Acromegaly

Acromegaly is a chronic, progressive endocrine disorder caused by excessive secretion of growth hormone (GH), almost always arising from a GH-secreting pituitary adenoma (somatotroph adenoma). The sustained hypersecretion of GH leads to overproduction of insulin-like growth factor 1 (IGF-1) from the liver and other tissues, resulting in characteristic somatic overgrowth, metabolic disturbances, and significant multi-system morbidity.

In Australia, the estimated annual incidence is 3–4 cases per million population, with a point prevalence of approximately 60–70 per million. These figures may underestimate the true burden, as diagnosis is typically delayed by 7–10 years owing to the insidious onset of clinical features. The condition is diagnosed most commonly in the fourth to fifth decades of life, with an equal sex distribution or slight female predominance in some series.

Untreated acromegaly is associated with a two- to three-fold increase in mortality, principally driven by cardiovascular disease, cerebrovascular events, and respiratory complications. Achievement of biochemical remission reduces mortality to that of the general population, underscoring the importance of early diagnosis and appropriate treatment. This guideline provides a comprehensive, Australian-contextualised approach to the diagnosis and management of acromegaly.

Molecular Pathogenesis

The vast majority of GH-secreting pituitary adenomas are sporadic, arising from clonal expansion of a single mutated somatotroph cell. Key molecular mechanisms include:

• GNAS1 gene mutations: Activating somatic mutations in the GNAS1 gene (encoding the Gsα subunit) occur in approximately 40% of GH-secreting adenomas, leading to constitutive cAMP production and unregulated GH secretion. These are somatic mutations confined to the tumour.
• AIP mutations: Aryl hydrocarbon receptor interacting protein (AIP) germline mutations account for approximately 20% of familial isolated pituitary adenoma (FIPA) and are associated with younger-onset, larger, and more aggressive somatotroph adenomas. Carriers require genetic counselling and family screening.
• MEN1 and other syndromes: Multiple endocrine neoplasia type 1 (MEN1) causes pituitary adenomas in ~40% of carriers. Carney complex (PRKAR1A mutations) and McCune–Albright syndrome (GNAS1 mosaic mutations) are rarer familial causes of GH excess.

GH–IGF-1 Axis Physiology

GH is secreted by somatotroph cells of the anterior pituitary gland in a pulsatile fashion, regulated by hypothalamic growth hormone-releasing hormone (GHRH, stimulatory) and somatostatin (inhibitory). Ghrelin from the stomach also stimulates GH release. GH acts on the liver and peripheral tissues to stimulate IGF-1 production, which mediates most of the growth-promoting and metabolic effects. In acromegaly, autonomous GH secretion overrides normal feedback mechanisms, resulting in sustained elevation of both GH and IGF-1.

Tumour Characteristics

GH-secreting adenomas are classified as microadenomas (<10 mm diameter) or macroadenomas (≥10 mm). Macroadenomas are more common at presentation (60–70%) and are associated with extrasellar extension, compression of surrounding structures, and lower surgical remission rates. Invasive adenomas (Knosp grade 3–4), which encase the carotid artery, are present in approximately 25–35% of cases.

Australian Epidemiological Context

Data from the Australian Pituitary Registry and population-based studies indicate that acromegaly accounts for approximately 10–15% of all pituitary adenomas managed at major tertiary centres (e.g., Royal Melbourne Hospital, Westmead Hospital, Royal Adelaide Hospital). Aboriginal and Torres Strait Islander populations may face diagnostic delays due to healthcare access barriers, although specific prevalence data in this population are limited. Comorbidities at diagnosis in Australian cohorts include hypertension (40–50%), diabetes mellitus (15–38%), and sleep apnoea (60–70%).

The clinical features of acromegaly develop gradually over years and are often attributed to ageing, contributing to the characteristic diagnostic delay. Features may be categorised by system:

Somatic / Musculoskeletal

• Enlargement of acral structures: hands (increased ring/glove size), feet (increased shoe size), jaw (prognathism, malocclusion), brow (frontal bossing)
• Soft tissue swelling leading to coarsened facial features, macroglossia, thickened skin
• Arthropathy — a major cause of morbidity; occurs in up to 70% of patients, involving weight-bearing joints initially with characteristic widened joint spaces, osteophyte formation, and eventual degenerative changes
• Carpal tunnel syndrome (50–60%), often bilateral
• Proximal myopathy with reduced exercise capacity

Cardiovascular

• Hypertension (40–50%) — multifactorial: sodium retention, endothelial dysfunction, sympathetic activation
• Acromegalic cardiomyopathy: concentric biventricular hypertrophy → diastolic dysfunction → systolic failure (in advanced cases); arrhythmias common
• Increased cardiovascular mortality is the leading cause of death in untreated acromegaly

Metabolic / Endocrine

• Insulin resistance → impaired glucose tolerance (16–46%) or overt diabetes mellitus (15–38%)
• Dyslipidaemia (hypertriglyceridaemia)
• Hypogonadism (from tumour mass effect or hyperprolactinaemia): 30–50% of men, menstrual irregularity in women
• Hypopituitarism from mass effect — GH, ACTH, TSH, gonadotrophin deficiency

