Acromegaly

Definition

Epidemiology

• Incidence: 0.2-1.1 per 100,000 per year
• Prevalence: 8-14 per 100,000
• Median age at diagnosis: fifth decade of life
• Diagnostic delay is typically ~5 years, so most tumors are macroadenomas (>1 cm) at the time of presentation (~75%)

Etiology and Pathophysiology

• GHRH (from hypothalamus) stimulates GH synthesis and release
• Somatostatin (somatotropin release-inhibiting factor, SRIF) inhibits GH release
• IGF-1 (produced by the liver) provides negative feedback, suppressing GH via somatostatin

• MEN1 (menin gene mutation) - pituitary adenomas in ~50% of patients; 10% secrete GH
• McCune-Albright syndrome (activating Gsα mutations - elevated cAMP, autonomous GH secretion)
• AIP mutations - familial isolated pituitary adenomas, often young onset

Clinical Features

Progressive coarsening of facial features in acromegaly over 9 years, alongside MRI of the causative pituitary adenoma - Goldman-Cecil Medicine

Facial and Skeletal Changes

• Frontal bossing, enlarged nose, macroglossia
• Prognathism (protruding lower jaw), splayed teeth, malocclusion, mandibular overbite
• Increased ring, shoe, and hat size

Features of acromegaly/gigantism: 22-year-old with GH excess vs. his identical twin. Increased height, prognathism, enlarged hands and feet - Harrison's 22e

Soft Tissue and Metabolic

• Hyperhidrosis (very common at rest)
• Multiple skin tags (associated with colonic polyps and colon cancer risk)
• Obstructive sleep apnea (soft tissue hypertrophy of the pharynx)
• Neuropathy - carpal tunnel syndrome (50%) from nerve entrapment

Cardiovascular

• Hypertension
• Cardiomegaly / biventricular hypertrophy (acromegalic cardiomyopathy)
• Increased risk of ischemic heart disease and heart failure

Metabolic

• Diabetes mellitus / glucose intolerance (GH is anti-insulin)
• Hyperlipidemia

Musculoskeletal

• Atypical osteoarthritis in ~75% - knees, shoulders, hips, lumbosacral and cervical spine are most symptomatic; hands show widened joint spaces (cartilage hypertrophy) - unlike primary OA which narrows them
• Raynaud phenomenon (~33%)
• Diffuse idiopathic skeletal hyperostosis (20%)
• Proximal muscle weakness (normal CK)

Mass Effects from the Tumor

• Headache (up to 60%)
• Bitemporal hemianopia (10%) - compression of the optic chiasm
• Hypopituitarism from tumor compression

Hormonal Co-secretion

• Co-secretion of prolactin is common (mixed GH-PRL adenomas ~25%); causes hypogonadism and galactorrhea

Diagnosis

Biochemical

Key point: Random GH is unreliable because GH is secreted in a pulsatile fashion. IGF-1 + OGTT are the diagnostic cornerstones.

Imaging

• MRI pituitary with gadolinium - after biochemical confirmation; ~90% show visible adenoma; 10% have an empty sella
• If MRI negative, consider ectopic sources - chest/abdomen imaging, selective venous GHRH sampling

Treatment

1. Surgery (First-line)

• GH normalizes within hours of tumor removal; IGF-1 normalizes within 3-4 days
• Hypopituitarism occurs in up to 15% post-surgery
• Recurrence in ~10% after apparent cure

2. Medical Therapy (Adjuvant or Primary)

Somatostatin Receptor Ligands (SRLs) - First-line medical therapy

• Octreotide LAR - long-acting intramuscular injection every 4 weeks
• Lanreotide autogel - deep subcutaneous injection every 4 weeks
• Pasireotide LAR (40-60 mg IM q28 days) - broader receptor binding (SST1,2,3,5); superior GH suppression but higher rate of hyperglycemia
• Oral octreotide capsules (40 mg/day as 20 mg twice daily) - for patients with proven response to injectable forms
• Normalize IGF-1 in ~50-60% of patients; modestly shrink tumor in ~50%
• Side effects: diarrhea, cholelithiasis (gallstones)

Dopamine Agonist

• Cabergoline (0.5-1 mg 2x/week) - normalizes IGF-1 in only ~30% as monotherapy; useful as add-on, especially in mixed GH+PRL tumors

GH Receptor Antagonist

• Pegvisomant (SC daily injection) - biosynthetic GH analogue that blocks GH receptor, preventing IGF-1 generation; normalizes IGF-1 in >90% of patients
• Does not reduce tumor size
• Reserved for patients unresponsive to SRLs, or as combination therapy
• Monitor: liver enzymes (can elevate); GH levels rise (expected - it blocks the receptor, not secretion)

3. Radiotherapy (Adjuvant - third line)

• Stereotactic radiosurgery (Gamma Knife) or conventional fractionated radiotherapy
• Disadvantages: slow biochemical response (5-15 years), high rate of hypopituitarism (up to 50% long-term)
• Not used as primary therapy; reserved for residual/recurrent disease after surgery and medical failure

Prognosis

• Untreated or poorly controlled acromegaly carries 2-3x increased mortality vs. general population, mainly due to cardiovascular disease and malignancy
• Cure criteria: GH <1 ng/mL on OGTT AND normal age-matched IGF-1
• When these are achieved, mortality returns to that of the general population
• Arthropathy may persist or progress in ~1/3 of patients even after biochemical cure
• Soft tissue changes (swelling, hyperhidrosis) improve quickly after treatment; bony changes are irreversible

Summary

• Goldman-Cecil Medicine International Edition, Ch. 205 (Growth hormone excess: acromegaly and gigantism)
• Harrison's Principles of Internal Medicine, 22e (2025), Ch. 392 (Pituitary Disorders)