.
- After pituitary surgery, think DI/SIADH and adrenal insufficiency.
- Cushing disease after bilateral adrenalectomy can progress to Nelson syndrome (tumour enlargement, pigmentation).
Practise related questions in the NEET PG Medicine PYQs, the INI-CET PYQs and the most repeated topics list.