Respiratory

• Obstructive sleep apnoea (60–70%): due to macroglossia, pharyngeal soft tissue hypertrophy, craniofacial changes
• Upper airway obstruction risk during anaesthesia

Neurological / Local Tumour Effects

• Headache (common, may be due to dural stretch or cavernous sinus invasion)
• Visual field defects (bitemporal hemianopia) from optic chiasm compression in macroadenomas
• Cranial nerve palsies (III, IV, VI) with lateral extension into the cavernous sinus
• Hyperprolactinaemia (30–40%) from co-secretion or stalk effect

Dermatological

• Skin tags (acrochordons) — associated with colonic polyps
• Hyperhidrosis, oily skin
• Acanthosis nigricans (associated with insulin resistance)

Neoplasia Risk

An increased risk of colorectal neoplasia (adenomas and possibly carcinoma) is well-documented; Australian guidelines recommend baseline colonoscopy at diagnosis and surveillance every 3–5 years, particularly in patients with additional risk factors (age >50, family history, skin tags). Thyroid nodules are also more prevalent and warrant ultrasound evaluation.

Biochemical Diagnosis

IGF-1 (Insulin-like Growth Factor 1)

Serum IGF-1, measured by immunoassay and interpreted against age- and sex-adjusted reference ranges, is the initial screening investigation. IGF-1 reflects integrated 24-hour GH secretion and is elevated in virtually all patients with active acromegaly. A normal age-adjusted IGF-1 effectively excludes the diagnosis. IGF-1 is available through most Australian pathology services (MBS item 66658, Growth factors).

Oral Glucose Tolerance Test (OGTT) — Confirmatory Test

The 75 g OGTT is the gold-standard confirmatory test for acromegaly. In healthy individuals, glucose loading suppresses GH to nadir <0.4 µg/L (ultrasensitive assay) or <1 µg/L (standard assay). In acromegaly, autonomous GH secretion fails to suppress:

• GH nadir ≥0.4 µg/L (ultrasensitive assay) — diagnostic of acromegaly
• GH nadir ≥1 µg/L (standard assay) — diagnostic of acromegaly
• GH nadir 0.4–1.0 µg/L on ultrasensitive assay — equivocal; requires specialist interpretation with IGF-1 and clinical context

OGTT is not reliable in uncontrolled diabetes mellitus. The test should be performed fasting, in the morning, with GH measured at 0, 30, 60, 90, and 120 minutes. MBS item 66658 applies.

Random GH

A single random GH measurement is insufficient for diagnosis due to pulsatile secretion, but a random GH <0.4 µg/L (ultrasensitive assay) in the setting of elevated IGF-1 may indicate assay discordance or an alternative cause of IGF-1 elevation. Serial GH measurements or the OGTT are needed for definitive diagnosis.

Additional Baseline Investigations

Treatment Targets / Criteria for Remission

Management of acromegaly requires a multidisciplinary pituitary tumour board (endocrinologist, neurosurgeon, neuroradiologist, ophthalmologist, pathologist) and should be coordinated through an accredited pituitary centre of excellence. Treatment goals are biochemical remission, tumour control, relief of mass effect, and management of comorbidities.

1. Surgery — Transsphenoidal Adenomectomy

Transsphenoidal surgery (TSS) is the first-line treatment for the majority of patients with acromegaly and is the only potentially curative modality. Surgery should be performed by an experienced pituitary neurosurgeon (volume ≥50 transsphenoidal cases per year) at a major centre.

Post-operative considerations include assessment of pituitary function (particularly cortisol, thyroid function) at 6–12 weeks, MRI at 3 months, and biochemical remission assessment (IGF-1 ± OGTT) at 12 weeks post-surgery. Transient diabetes insipidus occurs in 10–20%, with permanent diabetes insipidus in <5% in experienced hands. CSF leak, meningitis, and carotid artery injury are rare but serious complications.

2. Somatostatin Analogues — First-Line Medical Therapy

Somatostatin receptor ligands (SRLs) are the first-line medical therapy for residual or recurrent acromegaly post-surgery, or as primary therapy when surgery is contraindicated or declined. They act on somatostatin receptors (predominantly SSTR2 and SSTR5) on the adenoma to suppress GH secretion.

3. Pegvisomant — GH Receptor Antagonist

Pegvisomant is a genetically engineered GH receptor antagonist that blocks peripheral GH action, thereby reducing IGF-1 production. It does not directly reduce tumour GH secretion and therefore does not shrink the adenoma; regular MRI surveillance is essential.

4. Additional Medical Therapies

Dopamine Agonists

5. Radiotherapy

Pituitary radiotherapy (stereotactic radiosurgery or fractionated radiotherapy) is reserved for patients with tumour growth or biochemical activity uncontrolled despite surgery and medical therapy. Stereotactic radiosurgery (e.g., Gamma Knife, CyberKnife) is preferred for well-defined residual adenomas <30 mm, not abutting the optic chiasm (≥3–5 mm clearance). Biochemical remission may take 5–15 years to achieve, and hypopituitarism develops in 50–80% of patients over 10 years. Radiotherapy is available at major Australian centres including Peter MacCallum Cancer Centre, Royal North Shore Hospital, and GenesisCare facilities.

Management Algorithm

Lifelong monitoring is mandatory regardless of treatment modality, due to the risk of disease recurrence and comorbidity progression.

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